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 FP suspected that this could be a melanoma and took out his dermatoscope. (See “Dermoscopy in family medicine: A primer.”) The FP was initially concerned about melanoma because the lesion appeared chaotic, with multiple colors and an irregular border. Going through the ABCDE criteria, he noted that the macule was Asymmetric, the Border was irregular, the Colors were varied, the Diameter was >6 mm, but the history was insufficient to say whether it was Enlarging. Of course, 4 out of 5 positive criteria requires a tissue diagnosis.

Dermoscopy added evidence for regression in the center and an atypical network in the brown and black areas. The FP performed a deep shave biopsy (saucerization) with 2 mm margins to provide full sampling for the pathologist. (See the Watch & Learn video on “Shave biopsy.”) The depth of the tissue biopsy was approximately 1 to 1.5 mm, which was adequate for a lesion of this type. The pathology report confirmed melanoma in situ.

On a return visit, the FP performed a local wide excision with 5 mm margins down to the deep fat. The surgical specimen revealed only the scar at the biopsy site with no remaining cancer. This reassured the patient because it should provide a cure very near 100%. The FP provided counseling about sun protection and the need for regular skin exams.

‌

Photos and text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Karnes J, Usatine R. Melanoma. In: Usatine R, Smith M, Mayeaux EJ, et al. Color Atlas and Synopsis of Family Medicine. 3rd ed. New York, NY: McGraw-Hill; 2019:1112-1123.

To learn more about the newest 3rd edition of the Color Atlas and Synopsis of Family Medicine, see: https://www.amazon.com/Color-Atlas-Synopsis-Family-Medicine/dp/1259862046/

You can get the Color Atlas of Family Medicine app by clicking on this link: usatinemedia.com

The FP suspected that this could be a melanoma and took out his dermatoscope. (See “Dermoscopy in family medicine: A primer.”) The FP was initially concerned about melanoma because the lesion appeared chaotic, with multiple colors and an irregular border. Going through the ABCDE criteria, he noted that the macule was Asymmetric, the Border was irregular, the Colors were varied, the Diameter was >6 mm, but the history was insufficient to say whether it was Enlarging. Of course, 4 out of 5 positive criteria requires a tissue diagnosis.

Dermoscopy added evidence for regression in the center and an atypical network in the brown and black areas. The FP performed a deep shave biopsy (saucerization) with 2 mm margins to provide full sampling for the pathologist. (See the Watch & Learn video on “Shave biopsy.”) The depth of the tissue biopsy was approximately 1 to 1.5 mm, which was adequate for a lesion of this type. The pathology report confirmed melanoma in situ.

On a return visit, the FP performed a local wide excision with 5 mm margins down to the deep fat. The surgical specimen revealed only the scar at the biopsy site with no remaining cancer. This reassured the patient because it should provide a cure very near 100%. The FP provided counseling about sun protection and the need for regular skin exams.

‌

Photos and text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Karnes J, Usatine R. Melanoma. In: Usatine R, Smith M, Mayeaux EJ, et al. Color Atlas and Synopsis of Family Medicine. 3rd ed. New York, NY: McGraw-Hill; 2019:1112-1123.

To learn more about the newest 3rd edition of the Color Atlas and Synopsis of Family Medicine, see: https://www.amazon.com/Color-Atlas-Synopsis-Family-Medicine/dp/1259862046/

You can get the Color Atlas of Family Medicine app by clicking on this link: usatinemedia.com

The FP suspected that this could be a melanoma and took out his dermatoscope. (See “Dermoscopy in family medicine: A primer.”) The FP was initially concerned about melanoma because the lesion appeared chaotic, with multiple colors and an irregular border. Going through the ABCDE criteria, he noted that the macule was Asymmetric, the Border was irregular, the Colors were varied, the Diameter was >6 mm, but the history was insufficient to say whether it was Enlarging. Of course, 4 out of 5 positive criteria requires a tissue diagnosis.

Dermoscopy added evidence for regression in the center and an atypical network in the brown and black areas. The FP performed a deep shave biopsy (saucerization) with 2 mm margins to provide full sampling for the pathologist. (See the Watch & Learn video on “Shave biopsy.”) The depth of the tissue biopsy was approximately 1 to 1.5 mm, which was adequate for a lesion of this type. The pathology report confirmed melanoma in situ.

On a return visit, the FP performed a local wide excision with 5 mm margins down to the deep fat. The surgical specimen revealed only the scar at the biopsy site with no remaining cancer. This reassured the patient because it should provide a cure very near 100%. The FP provided counseling about sun protection and the need for regular skin exams.

‌

Photos and text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Karnes J, Usatine R. Melanoma. In: Usatine R, Smith M, Mayeaux EJ, et al. Color Atlas and Synopsis of Family Medicine. 3rd ed. New York, NY: McGraw-Hill; 2019:1112-1123.

To learn more about the newest 3rd edition of the Color Atlas and Synopsis of Family Medicine, see: https://www.amazon.com/Color-Atlas-Synopsis-Family-Medicine/dp/1259862046/

You can get the Color Atlas of Family Medicine app by clicking on this link: usatinemedia.com

Paint me like one of your French girls

If you’re trying to think of a fun Valentine’s activity, look no further than paint night! Normally associated with a ladies night out (and heavy on the wine), a recent study found that painting releases high levels of the “love hormone”, a.k.a. oxytocin, in men.

mixetto/E+

Researchers compared the levels of oxytocin with partners painting and partners playing board games, and were surprised by the results: While all the couples released oxytocin during these activities, men in paint class had the highest levels – twice as much as any other group.

Feel free to cite this study next time your man complains about being dragged to a paint-and-sip. Painting partners also experienced more touching than the gaming group (unless you count throwing Monopoly pieces at your significant other as touching).
 

You won’t get me sick, I’ll get me sick!

There are certain items that, after being used once, you really wouldn’t want to reuse. A snotty, mucus-filled tissue is pretty high up on that list ... or so you would hope. But that’s not thinking with real American entrepreneurial spirit! Welcome to Vaev Tissue, a startup based in Los Angeles that sells used tissues containing germs from a sick person for the bargain price of $79.99.

Cecilie_Arcurs/E+

Yes, you read that correctly. They sell an $80 used tissue. The purpose, according to Vaev’s mission statement, is “to get sick on your own terms,” as “using a tissue that carries a human sneeze is safer than needles or pills.”

As you might expect, the tissues are popular with young parents and adults who are “critical” of vaccines. Who else could hear advice from actual doctors who told Time magazine that “there is nothing positive that can come from this, only things that are adverse,” or that the tissues are an “incredible liability,” and continue on, regardless?

And if you’re thinking, “If these people want to get sick, why not just have someone sneeze on them?” Don’t be ridiculous. Focus testers responded highly negatively to simply being handed a dirty tissue. The premium packaging and high price tag are a necessity.

Our advice? Well, as tempting as all this sounds, we think we’ll stick with washing our hands and not sticking used tissues in our faces. You know, like reasonable people.

Why Bullwinkle thinks pink

Flying squirrels are secretly doing their best flamingo impression – who knew? A forestry professor discovered, by happy accident, that flying squirrels are fluorescent – they glow hot pink under ultraviolet light.

shabeerthurakkal/iStock/Getty Images Plus

Turns out, almost all species of gliders – even blue-helmeted Rocket “Rocky” J. Squirrel – are members of the Pink Ladies. They are one of the very few glowing mammals; the only other known mammalian species to have fluorescent fur are certain opossums.

But why do these airborne rodents glow pink? Is it because of an overintake of bubblegum? Are flying squirrels just really flamboyant but also shy? Are they huge fans of the singer Pink?

A biologist involved in studying these colorful critters hypothesized that the reason is slightly more related to environment than musical preference. Flying squirrels are nocturnal, making them most active when UV light is most prominent. The garish glow might have something to do with nighttime perception.

However, we don’t know the answer for sure. And in the meantime, we can choose to believe flying squirrels eat way too much cotton candy.
 

Buzz, feed, diet. Repeat

Guns don’t hurt this mass murderer. Police can’t arrest it. Background checks are pointless. A border wall won’t keep it out. So, how do you stop a mosquito?

James Gathany/CDC

Diet drugs.

Because female mosquitoes transmit malaria, Zika, and other diseases when they move from person to person feeding on human blood, investigators sought to curb that appetite by chemically re-creating the feeling of fullness they get after a big meal.

The lady killers in their study – Aedes aegypti, to be exact – when given an antiobesity drug that suppresses human appetite by activating neuropeptide receptors that regulate food intake, turned away from a tempting piece of nylon stocking that had been worn by one of the researchers. Further work showed that treated mosquitoes were as disinterested in feeding on a live mouse as mosquitoes that had already enjoyed a full blood meal.

The LOTME research staff (What? Of course, we have a research staff. You don’t?) is working on the mosquito problem too, although we’ve taken a somewhat different approach: The “volunteers” who walk into the mosquito-filled room wear a sign that says, “My blood will make your butt look bigger.”

Paint me like one of your French girls

If you’re trying to think of a fun Valentine’s activity, look no further than paint night! Normally associated with a ladies night out (and heavy on the wine), a recent study found that painting releases high levels of the “love hormone”, a.k.a. oxytocin, in men.

mixetto/E+

Researchers compared the levels of oxytocin with partners painting and partners playing board games, and were surprised by the results: While all the couples released oxytocin during these activities, men in paint class had the highest levels – twice as much as any other group.

Feel free to cite this study next time your man complains about being dragged to a paint-and-sip. Painting partners also experienced more touching than the gaming group (unless you count throwing Monopoly pieces at your significant other as touching).
 

You won’t get me sick, I’ll get me sick!

There are certain items that, after being used once, you really wouldn’t want to reuse. A snotty, mucus-filled tissue is pretty high up on that list ... or so you would hope. But that’s not thinking with real American entrepreneurial spirit! Welcome to Vaev Tissue, a startup based in Los Angeles that sells used tissues containing germs from a sick person for the bargain price of $79.99.

Cecilie_Arcurs/E+

Yes, you read that correctly. They sell an $80 used tissue. The purpose, according to Vaev’s mission statement, is “to get sick on your own terms,” as “using a tissue that carries a human sneeze is safer than needles or pills.”

As you might expect, the tissues are popular with young parents and adults who are “critical” of vaccines. Who else could hear advice from actual doctors who told Time magazine that “there is nothing positive that can come from this, only things that are adverse,” or that the tissues are an “incredible liability,” and continue on, regardless?

And if you’re thinking, “If these people want to get sick, why not just have someone sneeze on them?” Don’t be ridiculous. Focus testers responded highly negatively to simply being handed a dirty tissue. The premium packaging and high price tag are a necessity.

Our advice? Well, as tempting as all this sounds, we think we’ll stick with washing our hands and not sticking used tissues in our faces. You know, like reasonable people.

Why Bullwinkle thinks pink

Flying squirrels are secretly doing their best flamingo impression – who knew? A forestry professor discovered, by happy accident, that flying squirrels are fluorescent – they glow hot pink under ultraviolet light.

shabeerthurakkal/iStock/Getty Images Plus

Turns out, almost all species of gliders – even blue-helmeted Rocket “Rocky” J. Squirrel – are members of the Pink Ladies. They are one of the very few glowing mammals; the only other known mammalian species to have fluorescent fur are certain opossums.

But why do these airborne rodents glow pink? Is it because of an overintake of bubblegum? Are flying squirrels just really flamboyant but also shy? Are they huge fans of the singer Pink?

A biologist involved in studying these colorful critters hypothesized that the reason is slightly more related to environment than musical preference. Flying squirrels are nocturnal, making them most active when UV light is most prominent. The garish glow might have something to do with nighttime perception.

However, we don’t know the answer for sure. And in the meantime, we can choose to believe flying squirrels eat way too much cotton candy.
 

Buzz, feed, diet. Repeat

Guns don’t hurt this mass murderer. Police can’t arrest it. Background checks are pointless. A border wall won’t keep it out. So, how do you stop a mosquito?

James Gathany/CDC

Diet drugs.

Because female mosquitoes transmit malaria, Zika, and other diseases when they move from person to person feeding on human blood, investigators sought to curb that appetite by chemically re-creating the feeling of fullness they get after a big meal.

The lady killers in their study – Aedes aegypti, to be exact – when given an antiobesity drug that suppresses human appetite by activating neuropeptide receptors that regulate food intake, turned away from a tempting piece of nylon stocking that had been worn by one of the researchers. Further work showed that treated mosquitoes were as disinterested in feeding on a live mouse as mosquitoes that had already enjoyed a full blood meal.

The LOTME research staff (What? Of course, we have a research staff. You don’t?) is working on the mosquito problem too, although we’ve taken a somewhat different approach: The “volunteers” who walk into the mosquito-filled room wear a sign that says, “My blood will make your butt look bigger.”

Paint me like one of your French girls

If you’re trying to think of a fun Valentine’s activity, look no further than paint night! Normally associated with a ladies night out (and heavy on the wine), a recent study found that painting releases high levels of the “love hormone”, a.k.a. oxytocin, in men.

mixetto/E+

Researchers compared the levels of oxytocin with partners painting and partners playing board games, and were surprised by the results: While all the couples released oxytocin during these activities, men in paint class had the highest levels – twice as much as any other group.

Feel free to cite this study next time your man complains about being dragged to a paint-and-sip. Painting partners also experienced more touching than the gaming group (unless you count throwing Monopoly pieces at your significant other as touching).
 

You won’t get me sick, I’ll get me sick!

There are certain items that, after being used once, you really wouldn’t want to reuse. A snotty, mucus-filled tissue is pretty high up on that list ... or so you would hope. But that’s not thinking with real American entrepreneurial spirit! Welcome to Vaev Tissue, a startup based in Los Angeles that sells used tissues containing germs from a sick person for the bargain price of $79.99.

Cecilie_Arcurs/E+

Yes, you read that correctly. They sell an $80 used tissue. The purpose, according to Vaev’s mission statement, is “to get sick on your own terms,” as “using a tissue that carries a human sneeze is safer than needles or pills.”

As you might expect, the tissues are popular with young parents and adults who are “critical” of vaccines. Who else could hear advice from actual doctors who told Time magazine that “there is nothing positive that can come from this, only things that are adverse,” or that the tissues are an “incredible liability,” and continue on, regardless?

And if you’re thinking, “If these people want to get sick, why not just have someone sneeze on them?” Don’t be ridiculous. Focus testers responded highly negatively to simply being handed a dirty tissue. The premium packaging and high price tag are a necessity.

Our advice? Well, as tempting as all this sounds, we think we’ll stick with washing our hands and not sticking used tissues in our faces. You know, like reasonable people.

Why Bullwinkle thinks pink

Flying squirrels are secretly doing their best flamingo impression – who knew? A forestry professor discovered, by happy accident, that flying squirrels are fluorescent – they glow hot pink under ultraviolet light.

shabeerthurakkal/iStock/Getty Images Plus

Turns out, almost all species of gliders – even blue-helmeted Rocket “Rocky” J. Squirrel – are members of the Pink Ladies. They are one of the very few glowing mammals; the only other known mammalian species to have fluorescent fur are certain opossums.

But why do these airborne rodents glow pink? Is it because of an overintake of bubblegum? Are flying squirrels just really flamboyant but also shy? Are they huge fans of the singer Pink?

A biologist involved in studying these colorful critters hypothesized that the reason is slightly more related to environment than musical preference. Flying squirrels are nocturnal, making them most active when UV light is most prominent. The garish glow might have something to do with nighttime perception.

However, we don’t know the answer for sure. And in the meantime, we can choose to believe flying squirrels eat way too much cotton candy.
 

Buzz, feed, diet. Repeat

Guns don’t hurt this mass murderer. Police can’t arrest it. Background checks are pointless. A border wall won’t keep it out. So, how do you stop a mosquito?

James Gathany/CDC

Diet drugs.

Because female mosquitoes transmit malaria, Zika, and other diseases when they move from person to person feeding on human blood, investigators sought to curb that appetite by chemically re-creating the feeling of fullness they get after a big meal.

The lady killers in their study – Aedes aegypti, to be exact – when given an antiobesity drug that suppresses human appetite by activating neuropeptide receptors that regulate food intake, turned away from a tempting piece of nylon stocking that had been worn by one of the researchers. Further work showed that treated mosquitoes were as disinterested in feeding on a live mouse as mosquitoes that had already enjoyed a full blood meal.

The LOTME research staff (What? Of course, we have a research staff. You don’t?) is working on the mosquito problem too, although we’ve taken a somewhat different approach: The “volunteers” who walk into the mosquito-filled room wear a sign that says, “My blood will make your butt look bigger.”

E-cigarettes might be more effective for smoking cessation than nicotine replacement therapy, results of a randomized study of almost 900 adults suggest.

ArminStautBerlin/Thinkstock

Rates of abstinence at 1 year were 18% for adults who used refillable e-cigarettes to wean themselves off smoking, according to the reported results, compared with about 10% for those who tried nicotine replacement therapies.

“This is particularly noteworthy given that nicotine replacement was used under expert guidance, with access to the full range of nicotine replacement products, and with 88.1% of participants using combination treatments,” said investigator Peter Hajek, PhD, of Queen Mary University of London, and his coauthors in the New England Journal of Medicine.

The findings contrast with those of earlier studies, which showed a lesser effect of e-cigarettes as a stop-smoking strategy, Dr. Hajek and coauthors wrote.

In previous studies, participants used first-generation cartridge-based e-cigarettes, while in the present study, they were given second-generation refillable e-cigarettes and free choice of e-liquids, the authors noted. Moreover, those previous studies provided limited face-to-face support, they said, but this study included weekly behavioral support for at least 4 weeks in both the e-cigarette and nicotine replacement groups.

The randomized study by Dr. Hajek and his colleagues included 886 adults in the United Kingdom attending stop-smoking services provided by the U.K. National Health Service. They were randomized to receive either an e-cigarette starter pack and one bottle of nicotine-containing e-liquid, or 3 months’ worth of nicotine replacement products of their own choosing. At the 52-week validation visits, the study participants received about the equivalence of about $26 U.S. dollars for their travel and time.

Abstinence from smoking at 52 weeks, which was verified by measuring expired carbon monoxide levels, was achieved in 18.0% of the e-cigarette group and 9.9% of the nicotine replacement group (relative risk, 1.83; 95% confidence interval, 1.30-2.58; P less than .001), according to the report.

However, the rate of continued e-cigarette use was “fairly high,” investigators wrote. Eighty percent of the e-cigarette group was still using their assigned product at 52 weeks, compared with just 9% in the nicotine replacement group.

“This can be seen as problematic if e-cigarette use for a year signals long-term use, which may pose as-yet-unknown health risks,” they said.

Tobacco withdrawal symptoms were less severe and satisfaction ratings were higher with e-cigarettes versus nicotine replacement therapy, similar to what had been observed in previous studies, investigators said.

They cited several limitations. For example, product assignments were not blinded. However, the investigators said they tried to “limit expectation effects by recruiting only participants with no strong product preference.”

Dr. Hajek reported grants and fees from Pfizer unrelated to the present study. Coauthors reported disclosures related to Pfizer and Johnson and Johnson, along with grants from the U.K. National Institute for Health Research.
 

SOURCE: Hajek P et al. N Engl J Med. 2019;380:629-37. doi: 10.1056/NEJMoa1808779.

E-cigarettes might be more effective for smoking cessation than nicotine replacement therapy, results of a randomized study of almost 900 adults suggest.

ArminStautBerlin/Thinkstock

Rates of abstinence at 1 year were 18% for adults who used refillable e-cigarettes to wean themselves off smoking, according to the reported results, compared with about 10% for those who tried nicotine replacement therapies.

“This is particularly noteworthy given that nicotine replacement was used under expert guidance, with access to the full range of nicotine replacement products, and with 88.1% of participants using combination treatments,” said investigator Peter Hajek, PhD, of Queen Mary University of London, and his coauthors in the New England Journal of Medicine.

The findings contrast with those of earlier studies, which showed a lesser effect of e-cigarettes as a stop-smoking strategy, Dr. Hajek and coauthors wrote.

In previous studies, participants used first-generation cartridge-based e-cigarettes, while in the present study, they were given second-generation refillable e-cigarettes and free choice of e-liquids, the authors noted. Moreover, those previous studies provided limited face-to-face support, they said, but this study included weekly behavioral support for at least 4 weeks in both the e-cigarette and nicotine replacement groups.

The randomized study by Dr. Hajek and his colleagues included 886 adults in the United Kingdom attending stop-smoking services provided by the U.K. National Health Service. They were randomized to receive either an e-cigarette starter pack and one bottle of nicotine-containing e-liquid, or 3 months’ worth of nicotine replacement products of their own choosing. At the 52-week validation visits, the study participants received about the equivalence of about $26 U.S. dollars for their travel and time.

Abstinence from smoking at 52 weeks, which was verified by measuring expired carbon monoxide levels, was achieved in 18.0% of the e-cigarette group and 9.9% of the nicotine replacement group (relative risk, 1.83; 95% confidence interval, 1.30-2.58; P less than .001), according to the report.

However, the rate of continued e-cigarette use was “fairly high,” investigators wrote. Eighty percent of the e-cigarette group was still using their assigned product at 52 weeks, compared with just 9% in the nicotine replacement group.

“This can be seen as problematic if e-cigarette use for a year signals long-term use, which may pose as-yet-unknown health risks,” they said.

Tobacco withdrawal symptoms were less severe and satisfaction ratings were higher with e-cigarettes versus nicotine replacement therapy, similar to what had been observed in previous studies, investigators said.

They cited several limitations. For example, product assignments were not blinded. However, the investigators said they tried to “limit expectation effects by recruiting only participants with no strong product preference.”

Dr. Hajek reported grants and fees from Pfizer unrelated to the present study. Coauthors reported disclosures related to Pfizer and Johnson and Johnson, along with grants from the U.K. National Institute for Health Research.
 

SOURCE: Hajek P et al. N Engl J Med. 2019;380:629-37. doi: 10.1056/NEJMoa1808779.

E-cigarettes might be more effective for smoking cessation than nicotine replacement therapy, results of a randomized study of almost 900 adults suggest.

ArminStautBerlin/Thinkstock

Rates of abstinence at 1 year were 18% for adults who used refillable e-cigarettes to wean themselves off smoking, according to the reported results, compared with about 10% for those who tried nicotine replacement therapies.

“This is particularly noteworthy given that nicotine replacement was used under expert guidance, with access to the full range of nicotine replacement products, and with 88.1% of participants using combination treatments,” said investigator Peter Hajek, PhD, of Queen Mary University of London, and his coauthors in the New England Journal of Medicine.

The findings contrast with those of earlier studies, which showed a lesser effect of e-cigarettes as a stop-smoking strategy, Dr. Hajek and coauthors wrote.

In previous studies, participants used first-generation cartridge-based e-cigarettes, while in the present study, they were given second-generation refillable e-cigarettes and free choice of e-liquids, the authors noted. Moreover, those previous studies provided limited face-to-face support, they said, but this study included weekly behavioral support for at least 4 weeks in both the e-cigarette and nicotine replacement groups.

The randomized study by Dr. Hajek and his colleagues included 886 adults in the United Kingdom attending stop-smoking services provided by the U.K. National Health Service. They were randomized to receive either an e-cigarette starter pack and one bottle of nicotine-containing e-liquid, or 3 months’ worth of nicotine replacement products of their own choosing. At the 52-week validation visits, the study participants received about the equivalence of about $26 U.S. dollars for their travel and time.

Abstinence from smoking at 52 weeks, which was verified by measuring expired carbon monoxide levels, was achieved in 18.0% of the e-cigarette group and 9.9% of the nicotine replacement group (relative risk, 1.83; 95% confidence interval, 1.30-2.58; P less than .001), according to the report.

However, the rate of continued e-cigarette use was “fairly high,” investigators wrote. Eighty percent of the e-cigarette group was still using their assigned product at 52 weeks, compared with just 9% in the nicotine replacement group.

“This can be seen as problematic if e-cigarette use for a year signals long-term use, which may pose as-yet-unknown health risks,” they said.

Tobacco withdrawal symptoms were less severe and satisfaction ratings were higher with e-cigarettes versus nicotine replacement therapy, similar to what had been observed in previous studies, investigators said.

They cited several limitations. For example, product assignments were not blinded. However, the investigators said they tried to “limit expectation effects by recruiting only participants with no strong product preference.”

Dr. Hajek reported grants and fees from Pfizer unrelated to the present study. Coauthors reported disclosures related to Pfizer and Johnson and Johnson, along with grants from the U.K. National Institute for Health Research.
 

SOURCE: Hajek P et al. N Engl J Med. 2019;380:629-37. doi: 10.1056/NEJMoa1808779.

LONDON – Being unable to take leave and experiencing poor mental health are just two of the reasons uncovered that may help explain why some women choose not to complete their surgical training, despite having wanted to be a surgeon for many years, a study of women in surgical training has found. The results were presented at a press briefing and published in a special edition of the Lancet.

These factors are in addition to some previously identified, such as the long working hours, fatigue and sleep deprivation, unpredictable lifestyle and its effects on maintaining personal relationships, and the ability to both start and maintain a family life. Then there are the more serious issues of sexism and discrimination, bullying, and sexual harassment and assault that women face in a still male-dominated field that have been noted in prior studies.

“Women are underrepresented in surgery and leave training in higher proportions than men,” study lead Rhea Liang, MBChB, and coauthors wrote (Lancet. 2019;393:541-9). Previous attempts to understand why this is the case “have been confounded by not fully understanding the problem,” they suggested in the briefing. Their research took a more qualitative and feminist approach than other studies, consulting women who had chosen to leave rather than those who continued their surgical training.

Dr. Liang is a consultant general and breast surgeon based at the Gold Coast Hospital and Health Service in Robina, Australia, who personally interviewed women who had decided to leave their surgical training, some as early as 6 months and others up to 4 years after initiation, for reasons other than underperformance.

A “snowball approach” was used to recruit women whereby women who had agreed to participate were asked to refer others. Although only 12 women were interviewed, it’s quality over quantity, Dr. Liang said in a response to a Twitter comment on the study size. “The study is carried out in Australia where about 300 training places are offered across all the specialties annually. About 30% are women; 20% of those women choose to leave. So, if you do the maths, you’ll see that we actually recruited quite well,” she said at the briefing.

According to The Royal College of Practitioners, women made up a very small percentage of consultant surgeons in England in 2016 (11.1%), which didn’t change much by 2018 (12.2%). This is despite a high percentage (58%) of women being accepted onto university courses in medicine and dentistry (58% in 2016). So why so do so few women end up as surgeons?

“Training is a ‘pinch point’ at which women leave surgery,” Tim Dornan, PhD, noted at the launch of the special edition of the Lancet in which the findings appear. Dr. Dornan is professor of medical and interprofessional education at Queen’s University Belfast (Ireland) and one of the coauthors of the research.

This choice to leave surgery deprives society of able surgeons-to-be,” Dr. Dornan said, noting that there was evidence to suggest that women make as good, if not better, surgeons than men. The decision to leave also deprives women of career opportunities and potentially deprives patients of receiving the best surgical care.

“Something very striking about this research is that women who left within an average of 6-18 months after starting surgical training might have wanted to be surgeons from their teenage years, so it seems something happens at that pinch point which makes women to choose to leave.”

Qualitative research is a good way to understand causality in complex social systems, Dr. Dornan explained. Furthermore, “it’s equitable. If you use an open exploratory method, it’s entirely up to the participants to frame the research, it’s not done a priori, and it has the potential for great policy impact.”

Dr. Liang and team found that multiple factors played a role in the decision to leave surgical training, which on their own might be seemingly small, but when stacked on top of each other formed a tower, which was in danger of toppling after a threshold of three or four factors was reached. To exhaustion and lack of opportunity to learn, for example, could be added bullying, and then being denied leave while it is granted for a male colleague for a similar requested reason. The cumulative impact of these factors may all add up to create the impetus to leave.

“Just as a tower of blocks can rebalanced with small adjustments, out study indicates that relatively small interventions (e.g., a cup of tea or a supportive chat) could have been effective in preventing them choosing to leave,” she said.

However, they advocate targeting interventions at all trainees and not just women, to reduce gender differences as focusing on women would be more likely to exaggerate the “otherness” of women further and alienate male trainees. They suggest: “Women might be best helped by interventions that are alert to the possibility of unplanned negative effects, do not unduly focus on gender, and address multiple factors.”

“If you really want to benefit women you should benefit everybody and address the root problem, which is the harsh conditions of training,” Dr. Dornan said. “The prediction would be that, if you do that, then you will actually retain men as well as women.”

The research appears in a special edition of the Lancet that promotes advancing women in science, medicine, and global health.
 

SOURCE: Liang R et al. Lancet. 2019;393:541-9.

LONDON – Being unable to take leave and experiencing poor mental health are just two of the reasons uncovered that may help explain why some women choose not to complete their surgical training, despite having wanted to be a surgeon for many years, a study of women in surgical training has found. The results were presented at a press briefing and published in a special edition of the Lancet.

These factors are in addition to some previously identified, such as the long working hours, fatigue and sleep deprivation, unpredictable lifestyle and its effects on maintaining personal relationships, and the ability to both start and maintain a family life. Then there are the more serious issues of sexism and discrimination, bullying, and sexual harassment and assault that women face in a still male-dominated field that have been noted in prior studies.

“Women are underrepresented in surgery and leave training in higher proportions than men,” study lead Rhea Liang, MBChB, and coauthors wrote (Lancet. 2019;393:541-9). Previous attempts to understand why this is the case “have been confounded by not fully understanding the problem,” they suggested in the briefing. Their research took a more qualitative and feminist approach than other studies, consulting women who had chosen to leave rather than those who continued their surgical training.

Dr. Liang is a consultant general and breast surgeon based at the Gold Coast Hospital and Health Service in Robina, Australia, who personally interviewed women who had decided to leave their surgical training, some as early as 6 months and others up to 4 years after initiation, for reasons other than underperformance.

A “snowball approach” was used to recruit women whereby women who had agreed to participate were asked to refer others. Although only 12 women were interviewed, it’s quality over quantity, Dr. Liang said in a response to a Twitter comment on the study size. “The study is carried out in Australia where about 300 training places are offered across all the specialties annually. About 30% are women; 20% of those women choose to leave. So, if you do the maths, you’ll see that we actually recruited quite well,” she said at the briefing.

According to The Royal College of Practitioners, women made up a very small percentage of consultant surgeons in England in 2016 (11.1%), which didn’t change much by 2018 (12.2%). This is despite a high percentage (58%) of women being accepted onto university courses in medicine and dentistry (58% in 2016). So why so do so few women end up as surgeons?

“Training is a ‘pinch point’ at which women leave surgery,” Tim Dornan, PhD, noted at the launch of the special edition of the Lancet in which the findings appear. Dr. Dornan is professor of medical and interprofessional education at Queen’s University Belfast (Ireland) and one of the coauthors of the research.

This choice to leave surgery deprives society of able surgeons-to-be,” Dr. Dornan said, noting that there was evidence to suggest that women make as good, if not better, surgeons than men. The decision to leave also deprives women of career opportunities and potentially deprives patients of receiving the best surgical care.

“Something very striking about this research is that women who left within an average of 6-18 months after starting surgical training might have wanted to be surgeons from their teenage years, so it seems something happens at that pinch point which makes women to choose to leave.”

Qualitative research is a good way to understand causality in complex social systems, Dr. Dornan explained. Furthermore, “it’s equitable. If you use an open exploratory method, it’s entirely up to the participants to frame the research, it’s not done a priori, and it has the potential for great policy impact.”

Dr. Liang and team found that multiple factors played a role in the decision to leave surgical training, which on their own might be seemingly small, but when stacked on top of each other formed a tower, which was in danger of toppling after a threshold of three or four factors was reached. To exhaustion and lack of opportunity to learn, for example, could be added bullying, and then being denied leave while it is granted for a male colleague for a similar requested reason. The cumulative impact of these factors may all add up to create the impetus to leave.

“Just as a tower of blocks can rebalanced with small adjustments, out study indicates that relatively small interventions (e.g., a cup of tea or a supportive chat) could have been effective in preventing them choosing to leave,” she said.

However, they advocate targeting interventions at all trainees and not just women, to reduce gender differences as focusing on women would be more likely to exaggerate the “otherness” of women further and alienate male trainees. They suggest: “Women might be best helped by interventions that are alert to the possibility of unplanned negative effects, do not unduly focus on gender, and address multiple factors.”

“If you really want to benefit women you should benefit everybody and address the root problem, which is the harsh conditions of training,” Dr. Dornan said. “The prediction would be that, if you do that, then you will actually retain men as well as women.”

The research appears in a special edition of the Lancet that promotes advancing women in science, medicine, and global health.
 

SOURCE: Liang R et al. Lancet. 2019;393:541-9.

LONDON – Being unable to take leave and experiencing poor mental health are just two of the reasons uncovered that may help explain why some women choose not to complete their surgical training, despite having wanted to be a surgeon for many years, a study of women in surgical training has found. The results were presented at a press briefing and published in a special edition of the Lancet.

These factors are in addition to some previously identified, such as the long working hours, fatigue and sleep deprivation, unpredictable lifestyle and its effects on maintaining personal relationships, and the ability to both start and maintain a family life. Then there are the more serious issues of sexism and discrimination, bullying, and sexual harassment and assault that women face in a still male-dominated field that have been noted in prior studies.

“Women are underrepresented in surgery and leave training in higher proportions than men,” study lead Rhea Liang, MBChB, and coauthors wrote (Lancet. 2019;393:541-9). Previous attempts to understand why this is the case “have been confounded by not fully understanding the problem,” they suggested in the briefing. Their research took a more qualitative and feminist approach than other studies, consulting women who had chosen to leave rather than those who continued their surgical training.

Dr. Liang is a consultant general and breast surgeon based at the Gold Coast Hospital and Health Service in Robina, Australia, who personally interviewed women who had decided to leave their surgical training, some as early as 6 months and others up to 4 years after initiation, for reasons other than underperformance.

A “snowball approach” was used to recruit women whereby women who had agreed to participate were asked to refer others. Although only 12 women were interviewed, it’s quality over quantity, Dr. Liang said in a response to a Twitter comment on the study size. “The study is carried out in Australia where about 300 training places are offered across all the specialties annually. About 30% are women; 20% of those women choose to leave. So, if you do the maths, you’ll see that we actually recruited quite well,” she said at the briefing.

According to The Royal College of Practitioners, women made up a very small percentage of consultant surgeons in England in 2016 (11.1%), which didn’t change much by 2018 (12.2%). This is despite a high percentage (58%) of women being accepted onto university courses in medicine and dentistry (58% in 2016). So why so do so few women end up as surgeons?

“Training is a ‘pinch point’ at which women leave surgery,” Tim Dornan, PhD, noted at the launch of the special edition of the Lancet in which the findings appear. Dr. Dornan is professor of medical and interprofessional education at Queen’s University Belfast (Ireland) and one of the coauthors of the research.

This choice to leave surgery deprives society of able surgeons-to-be,” Dr. Dornan said, noting that there was evidence to suggest that women make as good, if not better, surgeons than men. The decision to leave also deprives women of career opportunities and potentially deprives patients of receiving the best surgical care.

“Something very striking about this research is that women who left within an average of 6-18 months after starting surgical training might have wanted to be surgeons from their teenage years, so it seems something happens at that pinch point which makes women to choose to leave.”

Qualitative research is a good way to understand causality in complex social systems, Dr. Dornan explained. Furthermore, “it’s equitable. If you use an open exploratory method, it’s entirely up to the participants to frame the research, it’s not done a priori, and it has the potential for great policy impact.”

Dr. Liang and team found that multiple factors played a role in the decision to leave surgical training, which on their own might be seemingly small, but when stacked on top of each other formed a tower, which was in danger of toppling after a threshold of three or four factors was reached. To exhaustion and lack of opportunity to learn, for example, could be added bullying, and then being denied leave while it is granted for a male colleague for a similar requested reason. The cumulative impact of these factors may all add up to create the impetus to leave.

“Just as a tower of blocks can rebalanced with small adjustments, out study indicates that relatively small interventions (e.g., a cup of tea or a supportive chat) could have been effective in preventing them choosing to leave,” she said.

However, they advocate targeting interventions at all trainees and not just women, to reduce gender differences as focusing on women would be more likely to exaggerate the “otherness” of women further and alienate male trainees. They suggest: “Women might be best helped by interventions that are alert to the possibility of unplanned negative effects, do not unduly focus on gender, and address multiple factors.”

“If you really want to benefit women you should benefit everybody and address the root problem, which is the harsh conditions of training,” Dr. Dornan said. “The prediction would be that, if you do that, then you will actually retain men as well as women.”

The research appears in a special edition of the Lancet that promotes advancing women in science, medicine, and global health.
 

SOURCE: Liang R et al. Lancet. 2019;393:541-9.

The Diagnosis: Pigmented Bowen Disease

A biopsy of the lesion was performed for suspected acral malignant melanoma. Hematoxylin and eosin staining revealed acanthosis, elongation of rete ridges, and keratinocytes in complete disorder with atypical mitoses and pleomorphism affecting the full layer of the epidermis (Figure 1). The basement membrane was intact. Melanin pigmentation was increased in the lower epidermis and the upper dermis, and a lymphohistiocytic inflammatory infiltrate was present in the dermis. Staining for carcinoembryonic antigen (Figure 2) and melanoma
antigen (Figure 3) recognized by T cells (melan-A) both revealed negative results. Histopathologic findings led to the diagnosis of pigmented Bowen disease (BD).

Pigmented BD is a rare variant that accounts for 1.7% (N=420) to 5.5% (N=951) of all cases of BD.^1,2 It is reported to affect men more than women and to be more prevalent in individuals with higher Fitzpatrick skin types.³ Furthermore, exposure to UV radiation, chemicals (eg, arsenic), or human papillomavirus, as well as immunosuppression, are known to be related to pigmented BD.^2,4 Clinically, pigmented BD commonly involves nonexposed areas such as the anogenital area, trunk, and extremities, unlike typical BD that involves sun-exposed areas.⁵ In addition, it most frequently presents as a well-delineated, irregularly pigmented, asymptomatic
plaque and not as a scaly erythematous plaque. Therefore, the clinical diagnosis may be challenging. The differential diagnosis includes malignant melanoma, pigmented extramammary Paget disease, pigmented basal cell carcinoma, seborrheic keratosis, pigmented actinic keratosis, solar lentigo, and melanocytic nevi.

Histopathologically, a varying amount of melanin deposit is noted on hematoxylin and eosin staining, along with features of BD, including disarrayed atypical keratinocytes involving the full epidermis but not the basement membrane, with atypical individual cell keratinization.^3,5,6 Pigmented extramammary Paget disease can mimic pigmented BD clinically and pathologically, but Paget cells stain positive for anticytokeratin (CAM 5.2), carcinoembryonic antigen, and mucicarmine, whereas cells in pigmented BD stain negative.⁷ Moreover, negative staining for human melanoma black, melan-A, and S-100 helps differentiate malignant melanoma from pigmented BD.⁸

The prognosis of pigmented BD is similar to classic BD and is independent of the presence of melanin pigment.⁶ Therefore, the treatment options do not differ from those for typical BD and include surgical excision, cryotherapy, laser ablation, topical imiquimod or 5-fluorouracil, curettage, electrosurgery, and photodynamic therapy (PDT).

In our case, the patient and her family did not want surgical removal; therefore, 1 course of fractional laser-assisted PDT and 2 courses of ablative laser-assisted PDT were performed. Unfortunately, the lesion persisted, possibly because it was too large and pigmented. Two months later, ingenol mebutate gel 0.05% was applied (4 courses) after using an ablative laser over 3 consecutive days with a 1-month interval between courses. The lesion resolved without any adverse events.

The Diagnosis: Pigmented Bowen Disease

A biopsy of the lesion was performed for suspected acral malignant melanoma. Hematoxylin and eosin staining revealed acanthosis, elongation of rete ridges, and keratinocytes in complete disorder with atypical mitoses and pleomorphism affecting the full layer of the epidermis (Figure 1). The basement membrane was intact. Melanin pigmentation was increased in the lower epidermis and the upper dermis, and a lymphohistiocytic inflammatory infiltrate was present in the dermis. Staining for carcinoembryonic antigen (Figure 2) and melanoma
antigen (Figure 3) recognized by T cells (melan-A) both revealed negative results. Histopathologic findings led to the diagnosis of pigmented Bowen disease (BD).

Pigmented BD is a rare variant that accounts for 1.7% (N=420) to 5.5% (N=951) of all cases of BD.^1,2 It is reported to affect men more than women and to be more prevalent in individuals with higher Fitzpatrick skin types.³ Furthermore, exposure to UV radiation, chemicals (eg, arsenic), or human papillomavirus, as well as immunosuppression, are known to be related to pigmented BD.^2,4 Clinically, pigmented BD commonly involves nonexposed areas such as the anogenital area, trunk, and extremities, unlike typical BD that involves sun-exposed areas.⁵ In addition, it most frequently presents as a well-delineated, irregularly pigmented, asymptomatic
plaque and not as a scaly erythematous plaque. Therefore, the clinical diagnosis may be challenging. The differential diagnosis includes malignant melanoma, pigmented extramammary Paget disease, pigmented basal cell carcinoma, seborrheic keratosis, pigmented actinic keratosis, solar lentigo, and melanocytic nevi.

Histopathologically, a varying amount of melanin deposit is noted on hematoxylin and eosin staining, along with features of BD, including disarrayed atypical keratinocytes involving the full epidermis but not the basement membrane, with atypical individual cell keratinization.^3,5,6 Pigmented extramammary Paget disease can mimic pigmented BD clinically and pathologically, but Paget cells stain positive for anticytokeratin (CAM 5.2), carcinoembryonic antigen, and mucicarmine, whereas cells in pigmented BD stain negative.⁷ Moreover, negative staining for human melanoma black, melan-A, and S-100 helps differentiate malignant melanoma from pigmented BD.⁸

The prognosis of pigmented BD is similar to classic BD and is independent of the presence of melanin pigment.⁶ Therefore, the treatment options do not differ from those for typical BD and include surgical excision, cryotherapy, laser ablation, topical imiquimod or 5-fluorouracil, curettage, electrosurgery, and photodynamic therapy (PDT).

In our case, the patient and her family did not want surgical removal; therefore, 1 course of fractional laser-assisted PDT and 2 courses of ablative laser-assisted PDT were performed. Unfortunately, the lesion persisted, possibly because it was too large and pigmented. Two months later, ingenol mebutate gel 0.05% was applied (4 courses) after using an ablative laser over 3 consecutive days with a 1-month interval between courses. The lesion resolved without any adverse events.

The Diagnosis: Pigmented Bowen Disease

A biopsy of the lesion was performed for suspected acral malignant melanoma. Hematoxylin and eosin staining revealed acanthosis, elongation of rete ridges, and keratinocytes in complete disorder with atypical mitoses and pleomorphism affecting the full layer of the epidermis (Figure 1). The basement membrane was intact. Melanin pigmentation was increased in the lower epidermis and the upper dermis, and a lymphohistiocytic inflammatory infiltrate was present in the dermis. Staining for carcinoembryonic antigen (Figure 2) and melanoma
antigen (Figure 3) recognized by T cells (melan-A) both revealed negative results. Histopathologic findings led to the diagnosis of pigmented Bowen disease (BD).

Pigmented BD is a rare variant that accounts for 1.7% (N=420) to 5.5% (N=951) of all cases of BD.^1,2 It is reported to affect men more than women and to be more prevalent in individuals with higher Fitzpatrick skin types.³ Furthermore, exposure to UV radiation, chemicals (eg, arsenic), or human papillomavirus, as well as immunosuppression, are known to be related to pigmented BD.^2,4 Clinically, pigmented BD commonly involves nonexposed areas such as the anogenital area, trunk, and extremities, unlike typical BD that involves sun-exposed areas.⁵ In addition, it most frequently presents as a well-delineated, irregularly pigmented, asymptomatic
plaque and not as a scaly erythematous plaque. Therefore, the clinical diagnosis may be challenging. The differential diagnosis includes malignant melanoma, pigmented extramammary Paget disease, pigmented basal cell carcinoma, seborrheic keratosis, pigmented actinic keratosis, solar lentigo, and melanocytic nevi.

Histopathologically, a varying amount of melanin deposit is noted on hematoxylin and eosin staining, along with features of BD, including disarrayed atypical keratinocytes involving the full epidermis but not the basement membrane, with atypical individual cell keratinization.^3,5,6 Pigmented extramammary Paget disease can mimic pigmented BD clinically and pathologically, but Paget cells stain positive for anticytokeratin (CAM 5.2), carcinoembryonic antigen, and mucicarmine, whereas cells in pigmented BD stain negative.⁷ Moreover, negative staining for human melanoma black, melan-A, and S-100 helps differentiate malignant melanoma from pigmented BD.⁸

The prognosis of pigmented BD is similar to classic BD and is independent of the presence of melanin pigment.⁶ Therefore, the treatment options do not differ from those for typical BD and include surgical excision, cryotherapy, laser ablation, topical imiquimod or 5-fluorouracil, curettage, electrosurgery, and photodynamic therapy (PDT).

In our case, the patient and her family did not want surgical removal; therefore, 1 course of fractional laser-assisted PDT and 2 courses of ablative laser-assisted PDT were performed. Unfortunately, the lesion persisted, possibly because it was too large and pigmented. Two months later, ingenol mebutate gel 0.05% was applied (4 courses) after using an ablative laser over 3 consecutive days with a 1-month interval between courses. The lesion resolved without any adverse events.

To the Editor:

Cutaneous microangiopathy describes pathology of the small blood vessels within the dermis. Cutaneous collagenous vasculopathy (CCV) is a rare manifestation of cutaneous microangiopathy with only 38 reported cases in the literature, according to a PubMed search of articles indexed for MEDLINE using the term cutaneous collagenous vasculopathy. This disorder must be distinguished from generalized essential telangiectasia, which generally does not warrant a biopsy. Prior case reports have demonstrated predominance of CCV in middle-aged men; however, women and adolescents also may be affected.^1-5

We report a case of CCV in a 41-year-old woman who presented for evaluation of a rash on the bilateral lower extremities of 7 to 8 months’ duration. The eruption had started on the left ankle and spread over several weeks to the bilateral dorsal feet followed by the ankles and shins. The patient noted associated swelling and a pressure like dysesthesia of the lower legs. She was otherwise in good health, though she had started an oral contraceptive 1 year prior for heavy menstrual bleeding. A review of systems was negative for deep vein thrombosis, pulmonary embolus, and other thromboembolic phenomena, and the patient had no history of hepatic or renal dysfunction, cancer, or heart disease. Her family history was negative for clotting disorders or bleeding diatheses.

On physical examination, telangiectatic matting was present on the bilateral ankles and dorsal feet with an associated blanchable erythema (Figure 1). The matting extended into a fine, mottled, pretibial telangiectasia associated with Schamberg purpura. She had no pitting edema, and both dorsalis pedis and posterior popliteal pulses were intact and symmetric bilaterally. No popliteal lymphadenopathy or palpable cords were present.

To the Editor:

Cutaneous microangiopathy describes pathology of the small blood vessels within the dermis. Cutaneous collagenous vasculopathy (CCV) is a rare manifestation of cutaneous microangiopathy with only 38 reported cases in the literature, according to a PubMed search of articles indexed for MEDLINE using the term cutaneous collagenous vasculopathy. This disorder must be distinguished from generalized essential telangiectasia, which generally does not warrant a biopsy. Prior case reports have demonstrated predominance of CCV in middle-aged men; however, women and adolescents also may be affected.^1-5

We report a case of CCV in a 41-year-old woman who presented for evaluation of a rash on the bilateral lower extremities of 7 to 8 months’ duration. The eruption had started on the left ankle and spread over several weeks to the bilateral dorsal feet followed by the ankles and shins. The patient noted associated swelling and a pressure like dysesthesia of the lower legs. She was otherwise in good health, though she had started an oral contraceptive 1 year prior for heavy menstrual bleeding. A review of systems was negative for deep vein thrombosis, pulmonary embolus, and other thromboembolic phenomena, and the patient had no history of hepatic or renal dysfunction, cancer, or heart disease. Her family history was negative for clotting disorders or bleeding diatheses.

On physical examination, telangiectatic matting was present on the bilateral ankles and dorsal feet with an associated blanchable erythema (Figure 1). The matting extended into a fine, mottled, pretibial telangiectasia associated with Schamberg purpura. She had no pitting edema, and both dorsalis pedis and posterior popliteal pulses were intact and symmetric bilaterally. No popliteal lymphadenopathy or palpable cords were present.

To the Editor:

Cutaneous microangiopathy describes pathology of the small blood vessels within the dermis. Cutaneous collagenous vasculopathy (CCV) is a rare manifestation of cutaneous microangiopathy with only 38 reported cases in the literature, according to a PubMed search of articles indexed for MEDLINE using the term cutaneous collagenous vasculopathy. This disorder must be distinguished from generalized essential telangiectasia, which generally does not warrant a biopsy. Prior case reports have demonstrated predominance of CCV in middle-aged men; however, women and adolescents also may be affected.^1-5

We report a case of CCV in a 41-year-old woman who presented for evaluation of a rash on the bilateral lower extremities of 7 to 8 months’ duration. The eruption had started on the left ankle and spread over several weeks to the bilateral dorsal feet followed by the ankles and shins. The patient noted associated swelling and a pressure like dysesthesia of the lower legs. She was otherwise in good health, though she had started an oral contraceptive 1 year prior for heavy menstrual bleeding. A review of systems was negative for deep vein thrombosis, pulmonary embolus, and other thromboembolic phenomena, and the patient had no history of hepatic or renal dysfunction, cancer, or heart disease. Her family history was negative for clotting disorders or bleeding diatheses.

On physical examination, telangiectatic matting was present on the bilateral ankles and dorsal feet with an associated blanchable erythema (Figure 1). The matting extended into a fine, mottled, pretibial telangiectasia associated with Schamberg purpura. She had no pitting edema, and both dorsalis pedis and posterior popliteal pulses were intact and symmetric bilaterally. No popliteal lymphadenopathy or palpable cords were present.

To the Editor:

Elephantiasis nostras verrucosa (ENV) is a skin disorder caused by marked underlying lymphedema that leads to hyperkeratosis, papillomatosis, and verrucous growths on the epidermis.¹ The pathophysiology of ENV relates to noninfectious lymphatic obstruction and lymphatic fibrosis secondary to venous stasis, malignancy, radiation therapy, or trauma.² We present an unusual case of lymphedema and subsequent ENV limited to the arms and hands in a patient with scleroderma, an autoimmune fibrosing disorder.

A 54-year-old woman with a 5-year history of scleroderma presented to our dermatology clinic for treatment of progressive skin changes including pruritus, tightness, finger ulcerations, and pus exuding from papules on the dorsal arms and hands. She had been experiencing several systemic symptoms including dysphagia and lung involvement, necessitating oxygen therapy and a continuous positive airway pressure device for pulmonary arterial hypertension. A computed tomography scan of the lungs demonstrated an increase in ground-glass infiltrates in the right lower lobe and an air-fluid level in the esophagus. At the time of presentation, she was being treated with bosentan and sildenafil for pulmonary arterial hypertension, in addition to prednisone, venlafaxine, lansoprazole, metoclopramide, levothyroxine, temazepam, aspirin, and oxycodone. In the 2 years prior to presentation, she had been treated with intravenous cyclophosphamide once monthly for 6 months, adalimumab for 1 year, and 1 session of photodynamic therapy to the arms, all without benefit.

Physical examination showed cutaneous signs of scleroderma including marked sclerosis of the skin on the face, hands, V of the neck, proximal arms, and mid and proximal thighs. Excoriated papules with overlying crusting and pustulation were superimposed on the sclerotic skin of the arms (Figure 1).

At 3-week follow-up, a trial of narrowband UVB therapy was recommended for control of pruritus. Two weeks later, a modified wet-wrap regimen using clobetasol ointment 0.5% twice daily covered with wet gauze followed by a self-adherent dressing was initiated only on the right arm for comparison purposes. This treatment was not successful. A biopsy taken from the left arm showed lymphedema with perivascular fibroplasia and epidermal hyperplasia consistent with ENV (Figure 2).

Elephantiasis nostras verrucosa is differentiated from elephantiasis tropica, which is caused by a filarial infection of the lymphatic system. The chronic obstructive lymphedema characteristic of ENV can present as a result of various primary or secondary etiologies including trauma, malignancy, venous stasis, inflammation, or infection.³ In systemic sclerosis, extravascular fibrosis theoretically can lead to lymphatic obstruction and subsequent lymphatic stasis. In turn, the pathophysiology of dermal and subcutaneous fibrosis likely reflects autoantibodies (eg, anticardiolipin antibodies) that can damage lymphatic and nonlymphatic vessels.^4,5 With prolonged lymphostasis, excess protein-rich interstitial fluid accumulates, inducing fibroblast proliferation and inhibiting the local immune response.¹

As the underlying mechanism of ENV, fibrosis of lymphatic vessels in systemic sclerosis is not well documented. Characteristic features of systemic sclerosis include extensive fibrosis, fibroproliferative vasculopathy, and inflammation, which are all possible mechanisms for the internal lymphatic obstruction resulting in the skin changes observed in ENV.⁶ It seemed unusual that the fibrotic changes of lymphatic vessels in our patient were extensive enough to cause ENV of the upper extremities; lower extremity involvement is the more common presentation because of the greater likelihood of lymphedema manifesting in the legs and feet. Lower extremity ENV has been reported in association with scleroderma.^7,8

Regarding therapeutic options, Boyd et al⁹ reported a good response in a patient with ENV of the abdomen who was treated with topical tazarotene. Additionally, PUVA and MTX have been reported to be beneficial for the progressive skin changes of systemic sclerosis.¹⁰ Mycophenolate mofetil has been used in patients who fail MTX therapy because of its antifibrotic properties without the side-effect profiles of other immunosuppressives, such as imatinib.^10,11 In our patient, skin lesions persisted following these varied approaches, and compression therapy was not advised due to the underlying sclerosis.

Because options for medical treatment of severe ENV are limited, surgical debridement of the affected limb often remains the only viable option in advanced cases.¹² A PubMed search of articles indexed for MEDLINE using the terms elephantiasis (MeSH terms) or elephantiasis (all fields) and scleroderma, systemic (MeSH terms) or scleroderma (all fields) and systemic (all fields) or systemic scleroderma (all fields) or scleroderma (all fields) or scleroderma, localized (MeSH terms) or scleroderma (all fields) and localized (all fields) or localized scleroderma (all fields) yielded only 1 other case report of lower extremity ENV in a patient with systemic sclerosis who ultimately required bilateral leg amputation.⁸ When possible, avoiding lymphostasis through compression and control of any underlying infections is important in the treatment and prevention of ENV.³

To the Editor:

Elephantiasis nostras verrucosa (ENV) is a skin disorder caused by marked underlying lymphedema that leads to hyperkeratosis, papillomatosis, and verrucous growths on the epidermis.¹ The pathophysiology of ENV relates to noninfectious lymphatic obstruction and lymphatic fibrosis secondary to venous stasis, malignancy, radiation therapy, or trauma.² We present an unusual case of lymphedema and subsequent ENV limited to the arms and hands in a patient with scleroderma, an autoimmune fibrosing disorder.

A 54-year-old woman with a 5-year history of scleroderma presented to our dermatology clinic for treatment of progressive skin changes including pruritus, tightness, finger ulcerations, and pus exuding from papules on the dorsal arms and hands. She had been experiencing several systemic symptoms including dysphagia and lung involvement, necessitating oxygen therapy and a continuous positive airway pressure device for pulmonary arterial hypertension. A computed tomography scan of the lungs demonstrated an increase in ground-glass infiltrates in the right lower lobe and an air-fluid level in the esophagus. At the time of presentation, she was being treated with bosentan and sildenafil for pulmonary arterial hypertension, in addition to prednisone, venlafaxine, lansoprazole, metoclopramide, levothyroxine, temazepam, aspirin, and oxycodone. In the 2 years prior to presentation, she had been treated with intravenous cyclophosphamide once monthly for 6 months, adalimumab for 1 year, and 1 session of photodynamic therapy to the arms, all without benefit.

Physical examination showed cutaneous signs of scleroderma including marked sclerosis of the skin on the face, hands, V of the neck, proximal arms, and mid and proximal thighs. Excoriated papules with overlying crusting and pustulation were superimposed on the sclerotic skin of the arms (Figure 1).

At 3-week follow-up, a trial of narrowband UVB therapy was recommended for control of pruritus. Two weeks later, a modified wet-wrap regimen using clobetasol ointment 0.5% twice daily covered with wet gauze followed by a self-adherent dressing was initiated only on the right arm for comparison purposes. This treatment was not successful. A biopsy taken from the left arm showed lymphedema with perivascular fibroplasia and epidermal hyperplasia consistent with ENV (Figure 2).

Elephantiasis nostras verrucosa is differentiated from elephantiasis tropica, which is caused by a filarial infection of the lymphatic system. The chronic obstructive lymphedema characteristic of ENV can present as a result of various primary or secondary etiologies including trauma, malignancy, venous stasis, inflammation, or infection.³ In systemic sclerosis, extravascular fibrosis theoretically can lead to lymphatic obstruction and subsequent lymphatic stasis. In turn, the pathophysiology of dermal and subcutaneous fibrosis likely reflects autoantibodies (eg, anticardiolipin antibodies) that can damage lymphatic and nonlymphatic vessels.^4,5 With prolonged lymphostasis, excess protein-rich interstitial fluid accumulates, inducing fibroblast proliferation and inhibiting the local immune response.¹

As the underlying mechanism of ENV, fibrosis of lymphatic vessels in systemic sclerosis is not well documented. Characteristic features of systemic sclerosis include extensive fibrosis, fibroproliferative vasculopathy, and inflammation, which are all possible mechanisms for the internal lymphatic obstruction resulting in the skin changes observed in ENV.⁶ It seemed unusual that the fibrotic changes of lymphatic vessels in our patient were extensive enough to cause ENV of the upper extremities; lower extremity involvement is the more common presentation because of the greater likelihood of lymphedema manifesting in the legs and feet. Lower extremity ENV has been reported in association with scleroderma.^7,8

Regarding therapeutic options, Boyd et al⁹ reported a good response in a patient with ENV of the abdomen who was treated with topical tazarotene. Additionally, PUVA and MTX have been reported to be beneficial for the progressive skin changes of systemic sclerosis.¹⁰ Mycophenolate mofetil has been used in patients who fail MTX therapy because of its antifibrotic properties without the side-effect profiles of other immunosuppressives, such as imatinib.^10,11 In our patient, skin lesions persisted following these varied approaches, and compression therapy was not advised due to the underlying sclerosis.

Because options for medical treatment of severe ENV are limited, surgical debridement of the affected limb often remains the only viable option in advanced cases.¹² A PubMed search of articles indexed for MEDLINE using the terms elephantiasis (MeSH terms) or elephantiasis (all fields) and scleroderma, systemic (MeSH terms) or scleroderma (all fields) and systemic (all fields) or systemic scleroderma (all fields) or scleroderma (all fields) or scleroderma, localized (MeSH terms) or scleroderma (all fields) and localized (all fields) or localized scleroderma (all fields) yielded only 1 other case report of lower extremity ENV in a patient with systemic sclerosis who ultimately required bilateral leg amputation.⁸ When possible, avoiding lymphostasis through compression and control of any underlying infections is important in the treatment and prevention of ENV.³

To the Editor:

Elephantiasis nostras verrucosa (ENV) is a skin disorder caused by marked underlying lymphedema that leads to hyperkeratosis, papillomatosis, and verrucous growths on the epidermis.¹ The pathophysiology of ENV relates to noninfectious lymphatic obstruction and lymphatic fibrosis secondary to venous stasis, malignancy, radiation therapy, or trauma.² We present an unusual case of lymphedema and subsequent ENV limited to the arms and hands in a patient with scleroderma, an autoimmune fibrosing disorder.

A 54-year-old woman with a 5-year history of scleroderma presented to our dermatology clinic for treatment of progressive skin changes including pruritus, tightness, finger ulcerations, and pus exuding from papules on the dorsal arms and hands. She had been experiencing several systemic symptoms including dysphagia and lung involvement, necessitating oxygen therapy and a continuous positive airway pressure device for pulmonary arterial hypertension. A computed tomography scan of the lungs demonstrated an increase in ground-glass infiltrates in the right lower lobe and an air-fluid level in the esophagus. At the time of presentation, she was being treated with bosentan and sildenafil for pulmonary arterial hypertension, in addition to prednisone, venlafaxine, lansoprazole, metoclopramide, levothyroxine, temazepam, aspirin, and oxycodone. In the 2 years prior to presentation, she had been treated with intravenous cyclophosphamide once monthly for 6 months, adalimumab for 1 year, and 1 session of photodynamic therapy to the arms, all without benefit.

Physical examination showed cutaneous signs of scleroderma including marked sclerosis of the skin on the face, hands, V of the neck, proximal arms, and mid and proximal thighs. Excoriated papules with overlying crusting and pustulation were superimposed on the sclerotic skin of the arms (Figure 1).

At 3-week follow-up, a trial of narrowband UVB therapy was recommended for control of pruritus. Two weeks later, a modified wet-wrap regimen using clobetasol ointment 0.5% twice daily covered with wet gauze followed by a self-adherent dressing was initiated only on the right arm for comparison purposes. This treatment was not successful. A biopsy taken from the left arm showed lymphedema with perivascular fibroplasia and epidermal hyperplasia consistent with ENV (Figure 2).

Elephantiasis nostras verrucosa is differentiated from elephantiasis tropica, which is caused by a filarial infection of the lymphatic system. The chronic obstructive lymphedema characteristic of ENV can present as a result of various primary or secondary etiologies including trauma, malignancy, venous stasis, inflammation, or infection.³ In systemic sclerosis, extravascular fibrosis theoretically can lead to lymphatic obstruction and subsequent lymphatic stasis. In turn, the pathophysiology of dermal and subcutaneous fibrosis likely reflects autoantibodies (eg, anticardiolipin antibodies) that can damage lymphatic and nonlymphatic vessels.^4,5 With prolonged lymphostasis, excess protein-rich interstitial fluid accumulates, inducing fibroblast proliferation and inhibiting the local immune response.¹

As the underlying mechanism of ENV, fibrosis of lymphatic vessels in systemic sclerosis is not well documented. Characteristic features of systemic sclerosis include extensive fibrosis, fibroproliferative vasculopathy, and inflammation, which are all possible mechanisms for the internal lymphatic obstruction resulting in the skin changes observed in ENV.⁶ It seemed unusual that the fibrotic changes of lymphatic vessels in our patient were extensive enough to cause ENV of the upper extremities; lower extremity involvement is the more common presentation because of the greater likelihood of lymphedema manifesting in the legs and feet. Lower extremity ENV has been reported in association with scleroderma.^7,8

Regarding therapeutic options, Boyd et al⁹ reported a good response in a patient with ENV of the abdomen who was treated with topical tazarotene. Additionally, PUVA and MTX have been reported to be beneficial for the progressive skin changes of systemic sclerosis.¹⁰ Mycophenolate mofetil has been used in patients who fail MTX therapy because of its antifibrotic properties without the side-effect profiles of other immunosuppressives, such as imatinib.^10,11 In our patient, skin lesions persisted following these varied approaches, and compression therapy was not advised due to the underlying sclerosis.

Because options for medical treatment of severe ENV are limited, surgical debridement of the affected limb often remains the only viable option in advanced cases.¹² A PubMed search of articles indexed for MEDLINE using the terms elephantiasis (MeSH terms) or elephantiasis (all fields) and scleroderma, systemic (MeSH terms) or scleroderma (all fields) and systemic (all fields) or systemic scleroderma (all fields) or scleroderma (all fields) or scleroderma, localized (MeSH terms) or scleroderma (all fields) and localized (all fields) or localized scleroderma (all fields) yielded only 1 other case report of lower extremity ENV in a patient with systemic sclerosis who ultimately required bilateral leg amputation.⁸ When possible, avoiding lymphostasis through compression and control of any underlying infections is important in the treatment and prevention of ENV.³

To the Editor:

Patients with concurrent neurofibromatosis type 1 (NF-1) and systemic lupus erythematosus (SLE) rarely have been reported in the literature. Neurofibromatosis type 1 is one of the most common genetic disorders, with a worldwide birth incidence of 1 in 2500 individuals and prevalence of 1 in 4000 individuals.¹ The incidence and prevalence of SLE varies widely depending on race and geographic location. Estimated incidence rates for SLE range from 1 to 25 per 100,000 individuals annually in North America, South America, Europe, and Asia.^2,3 The reported worldwide prevalence is 20 to 150 cases per 100,000 individuals annually.^2,4,5

Given the high prevalence of both conditions, the association between SLE and NF-1 likely is underrecognized; therefore, identifying more patients with concurrent SLE and NF-1 and describing the interplay between the 2 conditions may have important therapeutic implications. We present the case of a middle-aged woman with a history of SLE who had cutaneous lesions characteristic of NF-1 to further the understanding of these concurrent conditions.

A middle-aged woman presented to our academic dermatology clinic for evaluation and removal of dark spots that had been present diffusely on the trunk and extremities since birth. She reported a history of SLE with lupus nephritis, hypertension, and a nodular goiter following a partial thyroidectomy. She noted that she did not seek treatment for the skin findings sooner because she was more concerned about her other medical conditions; however, because she felt these conditions were now stable, she decided to seek treatment for the “rash.” Physical examination revealed hundreds of café au lait macules and numerous neurofibromas diffusely distributed on the trunk and extremities (Figure 1) as well as bilateral axillary freckling. A clinical diagnosis of NF-1 was made.

The interplay between an autoimmune condition such as SLE and NF-1, a condition traditionally thought to be due to a genetic mutation, may have greater clinical and therapeutic implications beyond just these two disorders. Although it is well established that RAS pathway disruption causes NF-1, it has been uncovered that dysfunction in the RAS pathway also can contribute to melanoma oncogenesis.^13,14 These insights have led to the development of and approval of targeted drugs designed to inhibit the RAS pathway (eg, vemurafenib, dabrafenib, trametinib).^14-17 Melanoma also is considered a “model” tumor for studying the relationship between the immune system and cancer.¹⁸AKT is a signal transduction pathway that promotes cell survival and growth in various cancers.¹⁵ In addition, deactivation of MEK (part of the RAS pathway) can cause activation of AKT (protein kinase B) signaling and lupus like autoimmune conditions¹⁹ (Figure 2). Likewise, an understanding of the RAS pathway and T-cell function in patients with both SLE and NF-1 may give us more information about melanoma and other cancers.

To make a clinical diagnosis of NF-1, a patient must have 2 of 7 cardinal clinical features as defined by the National Institutes of Health (Table).²⁴ In our patient with hundreds of café au lait macules and dozens of neurofibromas, the diagnosis was clear; however, in other patients, the skin findings of NF-1 may not be as prominent. A patient could meet criteria for NF-1 diagnosis with the inconspicuous presentation of 6 café au lait macules and either 1 plexiform neurofibroma or 2 neurofibromas (of any type) on the entire body.

To the Editor:

Patients with concurrent neurofibromatosis type 1 (NF-1) and systemic lupus erythematosus (SLE) rarely have been reported in the literature. Neurofibromatosis type 1 is one of the most common genetic disorders, with a worldwide birth incidence of 1 in 2500 individuals and prevalence of 1 in 4000 individuals.¹ The incidence and prevalence of SLE varies widely depending on race and geographic location. Estimated incidence rates for SLE range from 1 to 25 per 100,000 individuals annually in North America, South America, Europe, and Asia.^2,3 The reported worldwide prevalence is 20 to 150 cases per 100,000 individuals annually.^2,4,5

Given the high prevalence of both conditions, the association between SLE and NF-1 likely is underrecognized; therefore, identifying more patients with concurrent SLE and NF-1 and describing the interplay between the 2 conditions may have important therapeutic implications. We present the case of a middle-aged woman with a history of SLE who had cutaneous lesions characteristic of NF-1 to further the understanding of these concurrent conditions.

A middle-aged woman presented to our academic dermatology clinic for evaluation and removal of dark spots that had been present diffusely on the trunk and extremities since birth. She reported a history of SLE with lupus nephritis, hypertension, and a nodular goiter following a partial thyroidectomy. She noted that she did not seek treatment for the skin findings sooner because she was more concerned about her other medical conditions; however, because she felt these conditions were now stable, she decided to seek treatment for the “rash.” Physical examination revealed hundreds of café au lait macules and numerous neurofibromas diffusely distributed on the trunk and extremities (Figure 1) as well as bilateral axillary freckling. A clinical diagnosis of NF-1 was made.

The interplay between an autoimmune condition such as SLE and NF-1, a condition traditionally thought to be due to a genetic mutation, may have greater clinical and therapeutic implications beyond just these two disorders. Although it is well established that RAS pathway disruption causes NF-1, it has been uncovered that dysfunction in the RAS pathway also can contribute to melanoma oncogenesis.^13,14 These insights have led to the development of and approval of targeted drugs designed to inhibit the RAS pathway (eg, vemurafenib, dabrafenib, trametinib).^14-17 Melanoma also is considered a “model” tumor for studying the relationship between the immune system and cancer.¹⁸AKT is a signal transduction pathway that promotes cell survival and growth in various cancers.¹⁵ In addition, deactivation of MEK (part of the RAS pathway) can cause activation of AKT (protein kinase B) signaling and lupus like autoimmune conditions¹⁹ (Figure 2). Likewise, an understanding of the RAS pathway and T-cell function in patients with both SLE and NF-1 may give us more information about melanoma and other cancers.

To make a clinical diagnosis of NF-1, a patient must have 2 of 7 cardinal clinical features as defined by the National Institutes of Health (Table).²⁴ In our patient with hundreds of café au lait macules and dozens of neurofibromas, the diagnosis was clear; however, in other patients, the skin findings of NF-1 may not be as prominent. A patient could meet criteria for NF-1 diagnosis with the inconspicuous presentation of 6 café au lait macules and either 1 plexiform neurofibroma or 2 neurofibromas (of any type) on the entire body.

To the Editor:

Patients with concurrent neurofibromatosis type 1 (NF-1) and systemic lupus erythematosus (SLE) rarely have been reported in the literature. Neurofibromatosis type 1 is one of the most common genetic disorders, with a worldwide birth incidence of 1 in 2500 individuals and prevalence of 1 in 4000 individuals.¹ The incidence and prevalence of SLE varies widely depending on race and geographic location. Estimated incidence rates for SLE range from 1 to 25 per 100,000 individuals annually in North America, South America, Europe, and Asia.^2,3 The reported worldwide prevalence is 20 to 150 cases per 100,000 individuals annually.^2,4,5

Given the high prevalence of both conditions, the association between SLE and NF-1 likely is underrecognized; therefore, identifying more patients with concurrent SLE and NF-1 and describing the interplay between the 2 conditions may have important therapeutic implications. We present the case of a middle-aged woman with a history of SLE who had cutaneous lesions characteristic of NF-1 to further the understanding of these concurrent conditions.

A middle-aged woman presented to our academic dermatology clinic for evaluation and removal of dark spots that had been present diffusely on the trunk and extremities since birth. She reported a history of SLE with lupus nephritis, hypertension, and a nodular goiter following a partial thyroidectomy. She noted that she did not seek treatment for the skin findings sooner because she was more concerned about her other medical conditions; however, because she felt these conditions were now stable, she decided to seek treatment for the “rash.” Physical examination revealed hundreds of café au lait macules and numerous neurofibromas diffusely distributed on the trunk and extremities (Figure 1) as well as bilateral axillary freckling. A clinical diagnosis of NF-1 was made.

The interplay between an autoimmune condition such as SLE and NF-1, a condition traditionally thought to be due to a genetic mutation, may have greater clinical and therapeutic implications beyond just these two disorders. Although it is well established that RAS pathway disruption causes NF-1, it has been uncovered that dysfunction in the RAS pathway also can contribute to melanoma oncogenesis.^13,14 These insights have led to the development of and approval of targeted drugs designed to inhibit the RAS pathway (eg, vemurafenib, dabrafenib, trametinib).^14-17 Melanoma also is considered a “model” tumor for studying the relationship between the immune system and cancer.¹⁸AKT is a signal transduction pathway that promotes cell survival and growth in various cancers.¹⁵ In addition, deactivation of MEK (part of the RAS pathway) can cause activation of AKT (protein kinase B) signaling and lupus like autoimmune conditions¹⁹ (Figure 2). Likewise, an understanding of the RAS pathway and T-cell function in patients with both SLE and NF-1 may give us more information about melanoma and other cancers.

To make a clinical diagnosis of NF-1, a patient must have 2 of 7 cardinal clinical features as defined by the National Institutes of Health (Table).²⁴ In our patient with hundreds of café au lait macules and dozens of neurofibromas, the diagnosis was clear; however, in other patients, the skin findings of NF-1 may not be as prominent. A patient could meet criteria for NF-1 diagnosis with the inconspicuous presentation of 6 café au lait macules and either 1 plexiform neurofibroma or 2 neurofibromas (of any type) on the entire body.

I have to admit that I am not sure I am a legacy in hospital medicine, and the term legacy throws me off a bit. I came to medical school after working at McKinsey & Co. consulting, and I chose pediatrics because of my love of working with children and families, as well as a vague notion that I wanted to work on “system” issues, and therefore, more generalist-type training seemed applicable.

I met Chris Landrigan, MD, MPH, and Vinny Chiang, MD, and learned what a hospitalist was, as an intern in 2002. We had a research elective and I was able to publish a couple of papers in Pediatrics on pediatric hospital medicine with Chris and Raj Srivastava, MD, MPH. In 2004, I went to my first Society of Hospital Medicine meeting and met Larry Wellikson, MD, MHM, and others. From there, I went to the Robert Wood Johnson Clinical Scholars Program, with Ron Keren, MD, MPH, and others, and along with faculty from the Cincinnati Children’s in hospital medicine.

In 2007, I applied for a White House Fellowship and told my wife that I didn’t think there was a chance that I would get it, so we should keep building our new home in Cincinnati. We were both surprised when I was selected. I served Michael Leavitt, the then-Secretary of the Department of Health & Human Services, as his White House fellow during the Bush administration, and then served as his chief medical officer. Exposure to health policy and leadership at that level was career shaping. Cincinnati Children’s was searching for a leader for the conversion of pediatric hospital medicine into a full division in 2009. So I returned to Cincinnati to take on leading pediatric hospital medicine, and a role leading quality measurement and improvement efforts for the entire health system. I loved the work and thought I would remain in that role, and our family would be in Cincinnati for a long time. Best laid plans …

In early 2011, Don Berwick, MD, who was then the administrator of the Centers for Medicare & Medicaid Services called and asked whether I “would come talk with him in D.C.” That talk quickly became a series of interviews, and he offered me the opportunity to be chief medical officer of CMS. He said “this platform is like no other to drive change.” He was right. I have been fortunate to have a few step-change opportunities in my life, and that was one.

On my first day at CMS, I looked around the table of senior executives reporting to me and realized they had more than 200 years of CMS experience. I was a bit scared. Together, we led the implementation of Hospital Value-Based Purchasing, the Compare websites, and numerous quality measurement and improvement programs. Partnership for Patients works on patient safety and was associated with preventing more than 3 million infections and adverse events, over 125,000 lives saved, and more than $26 billion in savings.

In early 2013, I was asked to lead the CMS Innovation Center (CMMI). The goal was to launch new payment and service delivery models to improve quality and lower costs. We launched Accountable Care Organizations, Bundled Payment programs, primary care medical homes, state-based innovation, and so much more. Medicare went from zero dollars in alternative payment models, where providers are accountable for quality and total cost of care, to more than 30% of Medicare payments, representing over $200 billion through agreements with more than 200,000 providers in these alternative payment models. It was the biggest shift in U.S. history in how CMS paid for care. Later, I became principal deputy administrator and acting administrator of CMS, leading an agency that spends over $1 trillion per year, or more than $2.5 billion per day and insures over 130 million Americans. We also improved from being bottom quintile in employee engagement and satisfaction across the federal government to No. 2.

I had assumed that, after working at CMS, I would return to a hospital/health system leadership role. But then, a recruiter called about the CEO role at Blue Cross Blue Shield of North Carolina. It is one of the largest not-for-profit health plans in the country and insures most of the people in North Carolina, many for most of their lives. I met a 75-year-old woman the other day that we have insured every day of her life. I am almost a year into the role and it is a mission-driven organization that drives positive change. I love it so far.

We are going to partner with providers, so that more than half of our payments will be in advanced alternative payment models. No payer in the United States has done that yet. This allows us to innovate and decrease friction in the system (e.g., turn off prior authorization) and be jointly accountable with providers for quality and total cost of care. We insure people through the ACA [Affordable Care Act], commercial, and Medicare markets, and are competing to serve Medicaid as well. We have invested more than $50 million to address social determinants of health across the state. We are making major investments in primary care, and mental and behavioral health. Our goal is to be a Model Blue – or a Model of Health Transformation for our state and nation – and achieve better health outcomes, lower costs, and best-in-class experience for all people we serve. I have learned that no physician leads a health plan of this size, and apparently, no practicing physician has ever led a health plan of this size.

What are some lessons learned over my career? I have had five criteria for all my career decisions: 1) family; 2) impact – better care and outcomes, lower costs, and exceptional experience for populations of patients; 3) people – mentors and colleagues; 4) learning; and 5) joy in work. If someone gives you a chance to lead people in your career as a physician, jump at the chance. We do a relatively poor job of providing this type of opportunity to those early in their careers in medicine, and learning how to manage people and money allows you to progress as a leader and manager.

Don’t listen to the people who say “you must do X before Y” or “you must take this path.” They are usually wrong. Take chances. I applied for many roles for which I was a long shot, and I didn’t always succeed. That’s life and learning. Hospital medicine is a great career. I worked in the hospital on a recent weekend and was able to help families through everything from palliative care decisions and new diagnoses, to recovering from illness. It is an honor to serve and help families in their time of need. Hospitalists have been – and should continue to be – primary drivers of the shift in our health system to value-based care.

As I look back on my career (and I hope I am only halfway done), I could not have predicted more than 90% of it. I was blessed with many opportunities, mentors, and teachers along the way. I try to pass this on by mentoring and teaching others. How did my career happen? I am not sure, but it has been a fun ride! And hopefully I have helped improve the health system some, along the way.
 

Dr. Conway is president and CEO of Blue Cross and Blue Shield of North Carolina. He is a hospitalist and former deputy administrator for innovation and quality at the Centers for Medicare and Medicaid Services.

I have to admit that I am not sure I am a legacy in hospital medicine, and the term legacy throws me off a bit. I came to medical school after working at McKinsey & Co. consulting, and I chose pediatrics because of my love of working with children and families, as well as a vague notion that I wanted to work on “system” issues, and therefore, more generalist-type training seemed applicable.

I met Chris Landrigan, MD, MPH, and Vinny Chiang, MD, and learned what a hospitalist was, as an intern in 2002. We had a research elective and I was able to publish a couple of papers in Pediatrics on pediatric hospital medicine with Chris and Raj Srivastava, MD, MPH. In 2004, I went to my first Society of Hospital Medicine meeting and met Larry Wellikson, MD, MHM, and others. From there, I went to the Robert Wood Johnson Clinical Scholars Program, with Ron Keren, MD, MPH, and others, and along with faculty from the Cincinnati Children’s in hospital medicine.

In 2007, I applied for a White House Fellowship and told my wife that I didn’t think there was a chance that I would get it, so we should keep building our new home in Cincinnati. We were both surprised when I was selected. I served Michael Leavitt, the then-Secretary of the Department of Health & Human Services, as his White House fellow during the Bush administration, and then served as his chief medical officer. Exposure to health policy and leadership at that level was career shaping. Cincinnati Children’s was searching for a leader for the conversion of pediatric hospital medicine into a full division in 2009. So I returned to Cincinnati to take on leading pediatric hospital medicine, and a role leading quality measurement and improvement efforts for the entire health system. I loved the work and thought I would remain in that role, and our family would be in Cincinnati for a long time. Best laid plans …

In early 2011, Don Berwick, MD, who was then the administrator of the Centers for Medicare & Medicaid Services called and asked whether I “would come talk with him in D.C.” That talk quickly became a series of interviews, and he offered me the opportunity to be chief medical officer of CMS. He said “this platform is like no other to drive change.” He was right. I have been fortunate to have a few step-change opportunities in my life, and that was one.

On my first day at CMS, I looked around the table of senior executives reporting to me and realized they had more than 200 years of CMS experience. I was a bit scared. Together, we led the implementation of Hospital Value-Based Purchasing, the Compare websites, and numerous quality measurement and improvement programs. Partnership for Patients works on patient safety and was associated with preventing more than 3 million infections and adverse events, over 125,000 lives saved, and more than $26 billion in savings.

In early 2013, I was asked to lead the CMS Innovation Center (CMMI). The goal was to launch new payment and service delivery models to improve quality and lower costs. We launched Accountable Care Organizations, Bundled Payment programs, primary care medical homes, state-based innovation, and so much more. Medicare went from zero dollars in alternative payment models, where providers are accountable for quality and total cost of care, to more than 30% of Medicare payments, representing over $200 billion through agreements with more than 200,000 providers in these alternative payment models. It was the biggest shift in U.S. history in how CMS paid for care. Later, I became principal deputy administrator and acting administrator of CMS, leading an agency that spends over $1 trillion per year, or more than $2.5 billion per day and insures over 130 million Americans. We also improved from being bottom quintile in employee engagement and satisfaction across the federal government to No. 2.

I had assumed that, after working at CMS, I would return to a hospital/health system leadership role. But then, a recruiter called about the CEO role at Blue Cross Blue Shield of North Carolina. It is one of the largest not-for-profit health plans in the country and insures most of the people in North Carolina, many for most of their lives. I met a 75-year-old woman the other day that we have insured every day of her life. I am almost a year into the role and it is a mission-driven organization that drives positive change. I love it so far.

We are going to partner with providers, so that more than half of our payments will be in advanced alternative payment models. No payer in the United States has done that yet. This allows us to innovate and decrease friction in the system (e.g., turn off prior authorization) and be jointly accountable with providers for quality and total cost of care. We insure people through the ACA [Affordable Care Act], commercial, and Medicare markets, and are competing to serve Medicaid as well. We have invested more than $50 million to address social determinants of health across the state. We are making major investments in primary care, and mental and behavioral health. Our goal is to be a Model Blue – or a Model of Health Transformation for our state and nation – and achieve better health outcomes, lower costs, and best-in-class experience for all people we serve. I have learned that no physician leads a health plan of this size, and apparently, no practicing physician has ever led a health plan of this size.

What are some lessons learned over my career? I have had five criteria for all my career decisions: 1) family; 2) impact – better care and outcomes, lower costs, and exceptional experience for populations of patients; 3) people – mentors and colleagues; 4) learning; and 5) joy in work. If someone gives you a chance to lead people in your career as a physician, jump at the chance. We do a relatively poor job of providing this type of opportunity to those early in their careers in medicine, and learning how to manage people and money allows you to progress as a leader and manager.

Don’t listen to the people who say “you must do X before Y” or “you must take this path.” They are usually wrong. Take chances. I applied for many roles for which I was a long shot, and I didn’t always succeed. That’s life and learning. Hospital medicine is a great career. I worked in the hospital on a recent weekend and was able to help families through everything from palliative care decisions and new diagnoses, to recovering from illness. It is an honor to serve and help families in their time of need. Hospitalists have been – and should continue to be – primary drivers of the shift in our health system to value-based care.

As I look back on my career (and I hope I am only halfway done), I could not have predicted more than 90% of it. I was blessed with many opportunities, mentors, and teachers along the way. I try to pass this on by mentoring and teaching others. How did my career happen? I am not sure, but it has been a fun ride! And hopefully I have helped improve the health system some, along the way.
 

Dr. Conway is president and CEO of Blue Cross and Blue Shield of North Carolina. He is a hospitalist and former deputy administrator for innovation and quality at the Centers for Medicare and Medicaid Services.

I have to admit that I am not sure I am a legacy in hospital medicine, and the term legacy throws me off a bit. I came to medical school after working at McKinsey & Co. consulting, and I chose pediatrics because of my love of working with children and families, as well as a vague notion that I wanted to work on “system” issues, and therefore, more generalist-type training seemed applicable.

I met Chris Landrigan, MD, MPH, and Vinny Chiang, MD, and learned what a hospitalist was, as an intern in 2002. We had a research elective and I was able to publish a couple of papers in Pediatrics on pediatric hospital medicine with Chris and Raj Srivastava, MD, MPH. In 2004, I went to my first Society of Hospital Medicine meeting and met Larry Wellikson, MD, MHM, and others. From there, I went to the Robert Wood Johnson Clinical Scholars Program, with Ron Keren, MD, MPH, and others, and along with faculty from the Cincinnati Children’s in hospital medicine.

In 2007, I applied for a White House Fellowship and told my wife that I didn’t think there was a chance that I would get it, so we should keep building our new home in Cincinnati. We were both surprised when I was selected. I served Michael Leavitt, the then-Secretary of the Department of Health & Human Services, as his White House fellow during the Bush administration, and then served as his chief medical officer. Exposure to health policy and leadership at that level was career shaping. Cincinnati Children’s was searching for a leader for the conversion of pediatric hospital medicine into a full division in 2009. So I returned to Cincinnati to take on leading pediatric hospital medicine, and a role leading quality measurement and improvement efforts for the entire health system. I loved the work and thought I would remain in that role, and our family would be in Cincinnati for a long time. Best laid plans …

In early 2011, Don Berwick, MD, who was then the administrator of the Centers for Medicare & Medicaid Services called and asked whether I “would come talk with him in D.C.” That talk quickly became a series of interviews, and he offered me the opportunity to be chief medical officer of CMS. He said “this platform is like no other to drive change.” He was right. I have been fortunate to have a few step-change opportunities in my life, and that was one.

On my first day at CMS, I looked around the table of senior executives reporting to me and realized they had more than 200 years of CMS experience. I was a bit scared. Together, we led the implementation of Hospital Value-Based Purchasing, the Compare websites, and numerous quality measurement and improvement programs. Partnership for Patients works on patient safety and was associated with preventing more than 3 million infections and adverse events, over 125,000 lives saved, and more than $26 billion in savings.

In early 2013, I was asked to lead the CMS Innovation Center (CMMI). The goal was to launch new payment and service delivery models to improve quality and lower costs. We launched Accountable Care Organizations, Bundled Payment programs, primary care medical homes, state-based innovation, and so much more. Medicare went from zero dollars in alternative payment models, where providers are accountable for quality and total cost of care, to more than 30% of Medicare payments, representing over $200 billion through agreements with more than 200,000 providers in these alternative payment models. It was the biggest shift in U.S. history in how CMS paid for care. Later, I became principal deputy administrator and acting administrator of CMS, leading an agency that spends over $1 trillion per year, or more than $2.5 billion per day and insures over 130 million Americans. We also improved from being bottom quintile in employee engagement and satisfaction across the federal government to No. 2.

I had assumed that, after working at CMS, I would return to a hospital/health system leadership role. But then, a recruiter called about the CEO role at Blue Cross Blue Shield of North Carolina. It is one of the largest not-for-profit health plans in the country and insures most of the people in North Carolina, many for most of their lives. I met a 75-year-old woman the other day that we have insured every day of her life. I am almost a year into the role and it is a mission-driven organization that drives positive change. I love it so far.

We are going to partner with providers, so that more than half of our payments will be in advanced alternative payment models. No payer in the United States has done that yet. This allows us to innovate and decrease friction in the system (e.g., turn off prior authorization) and be jointly accountable with providers for quality and total cost of care. We insure people through the ACA [Affordable Care Act], commercial, and Medicare markets, and are competing to serve Medicaid as well. We have invested more than $50 million to address social determinants of health across the state. We are making major investments in primary care, and mental and behavioral health. Our goal is to be a Model Blue – or a Model of Health Transformation for our state and nation – and achieve better health outcomes, lower costs, and best-in-class experience for all people we serve. I have learned that no physician leads a health plan of this size, and apparently, no practicing physician has ever led a health plan of this size.

What are some lessons learned over my career? I have had five criteria for all my career decisions: 1) family; 2) impact – better care and outcomes, lower costs, and exceptional experience for populations of patients; 3) people – mentors and colleagues; 4) learning; and 5) joy in work. If someone gives you a chance to lead people in your career as a physician, jump at the chance. We do a relatively poor job of providing this type of opportunity to those early in their careers in medicine, and learning how to manage people and money allows you to progress as a leader and manager.

Don’t listen to the people who say “you must do X before Y” or “you must take this path.” They are usually wrong. Take chances. I applied for many roles for which I was a long shot, and I didn’t always succeed. That’s life and learning. Hospital medicine is a great career. I worked in the hospital on a recent weekend and was able to help families through everything from palliative care decisions and new diagnoses, to recovering from illness. It is an honor to serve and help families in their time of need. Hospitalists have been – and should continue to be – primary drivers of the shift in our health system to value-based care.

As I look back on my career (and I hope I am only halfway done), I could not have predicted more than 90% of it. I was blessed with many opportunities, mentors, and teachers along the way. I try to pass this on by mentoring and teaching others. How did my career happen? I am not sure, but it has been a fun ride! And hopefully I have helped improve the health system some, along the way.
 

Dr. Conway is president and CEO of Blue Cross and Blue Shield of North Carolina. He is a hospitalist and former deputy administrator for innovation and quality at the Centers for Medicare and Medicaid Services.