Leukemia, Myelodysplasia, Transplantation

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm that arises from a reciprocal translocation between the Abelson (ABL) region on chromosome 9 and the breakpoint cluster region (BCR) of chromosome 22, t(9;22)(q34;q11.2) (the Philadelphia chromosome), resulting in the generation of the BCR-ABL1 fusion gene and its protein product, BCR-ABL tyrosine kinase. BCR-ABL is a constitutively active fusion kinase that confers proliferative and survival advantage to hematopoietic cells through activation of downstream pathways.

CML is divided into 3 phases based on the number of myeloblasts observed in the blood or bone marrow: chronic, accelerated, and blast. Most cases of CML are diagnosed in the chronic phase (CP), which is marked by proliferation of primarily the myeloid element.

The advent of tyrosine kinase inhibitors (TKIs), a class of small molecules targeting the tyrosine kinases, particularly the BCR-ABL tyrosine kinase, led to rapid changes in the management of CML and improved survival for patients. Patients diagnosed with CP-CML now a have life-expectancy that is similar to that of the general population, as long as they receive the appropriate TKI therapy and adhere to treatment. As such, it is crucial to identify patients with CML, ensure they receive a complete, appropriate diagnostic work-up, and select the best therapy for each individual patient. The diagnosis and work-up of CML are reviewed in a separate article; here, the selection of TKI therapy for a patient with newly diagnosed CP-CML is reviewed. 

Case Presentation

A 53-year-old woman who recently was diagnosed with CML presents to review her treatment options. The diagnosis was made after she presented to her primary care physician with fatigue, early satiety, left upper quadrant abdominal pain, and an 8-lb unintentional weight loss over the prior month. On physical exam her spleen was palpated 8 cm below the left costal margin. Laboratory evaluation showed a total white blood cell (WBC) count of 124,000/μL with a left-shifted differential including 6% basophils, 3% eosinophils, and 3% blasts; hemoglobin and platelet count were 12.4 g/dL and 801 × 10³/µL, respectively. Fluorescent in-situ hybridization for BCR-ABL gene rearrangement using peripheral blood was positive in 87% of cells. Bone marrow biopsy and aspiration showed a 95% cellular bone marrow with granulocytic hyperplasia and 1% blasts. Cytogenetics were 46,XX,t(9;22)(q34;q11.2), and quantitative real-time polymerase chain reaction (RQ-PCR) to measure BCR-ABL1 transcripts in the peripheral blood showed a value of 98% international standard (IS). Her Sokal risk score was 1.42 (high risk). In addition, prior review of her past medical history revealed uncontrolled diabetes, coronary artery disease requiring placement of 3 cardiac stents 2 years prior, and chronic obstructive pulmonary disease (COPD) related to a 30-pack-year history of smoking.

• What factors must be considered when selecting first-line therapy for this patient?

Selection of the most appropriate first-line TKI for newly diagnosed CP-CML patients requires incorporation of many patient-specific factors. These factors include baseline karyotype and confirmation of CP-CML through bone marrow biopsy, Sokal or EURO risk score, and a thorough patient history, including a clear understanding of the patient's comorbidities. In this case, the patient's high Sokal risk score along with her history of diabetes, coronary artery disease, and COPD are all factors that must be accounted for when choosing the most appropriate TKI. The adverse effect profile of all TKIs must be considered in conjunction with the patient's ongoing medical issues in order to decrease the likelihood of worsening her current symptoms or causing a severe complication from TKI therapy.

Imatinib

The management of CML was revolutionized by the development and ultimate regulatory approval of imatinib mesylate in 2001. Imatinib was the first small-molecule cancer therapy developed and approved. It acts by binding to the adenosine triphosphate (ATP) binding site in the catalytic domain of BCR-ABL, thus inhibiting the oncoprotein's tyrosine kinase activity.¹

The International Randomized Study of Interferon versus STI571 (IRIS) trial was a randomized phase 3 study that compared imatinib 400 mg daily to interferon α (IFNα) plus cytarabine. More than 1000 CP-CML patients were randomly assigned 1:1 to either imatinib or IFNα plus cytarabine and were assessed for event-free survival, hematologic and cytogenetic responses, freedom from progression to accelerated phase (AP) or blast phase (BP), and toxicity. Imatinib was superior to the prior standard of care for all these outcomes.² The long-term follow up of the IRIS trial reported an 83% estimated 10-year overall survival (OS) and 79% estimated event-free survival for patients on the imatinib arm of this study.³ The cumulative rate of complete cytogenetic response (CCyR) was 82.8%. Of the 204 imatinib-treated patients who could undergo a molecular response evaluation at 10 years, 93.1% had a major molecular response (MMR) and 63.2% had a molecular response 4.5 (MR4.5), suggesting durable, deep molecular responses for many patients (see Chronic Myeloid Leukemia: Evaluation and Diagnosis for discussion of the hematologic parameters, cytogenetic results, and molecular responses ussed in monitoring response to TKI therapy). The estimated 10-year rate of freedom from progression to AP or BP was 92.1%.

Higher doses of imatinib (600-800 mg daily) have been studied in an attempt to overcome resistance and improve cytogenetic and molecular response rates. The Tyrosine Kinase Inhibitor Optimization and Selectivity (TOPS) trial was a randomized phase 3 study that compared imatinib 800 mg daily to imatinib 400 mg daily. Although the 6-month assessments found increased rates of CCyR and a MMR in the higher-dose imatinib arm, these differences were no longer present at the 12-month assessment. Furthermore, the higher dose of imatinib led to a significantly higher incidence of grade 3/4 hematologic adverse events, and approximately 50% of patients on imatinib 800 mg daily required a dose reduction to less than 600 mg daily because of toxicity.⁴ 

The Therapeutic Intensification in De Novo Leukaemia (TIDEL) -II study used plasma trough levels of imatinib on day 22 of treatment with imatinib 600 mg daily to determine if patients should escalate the imatinib dose to 800 mg daily. In patients who did not meet molecular milestones at 3, 6, or 12 months, cohort 1 was dose escalated to imatinib 800 mg daily and subsequently switched to nilotinib 400 mg twice daily for failing the same target 3 months later, and cohort 2 was switched to nilotinib. At 2 years, 73% of patients achieved MMR and 34% achieved MR4.5, suggesting that initial treatment with higher-dose imatinib subsequently followed by a switch to nilotinib in those failing to achieve desired milestones could be an effective strategy for managing newly diagnosed CP-CML.⁵

Toxicity

Imatinib 400 mg is considered the standard starting dose in CP-CML patients. The safety profile of imatinib has been very well established. In the IRIS trial, the most common adverse events (all grades in decreasing order of frequency) were peripheral and periorbital edema (60%), nausea (50%), muscle cramps (49%), musculoskeletal pain (47%), diarrhea (45%), rash (40%), fatigue (39%), abdominal pain (37%), headache (37%), and joint pain (31%). Grade 3/4 liver enzyme elevation can occur in 5% of patients.⁶ In the event of severe liver toxicity or fluid retention, imatinib should be held until the event resolves. At that time, imatinib can be restarted if deemed appropriate, but this is dependent on the severity of the inciting event. Fluid retention can be managed by the use of supportive care, diuretics, imatinib dose reduction, dose interruption, or imatinib discontinuation if the fluid retention is severe. Muscle cramps can be managed by the use of a calcium supplements or tonic water. Management of rash can include topical or systemic steroids, or in some cases imatinib dose reduction, interruption, or discontinuation.⁷  

Grade 3/4 imatinib-induced hematologic toxicity is not uncommon, with 17% of patients experiencing neutropenia, 9% thrombocytopenia, and 4% anemia. These adverse events occurred most commonly during the first year of therapy, and the frequency decreased over time.^3,6 Depending on the degree of cytopenias, imatinib dosing should be interrupted until recovery of the absolute neutrophil count or platelet count, and can often be resumed at 400 mg daily. However, if cytopenias recur, imatinib should be held and subsequently restarted at 300 mg daily.⁷ 

Dasatinib

Dasatinib is a second-generation TKI that has regulatory approval for treatment of adult patients with newly diagnosed CP-CML or CP-CML in patients with resistance or intolerance to prior TKIs. In addition to dasatinib's ability to inhibit ABL kinases, it is also known to be a potent inhibitor of Src family kinases. Dasatinib has shown efficacy in patients who have developed imatinib-resistant ABL kinase domain mutations. 

Dasatinib was initially approved as second-line therapy in patients with resistance or intolerance to imatinib. This indication was based on the results of the phase 3 CA180-034 trial which ultimately identified dasatinib 100 mg daily as the optimal dose. In this trial, 74% of patients enrolled had resistance to imatinib and the remainder were intolerant. The 7-year follow-up of patients randomized to dasatinib 100 mg (n = 167) daily indicated that 46% achieved MMR while on study. Of the 124 imatinib-resistant patients on dasatinib 100 mg daily, the 7-year progression-free survival (PFS) was 39% and OS was 63%. In the 43 imatinib-intolerant patients, the 7-year PFS was 51% and OS was 70%.⁸

Dasatinib 100 mg daily was compared to imatinib 400 mg daily in newly diagnosed CP-CML patients in the randomized phase 3 DASISION trial. More patients on the dasatinib arm achieved an early molecular response of BCR-ABL1 transcripts ≤10% IS after 3 months on treatment compared to imatinib (84% versus 64%). Furthermore, the 5-year follow-up reports that the cumulative incidence of MMR and MR4.5 in dasatinib-treated patients was 76% and 42%, and was 64% and 33%, with imatinib (P = 0.0022 and P = 0.0251, respectively). Fewer patients treated with dasatinib progressed to AP or BP (4.6%) compared to imatinib (7.3%), but the estimated 5-year OS was similar between the 2 arms (91% for dasatinib versus 90% for imatinib).⁹ Regulatory approval for dasatinib as first-line therapy in newly diagnosed CML patients was based on results of the DASISION trial. 

Toxicity

Most dasatinib-related toxicities are reported as grade 1 or grade 2, but grade 3/4 hematologic adverse events are fairly common. In the DASISION trial, grade 3/4 neutropenia, anemia, and thrombocytopenia occurred in 29%, 13%, and 22% of dasatinib-treated patients, respectively. Cytopenias can generally be managed with temporary dose interruptions or dose reductions.

During the 5-year follow-up of the DASISION trial, pleural effusions were reported in 28% of patients, most of which were grade 1/2. This occurred at a rate of approximately ≤ 8% per year, suggesting a stable incidence over time, and the effusions appear to be dose-dependent.⁹ Depending on the severity of the effusion, this may be treated with diuretics, dose interruption, and in some instances, steroids or a thoracentesis. Typically, dasatinib can be restarted at 1 dose level lower than the previous dose once the effusion has resolved.⁷ Other, less common side effects of dasatinib include pulmonary hypertension (5% of patients), as well as abdominal pain, fluid retention, headaches, fatigue, musculoskeletal pain, rash, nausea, and diarrhea. Pulmonary hypertension is typically reversible after cessation of dasatinib, and thus dasatinib should be permanently discontinued once the diagnosis is confirmed. Fluid retention is often treated with diuretics and supportive care. Nausea and diarrhea are generally manageable and occur less frequently when dasatinib is taken with food and a large glass of water. Antiemetics and antidiarrheals can be used as needed. Troublesome rash can be best managed with topical or systemic steroids as well as possible dose reduction or dose interruption.^7,9 In the DASISION trial, adverse events led to therapy discontinuation more often in  the dasatinib group than in the imatinib group (16% versus 7%).⁹ Bleeding, particularly in the setting of thrombocytopenia, has been reported in patients being treated with dasatinib as a result of the drug-induced reversible inhibition of platelet aggregation.¹⁰

Nilotinib

The structure of nilotinib is similar to that of imatinib; however, it has a markedly increased affinity for the ATP‐binding site on the BCR-ABL1 protein. It was initially given regulatory approval in the setting of imatinib failure. Nilotinib was studied at a dose of 400 mg twice daily in 321 patients who were imatinib-resistant or -intolerant. It proved to be highly effective at inducing cytogenetic remissions in the second-line setting, with 59% of patients achieving a major cytogenetic response (MCyR) and 45% achieving CCyR. With a median follow-up time of 4 years, the OS was 78%.¹¹ 

Nilotinib gained regulatory approval for use as a first-line TKI after completion of the randomized phase 3 ENESTnd (Evaluating Nilotinib Efficacy and Safety in Clinical Trials-Newly Diagnosed Patients) trial. ENESTnd was a 3-arm study comparing nilotinib 300 mg twice daily versus nilotinib 400 mg twice daily versus imatinib 400 mg daily in newly diagnosed, previously untreated patients diagnosed with CP-CML. The primary endpoint of this clinical trial was rate of MMR at 12 months.¹² Nilotinib surpassed imatinib in this regard, with 44% of patients on nilotinib 300 mg twice daily achieving MMR at 12 months versus 43% of nilotinib 400 mg twice daily patients versus 22% of the imatinib-treated patients (P < 0.001 for both comparisons). Furthermore, the rate of CCyR by 12 months was significantly higher for both nilotinib arms compared with imatinib (80% for nilotinib 300 mg, 78% for nilotinib 400 mg, and 65% for imatinib) (P < 0.001).¹² Based on this data, nilotinib 300 mg twice daily was chosen as the standard dose of nilotinib in the first-line setting. After 5 years of follow-up on the ENESTnd study, there were fewer progressions to AP/BP CML in nilotinib-treated patients compared with imatinib. MMR was achieved in 77% of nilotinib 300 mg patients compared with 60.4% of patients on the imatinib arm. MR4.5 was also more common in patients treated with nilotinib 300 mg twice daily, with a rate of 53.5% at 5 years versus 31.4% in the imatinib arm.¹³ In spite of the deeper cytogenetic and molecular responses achieved with nilotinib, this did not translate into a significant improvement in OS. The 5-year OS rate was 93.7%  in nilotinib 300 mg patients versus 91.7% in imatinib-treated patients, and this difference lacked statistical significance.¹³

Toxicity

Although some similarities exist between the toxicity profiles of nilotinib and imatinib, each drug has some distinct adverse events. On the ENESTnd trial, the rate of any grade 3/4 non-hematologic adverse event was fairly low; however, lower-grade toxicities were not uncommon. Patients treated with nilotinib 300 mg twice daily experienced rash (31%), headache (14%), pruritis (15%), and fatigue (11%) most commonly. The most frequently reported laboratory abnormalities included increased total bilirubin (53%), hypophosphatemia (32%), hyperglycemia (36%), elevated lipase (24%), increased alanine aminotransferase (ALT; 66%), and increased aspartate aminotransferase (AST; 40%). Any grade of neutropenia, thrombocytopenia, or anemia occurred at rates of 43%, 48%, and 38%, respectively.¹² Although nilotinib has a Black Box Warning from the US Food and Drug Administration for QT interval prolongation, no patients on the ENESTnd trial experienced a QT interval corrected for heart rate greater than 500 msec.¹²

More recent concerns have emerged regarding the potential for cardiovascular toxicity after long-term use of nilotinib. The 5-year update of ENESTnd reports cardiovascular events, including ischemic heart disease, ischemic cerebrovascular events, or peripheral arterial disease occurring in 7.5% of patients treated with nilotinib 300 mg twice daily compared with a rate of 2.1% in imatinib-treated patients. The frequency of these cardiovascular events increased linearly over time in both arms. Elevations in total cholesterol from baseline occurred in 27.6% of nilotinib patients compared with 3.9% of imatinib patients. Furthermore, clinically meaningful increases in low-density lipoprotein cholesterol and glycated hemoglobin occurred more frequently with nilotinib therapy.¹² 

Nilotinib should be taken on an empty stomach; therefore, patients should be made aware of the need to fast for 2 hours prior to each dose and 1 hour after each dose. Given the potential risk of QT interval prolongation, a baseline electrocardiogram (ECG) is recommended prior to initiating treatment to ensure the QT interval is within a normal range. A repeat ECG should be done approximately 7 days after nilotinib initiation to ensure no prolongation of the QT interval after starting. Close monitoring of potassium and magnesium levels is important to decrease the risk of cardiac arrhythmias, and concomitant use of drugs considered strong CYP3A4 inhibitors should be avoided.⁷

If the patient experiences any grade 3 or higher laboratory abnormalities, nilotinib should be held until resolution of the toxicity, and then restarted at a lower dose. Similarly, if patients develop significant neutropenia or thrombocytopenia, nilotinib doses should be interrupted until resolution of the cytopenias. At that point, nilotinib can be reinitiated at either the same or a lower dose. Rash can be managed by the use of topical or systemic steroids as well as potential dose reduction, interruption, or discontinuation.

Given the concerns for potential cardiovascular events with long-term use of nilotinib, caution is advised when prescribing it to any patient with a history of cardiovascular disease or peripheral arterial occlusive disease. At the first sign of new occlusive disease, nilotinib should be discontinued.⁷

Bosutinib

Bosutinib is a second-generation BCR-ABL1 TKI with activity against the Src family of kinases that was initially approved to treat patients with CP-, AP-, or BP-CML after resistance or intolerance to imatinib. Long-term data has been reported from the phase 1/2 trial of bosutinib therapy in patients with CP-CML who developed resistance or intolerance to imatinib plus dasatinib and/or nilotinib. A total of 119 patients were included in the 4-year follow-up; 38 were resistant/intolerant to imatinib and resistant to dasatinib, 50 were resistant/intolerant to imatinib and intolerant to dasatinib, 26 were resistant/intolerant to imatinib and resistant to nilotinib, and 5 were resistant/intolerant to imatinib and intolerant to nilotinib or resistant/intolerant to dasatinib and nilotinib. Bosutinib 400 mg daily was studied in this setting. Of the 38 patients with imatinib resistance/intolerance and dasatinib resistance, 39% achieved MCyR, 22% achieved CCyR, and the OS was 67%. Of the 50 patients with imatinib resistance/intolerance and dasatinib intolerance, 42% achieved MCyR, 40% achieved CCyR, and the OS was 80%. Finally, in the 26 patients with imatinib resistance/intolerance and nilotinib resistance, 38% achieved MCyR, 31% achieved CcyR, and the OS was 87%.¹⁴ 

Five-year follow-up from the phase 1/2 clinical trial which studied bosutinib 500 mg daily in CP-CML patients after imatinib failure reported data on 284 patients. By 5 years on study, 60% of patients had achieved MCyR and 50% achieved CCyR with a 71% and 69% probability, respectively, of maintaining these responses at 5 years. The 5-year OS was 84%.¹⁵ These data led to the regulatory approval of bosutinib 500 mg daily as second-line or later therapy. 

Bosutinib was initially studied in the first-line setting in the randomized phase 3 BELA (Bosutinib Efficacy and Safety in Newly Diagnosed Chronic Myeloid Leukemia) trial. This trial compared bosutinib 500 mg daily to imatinib 400 mg daily in newly diagnosed, previously untreated CP-CML patients. This trial failed to meet its primary endpoint of increased rate of CCyR at 12 months, with 70% of bosutinib patients achieving this response compared to 68% of imatinib-treated patients (P = 0.601). In spite of this, the rate of MMR at 12 months was significantly higher in the bosutinib arm (41%) compared to the imatinib arm (27%; P = 0.001).¹⁶ 

A second phase 3 trial (BFORE) was designed to study bosutinib 400 mg daily versus imatinib in newly diagnosed, previously untreated CP-CML patients. This study enrolled 536 patients who were randomly assigned 1:1 to bosutinib versus imatinib. The primary endpoint of this trial was rate of MMR at 12 months. A significantly higher number of bosutinib-treated patients achieved this response (47.2%) compared with imatinib-treated patients (36.9%, P = 0.02). Furthermore, by 12 months 77.2% of patients on the bosutinib arm had achieved CCyR compared with 66.4% on the imatinib arm, and this difference did meet statistical significance (P = 0.0075). A lower rate of progression to AP- or BP-CML was noted in bosutinib-treated patients as well (1.6% versus 2.5%). Based on this data, bosutinib gained regulatory approval for first-line therapy in CP-CML at a dose of 400 mg daily.¹⁷ 

Toxicity

On the BFORE trial, the most common treatment-emergent adverse events of any grade reported in the bosutinib-treated patients were diarrhea (70.1%), nausea (35.1%), increased ALT (30.6%), and increased AST (22.8%). Musculoskeletal pain or spasms occurred in 29.5% of patients, rash in 19.8%, fatigue in 19.4%, and headache in 18.7%. Hematologic toxicity was also reported, but most was grade 1/2. Thrombocytopenia was reported in 35.1%, anemia in 18.7%, and neutropenia in 11.2%.¹⁷

Cardiovascular events occurred in 5.2% of patients on the bosutinib arm of the BFORE trial, which was similar to the rate observed in imatinib patients. The most common cardiovascular event was QT interval prolongation, which occurred in 1.5% of patients. Pleural effusions were reported in 1.9% of patients treated with bosutinib, and none were grade 3 or higher.¹⁷

If liver enzyme elevation occurs at a value greater than 5 times the institutional upper limit of normal, bosutinib should be held until the level recovers to ≤2.5 times the upper limit of normal, at which point bosutinib can be restarted at a lower dose. If recovery takes longer than 4 weeks, bosutinib should be permanently discontinued. Liver enzymes  elevated greater than 3 times the institutional upper limit of normal and a concurrent elevation in total bilirubin to 2 times the upper limit of normal is consistent with Hy's law, and bosutinib should be discontinued. Although diarrhea is the most common toxicity associated with bosutinib, it is commonly low grade and transient. Diarrhea occurs most frequently in the first few days after initiating bosutinib. It can often be managed with over-the-counter antidiarrheal medications, but if the diarrhea is grade or higher, bosutinib should be held until recovery to grade 1 or lower. Gastrointestinal side effects may be improved by taking bosutinib with a meal and a large glass of water. Fluid retention can be managed with diuretics and supportive care. Finally, if rash occurs, this can be addressed with topical or systemic steroids as well as bosutinib dose reduction, interruption, or discontinuation.⁷

Similar to other TKIs, if bosutinib-induced cytopenias occur, treatment should be held and restarted at the same or a lower dose upon blood count recovery.⁷

Ponatinib

The most common cause of TKI resistance in CP-CML is the development of ABL kinase domain mutations. The majority of imatinib-resistant mutations can be overcome by the use of second-generation TKIs including dasatinib, nilotinib, or bosutinib. However, ponatinib is the only BCR-ABL1 TKI able to overcome a T315I mutation. The phase 2 PACE (Ponatinib Ph-positive ALL and CML Evaluation) trial enrolled patients with CP-, AP-, or BP-CML as well as patients with Ph-positive acute lymphoblastic leukemia who were resistant or intolerant to nilotinib or dasatinib, or who had evidence of a T315I mutation. The starting dose of ponatinib on this trial was 45 mg daily.¹⁸ The PACE trial enrolled 267 patients with CP-CML: 203 with resistance or intolerance to nilotinib or dasatinib, and 64 with a T315I mutation. The primary endpoint in the CP cohort was rate of MCyR at any time within 12 months of starting ponatinib. The overall rate of MCyR by 12 months in the CP-CML patients was 56%. In those with a T315I mutation, 70% achieved MCyR, which compared favorably with those with resistance or intolerance to nilotinib or dasatinib, 51% of whom achieved MCyR. CCyR was achieved in 46% of CP-CML patients (40% in the resistant/intolerant cohort and 66% in the T315I cohort). In general, patients with T315I mutations received fewer prior therapies than those in the resistant/intolerant cohort, which likely contributed to the higher response rates in the T315I patients. MR4.5 was achieved in 15% of CP-CML patients by 12 months on the PACE trial.¹⁸ The 5-year update to this study reported that 60%, 40%, and 24% of CP-CML patients achieved MCyR, MMR, and MR4.5, respectively. In the patients who achieved MCyR, the probability of maintaining this response for 5 years was 82% and the estimated 5-year OS was 73%.¹⁹

Toxicity

In 2013, after the regulatory approval of ponatinib, reports became available that the drug can cause an increase in arterial occlusive events including fatal myocardial infarctions and cerebral vascular accidents. For this reason, dose reductions were implemented in patients who were deriving clinical benefit from ponatinib. In spite of these dose reductions, ≥90% of responders maintained their response for up to 40 months.¹⁹ Although the likelihood of developing an arterial occlusive event appears higher in the first year after starting ponatinib than in later years, the cumulative incidence of events continues to increase. The 5-year follow-up to the PACE trial reports 31% of patients experiencing any grade of arterial occlusive event while on ponatinib. Aside from these events, the most common treatment-emergent adverse events in ponatinib-treated patients on the PACE trial included rash (47%), abdominal pain (46%), headache (43%), dry skin (42%), constipation (41%), and hypertension (37%). Hematologic toxicity was also common, with 46% of patients experiencing any grade of thrombocytopenia, 20% experiencing neutropenia, and 20% anemia.¹⁹

Patients receiving ponatinib therapy should be monitored closely for any evidence of arterial or venous thrombosis. In the event of an occlusive event, ponatinib should be discontinued. Similarly, in the setting of any new or worsening heart failure symptoms, ponatinib should be promptly discontinued. Management of any underlying cardiovascular risk factors including hypertension, hyperlipidemia, diabetes, or smoking history is recommended, and these patients should be referred to a cardiologist for a full evaluation. In the absence of any contraindications to aspirin, low-dose aspirin should be considered as a means of decreasing cardiovascular risks associated with ponatinib. In patients with known risk factors, a ponatinib starting dose of 30 mg daily rather than the standard 45 mg daily may be a safer option resulting in fewer arterial occlusive events, although the efficacy of this dose is still being studied in comparison to 45 mg daily.⁷

In the event of ponatinib-induced transaminitis greater than 3 times the upper limit of normal, ponatinib should be held until resolution to less than 3 times the upper limit of normal, at which point it should be resumed at a lower dose. Similarly, in the setting of elevated serum lipase or symptomatic pancreatitis, ponatinib should be held and restarted at a lower dose after resolution of symptoms.⁷ 

In the event of neutropenia or thrombocytopenia, ponatinib should be held until blood count recovery and then restarted at the same dose. If cytopenias occur for a second time, the dose of ponatinib should be lowered at the time of treatment reinitiation. If rash occurs, it can be addressed with topical or systemic steroids as well as dose reduction, interruption, or discontinuation.⁷

Case Conclusion

Given the patient's high-risk Sokal score, ideal first-line treatment is a second-generation TKI in order to increase the likelihood of achieving the desired treatment milestones and improving long-term outcomes. Her history of uncontrolled diabetes and coronary artery disease raises concerns for using nilotinib. Furthermore, her history of COPD makes dasatinib suboptimal because she would have little pulmonary reserve if she were to develop a pleural effusion. For this reason, bosutinib 400 mg daily is chosen as her first-line TKI. Shortly after starting bosutinib, she experiences diarrhea that occurs approximately 3 or 4 times daily during the first week on treatment. She is able to manage this with over-the-counter loperamide and the diarrhea resolves shortly thereafter.

After 3 months of bosutinib therapy, quantitative real-time PCR (RQ-PCR) assay on peripheral blood is done to measure BCR-ABL1 transcripts, and the result is reported at 1.2% IS. This indicates that the patient has achieved an early molecular response, which is defined as a RQ-PCR value of ≤10% IS. She undergoes RQ-PCR monitoring every 3 months, and at 12 months her results indicate a value of 0.07% IS, suggesting she has achieved a MMR. 

Conclusion

With the development of imatinib and the subsequent TKIs, dasatinib, nilotinib, bosutinib, and ponatinib, CP-CML has become a chronic disease with a life-expectancy that is similar to the general population. Given the successful treatments available for these patients, it is crucial to identify patients with this diagnosis, ensure they receive a complete, appropriate diagnostic workup including a bone marrow biopsy and aspiration with cytogenetic testing, and select the best therapy for each individual patient. Once on treatment, the importance of frequent monitoring cannot be overstated. This is the only way to be certain patients are achieving the desired treatment milestones that correlate with the favorable long-term outcomes that have been observed with TKI-based treatment of CP-CML. 

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm that arises from a reciprocal translocation between the Abelson (ABL) region on chromosome 9 and the breakpoint cluster region (BCR) of chromosome 22, t(9;22)(q34;q11.2) (the Philadelphia chromosome), resulting in the generation of the BCR-ABL1 fusion gene and its protein product, BCR-ABL tyrosine kinase. BCR-ABL is a constitutively active fusion kinase that confers proliferative and survival advantage to hematopoietic cells through activation of downstream pathways.

CML is divided into 3 phases based on the number of myeloblasts observed in the blood or bone marrow: chronic, accelerated, and blast. Most cases of CML are diagnosed in the chronic phase (CP), which is marked by proliferation of primarily the myeloid element.

The advent of tyrosine kinase inhibitors (TKIs), a class of small molecules targeting the tyrosine kinases, particularly the BCR-ABL tyrosine kinase, led to rapid changes in the management of CML and improved survival for patients. Patients diagnosed with CP-CML now a have life-expectancy that is similar to that of the general population, as long as they receive the appropriate TKI therapy and adhere to treatment. As such, it is crucial to identify patients with CML, ensure they receive a complete, appropriate diagnostic work-up, and select the best therapy for each individual patient. The diagnosis and work-up of CML are reviewed in a separate article; here, the selection of TKI therapy for a patient with newly diagnosed CP-CML is reviewed. 

Case Presentation

A 53-year-old woman who recently was diagnosed with CML presents to review her treatment options. The diagnosis was made after she presented to her primary care physician with fatigue, early satiety, left upper quadrant abdominal pain, and an 8-lb unintentional weight loss over the prior month. On physical exam her spleen was palpated 8 cm below the left costal margin. Laboratory evaluation showed a total white blood cell (WBC) count of 124,000/μL with a left-shifted differential including 6% basophils, 3% eosinophils, and 3% blasts; hemoglobin and platelet count were 12.4 g/dL and 801 × 10³/µL, respectively. Fluorescent in-situ hybridization for BCR-ABL gene rearrangement using peripheral blood was positive in 87% of cells. Bone marrow biopsy and aspiration showed a 95% cellular bone marrow with granulocytic hyperplasia and 1% blasts. Cytogenetics were 46,XX,t(9;22)(q34;q11.2), and quantitative real-time polymerase chain reaction (RQ-PCR) to measure BCR-ABL1 transcripts in the peripheral blood showed a value of 98% international standard (IS). Her Sokal risk score was 1.42 (high risk). In addition, prior review of her past medical history revealed uncontrolled diabetes, coronary artery disease requiring placement of 3 cardiac stents 2 years prior, and chronic obstructive pulmonary disease (COPD) related to a 30-pack-year history of smoking.

• What factors must be considered when selecting first-line therapy for this patient?

Selection of the most appropriate first-line TKI for newly diagnosed CP-CML patients requires incorporation of many patient-specific factors. These factors include baseline karyotype and confirmation of CP-CML through bone marrow biopsy, Sokal or EURO risk score, and a thorough patient history, including a clear understanding of the patient's comorbidities. In this case, the patient's high Sokal risk score along with her history of diabetes, coronary artery disease, and COPD are all factors that must be accounted for when choosing the most appropriate TKI. The adverse effect profile of all TKIs must be considered in conjunction with the patient's ongoing medical issues in order to decrease the likelihood of worsening her current symptoms or causing a severe complication from TKI therapy.

Imatinib

The management of CML was revolutionized by the development and ultimate regulatory approval of imatinib mesylate in 2001. Imatinib was the first small-molecule cancer therapy developed and approved. It acts by binding to the adenosine triphosphate (ATP) binding site in the catalytic domain of BCR-ABL, thus inhibiting the oncoprotein's tyrosine kinase activity.¹

The International Randomized Study of Interferon versus STI571 (IRIS) trial was a randomized phase 3 study that compared imatinib 400 mg daily to interferon α (IFNα) plus cytarabine. More than 1000 CP-CML patients were randomly assigned 1:1 to either imatinib or IFNα plus cytarabine and were assessed for event-free survival, hematologic and cytogenetic responses, freedom from progression to accelerated phase (AP) or blast phase (BP), and toxicity. Imatinib was superior to the prior standard of care for all these outcomes.² The long-term follow up of the IRIS trial reported an 83% estimated 10-year overall survival (OS) and 79% estimated event-free survival for patients on the imatinib arm of this study.³ The cumulative rate of complete cytogenetic response (CCyR) was 82.8%. Of the 204 imatinib-treated patients who could undergo a molecular response evaluation at 10 years, 93.1% had a major molecular response (MMR) and 63.2% had a molecular response 4.5 (MR4.5), suggesting durable, deep molecular responses for many patients (see Chronic Myeloid Leukemia: Evaluation and Diagnosis for discussion of the hematologic parameters, cytogenetic results, and molecular responses ussed in monitoring response to TKI therapy). The estimated 10-year rate of freedom from progression to AP or BP was 92.1%.

Higher doses of imatinib (600-800 mg daily) have been studied in an attempt to overcome resistance and improve cytogenetic and molecular response rates. The Tyrosine Kinase Inhibitor Optimization and Selectivity (TOPS) trial was a randomized phase 3 study that compared imatinib 800 mg daily to imatinib 400 mg daily. Although the 6-month assessments found increased rates of CCyR and a MMR in the higher-dose imatinib arm, these differences were no longer present at the 12-month assessment. Furthermore, the higher dose of imatinib led to a significantly higher incidence of grade 3/4 hematologic adverse events, and approximately 50% of patients on imatinib 800 mg daily required a dose reduction to less than 600 mg daily because of toxicity.⁴ 

The Therapeutic Intensification in De Novo Leukaemia (TIDEL) -II study used plasma trough levels of imatinib on day 22 of treatment with imatinib 600 mg daily to determine if patients should escalate the imatinib dose to 800 mg daily. In patients who did not meet molecular milestones at 3, 6, or 12 months, cohort 1 was dose escalated to imatinib 800 mg daily and subsequently switched to nilotinib 400 mg twice daily for failing the same target 3 months later, and cohort 2 was switched to nilotinib. At 2 years, 73% of patients achieved MMR and 34% achieved MR4.5, suggesting that initial treatment with higher-dose imatinib subsequently followed by a switch to nilotinib in those failing to achieve desired milestones could be an effective strategy for managing newly diagnosed CP-CML.⁵

Toxicity

Imatinib 400 mg is considered the standard starting dose in CP-CML patients. The safety profile of imatinib has been very well established. In the IRIS trial, the most common adverse events (all grades in decreasing order of frequency) were peripheral and periorbital edema (60%), nausea (50%), muscle cramps (49%), musculoskeletal pain (47%), diarrhea (45%), rash (40%), fatigue (39%), abdominal pain (37%), headache (37%), and joint pain (31%). Grade 3/4 liver enzyme elevation can occur in 5% of patients.⁶ In the event of severe liver toxicity or fluid retention, imatinib should be held until the event resolves. At that time, imatinib can be restarted if deemed appropriate, but this is dependent on the severity of the inciting event. Fluid retention can be managed by the use of supportive care, diuretics, imatinib dose reduction, dose interruption, or imatinib discontinuation if the fluid retention is severe. Muscle cramps can be managed by the use of a calcium supplements or tonic water. Management of rash can include topical or systemic steroids, or in some cases imatinib dose reduction, interruption, or discontinuation.⁷  

Grade 3/4 imatinib-induced hematologic toxicity is not uncommon, with 17% of patients experiencing neutropenia, 9% thrombocytopenia, and 4% anemia. These adverse events occurred most commonly during the first year of therapy, and the frequency decreased over time.^3,6 Depending on the degree of cytopenias, imatinib dosing should be interrupted until recovery of the absolute neutrophil count or platelet count, and can often be resumed at 400 mg daily. However, if cytopenias recur, imatinib should be held and subsequently restarted at 300 mg daily.⁷ 

Dasatinib

Dasatinib is a second-generation TKI that has regulatory approval for treatment of adult patients with newly diagnosed CP-CML or CP-CML in patients with resistance or intolerance to prior TKIs. In addition to dasatinib's ability to inhibit ABL kinases, it is also known to be a potent inhibitor of Src family kinases. Dasatinib has shown efficacy in patients who have developed imatinib-resistant ABL kinase domain mutations. 

Dasatinib was initially approved as second-line therapy in patients with resistance or intolerance to imatinib. This indication was based on the results of the phase 3 CA180-034 trial which ultimately identified dasatinib 100 mg daily as the optimal dose. In this trial, 74% of patients enrolled had resistance to imatinib and the remainder were intolerant. The 7-year follow-up of patients randomized to dasatinib 100 mg (n = 167) daily indicated that 46% achieved MMR while on study. Of the 124 imatinib-resistant patients on dasatinib 100 mg daily, the 7-year progression-free survival (PFS) was 39% and OS was 63%. In the 43 imatinib-intolerant patients, the 7-year PFS was 51% and OS was 70%.⁸

Dasatinib 100 mg daily was compared to imatinib 400 mg daily in newly diagnosed CP-CML patients in the randomized phase 3 DASISION trial. More patients on the dasatinib arm achieved an early molecular response of BCR-ABL1 transcripts ≤10% IS after 3 months on treatment compared to imatinib (84% versus 64%). Furthermore, the 5-year follow-up reports that the cumulative incidence of MMR and MR4.5 in dasatinib-treated patients was 76% and 42%, and was 64% and 33%, with imatinib (P = 0.0022 and P = 0.0251, respectively). Fewer patients treated with dasatinib progressed to AP or BP (4.6%) compared to imatinib (7.3%), but the estimated 5-year OS was similar between the 2 arms (91% for dasatinib versus 90% for imatinib).⁹ Regulatory approval for dasatinib as first-line therapy in newly diagnosed CML patients was based on results of the DASISION trial. 

Toxicity

Most dasatinib-related toxicities are reported as grade 1 or grade 2, but grade 3/4 hematologic adverse events are fairly common. In the DASISION trial, grade 3/4 neutropenia, anemia, and thrombocytopenia occurred in 29%, 13%, and 22% of dasatinib-treated patients, respectively. Cytopenias can generally be managed with temporary dose interruptions or dose reductions.

During the 5-year follow-up of the DASISION trial, pleural effusions were reported in 28% of patients, most of which were grade 1/2. This occurred at a rate of approximately ≤ 8% per year, suggesting a stable incidence over time, and the effusions appear to be dose-dependent.⁹ Depending on the severity of the effusion, this may be treated with diuretics, dose interruption, and in some instances, steroids or a thoracentesis. Typically, dasatinib can be restarted at 1 dose level lower than the previous dose once the effusion has resolved.⁷ Other, less common side effects of dasatinib include pulmonary hypertension (5% of patients), as well as abdominal pain, fluid retention, headaches, fatigue, musculoskeletal pain, rash, nausea, and diarrhea. Pulmonary hypertension is typically reversible after cessation of dasatinib, and thus dasatinib should be permanently discontinued once the diagnosis is confirmed. Fluid retention is often treated with diuretics and supportive care. Nausea and diarrhea are generally manageable and occur less frequently when dasatinib is taken with food and a large glass of water. Antiemetics and antidiarrheals can be used as needed. Troublesome rash can be best managed with topical or systemic steroids as well as possible dose reduction or dose interruption.^7,9 In the DASISION trial, adverse events led to therapy discontinuation more often in  the dasatinib group than in the imatinib group (16% versus 7%).⁹ Bleeding, particularly in the setting of thrombocytopenia, has been reported in patients being treated with dasatinib as a result of the drug-induced reversible inhibition of platelet aggregation.¹⁰

Nilotinib

The structure of nilotinib is similar to that of imatinib; however, it has a markedly increased affinity for the ATP‐binding site on the BCR-ABL1 protein. It was initially given regulatory approval in the setting of imatinib failure. Nilotinib was studied at a dose of 400 mg twice daily in 321 patients who were imatinib-resistant or -intolerant. It proved to be highly effective at inducing cytogenetic remissions in the second-line setting, with 59% of patients achieving a major cytogenetic response (MCyR) and 45% achieving CCyR. With a median follow-up time of 4 years, the OS was 78%.¹¹ 

Nilotinib gained regulatory approval for use as a first-line TKI after completion of the randomized phase 3 ENESTnd (Evaluating Nilotinib Efficacy and Safety in Clinical Trials-Newly Diagnosed Patients) trial. ENESTnd was a 3-arm study comparing nilotinib 300 mg twice daily versus nilotinib 400 mg twice daily versus imatinib 400 mg daily in newly diagnosed, previously untreated patients diagnosed with CP-CML. The primary endpoint of this clinical trial was rate of MMR at 12 months.¹² Nilotinib surpassed imatinib in this regard, with 44% of patients on nilotinib 300 mg twice daily achieving MMR at 12 months versus 43% of nilotinib 400 mg twice daily patients versus 22% of the imatinib-treated patients (P < 0.001 for both comparisons). Furthermore, the rate of CCyR by 12 months was significantly higher for both nilotinib arms compared with imatinib (80% for nilotinib 300 mg, 78% for nilotinib 400 mg, and 65% for imatinib) (P < 0.001).¹² Based on this data, nilotinib 300 mg twice daily was chosen as the standard dose of nilotinib in the first-line setting. After 5 years of follow-up on the ENESTnd study, there were fewer progressions to AP/BP CML in nilotinib-treated patients compared with imatinib. MMR was achieved in 77% of nilotinib 300 mg patients compared with 60.4% of patients on the imatinib arm. MR4.5 was also more common in patients treated with nilotinib 300 mg twice daily, with a rate of 53.5% at 5 years versus 31.4% in the imatinib arm.¹³ In spite of the deeper cytogenetic and molecular responses achieved with nilotinib, this did not translate into a significant improvement in OS. The 5-year OS rate was 93.7%  in nilotinib 300 mg patients versus 91.7% in imatinib-treated patients, and this difference lacked statistical significance.¹³

Toxicity

Although some similarities exist between the toxicity profiles of nilotinib and imatinib, each drug has some distinct adverse events. On the ENESTnd trial, the rate of any grade 3/4 non-hematologic adverse event was fairly low; however, lower-grade toxicities were not uncommon. Patients treated with nilotinib 300 mg twice daily experienced rash (31%), headache (14%), pruritis (15%), and fatigue (11%) most commonly. The most frequently reported laboratory abnormalities included increased total bilirubin (53%), hypophosphatemia (32%), hyperglycemia (36%), elevated lipase (24%), increased alanine aminotransferase (ALT; 66%), and increased aspartate aminotransferase (AST; 40%). Any grade of neutropenia, thrombocytopenia, or anemia occurred at rates of 43%, 48%, and 38%, respectively.¹² Although nilotinib has a Black Box Warning from the US Food and Drug Administration for QT interval prolongation, no patients on the ENESTnd trial experienced a QT interval corrected for heart rate greater than 500 msec.¹²

More recent concerns have emerged regarding the potential for cardiovascular toxicity after long-term use of nilotinib. The 5-year update of ENESTnd reports cardiovascular events, including ischemic heart disease, ischemic cerebrovascular events, or peripheral arterial disease occurring in 7.5% of patients treated with nilotinib 300 mg twice daily compared with a rate of 2.1% in imatinib-treated patients. The frequency of these cardiovascular events increased linearly over time in both arms. Elevations in total cholesterol from baseline occurred in 27.6% of nilotinib patients compared with 3.9% of imatinib patients. Furthermore, clinically meaningful increases in low-density lipoprotein cholesterol and glycated hemoglobin occurred more frequently with nilotinib therapy.¹² 

Nilotinib should be taken on an empty stomach; therefore, patients should be made aware of the need to fast for 2 hours prior to each dose and 1 hour after each dose. Given the potential risk of QT interval prolongation, a baseline electrocardiogram (ECG) is recommended prior to initiating treatment to ensure the QT interval is within a normal range. A repeat ECG should be done approximately 7 days after nilotinib initiation to ensure no prolongation of the QT interval after starting. Close monitoring of potassium and magnesium levels is important to decrease the risk of cardiac arrhythmias, and concomitant use of drugs considered strong CYP3A4 inhibitors should be avoided.⁷

If the patient experiences any grade 3 or higher laboratory abnormalities, nilotinib should be held until resolution of the toxicity, and then restarted at a lower dose. Similarly, if patients develop significant neutropenia or thrombocytopenia, nilotinib doses should be interrupted until resolution of the cytopenias. At that point, nilotinib can be reinitiated at either the same or a lower dose. Rash can be managed by the use of topical or systemic steroids as well as potential dose reduction, interruption, or discontinuation.

Given the concerns for potential cardiovascular events with long-term use of nilotinib, caution is advised when prescribing it to any patient with a history of cardiovascular disease or peripheral arterial occlusive disease. At the first sign of new occlusive disease, nilotinib should be discontinued.⁷

Bosutinib

Bosutinib is a second-generation BCR-ABL1 TKI with activity against the Src family of kinases that was initially approved to treat patients with CP-, AP-, or BP-CML after resistance or intolerance to imatinib. Long-term data has been reported from the phase 1/2 trial of bosutinib therapy in patients with CP-CML who developed resistance or intolerance to imatinib plus dasatinib and/or nilotinib. A total of 119 patients were included in the 4-year follow-up; 38 were resistant/intolerant to imatinib and resistant to dasatinib, 50 were resistant/intolerant to imatinib and intolerant to dasatinib, 26 were resistant/intolerant to imatinib and resistant to nilotinib, and 5 were resistant/intolerant to imatinib and intolerant to nilotinib or resistant/intolerant to dasatinib and nilotinib. Bosutinib 400 mg daily was studied in this setting. Of the 38 patients with imatinib resistance/intolerance and dasatinib resistance, 39% achieved MCyR, 22% achieved CCyR, and the OS was 67%. Of the 50 patients with imatinib resistance/intolerance and dasatinib intolerance, 42% achieved MCyR, 40% achieved CCyR, and the OS was 80%. Finally, in the 26 patients with imatinib resistance/intolerance and nilotinib resistance, 38% achieved MCyR, 31% achieved CcyR, and the OS was 87%.¹⁴ 

Five-year follow-up from the phase 1/2 clinical trial which studied bosutinib 500 mg daily in CP-CML patients after imatinib failure reported data on 284 patients. By 5 years on study, 60% of patients had achieved MCyR and 50% achieved CCyR with a 71% and 69% probability, respectively, of maintaining these responses at 5 years. The 5-year OS was 84%.¹⁵ These data led to the regulatory approval of bosutinib 500 mg daily as second-line or later therapy. 

Bosutinib was initially studied in the first-line setting in the randomized phase 3 BELA (Bosutinib Efficacy and Safety in Newly Diagnosed Chronic Myeloid Leukemia) trial. This trial compared bosutinib 500 mg daily to imatinib 400 mg daily in newly diagnosed, previously untreated CP-CML patients. This trial failed to meet its primary endpoint of increased rate of CCyR at 12 months, with 70% of bosutinib patients achieving this response compared to 68% of imatinib-treated patients (P = 0.601). In spite of this, the rate of MMR at 12 months was significantly higher in the bosutinib arm (41%) compared to the imatinib arm (27%; P = 0.001).¹⁶ 

A second phase 3 trial (BFORE) was designed to study bosutinib 400 mg daily versus imatinib in newly diagnosed, previously untreated CP-CML patients. This study enrolled 536 patients who were randomly assigned 1:1 to bosutinib versus imatinib. The primary endpoint of this trial was rate of MMR at 12 months. A significantly higher number of bosutinib-treated patients achieved this response (47.2%) compared with imatinib-treated patients (36.9%, P = 0.02). Furthermore, by 12 months 77.2% of patients on the bosutinib arm had achieved CCyR compared with 66.4% on the imatinib arm, and this difference did meet statistical significance (P = 0.0075). A lower rate of progression to AP- or BP-CML was noted in bosutinib-treated patients as well (1.6% versus 2.5%). Based on this data, bosutinib gained regulatory approval for first-line therapy in CP-CML at a dose of 400 mg daily.¹⁷ 

Toxicity

On the BFORE trial, the most common treatment-emergent adverse events of any grade reported in the bosutinib-treated patients were diarrhea (70.1%), nausea (35.1%), increased ALT (30.6%), and increased AST (22.8%). Musculoskeletal pain or spasms occurred in 29.5% of patients, rash in 19.8%, fatigue in 19.4%, and headache in 18.7%. Hematologic toxicity was also reported, but most was grade 1/2. Thrombocytopenia was reported in 35.1%, anemia in 18.7%, and neutropenia in 11.2%.¹⁷

Cardiovascular events occurred in 5.2% of patients on the bosutinib arm of the BFORE trial, which was similar to the rate observed in imatinib patients. The most common cardiovascular event was QT interval prolongation, which occurred in 1.5% of patients. Pleural effusions were reported in 1.9% of patients treated with bosutinib, and none were grade 3 or higher.¹⁷

If liver enzyme elevation occurs at a value greater than 5 times the institutional upper limit of normal, bosutinib should be held until the level recovers to ≤2.5 times the upper limit of normal, at which point bosutinib can be restarted at a lower dose. If recovery takes longer than 4 weeks, bosutinib should be permanently discontinued. Liver enzymes  elevated greater than 3 times the institutional upper limit of normal and a concurrent elevation in total bilirubin to 2 times the upper limit of normal is consistent with Hy's law, and bosutinib should be discontinued. Although diarrhea is the most common toxicity associated with bosutinib, it is commonly low grade and transient. Diarrhea occurs most frequently in the first few days after initiating bosutinib. It can often be managed with over-the-counter antidiarrheal medications, but if the diarrhea is grade or higher, bosutinib should be held until recovery to grade 1 or lower. Gastrointestinal side effects may be improved by taking bosutinib with a meal and a large glass of water. Fluid retention can be managed with diuretics and supportive care. Finally, if rash occurs, this can be addressed with topical or systemic steroids as well as bosutinib dose reduction, interruption, or discontinuation.⁷

Similar to other TKIs, if bosutinib-induced cytopenias occur, treatment should be held and restarted at the same or a lower dose upon blood count recovery.⁷

Ponatinib

The most common cause of TKI resistance in CP-CML is the development of ABL kinase domain mutations. The majority of imatinib-resistant mutations can be overcome by the use of second-generation TKIs including dasatinib, nilotinib, or bosutinib. However, ponatinib is the only BCR-ABL1 TKI able to overcome a T315I mutation. The phase 2 PACE (Ponatinib Ph-positive ALL and CML Evaluation) trial enrolled patients with CP-, AP-, or BP-CML as well as patients with Ph-positive acute lymphoblastic leukemia who were resistant or intolerant to nilotinib or dasatinib, or who had evidence of a T315I mutation. The starting dose of ponatinib on this trial was 45 mg daily.¹⁸ The PACE trial enrolled 267 patients with CP-CML: 203 with resistance or intolerance to nilotinib or dasatinib, and 64 with a T315I mutation. The primary endpoint in the CP cohort was rate of MCyR at any time within 12 months of starting ponatinib. The overall rate of MCyR by 12 months in the CP-CML patients was 56%. In those with a T315I mutation, 70% achieved MCyR, which compared favorably with those with resistance or intolerance to nilotinib or dasatinib, 51% of whom achieved MCyR. CCyR was achieved in 46% of CP-CML patients (40% in the resistant/intolerant cohort and 66% in the T315I cohort). In general, patients with T315I mutations received fewer prior therapies than those in the resistant/intolerant cohort, which likely contributed to the higher response rates in the T315I patients. MR4.5 was achieved in 15% of CP-CML patients by 12 months on the PACE trial.¹⁸ The 5-year update to this study reported that 60%, 40%, and 24% of CP-CML patients achieved MCyR, MMR, and MR4.5, respectively. In the patients who achieved MCyR, the probability of maintaining this response for 5 years was 82% and the estimated 5-year OS was 73%.¹⁹

Toxicity

In 2013, after the regulatory approval of ponatinib, reports became available that the drug can cause an increase in arterial occlusive events including fatal myocardial infarctions and cerebral vascular accidents. For this reason, dose reductions were implemented in patients who were deriving clinical benefit from ponatinib. In spite of these dose reductions, ≥90% of responders maintained their response for up to 40 months.¹⁹ Although the likelihood of developing an arterial occlusive event appears higher in the first year after starting ponatinib than in later years, the cumulative incidence of events continues to increase. The 5-year follow-up to the PACE trial reports 31% of patients experiencing any grade of arterial occlusive event while on ponatinib. Aside from these events, the most common treatment-emergent adverse events in ponatinib-treated patients on the PACE trial included rash (47%), abdominal pain (46%), headache (43%), dry skin (42%), constipation (41%), and hypertension (37%). Hematologic toxicity was also common, with 46% of patients experiencing any grade of thrombocytopenia, 20% experiencing neutropenia, and 20% anemia.¹⁹

Patients receiving ponatinib therapy should be monitored closely for any evidence of arterial or venous thrombosis. In the event of an occlusive event, ponatinib should be discontinued. Similarly, in the setting of any new or worsening heart failure symptoms, ponatinib should be promptly discontinued. Management of any underlying cardiovascular risk factors including hypertension, hyperlipidemia, diabetes, or smoking history is recommended, and these patients should be referred to a cardiologist for a full evaluation. In the absence of any contraindications to aspirin, low-dose aspirin should be considered as a means of decreasing cardiovascular risks associated with ponatinib. In patients with known risk factors, a ponatinib starting dose of 30 mg daily rather than the standard 45 mg daily may be a safer option resulting in fewer arterial occlusive events, although the efficacy of this dose is still being studied in comparison to 45 mg daily.⁷

In the event of ponatinib-induced transaminitis greater than 3 times the upper limit of normal, ponatinib should be held until resolution to less than 3 times the upper limit of normal, at which point it should be resumed at a lower dose. Similarly, in the setting of elevated serum lipase or symptomatic pancreatitis, ponatinib should be held and restarted at a lower dose after resolution of symptoms.⁷ 

In the event of neutropenia or thrombocytopenia, ponatinib should be held until blood count recovery and then restarted at the same dose. If cytopenias occur for a second time, the dose of ponatinib should be lowered at the time of treatment reinitiation. If rash occurs, it can be addressed with topical or systemic steroids as well as dose reduction, interruption, or discontinuation.⁷

Case Conclusion

Given the patient's high-risk Sokal score, ideal first-line treatment is a second-generation TKI in order to increase the likelihood of achieving the desired treatment milestones and improving long-term outcomes. Her history of uncontrolled diabetes and coronary artery disease raises concerns for using nilotinib. Furthermore, her history of COPD makes dasatinib suboptimal because she would have little pulmonary reserve if she were to develop a pleural effusion. For this reason, bosutinib 400 mg daily is chosen as her first-line TKI. Shortly after starting bosutinib, she experiences diarrhea that occurs approximately 3 or 4 times daily during the first week on treatment. She is able to manage this with over-the-counter loperamide and the diarrhea resolves shortly thereafter.

After 3 months of bosutinib therapy, quantitative real-time PCR (RQ-PCR) assay on peripheral blood is done to measure BCR-ABL1 transcripts, and the result is reported at 1.2% IS. This indicates that the patient has achieved an early molecular response, which is defined as a RQ-PCR value of ≤10% IS. She undergoes RQ-PCR monitoring every 3 months, and at 12 months her results indicate a value of 0.07% IS, suggesting she has achieved a MMR. 

Conclusion

With the development of imatinib and the subsequent TKIs, dasatinib, nilotinib, bosutinib, and ponatinib, CP-CML has become a chronic disease with a life-expectancy that is similar to the general population. Given the successful treatments available for these patients, it is crucial to identify patients with this diagnosis, ensure they receive a complete, appropriate diagnostic workup including a bone marrow biopsy and aspiration with cytogenetic testing, and select the best therapy for each individual patient. Once on treatment, the importance of frequent monitoring cannot be overstated. This is the only way to be certain patients are achieving the desired treatment milestones that correlate with the favorable long-term outcomes that have been observed with TKI-based treatment of CP-CML. 

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm that arises from a reciprocal translocation between the Abelson (ABL) region on chromosome 9 and the breakpoint cluster region (BCR) of chromosome 22, t(9;22)(q34;q11.2) (the Philadelphia chromosome), resulting in the generation of the BCR-ABL1 fusion gene and its protein product, BCR-ABL tyrosine kinase. BCR-ABL is a constitutively active fusion kinase that confers proliferative and survival advantage to hematopoietic cells through activation of downstream pathways.

CML is divided into 3 phases based on the number of myeloblasts observed in the blood or bone marrow: chronic, accelerated, and blast. Most cases of CML are diagnosed in the chronic phase (CP), which is marked by proliferation of primarily the myeloid element.

The advent of tyrosine kinase inhibitors (TKIs), a class of small molecules targeting the tyrosine kinases, particularly the BCR-ABL tyrosine kinase, led to rapid changes in the management of CML and improved survival for patients. Patients diagnosed with CP-CML now a have life-expectancy that is similar to that of the general population, as long as they receive the appropriate TKI therapy and adhere to treatment. As such, it is crucial to identify patients with CML, ensure they receive a complete, appropriate diagnostic work-up, and select the best therapy for each individual patient. The diagnosis and work-up of CML are reviewed in a separate article; here, the selection of TKI therapy for a patient with newly diagnosed CP-CML is reviewed. 

Case Presentation

A 53-year-old woman who recently was diagnosed with CML presents to review her treatment options. The diagnosis was made after she presented to her primary care physician with fatigue, early satiety, left upper quadrant abdominal pain, and an 8-lb unintentional weight loss over the prior month. On physical exam her spleen was palpated 8 cm below the left costal margin. Laboratory evaluation showed a total white blood cell (WBC) count of 124,000/μL with a left-shifted differential including 6% basophils, 3% eosinophils, and 3% blasts; hemoglobin and platelet count were 12.4 g/dL and 801 × 10³/µL, respectively. Fluorescent in-situ hybridization for BCR-ABL gene rearrangement using peripheral blood was positive in 87% of cells. Bone marrow biopsy and aspiration showed a 95% cellular bone marrow with granulocytic hyperplasia and 1% blasts. Cytogenetics were 46,XX,t(9;22)(q34;q11.2), and quantitative real-time polymerase chain reaction (RQ-PCR) to measure BCR-ABL1 transcripts in the peripheral blood showed a value of 98% international standard (IS). Her Sokal risk score was 1.42 (high risk). In addition, prior review of her past medical history revealed uncontrolled diabetes, coronary artery disease requiring placement of 3 cardiac stents 2 years prior, and chronic obstructive pulmonary disease (COPD) related to a 30-pack-year history of smoking.

• What factors must be considered when selecting first-line therapy for this patient?

Selection of the most appropriate first-line TKI for newly diagnosed CP-CML patients requires incorporation of many patient-specific factors. These factors include baseline karyotype and confirmation of CP-CML through bone marrow biopsy, Sokal or EURO risk score, and a thorough patient history, including a clear understanding of the patient's comorbidities. In this case, the patient's high Sokal risk score along with her history of diabetes, coronary artery disease, and COPD are all factors that must be accounted for when choosing the most appropriate TKI. The adverse effect profile of all TKIs must be considered in conjunction with the patient's ongoing medical issues in order to decrease the likelihood of worsening her current symptoms or causing a severe complication from TKI therapy.

Imatinib

The management of CML was revolutionized by the development and ultimate regulatory approval of imatinib mesylate in 2001. Imatinib was the first small-molecule cancer therapy developed and approved. It acts by binding to the adenosine triphosphate (ATP) binding site in the catalytic domain of BCR-ABL, thus inhibiting the oncoprotein's tyrosine kinase activity.¹

The International Randomized Study of Interferon versus STI571 (IRIS) trial was a randomized phase 3 study that compared imatinib 400 mg daily to interferon α (IFNα) plus cytarabine. More than 1000 CP-CML patients were randomly assigned 1:1 to either imatinib or IFNα plus cytarabine and were assessed for event-free survival, hematologic and cytogenetic responses, freedom from progression to accelerated phase (AP) or blast phase (BP), and toxicity. Imatinib was superior to the prior standard of care for all these outcomes.² The long-term follow up of the IRIS trial reported an 83% estimated 10-year overall survival (OS) and 79% estimated event-free survival for patients on the imatinib arm of this study.³ The cumulative rate of complete cytogenetic response (CCyR) was 82.8%. Of the 204 imatinib-treated patients who could undergo a molecular response evaluation at 10 years, 93.1% had a major molecular response (MMR) and 63.2% had a molecular response 4.5 (MR4.5), suggesting durable, deep molecular responses for many patients (see Chronic Myeloid Leukemia: Evaluation and Diagnosis for discussion of the hematologic parameters, cytogenetic results, and molecular responses ussed in monitoring response to TKI therapy). The estimated 10-year rate of freedom from progression to AP or BP was 92.1%.

Higher doses of imatinib (600-800 mg daily) have been studied in an attempt to overcome resistance and improve cytogenetic and molecular response rates. The Tyrosine Kinase Inhibitor Optimization and Selectivity (TOPS) trial was a randomized phase 3 study that compared imatinib 800 mg daily to imatinib 400 mg daily. Although the 6-month assessments found increased rates of CCyR and a MMR in the higher-dose imatinib arm, these differences were no longer present at the 12-month assessment. Furthermore, the higher dose of imatinib led to a significantly higher incidence of grade 3/4 hematologic adverse events, and approximately 50% of patients on imatinib 800 mg daily required a dose reduction to less than 600 mg daily because of toxicity.⁴ 

The Therapeutic Intensification in De Novo Leukaemia (TIDEL) -II study used plasma trough levels of imatinib on day 22 of treatment with imatinib 600 mg daily to determine if patients should escalate the imatinib dose to 800 mg daily. In patients who did not meet molecular milestones at 3, 6, or 12 months, cohort 1 was dose escalated to imatinib 800 mg daily and subsequently switched to nilotinib 400 mg twice daily for failing the same target 3 months later, and cohort 2 was switched to nilotinib. At 2 years, 73% of patients achieved MMR and 34% achieved MR4.5, suggesting that initial treatment with higher-dose imatinib subsequently followed by a switch to nilotinib in those failing to achieve desired milestones could be an effective strategy for managing newly diagnosed CP-CML.⁵

Toxicity

Imatinib 400 mg is considered the standard starting dose in CP-CML patients. The safety profile of imatinib has been very well established. In the IRIS trial, the most common adverse events (all grades in decreasing order of frequency) were peripheral and periorbital edema (60%), nausea (50%), muscle cramps (49%), musculoskeletal pain (47%), diarrhea (45%), rash (40%), fatigue (39%), abdominal pain (37%), headache (37%), and joint pain (31%). Grade 3/4 liver enzyme elevation can occur in 5% of patients.⁶ In the event of severe liver toxicity or fluid retention, imatinib should be held until the event resolves. At that time, imatinib can be restarted if deemed appropriate, but this is dependent on the severity of the inciting event. Fluid retention can be managed by the use of supportive care, diuretics, imatinib dose reduction, dose interruption, or imatinib discontinuation if the fluid retention is severe. Muscle cramps can be managed by the use of a calcium supplements or tonic water. Management of rash can include topical or systemic steroids, or in some cases imatinib dose reduction, interruption, or discontinuation.⁷  

Grade 3/4 imatinib-induced hematologic toxicity is not uncommon, with 17% of patients experiencing neutropenia, 9% thrombocytopenia, and 4% anemia. These adverse events occurred most commonly during the first year of therapy, and the frequency decreased over time.^3,6 Depending on the degree of cytopenias, imatinib dosing should be interrupted until recovery of the absolute neutrophil count or platelet count, and can often be resumed at 400 mg daily. However, if cytopenias recur, imatinib should be held and subsequently restarted at 300 mg daily.⁷ 

Dasatinib

Dasatinib is a second-generation TKI that has regulatory approval for treatment of adult patients with newly diagnosed CP-CML or CP-CML in patients with resistance or intolerance to prior TKIs. In addition to dasatinib's ability to inhibit ABL kinases, it is also known to be a potent inhibitor of Src family kinases. Dasatinib has shown efficacy in patients who have developed imatinib-resistant ABL kinase domain mutations. 

Dasatinib was initially approved as second-line therapy in patients with resistance or intolerance to imatinib. This indication was based on the results of the phase 3 CA180-034 trial which ultimately identified dasatinib 100 mg daily as the optimal dose. In this trial, 74% of patients enrolled had resistance to imatinib and the remainder were intolerant. The 7-year follow-up of patients randomized to dasatinib 100 mg (n = 167) daily indicated that 46% achieved MMR while on study. Of the 124 imatinib-resistant patients on dasatinib 100 mg daily, the 7-year progression-free survival (PFS) was 39% and OS was 63%. In the 43 imatinib-intolerant patients, the 7-year PFS was 51% and OS was 70%.⁸

Dasatinib 100 mg daily was compared to imatinib 400 mg daily in newly diagnosed CP-CML patients in the randomized phase 3 DASISION trial. More patients on the dasatinib arm achieved an early molecular response of BCR-ABL1 transcripts ≤10% IS after 3 months on treatment compared to imatinib (84% versus 64%). Furthermore, the 5-year follow-up reports that the cumulative incidence of MMR and MR4.5 in dasatinib-treated patients was 76% and 42%, and was 64% and 33%, with imatinib (P = 0.0022 and P = 0.0251, respectively). Fewer patients treated with dasatinib progressed to AP or BP (4.6%) compared to imatinib (7.3%), but the estimated 5-year OS was similar between the 2 arms (91% for dasatinib versus 90% for imatinib).⁹ Regulatory approval for dasatinib as first-line therapy in newly diagnosed CML patients was based on results of the DASISION trial. 

Toxicity

Most dasatinib-related toxicities are reported as grade 1 or grade 2, but grade 3/4 hematologic adverse events are fairly common. In the DASISION trial, grade 3/4 neutropenia, anemia, and thrombocytopenia occurred in 29%, 13%, and 22% of dasatinib-treated patients, respectively. Cytopenias can generally be managed with temporary dose interruptions or dose reductions.

During the 5-year follow-up of the DASISION trial, pleural effusions were reported in 28% of patients, most of which were grade 1/2. This occurred at a rate of approximately ≤ 8% per year, suggesting a stable incidence over time, and the effusions appear to be dose-dependent.⁹ Depending on the severity of the effusion, this may be treated with diuretics, dose interruption, and in some instances, steroids or a thoracentesis. Typically, dasatinib can be restarted at 1 dose level lower than the previous dose once the effusion has resolved.⁷ Other, less common side effects of dasatinib include pulmonary hypertension (5% of patients), as well as abdominal pain, fluid retention, headaches, fatigue, musculoskeletal pain, rash, nausea, and diarrhea. Pulmonary hypertension is typically reversible after cessation of dasatinib, and thus dasatinib should be permanently discontinued once the diagnosis is confirmed. Fluid retention is often treated with diuretics and supportive care. Nausea and diarrhea are generally manageable and occur less frequently when dasatinib is taken with food and a large glass of water. Antiemetics and antidiarrheals can be used as needed. Troublesome rash can be best managed with topical or systemic steroids as well as possible dose reduction or dose interruption.^7,9 In the DASISION trial, adverse events led to therapy discontinuation more often in  the dasatinib group than in the imatinib group (16% versus 7%).⁹ Bleeding, particularly in the setting of thrombocytopenia, has been reported in patients being treated with dasatinib as a result of the drug-induced reversible inhibition of platelet aggregation.¹⁰

Nilotinib

The structure of nilotinib is similar to that of imatinib; however, it has a markedly increased affinity for the ATP‐binding site on the BCR-ABL1 protein. It was initially given regulatory approval in the setting of imatinib failure. Nilotinib was studied at a dose of 400 mg twice daily in 321 patients who were imatinib-resistant or -intolerant. It proved to be highly effective at inducing cytogenetic remissions in the second-line setting, with 59% of patients achieving a major cytogenetic response (MCyR) and 45% achieving CCyR. With a median follow-up time of 4 years, the OS was 78%.¹¹ 

Nilotinib gained regulatory approval for use as a first-line TKI after completion of the randomized phase 3 ENESTnd (Evaluating Nilotinib Efficacy and Safety in Clinical Trials-Newly Diagnosed Patients) trial. ENESTnd was a 3-arm study comparing nilotinib 300 mg twice daily versus nilotinib 400 mg twice daily versus imatinib 400 mg daily in newly diagnosed, previously untreated patients diagnosed with CP-CML. The primary endpoint of this clinical trial was rate of MMR at 12 months.¹² Nilotinib surpassed imatinib in this regard, with 44% of patients on nilotinib 300 mg twice daily achieving MMR at 12 months versus 43% of nilotinib 400 mg twice daily patients versus 22% of the imatinib-treated patients (P < 0.001 for both comparisons). Furthermore, the rate of CCyR by 12 months was significantly higher for both nilotinib arms compared with imatinib (80% for nilotinib 300 mg, 78% for nilotinib 400 mg, and 65% for imatinib) (P < 0.001).¹² Based on this data, nilotinib 300 mg twice daily was chosen as the standard dose of nilotinib in the first-line setting. After 5 years of follow-up on the ENESTnd study, there were fewer progressions to AP/BP CML in nilotinib-treated patients compared with imatinib. MMR was achieved in 77% of nilotinib 300 mg patients compared with 60.4% of patients on the imatinib arm. MR4.5 was also more common in patients treated with nilotinib 300 mg twice daily, with a rate of 53.5% at 5 years versus 31.4% in the imatinib arm.¹³ In spite of the deeper cytogenetic and molecular responses achieved with nilotinib, this did not translate into a significant improvement in OS. The 5-year OS rate was 93.7%  in nilotinib 300 mg patients versus 91.7% in imatinib-treated patients, and this difference lacked statistical significance.¹³

Toxicity

Although some similarities exist between the toxicity profiles of nilotinib and imatinib, each drug has some distinct adverse events. On the ENESTnd trial, the rate of any grade 3/4 non-hematologic adverse event was fairly low; however, lower-grade toxicities were not uncommon. Patients treated with nilotinib 300 mg twice daily experienced rash (31%), headache (14%), pruritis (15%), and fatigue (11%) most commonly. The most frequently reported laboratory abnormalities included increased total bilirubin (53%), hypophosphatemia (32%), hyperglycemia (36%), elevated lipase (24%), increased alanine aminotransferase (ALT; 66%), and increased aspartate aminotransferase (AST; 40%). Any grade of neutropenia, thrombocytopenia, or anemia occurred at rates of 43%, 48%, and 38%, respectively.¹² Although nilotinib has a Black Box Warning from the US Food and Drug Administration for QT interval prolongation, no patients on the ENESTnd trial experienced a QT interval corrected for heart rate greater than 500 msec.¹²

More recent concerns have emerged regarding the potential for cardiovascular toxicity after long-term use of nilotinib. The 5-year update of ENESTnd reports cardiovascular events, including ischemic heart disease, ischemic cerebrovascular events, or peripheral arterial disease occurring in 7.5% of patients treated with nilotinib 300 mg twice daily compared with a rate of 2.1% in imatinib-treated patients. The frequency of these cardiovascular events increased linearly over time in both arms. Elevations in total cholesterol from baseline occurred in 27.6% of nilotinib patients compared with 3.9% of imatinib patients. Furthermore, clinically meaningful increases in low-density lipoprotein cholesterol and glycated hemoglobin occurred more frequently with nilotinib therapy.¹² 

Nilotinib should be taken on an empty stomach; therefore, patients should be made aware of the need to fast for 2 hours prior to each dose and 1 hour after each dose. Given the potential risk of QT interval prolongation, a baseline electrocardiogram (ECG) is recommended prior to initiating treatment to ensure the QT interval is within a normal range. A repeat ECG should be done approximately 7 days after nilotinib initiation to ensure no prolongation of the QT interval after starting. Close monitoring of potassium and magnesium levels is important to decrease the risk of cardiac arrhythmias, and concomitant use of drugs considered strong CYP3A4 inhibitors should be avoided.⁷

If the patient experiences any grade 3 or higher laboratory abnormalities, nilotinib should be held until resolution of the toxicity, and then restarted at a lower dose. Similarly, if patients develop significant neutropenia or thrombocytopenia, nilotinib doses should be interrupted until resolution of the cytopenias. At that point, nilotinib can be reinitiated at either the same or a lower dose. Rash can be managed by the use of topical or systemic steroids as well as potential dose reduction, interruption, or discontinuation.

Given the concerns for potential cardiovascular events with long-term use of nilotinib, caution is advised when prescribing it to any patient with a history of cardiovascular disease or peripheral arterial occlusive disease. At the first sign of new occlusive disease, nilotinib should be discontinued.⁷

Bosutinib

Bosutinib is a second-generation BCR-ABL1 TKI with activity against the Src family of kinases that was initially approved to treat patients with CP-, AP-, or BP-CML after resistance or intolerance to imatinib. Long-term data has been reported from the phase 1/2 trial of bosutinib therapy in patients with CP-CML who developed resistance or intolerance to imatinib plus dasatinib and/or nilotinib. A total of 119 patients were included in the 4-year follow-up; 38 were resistant/intolerant to imatinib and resistant to dasatinib, 50 were resistant/intolerant to imatinib and intolerant to dasatinib, 26 were resistant/intolerant to imatinib and resistant to nilotinib, and 5 were resistant/intolerant to imatinib and intolerant to nilotinib or resistant/intolerant to dasatinib and nilotinib. Bosutinib 400 mg daily was studied in this setting. Of the 38 patients with imatinib resistance/intolerance and dasatinib resistance, 39% achieved MCyR, 22% achieved CCyR, and the OS was 67%. Of the 50 patients with imatinib resistance/intolerance and dasatinib intolerance, 42% achieved MCyR, 40% achieved CCyR, and the OS was 80%. Finally, in the 26 patients with imatinib resistance/intolerance and nilotinib resistance, 38% achieved MCyR, 31% achieved CcyR, and the OS was 87%.¹⁴ 

Five-year follow-up from the phase 1/2 clinical trial which studied bosutinib 500 mg daily in CP-CML patients after imatinib failure reported data on 284 patients. By 5 years on study, 60% of patients had achieved MCyR and 50% achieved CCyR with a 71% and 69% probability, respectively, of maintaining these responses at 5 years. The 5-year OS was 84%.¹⁵ These data led to the regulatory approval of bosutinib 500 mg daily as second-line or later therapy. 

Bosutinib was initially studied in the first-line setting in the randomized phase 3 BELA (Bosutinib Efficacy and Safety in Newly Diagnosed Chronic Myeloid Leukemia) trial. This trial compared bosutinib 500 mg daily to imatinib 400 mg daily in newly diagnosed, previously untreated CP-CML patients. This trial failed to meet its primary endpoint of increased rate of CCyR at 12 months, with 70% of bosutinib patients achieving this response compared to 68% of imatinib-treated patients (P = 0.601). In spite of this, the rate of MMR at 12 months was significantly higher in the bosutinib arm (41%) compared to the imatinib arm (27%; P = 0.001).¹⁶ 

A second phase 3 trial (BFORE) was designed to study bosutinib 400 mg daily versus imatinib in newly diagnosed, previously untreated CP-CML patients. This study enrolled 536 patients who were randomly assigned 1:1 to bosutinib versus imatinib. The primary endpoint of this trial was rate of MMR at 12 months. A significantly higher number of bosutinib-treated patients achieved this response (47.2%) compared with imatinib-treated patients (36.9%, P = 0.02). Furthermore, by 12 months 77.2% of patients on the bosutinib arm had achieved CCyR compared with 66.4% on the imatinib arm, and this difference did meet statistical significance (P = 0.0075). A lower rate of progression to AP- or BP-CML was noted in bosutinib-treated patients as well (1.6% versus 2.5%). Based on this data, bosutinib gained regulatory approval for first-line therapy in CP-CML at a dose of 400 mg daily.¹⁷ 

Toxicity

On the BFORE trial, the most common treatment-emergent adverse events of any grade reported in the bosutinib-treated patients were diarrhea (70.1%), nausea (35.1%), increased ALT (30.6%), and increased AST (22.8%). Musculoskeletal pain or spasms occurred in 29.5% of patients, rash in 19.8%, fatigue in 19.4%, and headache in 18.7%. Hematologic toxicity was also reported, but most was grade 1/2. Thrombocytopenia was reported in 35.1%, anemia in 18.7%, and neutropenia in 11.2%.¹⁷

Cardiovascular events occurred in 5.2% of patients on the bosutinib arm of the BFORE trial, which was similar to the rate observed in imatinib patients. The most common cardiovascular event was QT interval prolongation, which occurred in 1.5% of patients. Pleural effusions were reported in 1.9% of patients treated with bosutinib, and none were grade 3 or higher.¹⁷

If liver enzyme elevation occurs at a value greater than 5 times the institutional upper limit of normal, bosutinib should be held until the level recovers to ≤2.5 times the upper limit of normal, at which point bosutinib can be restarted at a lower dose. If recovery takes longer than 4 weeks, bosutinib should be permanently discontinued. Liver enzymes  elevated greater than 3 times the institutional upper limit of normal and a concurrent elevation in total bilirubin to 2 times the upper limit of normal is consistent with Hy's law, and bosutinib should be discontinued. Although diarrhea is the most common toxicity associated with bosutinib, it is commonly low grade and transient. Diarrhea occurs most frequently in the first few days after initiating bosutinib. It can often be managed with over-the-counter antidiarrheal medications, but if the diarrhea is grade or higher, bosutinib should be held until recovery to grade 1 or lower. Gastrointestinal side effects may be improved by taking bosutinib with a meal and a large glass of water. Fluid retention can be managed with diuretics and supportive care. Finally, if rash occurs, this can be addressed with topical or systemic steroids as well as bosutinib dose reduction, interruption, or discontinuation.⁷

Similar to other TKIs, if bosutinib-induced cytopenias occur, treatment should be held and restarted at the same or a lower dose upon blood count recovery.⁷

Ponatinib

The most common cause of TKI resistance in CP-CML is the development of ABL kinase domain mutations. The majority of imatinib-resistant mutations can be overcome by the use of second-generation TKIs including dasatinib, nilotinib, or bosutinib. However, ponatinib is the only BCR-ABL1 TKI able to overcome a T315I mutation. The phase 2 PACE (Ponatinib Ph-positive ALL and CML Evaluation) trial enrolled patients with CP-, AP-, or BP-CML as well as patients with Ph-positive acute lymphoblastic leukemia who were resistant or intolerant to nilotinib or dasatinib, or who had evidence of a T315I mutation. The starting dose of ponatinib on this trial was 45 mg daily.¹⁸ The PACE trial enrolled 267 patients with CP-CML: 203 with resistance or intolerance to nilotinib or dasatinib, and 64 with a T315I mutation. The primary endpoint in the CP cohort was rate of MCyR at any time within 12 months of starting ponatinib. The overall rate of MCyR by 12 months in the CP-CML patients was 56%. In those with a T315I mutation, 70% achieved MCyR, which compared favorably with those with resistance or intolerance to nilotinib or dasatinib, 51% of whom achieved MCyR. CCyR was achieved in 46% of CP-CML patients (40% in the resistant/intolerant cohort and 66% in the T315I cohort). In general, patients with T315I mutations received fewer prior therapies than those in the resistant/intolerant cohort, which likely contributed to the higher response rates in the T315I patients. MR4.5 was achieved in 15% of CP-CML patients by 12 months on the PACE trial.¹⁸ The 5-year update to this study reported that 60%, 40%, and 24% of CP-CML patients achieved MCyR, MMR, and MR4.5, respectively. In the patients who achieved MCyR, the probability of maintaining this response for 5 years was 82% and the estimated 5-year OS was 73%.¹⁹

Toxicity

In 2013, after the regulatory approval of ponatinib, reports became available that the drug can cause an increase in arterial occlusive events including fatal myocardial infarctions and cerebral vascular accidents. For this reason, dose reductions were implemented in patients who were deriving clinical benefit from ponatinib. In spite of these dose reductions, ≥90% of responders maintained their response for up to 40 months.¹⁹ Although the likelihood of developing an arterial occlusive event appears higher in the first year after starting ponatinib than in later years, the cumulative incidence of events continues to increase. The 5-year follow-up to the PACE trial reports 31% of patients experiencing any grade of arterial occlusive event while on ponatinib. Aside from these events, the most common treatment-emergent adverse events in ponatinib-treated patients on the PACE trial included rash (47%), abdominal pain (46%), headache (43%), dry skin (42%), constipation (41%), and hypertension (37%). Hematologic toxicity was also common, with 46% of patients experiencing any grade of thrombocytopenia, 20% experiencing neutropenia, and 20% anemia.¹⁹

Patients receiving ponatinib therapy should be monitored closely for any evidence of arterial or venous thrombosis. In the event of an occlusive event, ponatinib should be discontinued. Similarly, in the setting of any new or worsening heart failure symptoms, ponatinib should be promptly discontinued. Management of any underlying cardiovascular risk factors including hypertension, hyperlipidemia, diabetes, or smoking history is recommended, and these patients should be referred to a cardiologist for a full evaluation. In the absence of any contraindications to aspirin, low-dose aspirin should be considered as a means of decreasing cardiovascular risks associated with ponatinib. In patients with known risk factors, a ponatinib starting dose of 30 mg daily rather than the standard 45 mg daily may be a safer option resulting in fewer arterial occlusive events, although the efficacy of this dose is still being studied in comparison to 45 mg daily.⁷

In the event of ponatinib-induced transaminitis greater than 3 times the upper limit of normal, ponatinib should be held until resolution to less than 3 times the upper limit of normal, at which point it should be resumed at a lower dose. Similarly, in the setting of elevated serum lipase or symptomatic pancreatitis, ponatinib should be held and restarted at a lower dose after resolution of symptoms.⁷ 

In the event of neutropenia or thrombocytopenia, ponatinib should be held until blood count recovery and then restarted at the same dose. If cytopenias occur for a second time, the dose of ponatinib should be lowered at the time of treatment reinitiation. If rash occurs, it can be addressed with topical or systemic steroids as well as dose reduction, interruption, or discontinuation.⁷

Case Conclusion

Given the patient's high-risk Sokal score, ideal first-line treatment is a second-generation TKI in order to increase the likelihood of achieving the desired treatment milestones and improving long-term outcomes. Her history of uncontrolled diabetes and coronary artery disease raises concerns for using nilotinib. Furthermore, her history of COPD makes dasatinib suboptimal because she would have little pulmonary reserve if she were to develop a pleural effusion. For this reason, bosutinib 400 mg daily is chosen as her first-line TKI. Shortly after starting bosutinib, she experiences diarrhea that occurs approximately 3 or 4 times daily during the first week on treatment. She is able to manage this with over-the-counter loperamide and the diarrhea resolves shortly thereafter.

After 3 months of bosutinib therapy, quantitative real-time PCR (RQ-PCR) assay on peripheral blood is done to measure BCR-ABL1 transcripts, and the result is reported at 1.2% IS. This indicates that the patient has achieved an early molecular response, which is defined as a RQ-PCR value of ≤10% IS. She undergoes RQ-PCR monitoring every 3 months, and at 12 months her results indicate a value of 0.07% IS, suggesting she has achieved a MMR. 

Conclusion

With the development of imatinib and the subsequent TKIs, dasatinib, nilotinib, bosutinib, and ponatinib, CP-CML has become a chronic disease with a life-expectancy that is similar to the general population. Given the successful treatments available for these patients, it is crucial to identify patients with this diagnosis, ensure they receive a complete, appropriate diagnostic workup including a bone marrow biopsy and aspiration with cytogenetic testing, and select the best therapy for each individual patient. Once on treatment, the importance of frequent monitoring cannot be overstated. This is the only way to be certain patients are achieving the desired treatment milestones that correlate with the favorable long-term outcomes that have been observed with TKI-based treatment of CP-CML. 

The European Commission has approved dasatinib (Sprycel) for use in combination with chemotherapy for the treatment of pediatric patients with newly diagnosed, Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL).

Dasatinib will be available in tablet form and as a powder for oral suspension, Bristol-Myers Squib said in a press release.

The approval was based on an event-free survival rate of 65.5% (95% confidence interval, 57.7-73.7) and an overall survival rate of 91.5% (95% CI, 84.2-95.5) in a phase 2 trial that evaluated the addition of dasatinib to a chemotherapy regimen modeled on a Berlin-Frankfurt-Münster high-risk backbone in pediatric patients with newly diagnosed Ph+ ALL.

Patients treated in the study (n = 106) were all aged younger than 18 years and received dasatinib at a daily dose of 60 mg/m² on a continuous dosing regimen for up to 24 months, in combination with chemotherapy. About 77 % of patients (n = 82) received tablets exclusively; 23% of patients (n = 24) received the powder for oral suspension at least once.

Hematologic adverse events included grade 3 or 4 febrile neutropenia (75.5%), sepsis (23.6%), and bacteremia (24.5%). Nonhematologic, noninfectious grade 3 or 4 adverse events attributed to dasatinib and reported in more than 10% of patients included elevated ALT (21.7%) and AST (10.4%). Additional grade 3 or 4 adverse events attributed to dasatinib were pleural effusion (3.8%), edema (2.8%), hemorrhage (5.7%), and cardiac failure (0.8%). No events of pulmonary hypertension or pulmonary arterial hypertension were reported, the company said in the press release.

Dasatinib is already approved by the European Commission to treat children with Ph+ chronic myeloid leukemia in the chronic phase, which includes newly diagnosed patients and those with resistance or intolerance to imatinib.

[email protected]

The European Commission has approved dasatinib (Sprycel) for use in combination with chemotherapy for the treatment of pediatric patients with newly diagnosed, Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL).

Dasatinib will be available in tablet form and as a powder for oral suspension, Bristol-Myers Squib said in a press release.

The approval was based on an event-free survival rate of 65.5% (95% confidence interval, 57.7-73.7) and an overall survival rate of 91.5% (95% CI, 84.2-95.5) in a phase 2 trial that evaluated the addition of dasatinib to a chemotherapy regimen modeled on a Berlin-Frankfurt-Münster high-risk backbone in pediatric patients with newly diagnosed Ph+ ALL.

Patients treated in the study (n = 106) were all aged younger than 18 years and received dasatinib at a daily dose of 60 mg/m² on a continuous dosing regimen for up to 24 months, in combination with chemotherapy. About 77 % of patients (n = 82) received tablets exclusively; 23% of patients (n = 24) received the powder for oral suspension at least once.

Hematologic adverse events included grade 3 or 4 febrile neutropenia (75.5%), sepsis (23.6%), and bacteremia (24.5%). Nonhematologic, noninfectious grade 3 or 4 adverse events attributed to dasatinib and reported in more than 10% of patients included elevated ALT (21.7%) and AST (10.4%). Additional grade 3 or 4 adverse events attributed to dasatinib were pleural effusion (3.8%), edema (2.8%), hemorrhage (5.7%), and cardiac failure (0.8%). No events of pulmonary hypertension or pulmonary arterial hypertension were reported, the company said in the press release.

Dasatinib is already approved by the European Commission to treat children with Ph+ chronic myeloid leukemia in the chronic phase, which includes newly diagnosed patients and those with resistance or intolerance to imatinib.

[email protected]

The European Commission has approved dasatinib (Sprycel) for use in combination with chemotherapy for the treatment of pediatric patients with newly diagnosed, Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL).

Dasatinib will be available in tablet form and as a powder for oral suspension, Bristol-Myers Squib said in a press release.

The approval was based on an event-free survival rate of 65.5% (95% confidence interval, 57.7-73.7) and an overall survival rate of 91.5% (95% CI, 84.2-95.5) in a phase 2 trial that evaluated the addition of dasatinib to a chemotherapy regimen modeled on a Berlin-Frankfurt-Münster high-risk backbone in pediatric patients with newly diagnosed Ph+ ALL.

Patients treated in the study (n = 106) were all aged younger than 18 years and received dasatinib at a daily dose of 60 mg/m² on a continuous dosing regimen for up to 24 months, in combination with chemotherapy. About 77 % of patients (n = 82) received tablets exclusively; 23% of patients (n = 24) received the powder for oral suspension at least once.

Hematologic adverse events included grade 3 or 4 febrile neutropenia (75.5%), sepsis (23.6%), and bacteremia (24.5%). Nonhematologic, noninfectious grade 3 or 4 adverse events attributed to dasatinib and reported in more than 10% of patients included elevated ALT (21.7%) and AST (10.4%). Additional grade 3 or 4 adverse events attributed to dasatinib were pleural effusion (3.8%), edema (2.8%), hemorrhage (5.7%), and cardiac failure (0.8%). No events of pulmonary hypertension or pulmonary arterial hypertension were reported, the company said in the press release.

Dasatinib is already approved by the European Commission to treat children with Ph+ chronic myeloid leukemia in the chronic phase, which includes newly diagnosed patients and those with resistance or intolerance to imatinib.

[email protected]

The thrombopoietic agent eltrombopag (Promacta) did more harm than good when given to adults with acute myeloid leukemia (AML) during standard induction chemotherapy, results of a randomized phase 2 trial show.

Patients who were randomly assigned to receive standard induction chemotherapy with daunorubicin and cytarabine plus eltrombopag had a higher incidence of serious adverse events and death from hemorrhage within 30 days of the last eltrombopag dose, compared with patients who received chemotherapy and placebo, reported Noelle Frey, MD, from the University of Pennsylvania in Philadelphia, and colleagues.

“Overall survival was also numerically longer in the placebo group, compared with the eltrombopag group. It remains unclear why there were more deaths, particularly due to hemorrhage within 30 days after the last dose of treatment, in the eltrombopag group,” they wrote in the Lancet Haematology.

The investigators had expected better results, based on eltrombopag’s demonstrated efficacy against thrombocytopenia (a common feature of AML, exacerbated by chemotherapy), and because of evidence suggesting that the thrombopoietin-receptor agonist might also have antileukemic properties.

They set out to test the safety, tolerability, and efficacy of eltrombopag added to standard induction therapy in patients with treatment-naive AML of any subtype except M3 (acute promyelocytic leukemia) or M7 (acute megakaryocytic leukemia).

Patients received chemotherapy with daunorubicin in a bolus intravenous infusion at a dose of 90 mg/m² on days 1-3 for patients 18-60 years of age, or 60 mg/m² for patients older than 60 years, plus cytarabine continuous intravenous infusion at a dose of 100 mg/m² on days 1-7. The 148 patients were randomized in groups of 74 each to receive either eltrombopag 200 mg (100 mg for patients of east Asian heritage) or placebo, once daily.

Eltrombopag was continued until platelet counts were 200 × 10⁹/L or higher, remission, or 42 days after the start of induction chemotherapy.

Grade 3 or 4 adverse events occurring in 10% or more of patients – a primary endpoint – were febrile neutropenia, which occurred in 42% of patients receiving eltrombopag, compared with 39% receiving placebo, decreased white blood cell count in 11% vs. 7%, and hypophosphatemia in 4% and 13%, respectively,

Serious adverse events occurred in 34% of patients on eltrombopag, compared with 20% on placebo. Similarly, 53% of patients receiving eltrombopag died, compared with 41% of patients receiving the placebo.

Most of the deaths were attributable to AML, including 19 patients (26%) on eltrombopag and 10 (14%) on placebo. Eleven patients on eltrombopag and four on placebo died within 30 days of the last dose of study treatment.

Hemorrhage accounted for the deaths of five patients on eltrombopag and three on placebo, and sepsis accounted for the deaths of five and six patients, respectively.

Both the incidence of thromboembolic events and mean change in left ventricular ejection fraction were similar between the groups.

Median overall survival was 15.4 months in the eltrombopag group vs. 25.7 months in the placebo group, although this difference was not statistically significant, likely because of the sample size.

The investigators were at a loss to explain why the eltrombopag-treated patients had numerically worse outcomes.

“In the present study, eltrombopag did not improve the time to platelet recovery or the incidences of grade 3-4 thrombocytopenia, neutropenia, or anemia, compared with placebo. Furthermore, the study did not reveal any differences in investigator-assessed response to treatment. These findings were unexpected given outcomes from previous studies of eltrombopag monotherapy in patients with myelodysplastic syndromes or acute myeloid leukemia,” they wrote.

Although the reasons behind the findings are unclear, “the data from this trial do not support a favorable benefit-risk profile for eltrombopag in combination with induction chemotherapy in patients with acute myeloid leukemia,” the investigators wrote.

The study was funded by Novartis. Dr. Frey reported nonfinancial support from Novartis during the conduct of the study and consultancy fees from Novartis outside of the submitted work. Multiple coauthors reported similar relationships with Novartis and/or other companies.

SOURCE: Frey N et al. Lancet Haematol. 2019 Jan 28. doi: 10.1016/S2352-3026(18)30231-X.

The thrombopoietic agent eltrombopag (Promacta) did more harm than good when given to adults with acute myeloid leukemia (AML) during standard induction chemotherapy, results of a randomized phase 2 trial show.

Patients who were randomly assigned to receive standard induction chemotherapy with daunorubicin and cytarabine plus eltrombopag had a higher incidence of serious adverse events and death from hemorrhage within 30 days of the last eltrombopag dose, compared with patients who received chemotherapy and placebo, reported Noelle Frey, MD, from the University of Pennsylvania in Philadelphia, and colleagues.

“Overall survival was also numerically longer in the placebo group, compared with the eltrombopag group. It remains unclear why there were more deaths, particularly due to hemorrhage within 30 days after the last dose of treatment, in the eltrombopag group,” they wrote in the Lancet Haematology.

The investigators had expected better results, based on eltrombopag’s demonstrated efficacy against thrombocytopenia (a common feature of AML, exacerbated by chemotherapy), and because of evidence suggesting that the thrombopoietin-receptor agonist might also have antileukemic properties.

They set out to test the safety, tolerability, and efficacy of eltrombopag added to standard induction therapy in patients with treatment-naive AML of any subtype except M3 (acute promyelocytic leukemia) or M7 (acute megakaryocytic leukemia).

Patients received chemotherapy with daunorubicin in a bolus intravenous infusion at a dose of 90 mg/m² on days 1-3 for patients 18-60 years of age, or 60 mg/m² for patients older than 60 years, plus cytarabine continuous intravenous infusion at a dose of 100 mg/m² on days 1-7. The 148 patients were randomized in groups of 74 each to receive either eltrombopag 200 mg (100 mg for patients of east Asian heritage) or placebo, once daily.

Eltrombopag was continued until platelet counts were 200 × 10⁹/L or higher, remission, or 42 days after the start of induction chemotherapy.

Grade 3 or 4 adverse events occurring in 10% or more of patients – a primary endpoint – were febrile neutropenia, which occurred in 42% of patients receiving eltrombopag, compared with 39% receiving placebo, decreased white blood cell count in 11% vs. 7%, and hypophosphatemia in 4% and 13%, respectively,

Serious adverse events occurred in 34% of patients on eltrombopag, compared with 20% on placebo. Similarly, 53% of patients receiving eltrombopag died, compared with 41% of patients receiving the placebo.

Most of the deaths were attributable to AML, including 19 patients (26%) on eltrombopag and 10 (14%) on placebo. Eleven patients on eltrombopag and four on placebo died within 30 days of the last dose of study treatment.

Hemorrhage accounted for the deaths of five patients on eltrombopag and three on placebo, and sepsis accounted for the deaths of five and six patients, respectively.

Both the incidence of thromboembolic events and mean change in left ventricular ejection fraction were similar between the groups.

Median overall survival was 15.4 months in the eltrombopag group vs. 25.7 months in the placebo group, although this difference was not statistically significant, likely because of the sample size.

The investigators were at a loss to explain why the eltrombopag-treated patients had numerically worse outcomes.

“In the present study, eltrombopag did not improve the time to platelet recovery or the incidences of grade 3-4 thrombocytopenia, neutropenia, or anemia, compared with placebo. Furthermore, the study did not reveal any differences in investigator-assessed response to treatment. These findings were unexpected given outcomes from previous studies of eltrombopag monotherapy in patients with myelodysplastic syndromes or acute myeloid leukemia,” they wrote.

Although the reasons behind the findings are unclear, “the data from this trial do not support a favorable benefit-risk profile for eltrombopag in combination with induction chemotherapy in patients with acute myeloid leukemia,” the investigators wrote.

The study was funded by Novartis. Dr. Frey reported nonfinancial support from Novartis during the conduct of the study and consultancy fees from Novartis outside of the submitted work. Multiple coauthors reported similar relationships with Novartis and/or other companies.

SOURCE: Frey N et al. Lancet Haematol. 2019 Jan 28. doi: 10.1016/S2352-3026(18)30231-X.

The thrombopoietic agent eltrombopag (Promacta) did more harm than good when given to adults with acute myeloid leukemia (AML) during standard induction chemotherapy, results of a randomized phase 2 trial show.

Patients who were randomly assigned to receive standard induction chemotherapy with daunorubicin and cytarabine plus eltrombopag had a higher incidence of serious adverse events and death from hemorrhage within 30 days of the last eltrombopag dose, compared with patients who received chemotherapy and placebo, reported Noelle Frey, MD, from the University of Pennsylvania in Philadelphia, and colleagues.

“Overall survival was also numerically longer in the placebo group, compared with the eltrombopag group. It remains unclear why there were more deaths, particularly due to hemorrhage within 30 days after the last dose of treatment, in the eltrombopag group,” they wrote in the Lancet Haematology.

The investigators had expected better results, based on eltrombopag’s demonstrated efficacy against thrombocytopenia (a common feature of AML, exacerbated by chemotherapy), and because of evidence suggesting that the thrombopoietin-receptor agonist might also have antileukemic properties.

They set out to test the safety, tolerability, and efficacy of eltrombopag added to standard induction therapy in patients with treatment-naive AML of any subtype except M3 (acute promyelocytic leukemia) or M7 (acute megakaryocytic leukemia).

Patients received chemotherapy with daunorubicin in a bolus intravenous infusion at a dose of 90 mg/m² on days 1-3 for patients 18-60 years of age, or 60 mg/m² for patients older than 60 years, plus cytarabine continuous intravenous infusion at a dose of 100 mg/m² on days 1-7. The 148 patients were randomized in groups of 74 each to receive either eltrombopag 200 mg (100 mg for patients of east Asian heritage) or placebo, once daily.

Eltrombopag was continued until platelet counts were 200 × 10⁹/L or higher, remission, or 42 days after the start of induction chemotherapy.

Grade 3 or 4 adverse events occurring in 10% or more of patients – a primary endpoint – were febrile neutropenia, which occurred in 42% of patients receiving eltrombopag, compared with 39% receiving placebo, decreased white blood cell count in 11% vs. 7%, and hypophosphatemia in 4% and 13%, respectively,

Serious adverse events occurred in 34% of patients on eltrombopag, compared with 20% on placebo. Similarly, 53% of patients receiving eltrombopag died, compared with 41% of patients receiving the placebo.

Most of the deaths were attributable to AML, including 19 patients (26%) on eltrombopag and 10 (14%) on placebo. Eleven patients on eltrombopag and four on placebo died within 30 days of the last dose of study treatment.

Hemorrhage accounted for the deaths of five patients on eltrombopag and three on placebo, and sepsis accounted for the deaths of five and six patients, respectively.

Both the incidence of thromboembolic events and mean change in left ventricular ejection fraction were similar between the groups.

Median overall survival was 15.4 months in the eltrombopag group vs. 25.7 months in the placebo group, although this difference was not statistically significant, likely because of the sample size.

The investigators were at a loss to explain why the eltrombopag-treated patients had numerically worse outcomes.

“In the present study, eltrombopag did not improve the time to platelet recovery or the incidences of grade 3-4 thrombocytopenia, neutropenia, or anemia, compared with placebo. Furthermore, the study did not reveal any differences in investigator-assessed response to treatment. These findings were unexpected given outcomes from previous studies of eltrombopag monotherapy in patients with myelodysplastic syndromes or acute myeloid leukemia,” they wrote.

Although the reasons behind the findings are unclear, “the data from this trial do not support a favorable benefit-risk profile for eltrombopag in combination with induction chemotherapy in patients with acute myeloid leukemia,” the investigators wrote.

The study was funded by Novartis. Dr. Frey reported nonfinancial support from Novartis during the conduct of the study and consultancy fees from Novartis outside of the submitted work. Multiple coauthors reported similar relationships with Novartis and/or other companies.

SOURCE: Frey N et al. Lancet Haematol. 2019 Jan 28. doi: 10.1016/S2352-3026(18)30231-X.

SAN DIEGO – Checkpoint inhibition can be used safely and effectively with CD19-directed chimeric antigen receptor (CAR) T-cell therapy in children with relapsed B-cell acute lymphoblastic leukemia (ALL), and it may bolster CAR T-cell effects and persistence, suggest the findings in a series of 14 patients at the Children’s Hospital of Philadelphia.

Combined programmed death-1 (PD-1) blockade and CAR T-cell therapy appeared to have particular benefit in patients with early B-cell recovery and in those with bulky extramedullary disease, Shannon Maude, MD, PhD, reported during a press conference at the annual meeting of the American Society of Hematology.

The patients, aged 4-17 years with heavily pretreated relapsed B-ALL (13 patients) or B lymphoblastic lymphoma (1 patient), were treated with CD19-directed CAR T-cell therapy, including CTL019 in 4 patients and CTL119 in 10 patients, followed by pembrolizumab (in 13 patients) or nivolumab (in 1 patient).

Six patients received the combination therapy because of early B-cell recovery after initial CAR T-cell infusion, four patients had relapsed or refractory (R/R) bulky extramedullary disease, and four patients had failed to respond or relapsed after initial CAR T-cell therapy.

Three of the six with poor persistence of response reestablished B-cell aplasia (a reflection of CAR T-cell function) after reinfusion of the CAR T-cell product followed by infusion with PD-1 blockade, and they have “sustained CR [complete response] with B-cell aplasia, showing continued persistence of their CAR T cells,” said Dr. Maude, an attending physician in the Cancer Center at Children’s Hospital of Philadelphia.

Of the four patients with R/R bulky extramedullary disease, two patients had a partial response and two patients had CR, she said, explaining that it was hypothesized that the “PD-1 checkpoint pathway may be activated through the microenvironment in that extramedullary situation.”

However, all four patients who had partial or no response to initial CAR T-cell therapy progressed after PD-1 administration, she said, noting that “in one patient, this progression was marked by reduced CD19 expression, which was probably the mode of escape from CD19 CAR T cells.”

Prior studies have shown that patients who respond to CAR T-cell therapy have persistence of CD19 CAR T cells, whereas those with loss of CD19 CAR T cells within 6 months of infusion have a higher rate of relapse, Dr. Maude explained.

“Our hypothesis was that T cells, upon activation, may become exhausted through activation of immune checkpoint pathways, that one such pathway – PD-1 – may be involved in early loss of CD19 CAR T cells and therefore that the combination [of CD19 CAR T-cell therapy] with PD-1 checkpoint blockade may improve the function of the CAR T cells and their persistence,” she said.

The combined approach was well tolerated in this study, she said, noting that mild cytokine release syndrome symptoms and fever typical of CAR T-cell proliferative responses were observed in three patients within 2 days of starting pembrolizumab.

Other adverse effects associated with PD-1 inhibition, including acute pancreatitis, hypothyroidism, arthralgias, and urticaria, occurred in one patient each. There were four cases of grade 3-4 cytopenias that were deemed tolerable or reversible upon discontinuation.

“We show that PD-1 checkpoint inhibitors can be safely combined with CD19 CAR T-cell therapy and that this mechanism may be useful to improve CAR T-cell persistence,” Dr. Maude said.

These findings, which showed particular benefit in patients with poor persistence marked by early B-cell recovery and in those with R/R bulky extramedullary disease, should help inform future use of checkpoint inhibitors after CAR T-cell therapy, she added.

Dr. Maude reported financial ties to Novartis.

[email protected]

SOURCE: Li AM et al. ASH 2018, Abstract 556.

SAN DIEGO – Checkpoint inhibition can be used safely and effectively with CD19-directed chimeric antigen receptor (CAR) T-cell therapy in children with relapsed B-cell acute lymphoblastic leukemia (ALL), and it may bolster CAR T-cell effects and persistence, suggest the findings in a series of 14 patients at the Children’s Hospital of Philadelphia.

Combined programmed death-1 (PD-1) blockade and CAR T-cell therapy appeared to have particular benefit in patients with early B-cell recovery and in those with bulky extramedullary disease, Shannon Maude, MD, PhD, reported during a press conference at the annual meeting of the American Society of Hematology.

The patients, aged 4-17 years with heavily pretreated relapsed B-ALL (13 patients) or B lymphoblastic lymphoma (1 patient), were treated with CD19-directed CAR T-cell therapy, including CTL019 in 4 patients and CTL119 in 10 patients, followed by pembrolizumab (in 13 patients) or nivolumab (in 1 patient).

Six patients received the combination therapy because of early B-cell recovery after initial CAR T-cell infusion, four patients had relapsed or refractory (R/R) bulky extramedullary disease, and four patients had failed to respond or relapsed after initial CAR T-cell therapy.

Three of the six with poor persistence of response reestablished B-cell aplasia (a reflection of CAR T-cell function) after reinfusion of the CAR T-cell product followed by infusion with PD-1 blockade, and they have “sustained CR [complete response] with B-cell aplasia, showing continued persistence of their CAR T cells,” said Dr. Maude, an attending physician in the Cancer Center at Children’s Hospital of Philadelphia.

Of the four patients with R/R bulky extramedullary disease, two patients had a partial response and two patients had CR, she said, explaining that it was hypothesized that the “PD-1 checkpoint pathway may be activated through the microenvironment in that extramedullary situation.”

However, all four patients who had partial or no response to initial CAR T-cell therapy progressed after PD-1 administration, she said, noting that “in one patient, this progression was marked by reduced CD19 expression, which was probably the mode of escape from CD19 CAR T cells.”

Prior studies have shown that patients who respond to CAR T-cell therapy have persistence of CD19 CAR T cells, whereas those with loss of CD19 CAR T cells within 6 months of infusion have a higher rate of relapse, Dr. Maude explained.

“Our hypothesis was that T cells, upon activation, may become exhausted through activation of immune checkpoint pathways, that one such pathway – PD-1 – may be involved in early loss of CD19 CAR T cells and therefore that the combination [of CD19 CAR T-cell therapy] with PD-1 checkpoint blockade may improve the function of the CAR T cells and their persistence,” she said.

The combined approach was well tolerated in this study, she said, noting that mild cytokine release syndrome symptoms and fever typical of CAR T-cell proliferative responses were observed in three patients within 2 days of starting pembrolizumab.

Other adverse effects associated with PD-1 inhibition, including acute pancreatitis, hypothyroidism, arthralgias, and urticaria, occurred in one patient each. There were four cases of grade 3-4 cytopenias that were deemed tolerable or reversible upon discontinuation.

“We show that PD-1 checkpoint inhibitors can be safely combined with CD19 CAR T-cell therapy and that this mechanism may be useful to improve CAR T-cell persistence,” Dr. Maude said.

These findings, which showed particular benefit in patients with poor persistence marked by early B-cell recovery and in those with R/R bulky extramedullary disease, should help inform future use of checkpoint inhibitors after CAR T-cell therapy, she added.

Dr. Maude reported financial ties to Novartis.

[email protected]

SOURCE: Li AM et al. ASH 2018, Abstract 556.

SAN DIEGO – Checkpoint inhibition can be used safely and effectively with CD19-directed chimeric antigen receptor (CAR) T-cell therapy in children with relapsed B-cell acute lymphoblastic leukemia (ALL), and it may bolster CAR T-cell effects and persistence, suggest the findings in a series of 14 patients at the Children’s Hospital of Philadelphia.

Combined programmed death-1 (PD-1) blockade and CAR T-cell therapy appeared to have particular benefit in patients with early B-cell recovery and in those with bulky extramedullary disease, Shannon Maude, MD, PhD, reported during a press conference at the annual meeting of the American Society of Hematology.

The patients, aged 4-17 years with heavily pretreated relapsed B-ALL (13 patients) or B lymphoblastic lymphoma (1 patient), were treated with CD19-directed CAR T-cell therapy, including CTL019 in 4 patients and CTL119 in 10 patients, followed by pembrolizumab (in 13 patients) or nivolumab (in 1 patient).

Six patients received the combination therapy because of early B-cell recovery after initial CAR T-cell infusion, four patients had relapsed or refractory (R/R) bulky extramedullary disease, and four patients had failed to respond or relapsed after initial CAR T-cell therapy.

Three of the six with poor persistence of response reestablished B-cell aplasia (a reflection of CAR T-cell function) after reinfusion of the CAR T-cell product followed by infusion with PD-1 blockade, and they have “sustained CR [complete response] with B-cell aplasia, showing continued persistence of their CAR T cells,” said Dr. Maude, an attending physician in the Cancer Center at Children’s Hospital of Philadelphia.

Of the four patients with R/R bulky extramedullary disease, two patients had a partial response and two patients had CR, she said, explaining that it was hypothesized that the “PD-1 checkpoint pathway may be activated through the microenvironment in that extramedullary situation.”

However, all four patients who had partial or no response to initial CAR T-cell therapy progressed after PD-1 administration, she said, noting that “in one patient, this progression was marked by reduced CD19 expression, which was probably the mode of escape from CD19 CAR T cells.”

Prior studies have shown that patients who respond to CAR T-cell therapy have persistence of CD19 CAR T cells, whereas those with loss of CD19 CAR T cells within 6 months of infusion have a higher rate of relapse, Dr. Maude explained.

“Our hypothesis was that T cells, upon activation, may become exhausted through activation of immune checkpoint pathways, that one such pathway – PD-1 – may be involved in early loss of CD19 CAR T cells and therefore that the combination [of CD19 CAR T-cell therapy] with PD-1 checkpoint blockade may improve the function of the CAR T cells and their persistence,” she said.

The combined approach was well tolerated in this study, she said, noting that mild cytokine release syndrome symptoms and fever typical of CAR T-cell proliferative responses were observed in three patients within 2 days of starting pembrolizumab.

Other adverse effects associated with PD-1 inhibition, including acute pancreatitis, hypothyroidism, arthralgias, and urticaria, occurred in one patient each. There were four cases of grade 3-4 cytopenias that were deemed tolerable or reversible upon discontinuation.

“We show that PD-1 checkpoint inhibitors can be safely combined with CD19 CAR T-cell therapy and that this mechanism may be useful to improve CAR T-cell persistence,” Dr. Maude said.

These findings, which showed particular benefit in patients with poor persistence marked by early B-cell recovery and in those with R/R bulky extramedullary disease, should help inform future use of checkpoint inhibitors after CAR T-cell therapy, she added.

Dr. Maude reported financial ties to Novartis.

[email protected]

SOURCE: Li AM et al. ASH 2018, Abstract 556.

Chronic myeloid leukemia (CML) is a rare myeloproliferative neoplasm that is characterized by the presence of the Philadelphia (Ph) chromosome and uninhibited expansion of bone marrow stem cells. The Ph chromosome arises from a reciprocal translocation between the Abelson (ABL) region on chromosome 9 and the breakpoint cluster region (BCR) of chromosome 22 (t(9;22)(q34;q11.2), resulting in the BCR-ABL1 fusion gene.¹BCR-ABL1 encodes an oncoprotein with constitutive tyrosine kinase activity that promotes growth and replication through downstream pathways, which is the driving factor in the pathogenesis of CML.¹

Typical treatment for CML involves life-long use of oral BCR-ABL tyrosine kinase inhibitors (TKI). Currently, 5 TKIs have regulatory approval for treatment of this disease. With the introduction of imatinib in 2001 and the subsequent development of second- (dasatinib, nilotinib, bosutinib) and third-generation (ponatinib) TKIs, CML has become a chronic disease with a life-expectancy that is similar to that of the general population. This article reviews the diagnosis of CML and the parameters used for monitoring response to TKI therapy; the selection of initial TKI therapy is reviewed in a separate follow-up article.

Epidemiology

According to SEER data estimates, 8430 new cases of CML were diagnosed in the United States in 2018. CML is a disease of older adults, with a median age of 65 years at diagnosis, and there is a slight male predominance. Between 2011 and 2015, the number of new CML cases was 1.8 per 100,000 persons. The median overall survival (OS) in patients with newly diagnosed chronic-phase CML (CP-CML) has not been reached.² Given the effective treatments available for managing CML, it is estimated that the prevalence of CML in the United States will plateau at 180,000 patients by 2050.³

Diagnosis

Case Presentation

A 53-year-old woman presents to her primary care physician with complaints of fatigue, early satiety, left upper quadrant abdominal pain, and an 8-lb unintentional weight loss over the prior month. Her past medical history is significant for uncontrolled diabetes, coronary artery disease requiring placement of 3 cardiac stents 2 years prior, and chronic obstructive pulmonary disease (COPD) related to a 30-pack-year history of smoking. On physicial exam her spleen is palpated 8 cm below the left costal margin. A complete blood count (CBC) with differential identifies a total white blood cell (WBC) count of 124,000/μL, with a left-shifted differential including 6% basophils, 3% eosinophils, and 3% blasts; hemoglobin is 12.4 g/dL and platelet count is 801 × 10³/µL.

• How is the diagnosis of CML made?

Clinical Features

The diagnosis of CML is often suspected based on an incidental finding of leukocytosis and, in some cases, thrombocytosis. In many cases, this is an incidental finding on routine blood work, but approximately 50% of patients will present with constitutional symptoms associated with the disease. Characteristic features of the WBC differential include left-shifted maturation with neutrophilia and immature circulating myeloid cells. Basophilia and eosinophilia are often present as well. Splenomegaly is a common sign, present in 50% to 90% of patients at diagnosis. In those patients with symptoms related to CML at diagnosis, the most common presentation includes increasing fatigue, fevers, night sweats, early satiety, and weight loss. The diagnosis is confirmed by cytogenetic studies showing the Ph chromosome abnormality, t(9; 22)(q3.4;q1.1), and/or reverse transcriptase polymerase chain reaction (PCR) showing BCR-ABL1 transcripts.

• What further testing is needed when evaluating a patient for CML?

There are 3 distinct phases of CML: chronic phase (CP), accelerated phase (AP), and blast phase (BP). Bone marrow biopsy and aspiration at diagnosis are mandatory in order to determine the phase of the disease at diagnosis. This distinction is based on the percentage of blasts, promyelocytes, and basophils present as well as the platelet count and presence or absence of extramedullary disease.⁴ The vast majority of patients at diagnosis have CML that is in the chronic phase. The typical appearance in CP-CML is a hypercellular marrow with granulocytic and occasionally megakaryocytic hyperplasia. In many cases, basophilia and/or eosinophilia are noted as well. Dysplasia is not a typical finding in CML.⁵ Bone marrow fibrosis can be seen in up to one-third of patients at diagnosis, and may indicate a slightly worse prognosis.⁶ Although a diagnosis of CML can be made without a bone marrow biopsy, complete staging and prognostication are only possible with information gained from this test, including baseline karyotype and confirmation of CP versus a more advanced phase of CML.

The criteria for diagnosing AP-CML has not been agreed upon by various groups, but the modified MD Anderson Cancer Center (MDACC) criteria are used in the majority of clinical trials evaluating the efficacy of TKIs in preventing progression to advanced phases of CML. MDACC criteria define AP-CML as the presence of one of the following: 15% to 29% blasts in the peripheral blood or bone marrow, ≥ 30% peripheral blasts plus promyelocytes, ≥ 20% basophils in the blood or bone marrow, platelet count ≤ 100 × 10³/μL unrelated to therapy, and clonal cytogenetic evolution in Ph-positive metaphases (Table).⁷

BP-CML is typically defined using the criteria developed by the International Bone Marrow Transplant Registry (IBMTR): ≥ 30% blasts in the peripheral blood and/or the bone marrow or the presence of extramedullary disease.⁸ Although not typically used in clinical trials, the revised World Health Organization (WHO) criteria for BP-CML include ≥ 20% blasts in the peripheral blood or bone marrow, extramedullary blast proliferation, and large foci or clusters of blasts in the bone marrow biopsy (Table).⁹ The defining feature of CML is the presence of the Ph chromosome abnormality. In a small subset of patients, additional chromosomal abnormalities (ACA) in the Ph-positive cells may be identified at diagnosis. Some reports indicate that the presence of “major route” ACA (trisomy 8, isochromosome 17q, a second Ph chromosome, or trisomy 19) at diagnosis may negatively impact prognosis, but other reports contradict these findings.^10,11

The typical BCR breakpoint in CML is the major breakpoint cluster region (M-BCR), which results in a 210-kDa protein (p210). Alternate breakpoints that are less frequently identified are the minor BCR (mBCR or p190), which is more commonly found in Ph-positive acute lymphoblastic leukemia (ALL), and the micro BCR (µBCR or p230), which is much less common and is often characterized by chronic neutrophilia.¹² Identifying which BCR-ABL1 transcript is present in each patient using qualitative PCR is crucial in order to ensure proper monitoring during treatment.

The most sensitive method for detecting BCR-ABL1 mRNA transcripts is the quantitative real-time PCR (RQ-PCR) assay, which is typically done on peripheral blood. RQ-PCR is capable of detecting a single CML cell in the presence of ≥ 100,000 normal cells. This test should be done during the initial diagnostic workup in order to confirm the presence of BCR-ABL1 transcripts, and it is used as a standard method for monitoring response to TKI therapy.¹³ The International Scale (IS) is a standardized approach to reporting RQ-PCR results that was developed to allow comparison of results across various laboratories and has become the gold standard for reporting BCR-ABL1 transcript values.¹⁴

Determining Risk Scores

Calculating a patient’s Sokal score or EURO risk score at diagnosis remains an important component of the diagnostic workup in CP-CML, as this information has prognostic and therapeutic implications (an online calculator is available through European LeukemiaNet [ELN]). The risk for disease progression to the accelerated or blast phases is higher in patients with intermediate- or high-risk scores compared to those with a low-risk score at diagnosis. The risk of progression in intermediate- or high-risk patients is lower when a second-generation TKI (dasatinib, nilotinib, or bosutinib) is used as frontline therapy compared to imatinib, and therefore, the National Comprehensive Cancer Network (NCCN) CML Panel recommends starting with a second-generation TKI in these patients.^15-19

Case Continued

Fluorescent in-situ hybridization using a peripheral blood sample to detect the BCR-ABL gene rearrangement is performed and is positive in 87% of cells. Bone marrow biopsy and aspiration show a 95% cellular bone marrow with granulocytic hyperplasia and 1% blasts. Cytogenetics are 46,XX,t(9;22)(q34;q11.2).²⁰ RQ-PCR assay performed to measure BCR-ABL1 transcripts in the peripheral blood shows a value of 98% IS. The patient is ultimately given a diagnosis of CP-CML. Her Sokal risk score is 1.42, making her disease high risk.

• How is response to TKI therapy measured and monitored?

After confirming a diagnosis of CML and selecting the most appropriate TKI for first-line therapy, the successful management of a CML patient relies on close monitoring and follow-up to ensure patients are meeting the desired treatment milestones. Responses in CML can be assessed based on hematologic parameters, cytogenetic results, and molecular responses. A complete hematologic response (CHR) implies complete normalization of peripheral blood counts (with the exception of TKI-induced cytopenias) and resolution of any palpable splenomegaly. The majority of patients will achieve a CHR within 4 to 6 weeks after initiating CML-directed therapy.²¹

Cytogenetic Response

Cytogenetic responses are defined by the decrease in the number of Ph chromosome–positive metaphases when assessed on bone marrow cytogenetics. A partial cytogenetic response (PCyR) is defined as having 1% to 35% Ph-positive metaphases, a major cytogenetic response (MCyR) as having 0% to 35% Ph-positive metaphases, and a CCyR implies that no Ph-positive metaphases are identified on bone marrow cytogenetics. An ideal response is the achievement of PCyR after 3 months on a TKI and a CCyR after 12 months on a TKI.²²

Molecular Response

Once a patient has achieved a CCyR, monitoring their response to therapy can only be done using RQ-PCR to measure BCR-ABL1 transcripts in the peripheral blood. The NCCN and the ELN recommend monitoring RQ-PCR from the peripheral blood every 3 months in order to assess response to TKIs.^19,23 As noted, the International Scale (IS) has become the gold standard reporting system for all BCR-ABL1 transcript levels in the majority of laboratories worldwide.^14,24 Molecular responses are based on a log-reduction in BCR-ABL1 transcripts from a standardized baseline. Many molecular responses can be correlated with cytogenetic responses such that if reliable RQ-PCR testing is available, monitoring can be done using only peripheral blood RQ-PCR rather than repeat bone marrow biopsies. For example, an early molecular response (EMR) is defined as a RQ-PCR value of ≤ 10% IS, which is approximately equivalent to a PCyR.²⁵ A value of 1% IS is approximately equivalent to CCyR. A major molecular response (MMR) is a ≥ 3-log reduction in BCR-ABL1 transcripts from baseline and is a value of ≤ 0.1% IS. Deeper levels of molecular response are best described by the log-reduction in BCR-ABL1 transcripts, with a 4-log reduction denoted as MR4.0, a 4.5-log reduction as MR4.5, and so forth. Complete molecular response (CMR) is defined by the level of sensitivity of the RQ-PCR assay being used.¹⁴

The definition of relapsed disease in CML is dependent on the type of response the patient had previously achieved. Relapse could be the loss of a hematologic or cytogenetic response, but fluctuations in BCR-ABL1 transcripts on routine RQ-PCR do not necessarily indicate relapsed CML. A 1-log increase in the level of BCR-ABL1 transcripts with a concurrent loss of MMR should prompt a bone marrow biopsy in order to assess for the loss of CCyR, and thus a cytogenetic relapse; however, this loss of MMR does not define relapse in and of itself. In the setting of relapsed disease, testing should be done to look for possible ABL kinase domain mutations, and alternate therapy should be selected.¹⁹

Multiple reports have identified the prognostic relevance of achieving an EMR at 3 and 6 months after starting TKI therapy. Marin and colleagues reported that in 282 imatinib-treated patients, there was a significant improvement in 8-year OS, progression-free survival, and cumulative incidence of CCyR and CMR in patients who had BCR-ABL1 transcripts < 9.84% IS after 3 months on treatment.²⁵ This data highlights the importance of early molecular monitoring in order to ensure the best outcomes for patients with CP-CML.

The NCCN CML guidelines and ELN recommendations both agree that an ideal response after 3 months on a TKI is BCR-ABL1 transcripts < 10% IS, but treatment is not considered to be failing at this point if the patient marginally misses this milestone. After 6 months on treatment, an ideal response is considered BCR-ABL1 transcripts < 1%–10% IS. Ideally, patients will have BCR-ABL1 transcripts < 0.1%–1% IS by the time they complete 12 months of TKI therapy, suggesting that these patients have at least achieved a CCyR.^19,23 Even after patients achieve these early milestones, frequent monitoring by RQ-PCR is required to ensure that they are maintaining their response to treatment. This will help to ensure patient compliance with treatment and will also help to identify a select subset of patients who could potentially be considered for an attempt at TKI cessation (not discussed in detail here) after a minimum of 3 years on therapy.^19,26

Conclusion

Given the successful treatments available for patients with CML, it is crucial to identify patients with this disease, ensure they receive a complete, appropriate diagnostic workup including a bone marrow biopsy and aspiration with cytogenetic testing, and select the best therapy for each individual patient. Once on treatment, the importance of frequent monitoring cannot be overstated.

Chronic myeloid leukemia (CML) is a rare myeloproliferative neoplasm that is characterized by the presence of the Philadelphia (Ph) chromosome and uninhibited expansion of bone marrow stem cells. The Ph chromosome arises from a reciprocal translocation between the Abelson (ABL) region on chromosome 9 and the breakpoint cluster region (BCR) of chromosome 22 (t(9;22)(q34;q11.2), resulting in the BCR-ABL1 fusion gene.¹BCR-ABL1 encodes an oncoprotein with constitutive tyrosine kinase activity that promotes growth and replication through downstream pathways, which is the driving factor in the pathogenesis of CML.¹

Typical treatment for CML involves life-long use of oral BCR-ABL tyrosine kinase inhibitors (TKI). Currently, 5 TKIs have regulatory approval for treatment of this disease. With the introduction of imatinib in 2001 and the subsequent development of second- (dasatinib, nilotinib, bosutinib) and third-generation (ponatinib) TKIs, CML has become a chronic disease with a life-expectancy that is similar to that of the general population. This article reviews the diagnosis of CML and the parameters used for monitoring response to TKI therapy; the selection of initial TKI therapy is reviewed in a separate follow-up article.

Epidemiology

According to SEER data estimates, 8430 new cases of CML were diagnosed in the United States in 2018. CML is a disease of older adults, with a median age of 65 years at diagnosis, and there is a slight male predominance. Between 2011 and 2015, the number of new CML cases was 1.8 per 100,000 persons. The median overall survival (OS) in patients with newly diagnosed chronic-phase CML (CP-CML) has not been reached.² Given the effective treatments available for managing CML, it is estimated that the prevalence of CML in the United States will plateau at 180,000 patients by 2050.³

Diagnosis

Case Presentation

A 53-year-old woman presents to her primary care physician with complaints of fatigue, early satiety, left upper quadrant abdominal pain, and an 8-lb unintentional weight loss over the prior month. Her past medical history is significant for uncontrolled diabetes, coronary artery disease requiring placement of 3 cardiac stents 2 years prior, and chronic obstructive pulmonary disease (COPD) related to a 30-pack-year history of smoking. On physicial exam her spleen is palpated 8 cm below the left costal margin. A complete blood count (CBC) with differential identifies a total white blood cell (WBC) count of 124,000/μL, with a left-shifted differential including 6% basophils, 3% eosinophils, and 3% blasts; hemoglobin is 12.4 g/dL and platelet count is 801 × 10³/µL.

• How is the diagnosis of CML made?

Clinical Features

The diagnosis of CML is often suspected based on an incidental finding of leukocytosis and, in some cases, thrombocytosis. In many cases, this is an incidental finding on routine blood work, but approximately 50% of patients will present with constitutional symptoms associated with the disease. Characteristic features of the WBC differential include left-shifted maturation with neutrophilia and immature circulating myeloid cells. Basophilia and eosinophilia are often present as well. Splenomegaly is a common sign, present in 50% to 90% of patients at diagnosis. In those patients with symptoms related to CML at diagnosis, the most common presentation includes increasing fatigue, fevers, night sweats, early satiety, and weight loss. The diagnosis is confirmed by cytogenetic studies showing the Ph chromosome abnormality, t(9; 22)(q3.4;q1.1), and/or reverse transcriptase polymerase chain reaction (PCR) showing BCR-ABL1 transcripts.

• What further testing is needed when evaluating a patient for CML?

There are 3 distinct phases of CML: chronic phase (CP), accelerated phase (AP), and blast phase (BP). Bone marrow biopsy and aspiration at diagnosis are mandatory in order to determine the phase of the disease at diagnosis. This distinction is based on the percentage of blasts, promyelocytes, and basophils present as well as the platelet count and presence or absence of extramedullary disease.⁴ The vast majority of patients at diagnosis have CML that is in the chronic phase. The typical appearance in CP-CML is a hypercellular marrow with granulocytic and occasionally megakaryocytic hyperplasia. In many cases, basophilia and/or eosinophilia are noted as well. Dysplasia is not a typical finding in CML.⁵ Bone marrow fibrosis can be seen in up to one-third of patients at diagnosis, and may indicate a slightly worse prognosis.⁶ Although a diagnosis of CML can be made without a bone marrow biopsy, complete staging and prognostication are only possible with information gained from this test, including baseline karyotype and confirmation of CP versus a more advanced phase of CML.

The criteria for diagnosing AP-CML has not been agreed upon by various groups, but the modified MD Anderson Cancer Center (MDACC) criteria are used in the majority of clinical trials evaluating the efficacy of TKIs in preventing progression to advanced phases of CML. MDACC criteria define AP-CML as the presence of one of the following: 15% to 29% blasts in the peripheral blood or bone marrow, ≥ 30% peripheral blasts plus promyelocytes, ≥ 20% basophils in the blood or bone marrow, platelet count ≤ 100 × 10³/μL unrelated to therapy, and clonal cytogenetic evolution in Ph-positive metaphases (Table).⁷

BP-CML is typically defined using the criteria developed by the International Bone Marrow Transplant Registry (IBMTR): ≥ 30% blasts in the peripheral blood and/or the bone marrow or the presence of extramedullary disease.⁸ Although not typically used in clinical trials, the revised World Health Organization (WHO) criteria for BP-CML include ≥ 20% blasts in the peripheral blood or bone marrow, extramedullary blast proliferation, and large foci or clusters of blasts in the bone marrow biopsy (Table).⁹ The defining feature of CML is the presence of the Ph chromosome abnormality. In a small subset of patients, additional chromosomal abnormalities (ACA) in the Ph-positive cells may be identified at diagnosis. Some reports indicate that the presence of “major route” ACA (trisomy 8, isochromosome 17q, a second Ph chromosome, or trisomy 19) at diagnosis may negatively impact prognosis, but other reports contradict these findings.^10,11

The typical BCR breakpoint in CML is the major breakpoint cluster region (M-BCR), which results in a 210-kDa protein (p210). Alternate breakpoints that are less frequently identified are the minor BCR (mBCR or p190), which is more commonly found in Ph-positive acute lymphoblastic leukemia (ALL), and the micro BCR (µBCR or p230), which is much less common and is often characterized by chronic neutrophilia.¹² Identifying which BCR-ABL1 transcript is present in each patient using qualitative PCR is crucial in order to ensure proper monitoring during treatment.

The most sensitive method for detecting BCR-ABL1 mRNA transcripts is the quantitative real-time PCR (RQ-PCR) assay, which is typically done on peripheral blood. RQ-PCR is capable of detecting a single CML cell in the presence of ≥ 100,000 normal cells. This test should be done during the initial diagnostic workup in order to confirm the presence of BCR-ABL1 transcripts, and it is used as a standard method for monitoring response to TKI therapy.¹³ The International Scale (IS) is a standardized approach to reporting RQ-PCR results that was developed to allow comparison of results across various laboratories and has become the gold standard for reporting BCR-ABL1 transcript values.¹⁴

Determining Risk Scores

Calculating a patient’s Sokal score or EURO risk score at diagnosis remains an important component of the diagnostic workup in CP-CML, as this information has prognostic and therapeutic implications (an online calculator is available through European LeukemiaNet [ELN]). The risk for disease progression to the accelerated or blast phases is higher in patients with intermediate- or high-risk scores compared to those with a low-risk score at diagnosis. The risk of progression in intermediate- or high-risk patients is lower when a second-generation TKI (dasatinib, nilotinib, or bosutinib) is used as frontline therapy compared to imatinib, and therefore, the National Comprehensive Cancer Network (NCCN) CML Panel recommends starting with a second-generation TKI in these patients.^15-19

Case Continued

Fluorescent in-situ hybridization using a peripheral blood sample to detect the BCR-ABL gene rearrangement is performed and is positive in 87% of cells. Bone marrow biopsy and aspiration show a 95% cellular bone marrow with granulocytic hyperplasia and 1% blasts. Cytogenetics are 46,XX,t(9;22)(q34;q11.2).²⁰ RQ-PCR assay performed to measure BCR-ABL1 transcripts in the peripheral blood shows a value of 98% IS. The patient is ultimately given a diagnosis of CP-CML. Her Sokal risk score is 1.42, making her disease high risk.

• How is response to TKI therapy measured and monitored?

After confirming a diagnosis of CML and selecting the most appropriate TKI for first-line therapy, the successful management of a CML patient relies on close monitoring and follow-up to ensure patients are meeting the desired treatment milestones. Responses in CML can be assessed based on hematologic parameters, cytogenetic results, and molecular responses. A complete hematologic response (CHR) implies complete normalization of peripheral blood counts (with the exception of TKI-induced cytopenias) and resolution of any palpable splenomegaly. The majority of patients will achieve a CHR within 4 to 6 weeks after initiating CML-directed therapy.²¹

Cytogenetic Response

Cytogenetic responses are defined by the decrease in the number of Ph chromosome–positive metaphases when assessed on bone marrow cytogenetics. A partial cytogenetic response (PCyR) is defined as having 1% to 35% Ph-positive metaphases, a major cytogenetic response (MCyR) as having 0% to 35% Ph-positive metaphases, and a CCyR implies that no Ph-positive metaphases are identified on bone marrow cytogenetics. An ideal response is the achievement of PCyR after 3 months on a TKI and a CCyR after 12 months on a TKI.²²

Molecular Response

Once a patient has achieved a CCyR, monitoring their response to therapy can only be done using RQ-PCR to measure BCR-ABL1 transcripts in the peripheral blood. The NCCN and the ELN recommend monitoring RQ-PCR from the peripheral blood every 3 months in order to assess response to TKIs.^19,23 As noted, the International Scale (IS) has become the gold standard reporting system for all BCR-ABL1 transcript levels in the majority of laboratories worldwide.^14,24 Molecular responses are based on a log-reduction in BCR-ABL1 transcripts from a standardized baseline. Many molecular responses can be correlated with cytogenetic responses such that if reliable RQ-PCR testing is available, monitoring can be done using only peripheral blood RQ-PCR rather than repeat bone marrow biopsies. For example, an early molecular response (EMR) is defined as a RQ-PCR value of ≤ 10% IS, which is approximately equivalent to a PCyR.²⁵ A value of 1% IS is approximately equivalent to CCyR. A major molecular response (MMR) is a ≥ 3-log reduction in BCR-ABL1 transcripts from baseline and is a value of ≤ 0.1% IS. Deeper levels of molecular response are best described by the log-reduction in BCR-ABL1 transcripts, with a 4-log reduction denoted as MR4.0, a 4.5-log reduction as MR4.5, and so forth. Complete molecular response (CMR) is defined by the level of sensitivity of the RQ-PCR assay being used.¹⁴

The definition of relapsed disease in CML is dependent on the type of response the patient had previously achieved. Relapse could be the loss of a hematologic or cytogenetic response, but fluctuations in BCR-ABL1 transcripts on routine RQ-PCR do not necessarily indicate relapsed CML. A 1-log increase in the level of BCR-ABL1 transcripts with a concurrent loss of MMR should prompt a bone marrow biopsy in order to assess for the loss of CCyR, and thus a cytogenetic relapse; however, this loss of MMR does not define relapse in and of itself. In the setting of relapsed disease, testing should be done to look for possible ABL kinase domain mutations, and alternate therapy should be selected.¹⁹

Multiple reports have identified the prognostic relevance of achieving an EMR at 3 and 6 months after starting TKI therapy. Marin and colleagues reported that in 282 imatinib-treated patients, there was a significant improvement in 8-year OS, progression-free survival, and cumulative incidence of CCyR and CMR in patients who had BCR-ABL1 transcripts < 9.84% IS after 3 months on treatment.²⁵ This data highlights the importance of early molecular monitoring in order to ensure the best outcomes for patients with CP-CML.

The NCCN CML guidelines and ELN recommendations both agree that an ideal response after 3 months on a TKI is BCR-ABL1 transcripts < 10% IS, but treatment is not considered to be failing at this point if the patient marginally misses this milestone. After 6 months on treatment, an ideal response is considered BCR-ABL1 transcripts < 1%–10% IS. Ideally, patients will have BCR-ABL1 transcripts < 0.1%–1% IS by the time they complete 12 months of TKI therapy, suggesting that these patients have at least achieved a CCyR.^19,23 Even after patients achieve these early milestones, frequent monitoring by RQ-PCR is required to ensure that they are maintaining their response to treatment. This will help to ensure patient compliance with treatment and will also help to identify a select subset of patients who could potentially be considered for an attempt at TKI cessation (not discussed in detail here) after a minimum of 3 years on therapy.^19,26

Conclusion

Given the successful treatments available for patients with CML, it is crucial to identify patients with this disease, ensure they receive a complete, appropriate diagnostic workup including a bone marrow biopsy and aspiration with cytogenetic testing, and select the best therapy for each individual patient. Once on treatment, the importance of frequent monitoring cannot be overstated.

Chronic myeloid leukemia (CML) is a rare myeloproliferative neoplasm that is characterized by the presence of the Philadelphia (Ph) chromosome and uninhibited expansion of bone marrow stem cells. The Ph chromosome arises from a reciprocal translocation between the Abelson (ABL) region on chromosome 9 and the breakpoint cluster region (BCR) of chromosome 22 (t(9;22)(q34;q11.2), resulting in the BCR-ABL1 fusion gene.¹BCR-ABL1 encodes an oncoprotein with constitutive tyrosine kinase activity that promotes growth and replication through downstream pathways, which is the driving factor in the pathogenesis of CML.¹

Typical treatment for CML involves life-long use of oral BCR-ABL tyrosine kinase inhibitors (TKI). Currently, 5 TKIs have regulatory approval for treatment of this disease. With the introduction of imatinib in 2001 and the subsequent development of second- (dasatinib, nilotinib, bosutinib) and third-generation (ponatinib) TKIs, CML has become a chronic disease with a life-expectancy that is similar to that of the general population. This article reviews the diagnosis of CML and the parameters used for monitoring response to TKI therapy; the selection of initial TKI therapy is reviewed in a separate follow-up article.

Epidemiology

According to SEER data estimates, 8430 new cases of CML were diagnosed in the United States in 2018. CML is a disease of older adults, with a median age of 65 years at diagnosis, and there is a slight male predominance. Between 2011 and 2015, the number of new CML cases was 1.8 per 100,000 persons. The median overall survival (OS) in patients with newly diagnosed chronic-phase CML (CP-CML) has not been reached.² Given the effective treatments available for managing CML, it is estimated that the prevalence of CML in the United States will plateau at 180,000 patients by 2050.³

Diagnosis

Case Presentation

A 53-year-old woman presents to her primary care physician with complaints of fatigue, early satiety, left upper quadrant abdominal pain, and an 8-lb unintentional weight loss over the prior month. Her past medical history is significant for uncontrolled diabetes, coronary artery disease requiring placement of 3 cardiac stents 2 years prior, and chronic obstructive pulmonary disease (COPD) related to a 30-pack-year history of smoking. On physicial exam her spleen is palpated 8 cm below the left costal margin. A complete blood count (CBC) with differential identifies a total white blood cell (WBC) count of 124,000/μL, with a left-shifted differential including 6% basophils, 3% eosinophils, and 3% blasts; hemoglobin is 12.4 g/dL and platelet count is 801 × 10³/µL.

• How is the diagnosis of CML made?

Clinical Features

The diagnosis of CML is often suspected based on an incidental finding of leukocytosis and, in some cases, thrombocytosis. In many cases, this is an incidental finding on routine blood work, but approximately 50% of patients will present with constitutional symptoms associated with the disease. Characteristic features of the WBC differential include left-shifted maturation with neutrophilia and immature circulating myeloid cells. Basophilia and eosinophilia are often present as well. Splenomegaly is a common sign, present in 50% to 90% of patients at diagnosis. In those patients with symptoms related to CML at diagnosis, the most common presentation includes increasing fatigue, fevers, night sweats, early satiety, and weight loss. The diagnosis is confirmed by cytogenetic studies showing the Ph chromosome abnormality, t(9; 22)(q3.4;q1.1), and/or reverse transcriptase polymerase chain reaction (PCR) showing BCR-ABL1 transcripts.

• What further testing is needed when evaluating a patient for CML?

There are 3 distinct phases of CML: chronic phase (CP), accelerated phase (AP), and blast phase (BP). Bone marrow biopsy and aspiration at diagnosis are mandatory in order to determine the phase of the disease at diagnosis. This distinction is based on the percentage of blasts, promyelocytes, and basophils present as well as the platelet count and presence or absence of extramedullary disease.⁴ The vast majority of patients at diagnosis have CML that is in the chronic phase. The typical appearance in CP-CML is a hypercellular marrow with granulocytic and occasionally megakaryocytic hyperplasia. In many cases, basophilia and/or eosinophilia are noted as well. Dysplasia is not a typical finding in CML.⁵ Bone marrow fibrosis can be seen in up to one-third of patients at diagnosis, and may indicate a slightly worse prognosis.⁶ Although a diagnosis of CML can be made without a bone marrow biopsy, complete staging and prognostication are only possible with information gained from this test, including baseline karyotype and confirmation of CP versus a more advanced phase of CML.

The criteria for diagnosing AP-CML has not been agreed upon by various groups, but the modified MD Anderson Cancer Center (MDACC) criteria are used in the majority of clinical trials evaluating the efficacy of TKIs in preventing progression to advanced phases of CML. MDACC criteria define AP-CML as the presence of one of the following: 15% to 29% blasts in the peripheral blood or bone marrow, ≥ 30% peripheral blasts plus promyelocytes, ≥ 20% basophils in the blood or bone marrow, platelet count ≤ 100 × 10³/μL unrelated to therapy, and clonal cytogenetic evolution in Ph-positive metaphases (Table).⁷

BP-CML is typically defined using the criteria developed by the International Bone Marrow Transplant Registry (IBMTR): ≥ 30% blasts in the peripheral blood and/or the bone marrow or the presence of extramedullary disease.⁸ Although not typically used in clinical trials, the revised World Health Organization (WHO) criteria for BP-CML include ≥ 20% blasts in the peripheral blood or bone marrow, extramedullary blast proliferation, and large foci or clusters of blasts in the bone marrow biopsy (Table).⁹ The defining feature of CML is the presence of the Ph chromosome abnormality. In a small subset of patients, additional chromosomal abnormalities (ACA) in the Ph-positive cells may be identified at diagnosis. Some reports indicate that the presence of “major route” ACA (trisomy 8, isochromosome 17q, a second Ph chromosome, or trisomy 19) at diagnosis may negatively impact prognosis, but other reports contradict these findings.^10,11

The typical BCR breakpoint in CML is the major breakpoint cluster region (M-BCR), which results in a 210-kDa protein (p210). Alternate breakpoints that are less frequently identified are the minor BCR (mBCR or p190), which is more commonly found in Ph-positive acute lymphoblastic leukemia (ALL), and the micro BCR (µBCR or p230), which is much less common and is often characterized by chronic neutrophilia.¹² Identifying which BCR-ABL1 transcript is present in each patient using qualitative PCR is crucial in order to ensure proper monitoring during treatment.

The most sensitive method for detecting BCR-ABL1 mRNA transcripts is the quantitative real-time PCR (RQ-PCR) assay, which is typically done on peripheral blood. RQ-PCR is capable of detecting a single CML cell in the presence of ≥ 100,000 normal cells. This test should be done during the initial diagnostic workup in order to confirm the presence of BCR-ABL1 transcripts, and it is used as a standard method for monitoring response to TKI therapy.¹³ The International Scale (IS) is a standardized approach to reporting RQ-PCR results that was developed to allow comparison of results across various laboratories and has become the gold standard for reporting BCR-ABL1 transcript values.¹⁴

Determining Risk Scores

Calculating a patient’s Sokal score or EURO risk score at diagnosis remains an important component of the diagnostic workup in CP-CML, as this information has prognostic and therapeutic implications (an online calculator is available through European LeukemiaNet [ELN]). The risk for disease progression to the accelerated or blast phases is higher in patients with intermediate- or high-risk scores compared to those with a low-risk score at diagnosis. The risk of progression in intermediate- or high-risk patients is lower when a second-generation TKI (dasatinib, nilotinib, or bosutinib) is used as frontline therapy compared to imatinib, and therefore, the National Comprehensive Cancer Network (NCCN) CML Panel recommends starting with a second-generation TKI in these patients.^15-19

Case Continued

Fluorescent in-situ hybridization using a peripheral blood sample to detect the BCR-ABL gene rearrangement is performed and is positive in 87% of cells. Bone marrow biopsy and aspiration show a 95% cellular bone marrow with granulocytic hyperplasia and 1% blasts. Cytogenetics are 46,XX,t(9;22)(q34;q11.2).²⁰ RQ-PCR assay performed to measure BCR-ABL1 transcripts in the peripheral blood shows a value of 98% IS. The patient is ultimately given a diagnosis of CP-CML. Her Sokal risk score is 1.42, making her disease high risk.

• How is response to TKI therapy measured and monitored?

After confirming a diagnosis of CML and selecting the most appropriate TKI for first-line therapy, the successful management of a CML patient relies on close monitoring and follow-up to ensure patients are meeting the desired treatment milestones. Responses in CML can be assessed based on hematologic parameters, cytogenetic results, and molecular responses. A complete hematologic response (CHR) implies complete normalization of peripheral blood counts (with the exception of TKI-induced cytopenias) and resolution of any palpable splenomegaly. The majority of patients will achieve a CHR within 4 to 6 weeks after initiating CML-directed therapy.²¹

Cytogenetic Response

Cytogenetic responses are defined by the decrease in the number of Ph chromosome–positive metaphases when assessed on bone marrow cytogenetics. A partial cytogenetic response (PCyR) is defined as having 1% to 35% Ph-positive metaphases, a major cytogenetic response (MCyR) as having 0% to 35% Ph-positive metaphases, and a CCyR implies that no Ph-positive metaphases are identified on bone marrow cytogenetics. An ideal response is the achievement of PCyR after 3 months on a TKI and a CCyR after 12 months on a TKI.²²

Molecular Response

Once a patient has achieved a CCyR, monitoring their response to therapy can only be done using RQ-PCR to measure BCR-ABL1 transcripts in the peripheral blood. The NCCN and the ELN recommend monitoring RQ-PCR from the peripheral blood every 3 months in order to assess response to TKIs.^19,23 As noted, the International Scale (IS) has become the gold standard reporting system for all BCR-ABL1 transcript levels in the majority of laboratories worldwide.^14,24 Molecular responses are based on a log-reduction in BCR-ABL1 transcripts from a standardized baseline. Many molecular responses can be correlated with cytogenetic responses such that if reliable RQ-PCR testing is available, monitoring can be done using only peripheral blood RQ-PCR rather than repeat bone marrow biopsies. For example, an early molecular response (EMR) is defined as a RQ-PCR value of ≤ 10% IS, which is approximately equivalent to a PCyR.²⁵ A value of 1% IS is approximately equivalent to CCyR. A major molecular response (MMR) is a ≥ 3-log reduction in BCR-ABL1 transcripts from baseline and is a value of ≤ 0.1% IS. Deeper levels of molecular response are best described by the log-reduction in BCR-ABL1 transcripts, with a 4-log reduction denoted as MR4.0, a 4.5-log reduction as MR4.5, and so forth. Complete molecular response (CMR) is defined by the level of sensitivity of the RQ-PCR assay being used.¹⁴

The definition of relapsed disease in CML is dependent on the type of response the patient had previously achieved. Relapse could be the loss of a hematologic or cytogenetic response, but fluctuations in BCR-ABL1 transcripts on routine RQ-PCR do not necessarily indicate relapsed CML. A 1-log increase in the level of BCR-ABL1 transcripts with a concurrent loss of MMR should prompt a bone marrow biopsy in order to assess for the loss of CCyR, and thus a cytogenetic relapse; however, this loss of MMR does not define relapse in and of itself. In the setting of relapsed disease, testing should be done to look for possible ABL kinase domain mutations, and alternate therapy should be selected.¹⁹

Multiple reports have identified the prognostic relevance of achieving an EMR at 3 and 6 months after starting TKI therapy. Marin and colleagues reported that in 282 imatinib-treated patients, there was a significant improvement in 8-year OS, progression-free survival, and cumulative incidence of CCyR and CMR in patients who had BCR-ABL1 transcripts < 9.84% IS after 3 months on treatment.²⁵ This data highlights the importance of early molecular monitoring in order to ensure the best outcomes for patients with CP-CML.

The NCCN CML guidelines and ELN recommendations both agree that an ideal response after 3 months on a TKI is BCR-ABL1 transcripts < 10% IS, but treatment is not considered to be failing at this point if the patient marginally misses this milestone. After 6 months on treatment, an ideal response is considered BCR-ABL1 transcripts < 1%–10% IS. Ideally, patients will have BCR-ABL1 transcripts < 0.1%–1% IS by the time they complete 12 months of TKI therapy, suggesting that these patients have at least achieved a CCyR.^19,23 Even after patients achieve these early milestones, frequent monitoring by RQ-PCR is required to ensure that they are maintaining their response to treatment. This will help to ensure patient compliance with treatment and will also help to identify a select subset of patients who could potentially be considered for an attempt at TKI cessation (not discussed in detail here) after a minimum of 3 years on therapy.^19,26

Conclusion

Given the successful treatments available for patients with CML, it is crucial to identify patients with this disease, ensure they receive a complete, appropriate diagnostic workup including a bone marrow biopsy and aspiration with cytogenetic testing, and select the best therapy for each individual patient. Once on treatment, the importance of frequent monitoring cannot be overstated.

WASHINGTON – Unquestionably, immunotherapy is revolutionizing the care of patients with various solid tumors and hematologic malignancies.

Neil Osterweil/MDedge News

But it’s equally true that there’s no such thing as either a free lunch or a cancer therapy free of side effects, whether it’s increased risk for heart failure associated with anthracycline-based chemotherapy, or inflammatory conditions, arrhythmias, and thromboembolic events associated with immune checkpoint inhibitors, said R. Frank Cornell, MD, of Vanderbilt University Medical Center in Nashville, Tenn.

“Early awareness and intervention is critical for improved outcomes, and a multidisciplinary approach between oncology, cardiology, the clinic nurse, and other health care providers is critical in managing these patients with these complicated therapies,” he said at the American College of Cardiology’s Advancing the Cardiovascular Care of the Oncology Patient meeting.
 

Checkpoint inhibitors and the heart

Toxicities associated with immune checkpoint inhibitors such as the programmed death 1/ligand 1 (PD-1/PD-L1) inhibitors nivolumab (Opdivo) and pembrolizumab (Keytruda) and the cytotoxic T-lymphocyte antigen 4 antibody ipilimumab (Yervoy) tend to mimic autoimmune conditions, Dr. Cornell said.

Cardiovascular events associated with these agents, while uncommon, include myocarditis, pericarditis, arrhythmias, impaired ventricular function with heart failure, vasculitis, and venous thromboembolism, he said, citing an American Society of Clinical Oncology (ASCO) clinical practice guideline (J Clin Oncol 2018;36[17]:1714-68).

Dr. Cornell described the case of a 63-year-old woman with disseminated metastatic melanoma who presented to the emergency department 10 days after starting on combination therapy with ipilimumab and nivolumab. She had developed shortness of breath, pleuritic chest pain, and a mild cough for 1 or 2 days.

Her cardiac laboratory markers had been normal at baseline, but were markedly elevated on presentation, and electrocardiograms showed complete heart block and subsequent ventricular tachycardia.

The patient was started on high-dose prednisone, but she died in hospital, and an autopsy showed that the cause of death was infiltration into the myocardium of CD3-positive and CD8-positive T lymphocytes.

“So how do we manage this? This is a good opportunity, I think, for further cardiology and oncology collaboration to develop more robust guidelines for what we can do to best prevent this,” Dr. Cornell said.

Patients started on the ipilimumab/nivolumab combination should be tested weekly for cardiac troponin, creatine kinase (CK) and CK-muscle/brain (CK-MB) weekly for the first 3-4 weeks of therapy. Therapy should be stopped if troponin levels continue to rise, and the patient should be started on high-dose steroids, he said.

The role of other anti-inflammatory agents such as infliximab (Remicade and biosimilars) is unclear and needs further study, he added.

Dr. Cornell cited a 2018 letter to The Lancet by Javid J. Moslehi, MD, and colleagues from Vanderbilt describing an increase in reports of fatal myocarditis among patients treated with checkpoint inhibitors.

“We highlight the high mortality rate with severe immune checkpoint inhibitor–related myocarditis, which is more frequent with combination PD-1 and CTLA-4 blockade, but can also occur with monotherapy. Myocarditis was observed across immune checkpoint inhibitor regimens, although it remains too early to determine whether the incidence differs between use of anti-PD1 and anti-PD-L1 drugs. Furthermore, this condition occurs early on during therapy and across cancer types,” they wrote.

Most of the patients had no preexisting cardiovascular disease, and most were not taking medications for hypertension, cardiovascular disease, or diabetes.
 

CAR-T cells and cardiac disease

The primary cardiac complications associated with CAR-T cell therapy are related to the cytokine release syndrome (CRS), a condition marked by progressive elevation in inflammatory cytokines that in turn leads to marked elevations in C-reactive protein (CRP), interferon gamma, tumor necrosis factor al, and release of pro-inflammatory cytokines including interleukin (IL) 6, IL-10, IL-12, and IL-1 beta.

In rare instances, CRS can lead to disseminated intravascular coagulation (DIC), capillary leak syndrome, and a hemophagocytic lymphohistiocytosis-like (HLH) syndrome, Dr. Cornell said.

Package inserts for the two Food and Drug Administration–approved CAR-T cell products, axicabtagene ciloleucel (Yescarta) and tisagenlecleucel (Kymriah) show that each was associated in clinical trials with a high incidence of CRS.

Among patients treated with axicabtagene ciloleucel, 94% developed CRS, which was grade 3 or greater in severity in 13%. The median time to onset was 2 days, and the median duration was 7 days. Cardiovascular adverse events included grade 3 or greater tachycardia in 2%, arrhythmias in 7%, edema in 1%, dyspnea in 3%, pleural effusion in 2%, hypotension in 15%, hypertension in 6%, and thrombosis in 1%.

Among patients treated with tisagenlecleucel, 79% treated for B-cell acute lymphoblastic leukemia (B-ALL) and 74% treated for diffuse large B cell lymphoma (DLBCL) developed CRS, which was grade 3 or greater in 49% and 23% of patients, respectively. The median time to onset was 3 days, and the median duration of CRS was 8 days.

Cardiovascular adverse events of grade 3 or greater among these patients included tachycardia in 4%, fluid overload in 7%, edema in 1%, dyspnea in 12%, pulmonary edema in 4%, hypotension in 22%, and hypertension in 6%.

Risk factors for CRS include high pre-infusion tumor burden, active infections, and concurrent inflammatory processes, Dr. Cornell said.

Prevention of cardiovascular complications of CAR-T cell therapy requires management of CRS. Patients with grade 2 or greater CRS should receive the anti-IL-6 agent tocilizumab (Actemra) 8 mg/kg intravenously over 1 hour to a maximum dose of 800 mg. Tocilizumab infusions can be repeated every 8 hours as needed if the patient is not responsive to intravenous fluids or increasing supplement oxygen, but should be limited to a maximum of three doses over 24 hours, and a maximum total of four doses.

Patients with grade 3 CRS should also receive intravenous methylprednisolone 1 mg/kg twice daily or the equivalent amount of dexamethasone, with corticosteroids continued until the severity of CRS is grade 1 or less, then tapered over 3 days,

Patients with grade 4 CRS should also receive IV methylprednisolone 1,000 mg per day for 3 days, and if symptoms improve, continue management as per grade 3, Dr. Cornell said.

Dr. Cornell reported having nothing to disclose.

WASHINGTON – Unquestionably, immunotherapy is revolutionizing the care of patients with various solid tumors and hematologic malignancies.

Neil Osterweil/MDedge News

But it’s equally true that there’s no such thing as either a free lunch or a cancer therapy free of side effects, whether it’s increased risk for heart failure associated with anthracycline-based chemotherapy, or inflammatory conditions, arrhythmias, and thromboembolic events associated with immune checkpoint inhibitors, said R. Frank Cornell, MD, of Vanderbilt University Medical Center in Nashville, Tenn.

“Early awareness and intervention is critical for improved outcomes, and a multidisciplinary approach between oncology, cardiology, the clinic nurse, and other health care providers is critical in managing these patients with these complicated therapies,” he said at the American College of Cardiology’s Advancing the Cardiovascular Care of the Oncology Patient meeting.
 

Checkpoint inhibitors and the heart

Toxicities associated with immune checkpoint inhibitors such as the programmed death 1/ligand 1 (PD-1/PD-L1) inhibitors nivolumab (Opdivo) and pembrolizumab (Keytruda) and the cytotoxic T-lymphocyte antigen 4 antibody ipilimumab (Yervoy) tend to mimic autoimmune conditions, Dr. Cornell said.

Cardiovascular events associated with these agents, while uncommon, include myocarditis, pericarditis, arrhythmias, impaired ventricular function with heart failure, vasculitis, and venous thromboembolism, he said, citing an American Society of Clinical Oncology (ASCO) clinical practice guideline (J Clin Oncol 2018;36[17]:1714-68).

Dr. Cornell described the case of a 63-year-old woman with disseminated metastatic melanoma who presented to the emergency department 10 days after starting on combination therapy with ipilimumab and nivolumab. She had developed shortness of breath, pleuritic chest pain, and a mild cough for 1 or 2 days.

Her cardiac laboratory markers had been normal at baseline, but were markedly elevated on presentation, and electrocardiograms showed complete heart block and subsequent ventricular tachycardia.

The patient was started on high-dose prednisone, but she died in hospital, and an autopsy showed that the cause of death was infiltration into the myocardium of CD3-positive and CD8-positive T lymphocytes.

“So how do we manage this? This is a good opportunity, I think, for further cardiology and oncology collaboration to develop more robust guidelines for what we can do to best prevent this,” Dr. Cornell said.

Patients started on the ipilimumab/nivolumab combination should be tested weekly for cardiac troponin, creatine kinase (CK) and CK-muscle/brain (CK-MB) weekly for the first 3-4 weeks of therapy. Therapy should be stopped if troponin levels continue to rise, and the patient should be started on high-dose steroids, he said.

The role of other anti-inflammatory agents such as infliximab (Remicade and biosimilars) is unclear and needs further study, he added.

Dr. Cornell cited a 2018 letter to The Lancet by Javid J. Moslehi, MD, and colleagues from Vanderbilt describing an increase in reports of fatal myocarditis among patients treated with checkpoint inhibitors.

“We highlight the high mortality rate with severe immune checkpoint inhibitor–related myocarditis, which is more frequent with combination PD-1 and CTLA-4 blockade, but can also occur with monotherapy. Myocarditis was observed across immune checkpoint inhibitor regimens, although it remains too early to determine whether the incidence differs between use of anti-PD1 and anti-PD-L1 drugs. Furthermore, this condition occurs early on during therapy and across cancer types,” they wrote.

Most of the patients had no preexisting cardiovascular disease, and most were not taking medications for hypertension, cardiovascular disease, or diabetes.
 

CAR-T cells and cardiac disease

The primary cardiac complications associated with CAR-T cell therapy are related to the cytokine release syndrome (CRS), a condition marked by progressive elevation in inflammatory cytokines that in turn leads to marked elevations in C-reactive protein (CRP), interferon gamma, tumor necrosis factor al, and release of pro-inflammatory cytokines including interleukin (IL) 6, IL-10, IL-12, and IL-1 beta.

In rare instances, CRS can lead to disseminated intravascular coagulation (DIC), capillary leak syndrome, and a hemophagocytic lymphohistiocytosis-like (HLH) syndrome, Dr. Cornell said.

Package inserts for the two Food and Drug Administration–approved CAR-T cell products, axicabtagene ciloleucel (Yescarta) and tisagenlecleucel (Kymriah) show that each was associated in clinical trials with a high incidence of CRS.

Among patients treated with axicabtagene ciloleucel, 94% developed CRS, which was grade 3 or greater in severity in 13%. The median time to onset was 2 days, and the median duration was 7 days. Cardiovascular adverse events included grade 3 or greater tachycardia in 2%, arrhythmias in 7%, edema in 1%, dyspnea in 3%, pleural effusion in 2%, hypotension in 15%, hypertension in 6%, and thrombosis in 1%.

Among patients treated with tisagenlecleucel, 79% treated for B-cell acute lymphoblastic leukemia (B-ALL) and 74% treated for diffuse large B cell lymphoma (DLBCL) developed CRS, which was grade 3 or greater in 49% and 23% of patients, respectively. The median time to onset was 3 days, and the median duration of CRS was 8 days.

Cardiovascular adverse events of grade 3 or greater among these patients included tachycardia in 4%, fluid overload in 7%, edema in 1%, dyspnea in 12%, pulmonary edema in 4%, hypotension in 22%, and hypertension in 6%.

Risk factors for CRS include high pre-infusion tumor burden, active infections, and concurrent inflammatory processes, Dr. Cornell said.

Prevention of cardiovascular complications of CAR-T cell therapy requires management of CRS. Patients with grade 2 or greater CRS should receive the anti-IL-6 agent tocilizumab (Actemra) 8 mg/kg intravenously over 1 hour to a maximum dose of 800 mg. Tocilizumab infusions can be repeated every 8 hours as needed if the patient is not responsive to intravenous fluids or increasing supplement oxygen, but should be limited to a maximum of three doses over 24 hours, and a maximum total of four doses.

Patients with grade 3 CRS should also receive intravenous methylprednisolone 1 mg/kg twice daily or the equivalent amount of dexamethasone, with corticosteroids continued until the severity of CRS is grade 1 or less, then tapered over 3 days,

Patients with grade 4 CRS should also receive IV methylprednisolone 1,000 mg per day for 3 days, and if symptoms improve, continue management as per grade 3, Dr. Cornell said.

Dr. Cornell reported having nothing to disclose.

WASHINGTON – Unquestionably, immunotherapy is revolutionizing the care of patients with various solid tumors and hematologic malignancies.

Neil Osterweil/MDedge News

But it’s equally true that there’s no such thing as either a free lunch or a cancer therapy free of side effects, whether it’s increased risk for heart failure associated with anthracycline-based chemotherapy, or inflammatory conditions, arrhythmias, and thromboembolic events associated with immune checkpoint inhibitors, said R. Frank Cornell, MD, of Vanderbilt University Medical Center in Nashville, Tenn.

“Early awareness and intervention is critical for improved outcomes, and a multidisciplinary approach between oncology, cardiology, the clinic nurse, and other health care providers is critical in managing these patients with these complicated therapies,” he said at the American College of Cardiology’s Advancing the Cardiovascular Care of the Oncology Patient meeting.
 

Checkpoint inhibitors and the heart

Toxicities associated with immune checkpoint inhibitors such as the programmed death 1/ligand 1 (PD-1/PD-L1) inhibitors nivolumab (Opdivo) and pembrolizumab (Keytruda) and the cytotoxic T-lymphocyte antigen 4 antibody ipilimumab (Yervoy) tend to mimic autoimmune conditions, Dr. Cornell said.

Cardiovascular events associated with these agents, while uncommon, include myocarditis, pericarditis, arrhythmias, impaired ventricular function with heart failure, vasculitis, and venous thromboembolism, he said, citing an American Society of Clinical Oncology (ASCO) clinical practice guideline (J Clin Oncol 2018;36[17]:1714-68).

Dr. Cornell described the case of a 63-year-old woman with disseminated metastatic melanoma who presented to the emergency department 10 days after starting on combination therapy with ipilimumab and nivolumab. She had developed shortness of breath, pleuritic chest pain, and a mild cough for 1 or 2 days.

Her cardiac laboratory markers had been normal at baseline, but were markedly elevated on presentation, and electrocardiograms showed complete heart block and subsequent ventricular tachycardia.

The patient was started on high-dose prednisone, but she died in hospital, and an autopsy showed that the cause of death was infiltration into the myocardium of CD3-positive and CD8-positive T lymphocytes.

“So how do we manage this? This is a good opportunity, I think, for further cardiology and oncology collaboration to develop more robust guidelines for what we can do to best prevent this,” Dr. Cornell said.

Patients started on the ipilimumab/nivolumab combination should be tested weekly for cardiac troponin, creatine kinase (CK) and CK-muscle/brain (CK-MB) weekly for the first 3-4 weeks of therapy. Therapy should be stopped if troponin levels continue to rise, and the patient should be started on high-dose steroids, he said.

The role of other anti-inflammatory agents such as infliximab (Remicade and biosimilars) is unclear and needs further study, he added.

Dr. Cornell cited a 2018 letter to The Lancet by Javid J. Moslehi, MD, and colleagues from Vanderbilt describing an increase in reports of fatal myocarditis among patients treated with checkpoint inhibitors.

“We highlight the high mortality rate with severe immune checkpoint inhibitor–related myocarditis, which is more frequent with combination PD-1 and CTLA-4 blockade, but can also occur with monotherapy. Myocarditis was observed across immune checkpoint inhibitor regimens, although it remains too early to determine whether the incidence differs between use of anti-PD1 and anti-PD-L1 drugs. Furthermore, this condition occurs early on during therapy and across cancer types,” they wrote.

Most of the patients had no preexisting cardiovascular disease, and most were not taking medications for hypertension, cardiovascular disease, or diabetes.
 

CAR-T cells and cardiac disease

The primary cardiac complications associated with CAR-T cell therapy are related to the cytokine release syndrome (CRS), a condition marked by progressive elevation in inflammatory cytokines that in turn leads to marked elevations in C-reactive protein (CRP), interferon gamma, tumor necrosis factor al, and release of pro-inflammatory cytokines including interleukin (IL) 6, IL-10, IL-12, and IL-1 beta.

In rare instances, CRS can lead to disseminated intravascular coagulation (DIC), capillary leak syndrome, and a hemophagocytic lymphohistiocytosis-like (HLH) syndrome, Dr. Cornell said.

Package inserts for the two Food and Drug Administration–approved CAR-T cell products, axicabtagene ciloleucel (Yescarta) and tisagenlecleucel (Kymriah) show that each was associated in clinical trials with a high incidence of CRS.

Among patients treated with axicabtagene ciloleucel, 94% developed CRS, which was grade 3 or greater in severity in 13%. The median time to onset was 2 days, and the median duration was 7 days. Cardiovascular adverse events included grade 3 or greater tachycardia in 2%, arrhythmias in 7%, edema in 1%, dyspnea in 3%, pleural effusion in 2%, hypotension in 15%, hypertension in 6%, and thrombosis in 1%.

Among patients treated with tisagenlecleucel, 79% treated for B-cell acute lymphoblastic leukemia (B-ALL) and 74% treated for diffuse large B cell lymphoma (DLBCL) developed CRS, which was grade 3 or greater in 49% and 23% of patients, respectively. The median time to onset was 3 days, and the median duration of CRS was 8 days.

Cardiovascular adverse events of grade 3 or greater among these patients included tachycardia in 4%, fluid overload in 7%, edema in 1%, dyspnea in 12%, pulmonary edema in 4%, hypotension in 22%, and hypertension in 6%.

Risk factors for CRS include high pre-infusion tumor burden, active infections, and concurrent inflammatory processes, Dr. Cornell said.

Prevention of cardiovascular complications of CAR-T cell therapy requires management of CRS. Patients with grade 2 or greater CRS should receive the anti-IL-6 agent tocilizumab (Actemra) 8 mg/kg intravenously over 1 hour to a maximum dose of 800 mg. Tocilizumab infusions can be repeated every 8 hours as needed if the patient is not responsive to intravenous fluids or increasing supplement oxygen, but should be limited to a maximum of three doses over 24 hours, and a maximum total of four doses.

Patients with grade 3 CRS should also receive intravenous methylprednisolone 1 mg/kg twice daily or the equivalent amount of dexamethasone, with corticosteroids continued until the severity of CRS is grade 1 or less, then tapered over 3 days,

Patients with grade 4 CRS should also receive IV methylprednisolone 1,000 mg per day for 3 days, and if symptoms improve, continue management as per grade 3, Dr. Cornell said.

Dr. Cornell reported having nothing to disclose.

The Food and Drug Administration has approved ibrutinib (Imbruvica) for use in combination with obinutuzumab to treat adults with previously untreated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).

This is the tenth FDA approval for ibrutinib, a Bruton tyrosine kinase inhibitor jointly developed and commercialized by Pharmacyclics, an AbbVie company, and Janssen Biotech.

The approval is supported by the phase 3 iLLUMINATE trial (NCT02264574).

Results from this study were recently presented at the annual meeting of the American Society of Hematology (Blood. 2018;132:691) and published in the Lancet Oncology (2019 Jan;20[1]:43-56).

The iLLUMINATE trial enrolled newly diagnosed CLL patients who were randomized to receive ibrutinib plus obinutuzumab (n = 113) or chlorambucil plus obinutuzumab (n = 116).

The median follow-up was 31.3 months. The overall response rate was 88% in the ibrutinib arm and 73% in the chlorambucil arm. The complete response rate, including complete response with incomplete marrow recovery, was 19% and 8%, respectively.

The median progression-free survival was not reached in the ibrutinib arm and was 19.0 months in the chlorambucil arm (hazard ratio, 0.23; 95% confidence interval, 0.15-0.37; P less than .0001). The estimated 30-month progression-free survival was 79% and 31%, respectively.

The most common grade 3/4 adverse events in both arms were neutropenia (36% in the ibrutinib arm and 46% in the chlorambucil arm) and thrombocytopenia (19% and 10%, respectively).

There were 10 deaths caused by adverse events in the ibrutinib arm and 3 in the chlorambucil arm. One death was considered possibly related to ibrutinib (sudden death), and another was considered possibly related to chlorambucil (neuroendocrine carcinoma of the skin).

[email protected]

The Food and Drug Administration has approved ibrutinib (Imbruvica) for use in combination with obinutuzumab to treat adults with previously untreated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).

This is the tenth FDA approval for ibrutinib, a Bruton tyrosine kinase inhibitor jointly developed and commercialized by Pharmacyclics, an AbbVie company, and Janssen Biotech.

The approval is supported by the phase 3 iLLUMINATE trial (NCT02264574).

Results from this study were recently presented at the annual meeting of the American Society of Hematology (Blood. 2018;132:691) and published in the Lancet Oncology (2019 Jan;20[1]:43-56).

The iLLUMINATE trial enrolled newly diagnosed CLL patients who were randomized to receive ibrutinib plus obinutuzumab (n = 113) or chlorambucil plus obinutuzumab (n = 116).

The median follow-up was 31.3 months. The overall response rate was 88% in the ibrutinib arm and 73% in the chlorambucil arm. The complete response rate, including complete response with incomplete marrow recovery, was 19% and 8%, respectively.

The median progression-free survival was not reached in the ibrutinib arm and was 19.0 months in the chlorambucil arm (hazard ratio, 0.23; 95% confidence interval, 0.15-0.37; P less than .0001). The estimated 30-month progression-free survival was 79% and 31%, respectively.

The most common grade 3/4 adverse events in both arms were neutropenia (36% in the ibrutinib arm and 46% in the chlorambucil arm) and thrombocytopenia (19% and 10%, respectively).

There were 10 deaths caused by adverse events in the ibrutinib arm and 3 in the chlorambucil arm. One death was considered possibly related to ibrutinib (sudden death), and another was considered possibly related to chlorambucil (neuroendocrine carcinoma of the skin).

[email protected]

The Food and Drug Administration has approved ibrutinib (Imbruvica) for use in combination with obinutuzumab to treat adults with previously untreated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).

This is the tenth FDA approval for ibrutinib, a Bruton tyrosine kinase inhibitor jointly developed and commercialized by Pharmacyclics, an AbbVie company, and Janssen Biotech.

The approval is supported by the phase 3 iLLUMINATE trial (NCT02264574).

Results from this study were recently presented at the annual meeting of the American Society of Hematology (Blood. 2018;132:691) and published in the Lancet Oncology (2019 Jan;20[1]:43-56).

The iLLUMINATE trial enrolled newly diagnosed CLL patients who were randomized to receive ibrutinib plus obinutuzumab (n = 113) or chlorambucil plus obinutuzumab (n = 116).

The median follow-up was 31.3 months. The overall response rate was 88% in the ibrutinib arm and 73% in the chlorambucil arm. The complete response rate, including complete response with incomplete marrow recovery, was 19% and 8%, respectively.

The median progression-free survival was not reached in the ibrutinib arm and was 19.0 months in the chlorambucil arm (hazard ratio, 0.23; 95% confidence interval, 0.15-0.37; P less than .0001). The estimated 30-month progression-free survival was 79% and 31%, respectively.

The most common grade 3/4 adverse events in both arms were neutropenia (36% in the ibrutinib arm and 46% in the chlorambucil arm) and thrombocytopenia (19% and 10%, respectively).

There were 10 deaths caused by adverse events in the ibrutinib arm and 3 in the chlorambucil arm. One death was considered possibly related to ibrutinib (sudden death), and another was considered possibly related to chlorambucil (neuroendocrine carcinoma of the skin).

[email protected]

The European Commission (EC) has expanded the approved indication for blinatumomab (Blincyto).

The drug is now approved in Europe to treat adults with Philadelphia chromosome–negative (Ph–), CD19-positive B-cell precursor acute lymphoblastic leukemia (BCP-ALL) in first or second complete remission with minimal residual disease (MRD) of at least 0.1%.

Blinatumomab is already approved in Europe to treat adults with Ph–, CD19-positive relapsed/refractory BCP-ALL and children aged 1 year or older who have relapsed/refractory Ph–, CD19-positive BCP-ALL and have received at least two prior therapies or relapsed after allogeneic hematopoietic stem cell transplant.

The drug was approved in the United States in March 2018 for the treatment of adults and children with BCP-ALL in first or second complete remission with MRD of at least 0.1%.

The EC’s decision to approve blinatumomab in MRD-positive patients was supported by the phase 2 BLAST trial (Blood. 2018;131[14]:1522-31).

The EC’s approval is also based on a positive opinion from the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP).

That opinion, issued in November 2018, was a reversal of the opinion the committee issued in July 2018. At that time, the CHMP said the available data did not support approval for blinatumomab to treat MRD-positive BCP-ALL.

The CHMP acknowledged that blinatumomab produced MRD negativity in many patients in the BLAST trial but said there was no strong evidence that this led to improved survival. As a result, the CHMP said the benefits of blinatumomab do not outweigh its risks in MRD-positive BCP-ALL patients.

However, Amgen requested a reexamination of the CHMP’s opinion. During the reexamination, the CHMP reviewed all the data and consulted a group of experts.

The experts echoed the CHMP’s prior sentiment that there was no strong evidence of improved survival in MRD-positive patients treated with blinatumomab. However, they also said the data indicate a good response to blinatumomab, with around 78% of patients becoming negative for MRD after treatment.

Noting that MRD-positive patients have a high risk of relapse and few treatment options, the CHMP concluded that the benefits of blinatumomab outweigh its risks in this patient population.

The CHMP recommended expanding the approved indication for blinatumomab but also requested that Amgen provide data from ongoing studies of the drug in MRD-positive patients.

[email protected]

The European Commission (EC) has expanded the approved indication for blinatumomab (Blincyto).

The drug is now approved in Europe to treat adults with Philadelphia chromosome–negative (Ph–), CD19-positive B-cell precursor acute lymphoblastic leukemia (BCP-ALL) in first or second complete remission with minimal residual disease (MRD) of at least 0.1%.

Blinatumomab is already approved in Europe to treat adults with Ph–, CD19-positive relapsed/refractory BCP-ALL and children aged 1 year or older who have relapsed/refractory Ph–, CD19-positive BCP-ALL and have received at least two prior therapies or relapsed after allogeneic hematopoietic stem cell transplant.

The drug was approved in the United States in March 2018 for the treatment of adults and children with BCP-ALL in first or second complete remission with MRD of at least 0.1%.

The EC’s decision to approve blinatumomab in MRD-positive patients was supported by the phase 2 BLAST trial (Blood. 2018;131[14]:1522-31).

The EC’s approval is also based on a positive opinion from the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP).

That opinion, issued in November 2018, was a reversal of the opinion the committee issued in July 2018. At that time, the CHMP said the available data did not support approval for blinatumomab to treat MRD-positive BCP-ALL.

The CHMP acknowledged that blinatumomab produced MRD negativity in many patients in the BLAST trial but said there was no strong evidence that this led to improved survival. As a result, the CHMP said the benefits of blinatumomab do not outweigh its risks in MRD-positive BCP-ALL patients.

However, Amgen requested a reexamination of the CHMP’s opinion. During the reexamination, the CHMP reviewed all the data and consulted a group of experts.

The experts echoed the CHMP’s prior sentiment that there was no strong evidence of improved survival in MRD-positive patients treated with blinatumomab. However, they also said the data indicate a good response to blinatumomab, with around 78% of patients becoming negative for MRD after treatment.

Noting that MRD-positive patients have a high risk of relapse and few treatment options, the CHMP concluded that the benefits of blinatumomab outweigh its risks in this patient population.

The CHMP recommended expanding the approved indication for blinatumomab but also requested that Amgen provide data from ongoing studies of the drug in MRD-positive patients.

[email protected]

The European Commission (EC) has expanded the approved indication for blinatumomab (Blincyto).

The drug is now approved in Europe to treat adults with Philadelphia chromosome–negative (Ph–), CD19-positive B-cell precursor acute lymphoblastic leukemia (BCP-ALL) in first or second complete remission with minimal residual disease (MRD) of at least 0.1%.

Blinatumomab is already approved in Europe to treat adults with Ph–, CD19-positive relapsed/refractory BCP-ALL and children aged 1 year or older who have relapsed/refractory Ph–, CD19-positive BCP-ALL and have received at least two prior therapies or relapsed after allogeneic hematopoietic stem cell transplant.

The drug was approved in the United States in March 2018 for the treatment of adults and children with BCP-ALL in first or second complete remission with MRD of at least 0.1%.

The EC’s decision to approve blinatumomab in MRD-positive patients was supported by the phase 2 BLAST trial (Blood. 2018;131[14]:1522-31).

The EC’s approval is also based on a positive opinion from the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP).

That opinion, issued in November 2018, was a reversal of the opinion the committee issued in July 2018. At that time, the CHMP said the available data did not support approval for blinatumomab to treat MRD-positive BCP-ALL.

The CHMP acknowledged that blinatumomab produced MRD negativity in many patients in the BLAST trial but said there was no strong evidence that this led to improved survival. As a result, the CHMP said the benefits of blinatumomab do not outweigh its risks in MRD-positive BCP-ALL patients.

However, Amgen requested a reexamination of the CHMP’s opinion. During the reexamination, the CHMP reviewed all the data and consulted a group of experts.

The experts echoed the CHMP’s prior sentiment that there was no strong evidence of improved survival in MRD-positive patients treated with blinatumomab. However, they also said the data indicate a good response to blinatumomab, with around 78% of patients becoming negative for MRD after treatment.

Noting that MRD-positive patients have a high risk of relapse and few treatment options, the CHMP concluded that the benefits of blinatumomab outweigh its risks in this patient population.

The CHMP recommended expanding the approved indication for blinatumomab but also requested that Amgen provide data from ongoing studies of the drug in MRD-positive patients.

[email protected]

SAN DIEGO – Ibrutinib treatment continued before, during, and after infusion of the CD19-specific chimeric antigen receptor (CAR) T-cell therapy JCAR014 in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) appears to improve patient responses and decrease the risk of severe cytokine release syndrome.

The findings come from a comparison of sequential cohorts from a phase 1/2 study.

At 4 weeks after infusion, the approach was highly efficacious; overall response rates by 2008 International Workshop on CLL (IWCLL) criteria were 83% in 24 patients who received the uninterrupted ibrutinib regimen along with the JCAR014 therapy – a combination of CD4 and CD8 T cells – and 65% in 19 patients from a prior cohort who did not receive continuous ibrutinib, Jordan Gauthier, MD, reported at the annual meeting of the American Society of Hematology.

Concurrent ibrutinib was generally well tolerated, with 13 of 19 patients in the ibrutinib cohort receiving treatment as planned without discontinuation. The rates of grade 1 or higher cytokine release syndrome (CRS) were statistically similar in the ibrutinib and no-ibrutinib cohorts (74% and 92%, respectively). However, the rates of severe CRS (grade 3 or higher) were, strikingly, 0% and 25%, respectively, said Dr. Gauthier, a senior fellow in the Turtle Lab at Fred Hutchinson Cancer Center, Seattle.

Neurotoxicity occurred in 32% and 42% of patients in the groups; severe neurotoxicity occurred in 26% and 29%, respectively.

In the ibrutinib cohort, one patient with grade 2 CRS developed fatal presumed cardiac arrhythmia; in the no-ibrutinib cohort, one patient died from a CAR T cell–related toxicity.

Notably, a trend toward better expansion of CD8 CAR T cells and a significantly greater expansion of CD4 CAR T cells was observed in the ibrutinib cohort, he said.

The study was designed to assess JCAR014, and based on the initial cohort findings published in 2017, established a regimen of cyclophosphamide and fludarabine (Cy/Flu) lymphodepletion followed by JCAR014 infusion at 2 x 10⁶ CAR T cells/kg. The study was not a randomized, head-to-head comparison but the groups were similar with respect to both patient and disease characteristics, Dr. Gauthier noted.

The outcomes in the first cohort were then compared retrospectively with those from the subsequent cohort of patients who received Cy/Flu with 2 x 10⁶ CAR T cells/kg with concurrent ibrutinib administered at 420 mg per day from at least 2 weeks prior to leukapheresis until at least 3 months after JCAR014 infusion.

The rationale for uninterrupted ibrutinib in relapsed/refractory CLL patients receiving JCAR014 included potential prevention of tumor flare, mobilization of CLL cells into the blood from the lymph nodes, improvement of CAR T-cell function, and a decrease in CAR T-cell related toxicity, he said.

The concurrent administration of ibrutinib and JCAR014 was feasible for most patients. “[It] induced high response rates and deep responses early on at 4 weeks, and it was associated with higher in vivo expansion of CD4 CAR T cells and with lower rates of severe toxicity,” Dr. Gauthier said. “The next step is to hopefully validate these findings in a prospective phase 1/2 study.”

Dr. Gauthier reported having no financial disclosures.

[email protected]

SOURCE: Gauthier J et al. ASH 18, Abstract 299.

SAN DIEGO – Ibrutinib treatment continued before, during, and after infusion of the CD19-specific chimeric antigen receptor (CAR) T-cell therapy JCAR014 in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) appears to improve patient responses and decrease the risk of severe cytokine release syndrome.

The findings come from a comparison of sequential cohorts from a phase 1/2 study.

At 4 weeks after infusion, the approach was highly efficacious; overall response rates by 2008 International Workshop on CLL (IWCLL) criteria were 83% in 24 patients who received the uninterrupted ibrutinib regimen along with the JCAR014 therapy – a combination of CD4 and CD8 T cells – and 65% in 19 patients from a prior cohort who did not receive continuous ibrutinib, Jordan Gauthier, MD, reported at the annual meeting of the American Society of Hematology.

Concurrent ibrutinib was generally well tolerated, with 13 of 19 patients in the ibrutinib cohort receiving treatment as planned without discontinuation. The rates of grade 1 or higher cytokine release syndrome (CRS) were statistically similar in the ibrutinib and no-ibrutinib cohorts (74% and 92%, respectively). However, the rates of severe CRS (grade 3 or higher) were, strikingly, 0% and 25%, respectively, said Dr. Gauthier, a senior fellow in the Turtle Lab at Fred Hutchinson Cancer Center, Seattle.

Neurotoxicity occurred in 32% and 42% of patients in the groups; severe neurotoxicity occurred in 26% and 29%, respectively.

In the ibrutinib cohort, one patient with grade 2 CRS developed fatal presumed cardiac arrhythmia; in the no-ibrutinib cohort, one patient died from a CAR T cell–related toxicity.

Notably, a trend toward better expansion of CD8 CAR T cells and a significantly greater expansion of CD4 CAR T cells was observed in the ibrutinib cohort, he said.

The study was designed to assess JCAR014, and based on the initial cohort findings published in 2017, established a regimen of cyclophosphamide and fludarabine (Cy/Flu) lymphodepletion followed by JCAR014 infusion at 2 x 10⁶ CAR T cells/kg. The study was not a randomized, head-to-head comparison but the groups were similar with respect to both patient and disease characteristics, Dr. Gauthier noted.

The outcomes in the first cohort were then compared retrospectively with those from the subsequent cohort of patients who received Cy/Flu with 2 x 10⁶ CAR T cells/kg with concurrent ibrutinib administered at 420 mg per day from at least 2 weeks prior to leukapheresis until at least 3 months after JCAR014 infusion.

The rationale for uninterrupted ibrutinib in relapsed/refractory CLL patients receiving JCAR014 included potential prevention of tumor flare, mobilization of CLL cells into the blood from the lymph nodes, improvement of CAR T-cell function, and a decrease in CAR T-cell related toxicity, he said.

The concurrent administration of ibrutinib and JCAR014 was feasible for most patients. “[It] induced high response rates and deep responses early on at 4 weeks, and it was associated with higher in vivo expansion of CD4 CAR T cells and with lower rates of severe toxicity,” Dr. Gauthier said. “The next step is to hopefully validate these findings in a prospective phase 1/2 study.”

Dr. Gauthier reported having no financial disclosures.

[email protected]

SOURCE: Gauthier J et al. ASH 18, Abstract 299.

SAN DIEGO – Ibrutinib treatment continued before, during, and after infusion of the CD19-specific chimeric antigen receptor (CAR) T-cell therapy JCAR014 in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) appears to improve patient responses and decrease the risk of severe cytokine release syndrome.

The findings come from a comparison of sequential cohorts from a phase 1/2 study.

At 4 weeks after infusion, the approach was highly efficacious; overall response rates by 2008 International Workshop on CLL (IWCLL) criteria were 83% in 24 patients who received the uninterrupted ibrutinib regimen along with the JCAR014 therapy – a combination of CD4 and CD8 T cells – and 65% in 19 patients from a prior cohort who did not receive continuous ibrutinib, Jordan Gauthier, MD, reported at the annual meeting of the American Society of Hematology.

Concurrent ibrutinib was generally well tolerated, with 13 of 19 patients in the ibrutinib cohort receiving treatment as planned without discontinuation. The rates of grade 1 or higher cytokine release syndrome (CRS) were statistically similar in the ibrutinib and no-ibrutinib cohorts (74% and 92%, respectively). However, the rates of severe CRS (grade 3 or higher) were, strikingly, 0% and 25%, respectively, said Dr. Gauthier, a senior fellow in the Turtle Lab at Fred Hutchinson Cancer Center, Seattle.

Neurotoxicity occurred in 32% and 42% of patients in the groups; severe neurotoxicity occurred in 26% and 29%, respectively.

In the ibrutinib cohort, one patient with grade 2 CRS developed fatal presumed cardiac arrhythmia; in the no-ibrutinib cohort, one patient died from a CAR T cell–related toxicity.

Notably, a trend toward better expansion of CD8 CAR T cells and a significantly greater expansion of CD4 CAR T cells was observed in the ibrutinib cohort, he said.

The study was designed to assess JCAR014, and based on the initial cohort findings published in 2017, established a regimen of cyclophosphamide and fludarabine (Cy/Flu) lymphodepletion followed by JCAR014 infusion at 2 x 10⁶ CAR T cells/kg. The study was not a randomized, head-to-head comparison but the groups were similar with respect to both patient and disease characteristics, Dr. Gauthier noted.

The outcomes in the first cohort were then compared retrospectively with those from the subsequent cohort of patients who received Cy/Flu with 2 x 10⁶ CAR T cells/kg with concurrent ibrutinib administered at 420 mg per day from at least 2 weeks prior to leukapheresis until at least 3 months after JCAR014 infusion.

The rationale for uninterrupted ibrutinib in relapsed/refractory CLL patients receiving JCAR014 included potential prevention of tumor flare, mobilization of CLL cells into the blood from the lymph nodes, improvement of CAR T-cell function, and a decrease in CAR T-cell related toxicity, he said.

The concurrent administration of ibrutinib and JCAR014 was feasible for most patients. “[It] induced high response rates and deep responses early on at 4 weeks, and it was associated with higher in vivo expansion of CD4 CAR T cells and with lower rates of severe toxicity,” Dr. Gauthier said. “The next step is to hopefully validate these findings in a prospective phase 1/2 study.”

Dr. Gauthier reported having no financial disclosures.

[email protected]

SOURCE: Gauthier J et al. ASH 18, Abstract 299.

Aplastic anemia is a rare hematologic disorder marked by pancytopenia and a hypocellular marrow. Aplastic anemia results from either inherited or acquired causes, and the treatment approach varies significantly between the 2 causes. This article reviews the treatment of inherited and acquired forms of aplastic anemia. The approach to evaluation and diagnosis of aplastic anemia is reviewed in a separate article.

Inherited Aplastic Anemia

First-line treatment options for patients with inherited marrow failure syndromes (IMFS) are androgen therapy and hematopoietic stem cell transplant (HSCT). When evaluating patients for HSCT, it is critical to identify the presence of an IMFS, as the risk and mortality associated with the conditioning regimen, stem cell source, graft-versus-host disease (GVHD), and secondary malignancies differ between patients with IMFS and those with acquired marrow failure syndromes or hematologic malignancies.

Potential sibling donors need to be screened for donor candidacy as well as for the inherited defect.¹ Among patients with Fanconi anemia or a telomere biology disorder, the stem cell source must be considered, with bone marrow demonstrating lower rates of acute GVHD than a peripheral blood stem cell source.^2-4 In IMFS patients, the donor cell type may affect the choice of conditioning regimen.^5,6 Reduced-intensity conditioning in lieu of myeloablative conditioning without total body irradiation has proved feasible in patients with Fanconi anemia, and is associated with a reduced risk of secondary malignancies.^5,6 Incorporation of fludarabine in the conditioning regimen of patients without a matched sibling donor is associated with superior engraftment and survival^2,5,7 compared to cyclophosphamide conditioning, which was historically used in matched related donors.^6,8 The addition of fludarabine appears to be especially beneficial in older patients, in whom its use is associated with lower rates of graft failure, likely due to increased immunosuppression at the time of engraftment.^7,9 Fludarabine has also been incorporated into conditioning regimens for patients with a telomere biology disorder, but outcomes data is limited.⁵

For patients presenting with acute myeloid leukemia (AML) or a high-risk myelodysplastic syndrome (MDS) who are subsequently diagnosed with an IMFS, treatment can be more complex, as these patients are at high risk for toxicity from standard chemotherapy. Limited data suggests that induction therapy and transplantation are feasible in this group of patients, and this approach is associated with increased overall survival (OS) despite lower OS rates than those of IMFS patients who present prior to the development of MDS or AML.^10,11 Further work is needed to determine the optimal induction regimen that balances the risks of treatment-related mortality and complications associated with conditioning regimens, risk of relapse, and risk of secondary malignancies, especially in the cohort of patients diagnosed at an older age.

Acquired Aplastic Anemia

Supportive Care

While the workup and treatment plan is being established, attention should be directed at supportive care for prevention of complications. The most common complications leading to death in patients with significant pancytopenia and neutropenia are opportunistic infections and hemorrhagic complications.¹²

Transfusion support is critical to avoid symptomatic anemia and hemorrhagic complications related to thrombocytopenia, which typically occur with platelet counts lower than 10,000 cells/µL. However, transfusion carries the risk of alloimmunization (which may persist for years following transfusion) and transfusion-related graft versus host disease (trGVHD), and thus use of transfusion should be minimized when possible.^13,14 Transfusion support is often required to prevent complications associated with thrombocytopenia and anemia; all blood products given to patients with aplastic anemia should be irradiated and leukoreduced to reduce the risk of both alloimmunization and trGVHD. Guidelines from the British Society for Haematology recommend routine screening for Rh and Kell antibodies to reduce the risk of alloimmunization.¹⁵ Infectious complications remain a common cause of morbidity and mortality in patients with aplastic anemia who have prolonged neutropenia (defined as an absolute neutrophil count [ANC] < 500 cells/µL).^16-19 Therefore, patients should receive broad-spectrum antibiotics with antipseudomonal coverage. In a study by Tichelli and colleagues evaluating the role of granulocyte-colony stimulating factor (G-CSF) in patients with SAA receiving immunosuppressive therapy, 55% of all patient deaths were secondary to infection.²⁰ There was no OS benefit seen in patients who received G-CSF, though a significantly lower rate of infection was observed in the G-CSF arm compared to those not receiving G-CSF (56% versus 81%, P = 0.006).This difference was largely driven by a decrease in infectious episodes in patients with very severe aplastic anemia (VSAA) treated with G-CSF as compared to those who did not receive this therapy (22% versus 48%, P = 0.014).²⁰

Angio-invasive pulmonary aspergillosis and Zygomycetes (eg, Rhizopus, Mucor species) remain major causes of mortality related to opportunistic mycotic infections in patients with aplastic anemia.¹⁸ The infectious risk is directly related to the duration and severity of neutropenia, with one study demonstrating a significant increase in risk in AML patients with neutropenia lasting longer than 3 weeks.²¹ Invasive fungal infections carry a high mortality in patients with severe neutropenia, though due to earlier recognition and empiric antifungal therapy with extended-spectrum azoles, overall mortality secondary to invasive fungal infections is declining.^19,22

While neutropenia related to cytotoxic chemotherapy is commonly associated with gram-negative bacteria due to disruption of mucosal barriers, patients with aplastic anemia have an increased incidence of gram-positive bacteremia with staphylococcal species compared to other neutropenic populations.^18,19 This appears to be changing with time. Valdez and colleagues demonstrated a decrease in prevalence of coagulase-negative staphylococcal infections, increased prevalence of gram-positive bacilli bacteremia, and no change in prevalence of gram-negative bacteremia in patients with aplastic anemia treated between 1989 and 2008.²² Gram-negative bacteremia caused by Stenotrophomonas maltophila, Escherichia coli, Klebsiella pneumoniae, Citrobacter, and Proteus has also been reported.¹⁹ Despite a lack of clinical trials investigating the role of antifungal and antibacterial prophylaxis for patients with aplastic anemia, most centers initiate antifungal prophylaxis in patients with severe aplastic anema (SAA) or VSAA with an anti-mold agent such as voriconazole or posaconazole (which has the additional benefit compared to voriconazole of covering Mucor species).^17,23 This is especially true for patients who have received ATG or undergone HSCT. For antimicrobial prophylaxis, a fluoroquinolone antibiotic with a spectrum of activity against Pseudomonas should be considered for patients with an ANC < 500 cells/µL.¹⁷ Acyclovir or valacyclovir prophylaxis is recommended for varicella-zoster virus and herpes simplex virus. Cytomegalovirus reactivation is minimal in patients with aplastic anemia, unless multiple courses of ATG are used.

Iron overload is another complication the provider must be aware of in the setting of increased transfusions in aplastic anemia patients. Lee and colleagues demonstrated that iron chelation therapy using deferasirox is effective at reducing serum ferritin levels in patients with aplastic anemia (median ferritin level: 3254 ng/mL prior to therapy, 1854 ng/mL following), and is associated with no serious adverse events (most common adverse events included nausea, diarrhea, vomiting, and rash).²⁴ Approximately 25% of patients in this trial demonstrated an increase in creatinine, with patients taking concomitant cyclosporine more affected than those on chelation therapy alone.²⁴ For patients following HSCT or with improved hematopoiesis following immunosuppressive therapy, phlebotomy can be used to treat iron overload in lieu of chelation therapy.¹⁵

Approach to Therapy

The main treatment options for SAA and VSAA include allogeneic bone marrow transplant and immunosuppression. The deciding factors as to which treatment is best initially depends on the availability of HLA-matched related donors and age (Figure 1 and Figure 2). Survival is decreased in patients with SAA or VSAA who delay initiation of therapy, and therefore prompt referral for HLA typing and evaluation for bone marrow transplant is a very important first step in managing aplastic anemia.

Matched Sibling Donor Transplant

Current standards of care recommend HLA-matched sibling donor transplant for patients with SAA or VSAA who are younger than 50 years of age, with the caveat that integration of fludarabine and reduced cyclophosphamide dosing along with ATG shows the best overall outcomes. Locasciulli and colleagues examined outcomes in patients given either immunosuppressive therapy or sibling HSCT between 1991-1996 and 1997-2002, respectively, and found that sibling HSCT was associated with a superior 10-year OS compared to immunosuppressive therapy (73% versus 68%).²⁵ Interestingly in this study, there was no OS improvement seen with immunosuppressive therapy alone (69% versus 73%) between the 2 time periods, despite increased OS in both sibling HSCT (74% and 80%) and matched unrelated donor HSCT (38% and 65%).²⁵ Though total body irradiation has been used in the past, it is typically not included in current conditioning regimens for matched related donor transplants.²⁶

Current conditioning regimens typically use a combination of cyclophosphamide and ATG^27,28 with or without fludarabine. Fludarabine-based conditioning regimens have shown promise in patients undergoing sibling HSCT. Maury and colleagues evaluated the role of fludarabine in addition to low-dose cyclophosphamide and ATG compared to cyclophosphamide alone or in combination with ATG in patients over age 30 undergoing sibling HSCT.⁹ There was a nonsignificant improvement in 5-year OS in the fludarabine arm compared to controls (77% ± 8% versus 60% ± 3%, P = 0.14) in the pooled analysis, but when adjusted for age the fludarabine arm had a significantly lower relative risk (RR) of death (RR, 0.44; P = 0.04) compared to the control arm. Shin et al reported outcomes with fludarabine/cyclophosphamide/ATG, with excellent overall outcomes and no difference in patients older or younger than 40 years.²⁹ In addition, Kim et al evaluated their experience with patients older than 40 years of age receiving matched related donors, finding comparable outcomes in those aged 41 to 50 years compared to younger patients. Outcomes did decline in those over the age of 50 years.³⁰ Long-term data for matched related donor transplant for aplastic anemia shows excellent long-term outcomes, with minimal chronic GVHD and good performance status.³¹ Hence, these factors support the role of matched related donor transplant as the initial treatment in SAA and VSAA.

Regarding the role of transplant for patients who lack a matched related donor, a growing body of literature demonstrating identical outcomes between matched related and matched unrelated donor (MUD) transplants for pediatric patients^32,33 supports recent recommendations for upfront unrelated donor transplantation for aplastic anemia.^34,35

Immunosuppressive Therapy

For patients without an HLA-matched sibling donor or those who are older than 50 years of age, immunosuppressive therapy is the first-line therapy. ATG and cyclosporine A are the treatments of choice.³⁶ The potential effectiveness of immunosuppressive therapy in treating aplastic anemia was initially observed in patients in whom autologous transplant failed but who still experienced hematopoietic reconstitution despite the failed graft; this observation led to the hypothesis that the conditioning regimen may have an effect on hematopoiesis.^16,36,37

Anti-thymocyte globulin. Immunosuppressive therapy with ATG has been used for the treatment of aplastic anemia since the 1980s.³⁸ Historically, rabbit ATG had been used, but a 2011 study of horse ATG demonstrated superior hematological response at 6 months compared to rabbit ATG (68% versus 37%).¹⁶ Superior survival was also seen with horse ATG compared to rabbit ATG (3-year OS: 96% versus 76%). Due to these results, horse ATG is preferred over rabbit ATG. ATG should be used in combination with cyclosporine A to optimize outcomes.

Cyclosporine A. Early studies also demonstrated the efficacy of cyclosporine A in the treatment of aplastic anemia, with response rates equivalent to that of ATG monotherapy.³⁹ Recent publications still note the efficacy of cyclosporine A in the treatment of aplastic anemia. Its role as an affordable option for single-agent therapy in developing countries is intriguing.³⁹

The combination of the ATG and cyclosporine A was proven superior to either agent alone in a study by Frickhofen et al.³⁷ In this study patients were randomly assigned to a control arm that received ATG plus methylprednisolone or to an arm that received ATG plus cyclosporine A and methylprednisolone. At 6 months, 70% of patients in the cyclosporine A arm had a complete remission (CR) or partial remission compared to 46% in the control arm.⁴⁰ Further work confirmed the long-term efficacy of this regimen, reporting a 7-year OS of 55%.⁴¹ Among a pediatric population, immunosuppressive therapy was associated with an 83% 10-year OS.⁴²

It is recommended that patients remain on cyclosporine therapy for a minimum of 6 months, after which a gradual taper may be considered, although there is variation among practitioners, with some continuing immunosuppressive therapy for a minimum of 12 months due to a proportion of patients being cyclosporine dependent.^42,43 A study found that within a population of patients who responded to immunosuppressive therapy, 18% became cyclosporine dependent.⁴² The median duration of cyclosporine A treatment at full dose was 12 months, with tapering completed over a median of 19 months after patients had been in a stable CR for a minimum of 3 months. Relapse occurred more often when patients were tapered quickly (decrease ≥ 0.8 mg/kg/month) compared to slowly (0.4-0.7 mg/kg/month) or very slowly (< 0.3 mg/kg/month).

Immunosuppressive therapy plus eltrombopag. Townsley and colleagues recently investigated incorporating the use of the thrombopoietin receptor agonist eltrombopag with immunosuppressive therapy as first-line therapy in aplastic anemia.⁴⁴ When given at a dose of 150 mg daily in patients aged 12 years and older or 75 mg daily in patients younger than 12 years, in conjunction with cyclosporine A and ATG, patients demonstrated markedly improved hematological response compared to historical treatment with standard immunosuppressive therapy alone.⁴⁴ In the patient cohort administered eltrombopag starting on day 1 and continuing for 6 months, the complete response rate was 58%. Eltrombopag led to improvement in all cell lines among all treatment subgroups, and OS (censored for patients who proceeded to transplant) was 99% at 2 years.⁴⁵ Overall, toxicities associated with this therapy were low, with liver enzyme elevations most commonly observed.⁴⁴ Recently, a phase 2 trial of immunosuppressive therapy with or without eltrombopag was reported. Of the 38 patients enrolled, overall response, complete response, and time to response were not statistically different.⁴⁶ With this recent finding, the role of eltrombopag in addition to immunosuppressive therapy is not clearly defined, and further studies are warranted.

OS for patients who do not respond to immunosuppressive therapy is approximately 57% at 5 years, largely due to improved supportive measures among this patient population.^4,22 Therefore, it is important to recognize those patients who have a low chance of response so that second-line therapy can be pursued to improve outcomes.

Matched Unrelated Donor Transplant

For patients with refractory disease following immunosuppressive therapy who lack a matched sibling donor, MUD HSCT is considered standard therapy given the marked improvement in overall outcomes with modulating conditioning regimens and high-resolution HLA typing. A European Society for Blood and Marrow Transplantation analysis comparing matched sibling HSCT to MUD HSCT noted significantly higher rates of acute grade II-IV and grade III-V GVHD (grade II-IV 13% versus 25%, grade III-IV 5% versus 10%) among patients undergoing MUD transplant.⁴⁷ Chronic GVHD rates were 14% in the sibling group, as compared to 26% in the MUD group. Additional benefits seen in this analysis included improved survival when transplanted under age 20 years (84% versus 72%), when transplanted within 6 months of diagnosis (85% versus 72%), the use of ATG in the conditioning regimen (81% versus 73%), and when the donor and recipient were cytomegalovirus-negative compared to other combinations (82% versus 76%).⁴⁷ Interestingly, this study demonstrated that OS was not significantly increased when using a sibling HSCT compared to a MUD HSCT, likely as a result of improved understanding of conditioning regimens, GVHD prophylaxis, and supportive care.

Additional studies of MUD HSCT have shown outcomes similar to those seen in sibling HSCT.^4,43 A French study found a significant increase in survival in patients undergoing MUD HSCT compared to historical cohorts (2000-2005: OS 52%; 2006-2012: OS 74%).³³ The majority of patients underwent conditioning with cyclophosphamide or a combination of busulfan and cyclophosphamide, with or without fludarabine; 81% of patients included underwent in vivo T-cell depletion, and a bone marrow donor source was utilized. OS was significantly lower in patients over age 30 years undergoing MUD HSCT (57%) compared to those under age 30 years (70%). Improved OS was also seen when patients underwent transplant within 1 year of diagnosis and when a 10/10 matched donor (compared to a 9/10 mismatched donor) was utilized.⁴ A 2015 study investigated the role of MUD HSCT as frontline therapy instead of immunosuppressive therapy in patients without a matched sibling donor.³³ The 2-year OS was 96% in the MUD HSCT cohort compared to 91%, 94%, and 74% in historical cohorts of sibling HSCT, frontline immunosuppressive therapy, and second-line MUD HSCT following failed immunosuppressive therapy, respectively. Additionally, event-free survival in the MUD HSCT cohort (defined by the authors as death, lack of response, relapse, occurrence of clonal evolution/clinical paroxysmal nocturnal hemoglobinuria, malignancies developing over follow‐up, and transplant for patients receiving immunosuppressive therapy frontline) was similar compared to sibling HSCT and superior to frontline immunosuppressive therapy and second-line MUD HSCT. Furthermore, Samarasinghe et al highlighted the importance of in vivo T-cell depletion with either ATG or alemtuzumab (anti-CD52 monoclonal antibody) in the prevention of acute and chronic GVHD in both sibling HSCT and MUD HSCT.⁴⁸

With continued improvement of less toxic and more immunomodulating conditioning regimens, utilization of bone marrow as a donor cell source, in vivo T-cell depletion, and use of GVHD and antimicrobial prophylaxis, more clinical evidence supports elevating MUD HSCT in the treatment plan for patients without a matched sibling donor.⁴⁹ However, there is still a large population of patients without matched sibling or unrelated donor options. In an effort to expand the transplant pool and thus avoid clonal hematopoiesis, clinically significant paroxysmal nocturnal hemoglobinuria, and relapsed aplastic anemia, more work continues to recognize the expanding role of alternative donor transplants (cord blood and haploidentical) as another viable treatment strategy for aplastic anemia after immunosuppressive therapy failure.⁵⁰

Summary

Aplastic anemia is a rare but potentially life-threatening disorder characterized by pancytopenia and a marked reduction in the hematopoietic stem cell compartment. Treatment should be instituted as soon as the dignosis of aplastic anemia is established. Treatment outcomes are excellent with modern supportive care and the current approach to allogeneic transplantation, and therefore referral to a bone marrow transplant program to evaluate for early transplantation is the new standard of care.

Aplastic anemia is a rare hematologic disorder marked by pancytopenia and a hypocellular marrow. Aplastic anemia results from either inherited or acquired causes, and the treatment approach varies significantly between the 2 causes. This article reviews the treatment of inherited and acquired forms of aplastic anemia. The approach to evaluation and diagnosis of aplastic anemia is reviewed in a separate article.

Inherited Aplastic Anemia

First-line treatment options for patients with inherited marrow failure syndromes (IMFS) are androgen therapy and hematopoietic stem cell transplant (HSCT). When evaluating patients for HSCT, it is critical to identify the presence of an IMFS, as the risk and mortality associated with the conditioning regimen, stem cell source, graft-versus-host disease (GVHD), and secondary malignancies differ between patients with IMFS and those with acquired marrow failure syndromes or hematologic malignancies.

Potential sibling donors need to be screened for donor candidacy as well as for the inherited defect.¹ Among patients with Fanconi anemia or a telomere biology disorder, the stem cell source must be considered, with bone marrow demonstrating lower rates of acute GVHD than a peripheral blood stem cell source.^2-4 In IMFS patients, the donor cell type may affect the choice of conditioning regimen.^5,6 Reduced-intensity conditioning in lieu of myeloablative conditioning without total body irradiation has proved feasible in patients with Fanconi anemia, and is associated with a reduced risk of secondary malignancies.^5,6 Incorporation of fludarabine in the conditioning regimen of patients without a matched sibling donor is associated with superior engraftment and survival^2,5,7 compared to cyclophosphamide conditioning, which was historically used in matched related donors.^6,8 The addition of fludarabine appears to be especially beneficial in older patients, in whom its use is associated with lower rates of graft failure, likely due to increased immunosuppression at the time of engraftment.^7,9 Fludarabine has also been incorporated into conditioning regimens for patients with a telomere biology disorder, but outcomes data is limited.⁵

For patients presenting with acute myeloid leukemia (AML) or a high-risk myelodysplastic syndrome (MDS) who are subsequently diagnosed with an IMFS, treatment can be more complex, as these patients are at high risk for toxicity from standard chemotherapy. Limited data suggests that induction therapy and transplantation are feasible in this group of patients, and this approach is associated with increased overall survival (OS) despite lower OS rates than those of IMFS patients who present prior to the development of MDS or AML.^10,11 Further work is needed to determine the optimal induction regimen that balances the risks of treatment-related mortality and complications associated with conditioning regimens, risk of relapse, and risk of secondary malignancies, especially in the cohort of patients diagnosed at an older age.

Acquired Aplastic Anemia

Supportive Care

While the workup and treatment plan is being established, attention should be directed at supportive care for prevention of complications. The most common complications leading to death in patients with significant pancytopenia and neutropenia are opportunistic infections and hemorrhagic complications.¹²

Transfusion support is critical to avoid symptomatic anemia and hemorrhagic complications related to thrombocytopenia, which typically occur with platelet counts lower than 10,000 cells/µL. However, transfusion carries the risk of alloimmunization (which may persist for years following transfusion) and transfusion-related graft versus host disease (trGVHD), and thus use of transfusion should be minimized when possible.^13,14 Transfusion support is often required to prevent complications associated with thrombocytopenia and anemia; all blood products given to patients with aplastic anemia should be irradiated and leukoreduced to reduce the risk of both alloimmunization and trGVHD. Guidelines from the British Society for Haematology recommend routine screening for Rh and Kell antibodies to reduce the risk of alloimmunization.¹⁵ Infectious complications remain a common cause of morbidity and mortality in patients with aplastic anemia who have prolonged neutropenia (defined as an absolute neutrophil count [ANC] < 500 cells/µL).^16-19 Therefore, patients should receive broad-spectrum antibiotics with antipseudomonal coverage. In a study by Tichelli and colleagues evaluating the role of granulocyte-colony stimulating factor (G-CSF) in patients with SAA receiving immunosuppressive therapy, 55% of all patient deaths were secondary to infection.²⁰ There was no OS benefit seen in patients who received G-CSF, though a significantly lower rate of infection was observed in the G-CSF arm compared to those not receiving G-CSF (56% versus 81%, P = 0.006).This difference was largely driven by a decrease in infectious episodes in patients with very severe aplastic anemia (VSAA) treated with G-CSF as compared to those who did not receive this therapy (22% versus 48%, P = 0.014).²⁰

Angio-invasive pulmonary aspergillosis and Zygomycetes (eg, Rhizopus, Mucor species) remain major causes of mortality related to opportunistic mycotic infections in patients with aplastic anemia.¹⁸ The infectious risk is directly related to the duration and severity of neutropenia, with one study demonstrating a significant increase in risk in AML patients with neutropenia lasting longer than 3 weeks.²¹ Invasive fungal infections carry a high mortality in patients with severe neutropenia, though due to earlier recognition and empiric antifungal therapy with extended-spectrum azoles, overall mortality secondary to invasive fungal infections is declining.^19,22

While neutropenia related to cytotoxic chemotherapy is commonly associated with gram-negative bacteria due to disruption of mucosal barriers, patients with aplastic anemia have an increased incidence of gram-positive bacteremia with staphylococcal species compared to other neutropenic populations.^18,19 This appears to be changing with time. Valdez and colleagues demonstrated a decrease in prevalence of coagulase-negative staphylococcal infections, increased prevalence of gram-positive bacilli bacteremia, and no change in prevalence of gram-negative bacteremia in patients with aplastic anemia treated between 1989 and 2008.²² Gram-negative bacteremia caused by Stenotrophomonas maltophila, Escherichia coli, Klebsiella pneumoniae, Citrobacter, and Proteus has also been reported.¹⁹ Despite a lack of clinical trials investigating the role of antifungal and antibacterial prophylaxis for patients with aplastic anemia, most centers initiate antifungal prophylaxis in patients with severe aplastic anema (SAA) or VSAA with an anti-mold agent such as voriconazole or posaconazole (which has the additional benefit compared to voriconazole of covering Mucor species).^17,23 This is especially true for patients who have received ATG or undergone HSCT. For antimicrobial prophylaxis, a fluoroquinolone antibiotic with a spectrum of activity against Pseudomonas should be considered for patients with an ANC < 500 cells/µL.¹⁷ Acyclovir or valacyclovir prophylaxis is recommended for varicella-zoster virus and herpes simplex virus. Cytomegalovirus reactivation is minimal in patients with aplastic anemia, unless multiple courses of ATG are used.

Iron overload is another complication the provider must be aware of in the setting of increased transfusions in aplastic anemia patients. Lee and colleagues demonstrated that iron chelation therapy using deferasirox is effective at reducing serum ferritin levels in patients with aplastic anemia (median ferritin level: 3254 ng/mL prior to therapy, 1854 ng/mL following), and is associated with no serious adverse events (most common adverse events included nausea, diarrhea, vomiting, and rash).²⁴ Approximately 25% of patients in this trial demonstrated an increase in creatinine, with patients taking concomitant cyclosporine more affected than those on chelation therapy alone.²⁴ For patients following HSCT or with improved hematopoiesis following immunosuppressive therapy, phlebotomy can be used to treat iron overload in lieu of chelation therapy.¹⁵

Approach to Therapy

The main treatment options for SAA and VSAA include allogeneic bone marrow transplant and immunosuppression. The deciding factors as to which treatment is best initially depends on the availability of HLA-matched related donors and age (Figure 1 and Figure 2). Survival is decreased in patients with SAA or VSAA who delay initiation of therapy, and therefore prompt referral for HLA typing and evaluation for bone marrow transplant is a very important first step in managing aplastic anemia.

Matched Sibling Donor Transplant

Current standards of care recommend HLA-matched sibling donor transplant for patients with SAA or VSAA who are younger than 50 years of age, with the caveat that integration of fludarabine and reduced cyclophosphamide dosing along with ATG shows the best overall outcomes. Locasciulli and colleagues examined outcomes in patients given either immunosuppressive therapy or sibling HSCT between 1991-1996 and 1997-2002, respectively, and found that sibling HSCT was associated with a superior 10-year OS compared to immunosuppressive therapy (73% versus 68%).²⁵ Interestingly in this study, there was no OS improvement seen with immunosuppressive therapy alone (69% versus 73%) between the 2 time periods, despite increased OS in both sibling HSCT (74% and 80%) and matched unrelated donor HSCT (38% and 65%).²⁵ Though total body irradiation has been used in the past, it is typically not included in current conditioning regimens for matched related donor transplants.²⁶

Current conditioning regimens typically use a combination of cyclophosphamide and ATG^27,28 with or without fludarabine. Fludarabine-based conditioning regimens have shown promise in patients undergoing sibling HSCT. Maury and colleagues evaluated the role of fludarabine in addition to low-dose cyclophosphamide and ATG compared to cyclophosphamide alone or in combination with ATG in patients over age 30 undergoing sibling HSCT.⁹ There was a nonsignificant improvement in 5-year OS in the fludarabine arm compared to controls (77% ± 8% versus 60% ± 3%, P = 0.14) in the pooled analysis, but when adjusted for age the fludarabine arm had a significantly lower relative risk (RR) of death (RR, 0.44; P = 0.04) compared to the control arm. Shin et al reported outcomes with fludarabine/cyclophosphamide/ATG, with excellent overall outcomes and no difference in patients older or younger than 40 years.²⁹ In addition, Kim et al evaluated their experience with patients older than 40 years of age receiving matched related donors, finding comparable outcomes in those aged 41 to 50 years compared to younger patients. Outcomes did decline in those over the age of 50 years.³⁰ Long-term data for matched related donor transplant for aplastic anemia shows excellent long-term outcomes, with minimal chronic GVHD and good performance status.³¹ Hence, these factors support the role of matched related donor transplant as the initial treatment in SAA and VSAA.

Regarding the role of transplant for patients who lack a matched related donor, a growing body of literature demonstrating identical outcomes between matched related and matched unrelated donor (MUD) transplants for pediatric patients^32,33 supports recent recommendations for upfront unrelated donor transplantation for aplastic anemia.^34,35

Immunosuppressive Therapy

For patients without an HLA-matched sibling donor or those who are older than 50 years of age, immunosuppressive therapy is the first-line therapy. ATG and cyclosporine A are the treatments of choice.³⁶ The potential effectiveness of immunosuppressive therapy in treating aplastic anemia was initially observed in patients in whom autologous transplant failed but who still experienced hematopoietic reconstitution despite the failed graft; this observation led to the hypothesis that the conditioning regimen may have an effect on hematopoiesis.^16,36,37

Anti-thymocyte globulin. Immunosuppressive therapy with ATG has been used for the treatment of aplastic anemia since the 1980s.³⁸ Historically, rabbit ATG had been used, but a 2011 study of horse ATG demonstrated superior hematological response at 6 months compared to rabbit ATG (68% versus 37%).¹⁶ Superior survival was also seen with horse ATG compared to rabbit ATG (3-year OS: 96% versus 76%). Due to these results, horse ATG is preferred over rabbit ATG. ATG should be used in combination with cyclosporine A to optimize outcomes.

Cyclosporine A. Early studies also demonstrated the efficacy of cyclosporine A in the treatment of aplastic anemia, with response rates equivalent to that of ATG monotherapy.³⁹ Recent publications still note the efficacy of cyclosporine A in the treatment of aplastic anemia. Its role as an affordable option for single-agent therapy in developing countries is intriguing.³⁹

The combination of the ATG and cyclosporine A was proven superior to either agent alone in a study by Frickhofen et al.³⁷ In this study patients were randomly assigned to a control arm that received ATG plus methylprednisolone or to an arm that received ATG plus cyclosporine A and methylprednisolone. At 6 months, 70% of patients in the cyclosporine A arm had a complete remission (CR) or partial remission compared to 46% in the control arm.⁴⁰ Further work confirmed the long-term efficacy of this regimen, reporting a 7-year OS of 55%.⁴¹ Among a pediatric population, immunosuppressive therapy was associated with an 83% 10-year OS.⁴²

It is recommended that patients remain on cyclosporine therapy for a minimum of 6 months, after which a gradual taper may be considered, although there is variation among practitioners, with some continuing immunosuppressive therapy for a minimum of 12 months due to a proportion of patients being cyclosporine dependent.^42,43 A study found that within a population of patients who responded to immunosuppressive therapy, 18% became cyclosporine dependent.⁴² The median duration of cyclosporine A treatment at full dose was 12 months, with tapering completed over a median of 19 months after patients had been in a stable CR for a minimum of 3 months. Relapse occurred more often when patients were tapered quickly (decrease ≥ 0.8 mg/kg/month) compared to slowly (0.4-0.7 mg/kg/month) or very slowly (< 0.3 mg/kg/month).

Immunosuppressive therapy plus eltrombopag. Townsley and colleagues recently investigated incorporating the use of the thrombopoietin receptor agonist eltrombopag with immunosuppressive therapy as first-line therapy in aplastic anemia.⁴⁴ When given at a dose of 150 mg daily in patients aged 12 years and older or 75 mg daily in patients younger than 12 years, in conjunction with cyclosporine A and ATG, patients demonstrated markedly improved hematological response compared to historical treatment with standard immunosuppressive therapy alone.⁴⁴ In the patient cohort administered eltrombopag starting on day 1 and continuing for 6 months, the complete response rate was 58%. Eltrombopag led to improvement in all cell lines among all treatment subgroups, and OS (censored for patients who proceeded to transplant) was 99% at 2 years.⁴⁵ Overall, toxicities associated with this therapy were low, with liver enzyme elevations most commonly observed.⁴⁴ Recently, a phase 2 trial of immunosuppressive therapy with or without eltrombopag was reported. Of the 38 patients enrolled, overall response, complete response, and time to response were not statistically different.⁴⁶ With this recent finding, the role of eltrombopag in addition to immunosuppressive therapy is not clearly defined, and further studies are warranted.

OS for patients who do not respond to immunosuppressive therapy is approximately 57% at 5 years, largely due to improved supportive measures among this patient population.^4,22 Therefore, it is important to recognize those patients who have a low chance of response so that second-line therapy can be pursued to improve outcomes.

Matched Unrelated Donor Transplant

For patients with refractory disease following immunosuppressive therapy who lack a matched sibling donor, MUD HSCT is considered standard therapy given the marked improvement in overall outcomes with modulating conditioning regimens and high-resolution HLA typing. A European Society for Blood and Marrow Transplantation analysis comparing matched sibling HSCT to MUD HSCT noted significantly higher rates of acute grade II-IV and grade III-V GVHD (grade II-IV 13% versus 25%, grade III-IV 5% versus 10%) among patients undergoing MUD transplant.⁴⁷ Chronic GVHD rates were 14% in the sibling group, as compared to 26% in the MUD group. Additional benefits seen in this analysis included improved survival when transplanted under age 20 years (84% versus 72%), when transplanted within 6 months of diagnosis (85% versus 72%), the use of ATG in the conditioning regimen (81% versus 73%), and when the donor and recipient were cytomegalovirus-negative compared to other combinations (82% versus 76%).⁴⁷ Interestingly, this study demonstrated that OS was not significantly increased when using a sibling HSCT compared to a MUD HSCT, likely as a result of improved understanding of conditioning regimens, GVHD prophylaxis, and supportive care.

Additional studies of MUD HSCT have shown outcomes similar to those seen in sibling HSCT.^4,43 A French study found a significant increase in survival in patients undergoing MUD HSCT compared to historical cohorts (2000-2005: OS 52%; 2006-2012: OS 74%).³³ The majority of patients underwent conditioning with cyclophosphamide or a combination of busulfan and cyclophosphamide, with or without fludarabine; 81% of patients included underwent in vivo T-cell depletion, and a bone marrow donor source was utilized. OS was significantly lower in patients over age 30 years undergoing MUD HSCT (57%) compared to those under age 30 years (70%). Improved OS was also seen when patients underwent transplant within 1 year of diagnosis and when a 10/10 matched donor (compared to a 9/10 mismatched donor) was utilized.⁴ A 2015 study investigated the role of MUD HSCT as frontline therapy instead of immunosuppressive therapy in patients without a matched sibling donor.³³ The 2-year OS was 96% in the MUD HSCT cohort compared to 91%, 94%, and 74% in historical cohorts of sibling HSCT, frontline immunosuppressive therapy, and second-line MUD HSCT following failed immunosuppressive therapy, respectively. Additionally, event-free survival in the MUD HSCT cohort (defined by the authors as death, lack of response, relapse, occurrence of clonal evolution/clinical paroxysmal nocturnal hemoglobinuria, malignancies developing over follow‐up, and transplant for patients receiving immunosuppressive therapy frontline) was similar compared to sibling HSCT and superior to frontline immunosuppressive therapy and second-line MUD HSCT. Furthermore, Samarasinghe et al highlighted the importance of in vivo T-cell depletion with either ATG or alemtuzumab (anti-CD52 monoclonal antibody) in the prevention of acute and chronic GVHD in both sibling HSCT and MUD HSCT.⁴⁸

With continued improvement of less toxic and more immunomodulating conditioning regimens, utilization of bone marrow as a donor cell source, in vivo T-cell depletion, and use of GVHD and antimicrobial prophylaxis, more clinical evidence supports elevating MUD HSCT in the treatment plan for patients without a matched sibling donor.⁴⁹ However, there is still a large population of patients without matched sibling or unrelated donor options. In an effort to expand the transplant pool and thus avoid clonal hematopoiesis, clinically significant paroxysmal nocturnal hemoglobinuria, and relapsed aplastic anemia, more work continues to recognize the expanding role of alternative donor transplants (cord blood and haploidentical) as another viable treatment strategy for aplastic anemia after immunosuppressive therapy failure.⁵⁰

Summary

Aplastic anemia is a rare but potentially life-threatening disorder characterized by pancytopenia and a marked reduction in the hematopoietic stem cell compartment. Treatment should be instituted as soon as the dignosis of aplastic anemia is established. Treatment outcomes are excellent with modern supportive care and the current approach to allogeneic transplantation, and therefore referral to a bone marrow transplant program to evaluate for early transplantation is the new standard of care.

Aplastic anemia is a rare hematologic disorder marked by pancytopenia and a hypocellular marrow. Aplastic anemia results from either inherited or acquired causes, and the treatment approach varies significantly between the 2 causes. This article reviews the treatment of inherited and acquired forms of aplastic anemia. The approach to evaluation and diagnosis of aplastic anemia is reviewed in a separate article.

Inherited Aplastic Anemia

First-line treatment options for patients with inherited marrow failure syndromes (IMFS) are androgen therapy and hematopoietic stem cell transplant (HSCT). When evaluating patients for HSCT, it is critical to identify the presence of an IMFS, as the risk and mortality associated with the conditioning regimen, stem cell source, graft-versus-host disease (GVHD), and secondary malignancies differ between patients with IMFS and those with acquired marrow failure syndromes or hematologic malignancies.

Potential sibling donors need to be screened for donor candidacy as well as for the inherited defect.¹ Among patients with Fanconi anemia or a telomere biology disorder, the stem cell source must be considered, with bone marrow demonstrating lower rates of acute GVHD than a peripheral blood stem cell source.^2-4 In IMFS patients, the donor cell type may affect the choice of conditioning regimen.^5,6 Reduced-intensity conditioning in lieu of myeloablative conditioning without total body irradiation has proved feasible in patients with Fanconi anemia, and is associated with a reduced risk of secondary malignancies.^5,6 Incorporation of fludarabine in the conditioning regimen of patients without a matched sibling donor is associated with superior engraftment and survival^2,5,7 compared to cyclophosphamide conditioning, which was historically used in matched related donors.^6,8 The addition of fludarabine appears to be especially beneficial in older patients, in whom its use is associated with lower rates of graft failure, likely due to increased immunosuppression at the time of engraftment.^7,9 Fludarabine has also been incorporated into conditioning regimens for patients with a telomere biology disorder, but outcomes data is limited.⁵

For patients presenting with acute myeloid leukemia (AML) or a high-risk myelodysplastic syndrome (MDS) who are subsequently diagnosed with an IMFS, treatment can be more complex, as these patients are at high risk for toxicity from standard chemotherapy. Limited data suggests that induction therapy and transplantation are feasible in this group of patients, and this approach is associated with increased overall survival (OS) despite lower OS rates than those of IMFS patients who present prior to the development of MDS or AML.^10,11 Further work is needed to determine the optimal induction regimen that balances the risks of treatment-related mortality and complications associated with conditioning regimens, risk of relapse, and risk of secondary malignancies, especially in the cohort of patients diagnosed at an older age.

Acquired Aplastic Anemia

Supportive Care

While the workup and treatment plan is being established, attention should be directed at supportive care for prevention of complications. The most common complications leading to death in patients with significant pancytopenia and neutropenia are opportunistic infections and hemorrhagic complications.¹²

Transfusion support is critical to avoid symptomatic anemia and hemorrhagic complications related to thrombocytopenia, which typically occur with platelet counts lower than 10,000 cells/µL. However, transfusion carries the risk of alloimmunization (which may persist for years following transfusion) and transfusion-related graft versus host disease (trGVHD), and thus use of transfusion should be minimized when possible.^13,14 Transfusion support is often required to prevent complications associated with thrombocytopenia and anemia; all blood products given to patients with aplastic anemia should be irradiated and leukoreduced to reduce the risk of both alloimmunization and trGVHD. Guidelines from the British Society for Haematology recommend routine screening for Rh and Kell antibodies to reduce the risk of alloimmunization.¹⁵ Infectious complications remain a common cause of morbidity and mortality in patients with aplastic anemia who have prolonged neutropenia (defined as an absolute neutrophil count [ANC] < 500 cells/µL).^16-19 Therefore, patients should receive broad-spectrum antibiotics with antipseudomonal coverage. In a study by Tichelli and colleagues evaluating the role of granulocyte-colony stimulating factor (G-CSF) in patients with SAA receiving immunosuppressive therapy, 55% of all patient deaths were secondary to infection.²⁰ There was no OS benefit seen in patients who received G-CSF, though a significantly lower rate of infection was observed in the G-CSF arm compared to those not receiving G-CSF (56% versus 81%, P = 0.006).This difference was largely driven by a decrease in infectious episodes in patients with very severe aplastic anemia (VSAA) treated with G-CSF as compared to those who did not receive this therapy (22% versus 48%, P = 0.014).²⁰

Angio-invasive pulmonary aspergillosis and Zygomycetes (eg, Rhizopus, Mucor species) remain major causes of mortality related to opportunistic mycotic infections in patients with aplastic anemia.¹⁸ The infectious risk is directly related to the duration and severity of neutropenia, with one study demonstrating a significant increase in risk in AML patients with neutropenia lasting longer than 3 weeks.²¹ Invasive fungal infections carry a high mortality in patients with severe neutropenia, though due to earlier recognition and empiric antifungal therapy with extended-spectrum azoles, overall mortality secondary to invasive fungal infections is declining.^19,22

While neutropenia related to cytotoxic chemotherapy is commonly associated with gram-negative bacteria due to disruption of mucosal barriers, patients with aplastic anemia have an increased incidence of gram-positive bacteremia with staphylococcal species compared to other neutropenic populations.^18,19 This appears to be changing with time. Valdez and colleagues demonstrated a decrease in prevalence of coagulase-negative staphylococcal infections, increased prevalence of gram-positive bacilli bacteremia, and no change in prevalence of gram-negative bacteremia in patients with aplastic anemia treated between 1989 and 2008.²² Gram-negative bacteremia caused by Stenotrophomonas maltophila, Escherichia coli, Klebsiella pneumoniae, Citrobacter, and Proteus has also been reported.¹⁹ Despite a lack of clinical trials investigating the role of antifungal and antibacterial prophylaxis for patients with aplastic anemia, most centers initiate antifungal prophylaxis in patients with severe aplastic anema (SAA) or VSAA with an anti-mold agent such as voriconazole or posaconazole (which has the additional benefit compared to voriconazole of covering Mucor species).^17,23 This is especially true for patients who have received ATG or undergone HSCT. For antimicrobial prophylaxis, a fluoroquinolone antibiotic with a spectrum of activity against Pseudomonas should be considered for patients with an ANC < 500 cells/µL.¹⁷ Acyclovir or valacyclovir prophylaxis is recommended for varicella-zoster virus and herpes simplex virus. Cytomegalovirus reactivation is minimal in patients with aplastic anemia, unless multiple courses of ATG are used.

Iron overload is another complication the provider must be aware of in the setting of increased transfusions in aplastic anemia patients. Lee and colleagues demonstrated that iron chelation therapy using deferasirox is effective at reducing serum ferritin levels in patients with aplastic anemia (median ferritin level: 3254 ng/mL prior to therapy, 1854 ng/mL following), and is associated with no serious adverse events (most common adverse events included nausea, diarrhea, vomiting, and rash).²⁴ Approximately 25% of patients in this trial demonstrated an increase in creatinine, with patients taking concomitant cyclosporine more affected than those on chelation therapy alone.²⁴ For patients following HSCT or with improved hematopoiesis following immunosuppressive therapy, phlebotomy can be used to treat iron overload in lieu of chelation therapy.¹⁵

Approach to Therapy

The main treatment options for SAA and VSAA include allogeneic bone marrow transplant and immunosuppression. The deciding factors as to which treatment is best initially depends on the availability of HLA-matched related donors and age (Figure 1 and Figure 2). Survival is decreased in patients with SAA or VSAA who delay initiation of therapy, and therefore prompt referral for HLA typing and evaluation for bone marrow transplant is a very important first step in managing aplastic anemia.

Matched Sibling Donor Transplant

Current standards of care recommend HLA-matched sibling donor transplant for patients with SAA or VSAA who are younger than 50 years of age, with the caveat that integration of fludarabine and reduced cyclophosphamide dosing along with ATG shows the best overall outcomes. Locasciulli and colleagues examined outcomes in patients given either immunosuppressive therapy or sibling HSCT between 1991-1996 and 1997-2002, respectively, and found that sibling HSCT was associated with a superior 10-year OS compared to immunosuppressive therapy (73% versus 68%).²⁵ Interestingly in this study, there was no OS improvement seen with immunosuppressive therapy alone (69% versus 73%) between the 2 time periods, despite increased OS in both sibling HSCT (74% and 80%) and matched unrelated donor HSCT (38% and 65%).²⁵ Though total body irradiation has been used in the past, it is typically not included in current conditioning regimens for matched related donor transplants.²⁶

Current conditioning regimens typically use a combination of cyclophosphamide and ATG^27,28 with or without fludarabine. Fludarabine-based conditioning regimens have shown promise in patients undergoing sibling HSCT. Maury and colleagues evaluated the role of fludarabine in addition to low-dose cyclophosphamide and ATG compared to cyclophosphamide alone or in combination with ATG in patients over age 30 undergoing sibling HSCT.⁹ There was a nonsignificant improvement in 5-year OS in the fludarabine arm compared to controls (77% ± 8% versus 60% ± 3%, P = 0.14) in the pooled analysis, but when adjusted for age the fludarabine arm had a significantly lower relative risk (RR) of death (RR, 0.44; P = 0.04) compared to the control arm. Shin et al reported outcomes with fludarabine/cyclophosphamide/ATG, with excellent overall outcomes and no difference in patients older or younger than 40 years.²⁹ In addition, Kim et al evaluated their experience with patients older than 40 years of age receiving matched related donors, finding comparable outcomes in those aged 41 to 50 years compared to younger patients. Outcomes did decline in those over the age of 50 years.³⁰ Long-term data for matched related donor transplant for aplastic anemia shows excellent long-term outcomes, with minimal chronic GVHD and good performance status.³¹ Hence, these factors support the role of matched related donor transplant as the initial treatment in SAA and VSAA.

Regarding the role of transplant for patients who lack a matched related donor, a growing body of literature demonstrating identical outcomes between matched related and matched unrelated donor (MUD) transplants for pediatric patients^32,33 supports recent recommendations for upfront unrelated donor transplantation for aplastic anemia.^34,35

Immunosuppressive Therapy

For patients without an HLA-matched sibling donor or those who are older than 50 years of age, immunosuppressive therapy is the first-line therapy. ATG and cyclosporine A are the treatments of choice.³⁶ The potential effectiveness of immunosuppressive therapy in treating aplastic anemia was initially observed in patients in whom autologous transplant failed but who still experienced hematopoietic reconstitution despite the failed graft; this observation led to the hypothesis that the conditioning regimen may have an effect on hematopoiesis.^16,36,37

Anti-thymocyte globulin. Immunosuppressive therapy with ATG has been used for the treatment of aplastic anemia since the 1980s.³⁸ Historically, rabbit ATG had been used, but a 2011 study of horse ATG demonstrated superior hematological response at 6 months compared to rabbit ATG (68% versus 37%).¹⁶ Superior survival was also seen with horse ATG compared to rabbit ATG (3-year OS: 96% versus 76%). Due to these results, horse ATG is preferred over rabbit ATG. ATG should be used in combination with cyclosporine A to optimize outcomes.

Cyclosporine A. Early studies also demonstrated the efficacy of cyclosporine A in the treatment of aplastic anemia, with response rates equivalent to that of ATG monotherapy.³⁹ Recent publications still note the efficacy of cyclosporine A in the treatment of aplastic anemia. Its role as an affordable option for single-agent therapy in developing countries is intriguing.³⁹

The combination of the ATG and cyclosporine A was proven superior to either agent alone in a study by Frickhofen et al.³⁷ In this study patients were randomly assigned to a control arm that received ATG plus methylprednisolone or to an arm that received ATG plus cyclosporine A and methylprednisolone. At 6 months, 70% of patients in the cyclosporine A arm had a complete remission (CR) or partial remission compared to 46% in the control arm.⁴⁰ Further work confirmed the long-term efficacy of this regimen, reporting a 7-year OS of 55%.⁴¹ Among a pediatric population, immunosuppressive therapy was associated with an 83% 10-year OS.⁴²

It is recommended that patients remain on cyclosporine therapy for a minimum of 6 months, after which a gradual taper may be considered, although there is variation among practitioners, with some continuing immunosuppressive therapy for a minimum of 12 months due to a proportion of patients being cyclosporine dependent.^42,43 A study found that within a population of patients who responded to immunosuppressive therapy, 18% became cyclosporine dependent.⁴² The median duration of cyclosporine A treatment at full dose was 12 months, with tapering completed over a median of 19 months after patients had been in a stable CR for a minimum of 3 months. Relapse occurred more often when patients were tapered quickly (decrease ≥ 0.8 mg/kg/month) compared to slowly (0.4-0.7 mg/kg/month) or very slowly (< 0.3 mg/kg/month).

Immunosuppressive therapy plus eltrombopag. Townsley and colleagues recently investigated incorporating the use of the thrombopoietin receptor agonist eltrombopag with immunosuppressive therapy as first-line therapy in aplastic anemia.⁴⁴ When given at a dose of 150 mg daily in patients aged 12 years and older or 75 mg daily in patients younger than 12 years, in conjunction with cyclosporine A and ATG, patients demonstrated markedly improved hematological response compared to historical treatment with standard immunosuppressive therapy alone.⁴⁴ In the patient cohort administered eltrombopag starting on day 1 and continuing for 6 months, the complete response rate was 58%. Eltrombopag led to improvement in all cell lines among all treatment subgroups, and OS (censored for patients who proceeded to transplant) was 99% at 2 years.⁴⁵ Overall, toxicities associated with this therapy were low, with liver enzyme elevations most commonly observed.⁴⁴ Recently, a phase 2 trial of immunosuppressive therapy with or without eltrombopag was reported. Of the 38 patients enrolled, overall response, complete response, and time to response were not statistically different.⁴⁶ With this recent finding, the role of eltrombopag in addition to immunosuppressive therapy is not clearly defined, and further studies are warranted.

OS for patients who do not respond to immunosuppressive therapy is approximately 57% at 5 years, largely due to improved supportive measures among this patient population.^4,22 Therefore, it is important to recognize those patients who have a low chance of response so that second-line therapy can be pursued to improve outcomes.

Matched Unrelated Donor Transplant

For patients with refractory disease following immunosuppressive therapy who lack a matched sibling donor, MUD HSCT is considered standard therapy given the marked improvement in overall outcomes with modulating conditioning regimens and high-resolution HLA typing. A European Society for Blood and Marrow Transplantation analysis comparing matched sibling HSCT to MUD HSCT noted significantly higher rates of acute grade II-IV and grade III-V GVHD (grade II-IV 13% versus 25%, grade III-IV 5% versus 10%) among patients undergoing MUD transplant.⁴⁷ Chronic GVHD rates were 14% in the sibling group, as compared to 26% in the MUD group. Additional benefits seen in this analysis included improved survival when transplanted under age 20 years (84% versus 72%), when transplanted within 6 months of diagnosis (85% versus 72%), the use of ATG in the conditioning regimen (81% versus 73%), and when the donor and recipient were cytomegalovirus-negative compared to other combinations (82% versus 76%).⁴⁷ Interestingly, this study demonstrated that OS was not significantly increased when using a sibling HSCT compared to a MUD HSCT, likely as a result of improved understanding of conditioning regimens, GVHD prophylaxis, and supportive care.

Additional studies of MUD HSCT have shown outcomes similar to those seen in sibling HSCT.^4,43 A French study found a significant increase in survival in patients undergoing MUD HSCT compared to historical cohorts (2000-2005: OS 52%; 2006-2012: OS 74%).³³ The majority of patients underwent conditioning with cyclophosphamide or a combination of busulfan and cyclophosphamide, with or without fludarabine; 81% of patients included underwent in vivo T-cell depletion, and a bone marrow donor source was utilized. OS was significantly lower in patients over age 30 years undergoing MUD HSCT (57%) compared to those under age 30 years (70%). Improved OS was also seen when patients underwent transplant within 1 year of diagnosis and when a 10/10 matched donor (compared to a 9/10 mismatched donor) was utilized.⁴ A 2015 study investigated the role of MUD HSCT as frontline therapy instead of immunosuppressive therapy in patients without a matched sibling donor.³³ The 2-year OS was 96% in the MUD HSCT cohort compared to 91%, 94%, and 74% in historical cohorts of sibling HSCT, frontline immunosuppressive therapy, and second-line MUD HSCT following failed immunosuppressive therapy, respectively. Additionally, event-free survival in the MUD HSCT cohort (defined by the authors as death, lack of response, relapse, occurrence of clonal evolution/clinical paroxysmal nocturnal hemoglobinuria, malignancies developing over follow‐up, and transplant for patients receiving immunosuppressive therapy frontline) was similar compared to sibling HSCT and superior to frontline immunosuppressive therapy and second-line MUD HSCT. Furthermore, Samarasinghe et al highlighted the importance of in vivo T-cell depletion with either ATG or alemtuzumab (anti-CD52 monoclonal antibody) in the prevention of acute and chronic GVHD in both sibling HSCT and MUD HSCT.⁴⁸

With continued improvement of less toxic and more immunomodulating conditioning regimens, utilization of bone marrow as a donor cell source, in vivo T-cell depletion, and use of GVHD and antimicrobial prophylaxis, more clinical evidence supports elevating MUD HSCT in the treatment plan for patients without a matched sibling donor.⁴⁹ However, there is still a large population of patients without matched sibling or unrelated donor options. In an effort to expand the transplant pool and thus avoid clonal hematopoiesis, clinically significant paroxysmal nocturnal hemoglobinuria, and relapsed aplastic anemia, more work continues to recognize the expanding role of alternative donor transplants (cord blood and haploidentical) as another viable treatment strategy for aplastic anemia after immunosuppressive therapy failure.⁵⁰

Summary

Aplastic anemia is a rare but potentially life-threatening disorder characterized by pancytopenia and a marked reduction in the hematopoietic stem cell compartment. Treatment should be instituted as soon as the dignosis of aplastic anemia is established. Treatment outcomes are excellent with modern supportive care and the current approach to allogeneic transplantation, and therefore referral to a bone marrow transplant program to evaluate for early transplantation is the new standard of care.