Leukemia, Myelodysplasia, Transplantation

Newer targeted drugs for chronic lymphocytic leukemia also appear to have a beneficial impact on underlying autoimmune cytopenias (AICs), results of a large retrospective study suggest.

Many autoimmune cytopenias improved or resolved during treatment with ibrutinib, idelalisib, or venetoclax, according to authors of the study, which appears in the journal Blood.

Treatment-emergent autoimmune cytopenias were seen in a “negligible portion” of patients overall, according to the report. The prevalence was about 1% each for patients treated with ibrutinib or idelalisib, though seen more frequently (at 7%) among patients who received venetoclax.

Nevertheless, treatment-emergent autoimmune cytopenias were “easily manageable” without interventions such as steroids and rituximab, and without need to interrupt the targeted treatment for chronic lymphocytic leukemia (CLL), according to the authors, led by Candida Vitale, MD, PhD, of the department of molecular biotechnology and health sciences at the University of Torino in Italy.

“Ibrutinib, idelalisib, and venetoclax have a beneficial impact on CLL-related preexisting AICs, achieving in most patients, in parallel with the consolidated antitumor efficacy, an effective control of the autoimmune phenomena,” Dr. Vitale and coauthors wrote in their report.
 

Study results

The retrospective study included 815 patients, of whom 572 were treated with ibrutinib, 143 with idelalisib plus rituximab, and 100 with venetoclax. Nine percent of ibrutinib-treated patients and 12% of venetoclax-treated patients also received an anti-CD20 monoclonal antibody, rituximab or obinutuzumab.

One hundred and four patients (13%) had preexisting autoimmune cytopenias, though the majority were resolved or controlled at the time targeted therapy was started.

Of patients with autoimmune cytopenias that were unresolved at the beginning of targeted therapy, 80% improved or resolved after starting targeted treatment, authors reported.

Most patients who developed autoimmune cytopenias on treatment had high-risk features such as unmutated IGHV, del(17)p, or TP53 mutation, according to the report.

Those treatment-emergent autoimmune cytopenias were seen in 1% of the ibrutinib group, 0.9% of the idelalisib group, and 7% of the venetoclax group. Out of 12 total treatment-emergent autoimmune cytopenias, all but 2 were resolved or controlled with dose reductions or temporary suspensions and use of steroids or rituximab, the report shows.

The higher incidence of autoimmune cytopenias in the venetoclax group held steady even when considering just the patients who had relapsed/refractory disease or had at least two prior lines of therapy, suggesting a “more meaningful” incidence, compared to what was observed for ibrutinib and idelalisib, the investigators said.

“However, the risk of autoimmune cytopenia episodes should not limit the use of venetoclax, considering the strong efficacy of this drug in treating patients with CLL, including those with high-risk features, and the possibility of effectively managing autoimmune complications, mostly without treatment interruption,” they concluded in their report.
 

Implications for patients with CLL

Findings of this study indicate that targeted therapies are effective for managing both CLL and autoimmune cytopenias, according to Carol Moreno, MD, PhD, of Hospital Sant Pau in Barcelona.

Moreover, the targeted therapies do not appear to change the overall prevalence of autoimmune cytopenias, compared to untreated patients, Dr. Moreno said in a commentary on the findings also published in Blood.

“These results are consistent with the concept that targeted therapies are not associated with a higher risk of autoimmune cytopenias, and that, if present, can be managed with immunosuppressive agents,” she wrote.
 

Autoimmune cytopenias and CLL

Autoimmune cytopenias are a relatively common complication of CLL, occurring in 5%-9% of CLL patients, Dr. Vitale and coauthors said in their report. The most common presentations include autoimmune hemolytic anemia (AIHA) and immune thrombocytopenia (ITP).

Evidence from earlier studies suggests that treatment for CLL may trigger autoimmune cytopenias. Results of retrospective studies in the 1990s linked single-agent fludarabine to increased risk of AIHA, Dr. Moreno said in the commentary.

However, subsequent studies showed that fludarabine plus cyclophosphamide (FC) and fludarabine, cyclophosphamide, and rituximab (FCR) were associated with low proportions of AIHA.

“Taken together, these results convincingly suggest that rather than treatment, it is the lack of response to it that conveys a higher risk of AIC,” Dr. Moreno wrote.
 

Management considerations

There are currently no clinical practice guidelines that advise on how to manage patients who develop AICs during targeted treatment for CLL, Dr. Vitale and colleagues said in their report.

However, this new study data may help inform management of patients with CLL and an autoimmune cytopenia, Dr. Moreno said in the commentary.

If the patient doesn’t immediately require CLL treatment, patients can be managed according to existing guidelines for AIHA and ITP, she said. “Nonresponding patients should be given CLL therapy,” she added.

For CLL patients who do require therapy and have a preexisting or treatment-emergent AIC, a “CLL-oriented” treatment approach could be considered, according to Dr. Moreno.

“A reasonable approach consists of a short course (2 to 4 weeks) of corticosteroids followed by effective CLL therapy (i.e., FCR, bendamustine plus rituximab or ibrutinib), depending on the clinical situation,” she added.

Dr. Vitale reported receiving consultancy fees from Janssen outside the submitted work. Dr. Moreno declared no competing financial interests related to her commentary.

Newer targeted drugs for chronic lymphocytic leukemia also appear to have a beneficial impact on underlying autoimmune cytopenias (AICs), results of a large retrospective study suggest.

Many autoimmune cytopenias improved or resolved during treatment with ibrutinib, idelalisib, or venetoclax, according to authors of the study, which appears in the journal Blood.

Treatment-emergent autoimmune cytopenias were seen in a “negligible portion” of patients overall, according to the report. The prevalence was about 1% each for patients treated with ibrutinib or idelalisib, though seen more frequently (at 7%) among patients who received venetoclax.

Nevertheless, treatment-emergent autoimmune cytopenias were “easily manageable” without interventions such as steroids and rituximab, and without need to interrupt the targeted treatment for chronic lymphocytic leukemia (CLL), according to the authors, led by Candida Vitale, MD, PhD, of the department of molecular biotechnology and health sciences at the University of Torino in Italy.

“Ibrutinib, idelalisib, and venetoclax have a beneficial impact on CLL-related preexisting AICs, achieving in most patients, in parallel with the consolidated antitumor efficacy, an effective control of the autoimmune phenomena,” Dr. Vitale and coauthors wrote in their report.
 

Study results

The retrospective study included 815 patients, of whom 572 were treated with ibrutinib, 143 with idelalisib plus rituximab, and 100 with venetoclax. Nine percent of ibrutinib-treated patients and 12% of venetoclax-treated patients also received an anti-CD20 monoclonal antibody, rituximab or obinutuzumab.

One hundred and four patients (13%) had preexisting autoimmune cytopenias, though the majority were resolved or controlled at the time targeted therapy was started.

Of patients with autoimmune cytopenias that were unresolved at the beginning of targeted therapy, 80% improved or resolved after starting targeted treatment, authors reported.

Most patients who developed autoimmune cytopenias on treatment had high-risk features such as unmutated IGHV, del(17)p, or TP53 mutation, according to the report.

Those treatment-emergent autoimmune cytopenias were seen in 1% of the ibrutinib group, 0.9% of the idelalisib group, and 7% of the venetoclax group. Out of 12 total treatment-emergent autoimmune cytopenias, all but 2 were resolved or controlled with dose reductions or temporary suspensions and use of steroids or rituximab, the report shows.

The higher incidence of autoimmune cytopenias in the venetoclax group held steady even when considering just the patients who had relapsed/refractory disease or had at least two prior lines of therapy, suggesting a “more meaningful” incidence, compared to what was observed for ibrutinib and idelalisib, the investigators said.

“However, the risk of autoimmune cytopenia episodes should not limit the use of venetoclax, considering the strong efficacy of this drug in treating patients with CLL, including those with high-risk features, and the possibility of effectively managing autoimmune complications, mostly without treatment interruption,” they concluded in their report.
 

Implications for patients with CLL

Findings of this study indicate that targeted therapies are effective for managing both CLL and autoimmune cytopenias, according to Carol Moreno, MD, PhD, of Hospital Sant Pau in Barcelona.

Moreover, the targeted therapies do not appear to change the overall prevalence of autoimmune cytopenias, compared to untreated patients, Dr. Moreno said in a commentary on the findings also published in Blood.

“These results are consistent with the concept that targeted therapies are not associated with a higher risk of autoimmune cytopenias, and that, if present, can be managed with immunosuppressive agents,” she wrote.
 

Autoimmune cytopenias and CLL

Autoimmune cytopenias are a relatively common complication of CLL, occurring in 5%-9% of CLL patients, Dr. Vitale and coauthors said in their report. The most common presentations include autoimmune hemolytic anemia (AIHA) and immune thrombocytopenia (ITP).

Evidence from earlier studies suggests that treatment for CLL may trigger autoimmune cytopenias. Results of retrospective studies in the 1990s linked single-agent fludarabine to increased risk of AIHA, Dr. Moreno said in the commentary.

However, subsequent studies showed that fludarabine plus cyclophosphamide (FC) and fludarabine, cyclophosphamide, and rituximab (FCR) were associated with low proportions of AIHA.

“Taken together, these results convincingly suggest that rather than treatment, it is the lack of response to it that conveys a higher risk of AIC,” Dr. Moreno wrote.
 

Management considerations

There are currently no clinical practice guidelines that advise on how to manage patients who develop AICs during targeted treatment for CLL, Dr. Vitale and colleagues said in their report.

However, this new study data may help inform management of patients with CLL and an autoimmune cytopenia, Dr. Moreno said in the commentary.

If the patient doesn’t immediately require CLL treatment, patients can be managed according to existing guidelines for AIHA and ITP, she said. “Nonresponding patients should be given CLL therapy,” she added.

For CLL patients who do require therapy and have a preexisting or treatment-emergent AIC, a “CLL-oriented” treatment approach could be considered, according to Dr. Moreno.

“A reasonable approach consists of a short course (2 to 4 weeks) of corticosteroids followed by effective CLL therapy (i.e., FCR, bendamustine plus rituximab or ibrutinib), depending on the clinical situation,” she added.

Dr. Vitale reported receiving consultancy fees from Janssen outside the submitted work. Dr. Moreno declared no competing financial interests related to her commentary.

Newer targeted drugs for chronic lymphocytic leukemia also appear to have a beneficial impact on underlying autoimmune cytopenias (AICs), results of a large retrospective study suggest.

Many autoimmune cytopenias improved or resolved during treatment with ibrutinib, idelalisib, or venetoclax, according to authors of the study, which appears in the journal Blood.

Treatment-emergent autoimmune cytopenias were seen in a “negligible portion” of patients overall, according to the report. The prevalence was about 1% each for patients treated with ibrutinib or idelalisib, though seen more frequently (at 7%) among patients who received venetoclax.

Nevertheless, treatment-emergent autoimmune cytopenias were “easily manageable” without interventions such as steroids and rituximab, and without need to interrupt the targeted treatment for chronic lymphocytic leukemia (CLL), according to the authors, led by Candida Vitale, MD, PhD, of the department of molecular biotechnology and health sciences at the University of Torino in Italy.

“Ibrutinib, idelalisib, and venetoclax have a beneficial impact on CLL-related preexisting AICs, achieving in most patients, in parallel with the consolidated antitumor efficacy, an effective control of the autoimmune phenomena,” Dr. Vitale and coauthors wrote in their report.
 

Study results

The retrospective study included 815 patients, of whom 572 were treated with ibrutinib, 143 with idelalisib plus rituximab, and 100 with venetoclax. Nine percent of ibrutinib-treated patients and 12% of venetoclax-treated patients also received an anti-CD20 monoclonal antibody, rituximab or obinutuzumab.

One hundred and four patients (13%) had preexisting autoimmune cytopenias, though the majority were resolved or controlled at the time targeted therapy was started.

Of patients with autoimmune cytopenias that were unresolved at the beginning of targeted therapy, 80% improved or resolved after starting targeted treatment, authors reported.

Most patients who developed autoimmune cytopenias on treatment had high-risk features such as unmutated IGHV, del(17)p, or TP53 mutation, according to the report.

Those treatment-emergent autoimmune cytopenias were seen in 1% of the ibrutinib group, 0.9% of the idelalisib group, and 7% of the venetoclax group. Out of 12 total treatment-emergent autoimmune cytopenias, all but 2 were resolved or controlled with dose reductions or temporary suspensions and use of steroids or rituximab, the report shows.

The higher incidence of autoimmune cytopenias in the venetoclax group held steady even when considering just the patients who had relapsed/refractory disease or had at least two prior lines of therapy, suggesting a “more meaningful” incidence, compared to what was observed for ibrutinib and idelalisib, the investigators said.

“However, the risk of autoimmune cytopenia episodes should not limit the use of venetoclax, considering the strong efficacy of this drug in treating patients with CLL, including those with high-risk features, and the possibility of effectively managing autoimmune complications, mostly without treatment interruption,” they concluded in their report.
 

Implications for patients with CLL

Findings of this study indicate that targeted therapies are effective for managing both CLL and autoimmune cytopenias, according to Carol Moreno, MD, PhD, of Hospital Sant Pau in Barcelona.

Moreover, the targeted therapies do not appear to change the overall prevalence of autoimmune cytopenias, compared to untreated patients, Dr. Moreno said in a commentary on the findings also published in Blood.

“These results are consistent with the concept that targeted therapies are not associated with a higher risk of autoimmune cytopenias, and that, if present, can be managed with immunosuppressive agents,” she wrote.
 

Autoimmune cytopenias and CLL

Autoimmune cytopenias are a relatively common complication of CLL, occurring in 5%-9% of CLL patients, Dr. Vitale and coauthors said in their report. The most common presentations include autoimmune hemolytic anemia (AIHA) and immune thrombocytopenia (ITP).

Evidence from earlier studies suggests that treatment for CLL may trigger autoimmune cytopenias. Results of retrospective studies in the 1990s linked single-agent fludarabine to increased risk of AIHA, Dr. Moreno said in the commentary.

However, subsequent studies showed that fludarabine plus cyclophosphamide (FC) and fludarabine, cyclophosphamide, and rituximab (FCR) were associated with low proportions of AIHA.

“Taken together, these results convincingly suggest that rather than treatment, it is the lack of response to it that conveys a higher risk of AIC,” Dr. Moreno wrote.
 

Management considerations

There are currently no clinical practice guidelines that advise on how to manage patients who develop AICs during targeted treatment for CLL, Dr. Vitale and colleagues said in their report.

However, this new study data may help inform management of patients with CLL and an autoimmune cytopenia, Dr. Moreno said in the commentary.

If the patient doesn’t immediately require CLL treatment, patients can be managed according to existing guidelines for AIHA and ITP, she said. “Nonresponding patients should be given CLL therapy,” she added.

For CLL patients who do require therapy and have a preexisting or treatment-emergent AIC, a “CLL-oriented” treatment approach could be considered, according to Dr. Moreno.

“A reasonable approach consists of a short course (2 to 4 weeks) of corticosteroids followed by effective CLL therapy (i.e., FCR, bendamustine plus rituximab or ibrutinib), depending on the clinical situation,” she added.

Dr. Vitale reported receiving consultancy fees from Janssen outside the submitted work. Dr. Moreno declared no competing financial interests related to her commentary.

Dr. Michael Grunwald presents highlights in the latest studies involving several types of leukemia from the ASCO 2021 Virtual Congress.

In a dose-optimization study of ponatinib, patients with chronic-phase chronic myeloid leukemia were randomized 1:1:1 to receive 45, 30, or 15 mg daily, with dose reductions occurring once patients met the primary endpoint of ≤1% BCR-ABL1. At 12 months, response rate was highest with the 45 mg to 15 mg regimen, and 73.3% of patients in this cohort maintained response.

The phase 1/2 ZUMA-3 study evaluated KTE-X19 in adults with relapsed/refractory B-cell acute lymphoblastic leukemia. The drug’s efficacy, speed of manufacture, and ease of safety management were found to be sufficient to provide long-term clinical benefit.

Another study focused on the efficacy and safety of aspacytarabine (BST-236) for patients with acute myeloid leukemia (AML) who were unfit for chemotherapy. The rate of complete remission was 39% among the AML population, and 63% of the population in complete remission had minimal residual disease.

Dr. Grunwald closes with a study of ponatinib and blinatumomab in patients with Philadelphia chromosome–positive acute lymphoblastic leukemia. The combination of both drugs was proven to be a safe and effective chemotherapy-free regimen in both newly diagnosed patients and patients with relapsed/refractory disease.
 

--

Michael R. Grunwald, MD, Chief, Leukemia Division. Department of Hematologic Oncology and Blood Disorders. Levine Cancer Institute, Atrium Health. Charlotte, North Carolina.

Michael R. Grunwald, MD, has disclosed the following relevant financial relationships:
Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: AbbVie; Agios; Amgen; Astellas Pharma; Blueprint Medicines; Bristol Myers Squibb; Cardinal Health; Daiichi Sankyo; Gilead Sciences; Incyte; Karius; Pfizer; Premier Pharmaceuticals; Sierra Oncology; Stemline Therapeutics.
Received research grant from: Incyte; Janssen.
 

Dr. Michael Grunwald presents highlights in the latest studies involving several types of leukemia from the ASCO 2021 Virtual Congress.

In a dose-optimization study of ponatinib, patients with chronic-phase chronic myeloid leukemia were randomized 1:1:1 to receive 45, 30, or 15 mg daily, with dose reductions occurring once patients met the primary endpoint of ≤1% BCR-ABL1. At 12 months, response rate was highest with the 45 mg to 15 mg regimen, and 73.3% of patients in this cohort maintained response.

The phase 1/2 ZUMA-3 study evaluated KTE-X19 in adults with relapsed/refractory B-cell acute lymphoblastic leukemia. The drug’s efficacy, speed of manufacture, and ease of safety management were found to be sufficient to provide long-term clinical benefit.

Another study focused on the efficacy and safety of aspacytarabine (BST-236) for patients with acute myeloid leukemia (AML) who were unfit for chemotherapy. The rate of complete remission was 39% among the AML population, and 63% of the population in complete remission had minimal residual disease.

Dr. Grunwald closes with a study of ponatinib and blinatumomab in patients with Philadelphia chromosome–positive acute lymphoblastic leukemia. The combination of both drugs was proven to be a safe and effective chemotherapy-free regimen in both newly diagnosed patients and patients with relapsed/refractory disease.
 

--

Michael R. Grunwald, MD, Chief, Leukemia Division. Department of Hematologic Oncology and Blood Disorders. Levine Cancer Institute, Atrium Health. Charlotte, North Carolina.

Michael R. Grunwald, MD, has disclosed the following relevant financial relationships:
Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: AbbVie; Agios; Amgen; Astellas Pharma; Blueprint Medicines; Bristol Myers Squibb; Cardinal Health; Daiichi Sankyo; Gilead Sciences; Incyte; Karius; Pfizer; Premier Pharmaceuticals; Sierra Oncology; Stemline Therapeutics.
Received research grant from: Incyte; Janssen.
 

Dr. Michael Grunwald presents highlights in the latest studies involving several types of leukemia from the ASCO 2021 Virtual Congress.

In a dose-optimization study of ponatinib, patients with chronic-phase chronic myeloid leukemia were randomized 1:1:1 to receive 45, 30, or 15 mg daily, with dose reductions occurring once patients met the primary endpoint of ≤1% BCR-ABL1. At 12 months, response rate was highest with the 45 mg to 15 mg regimen, and 73.3% of patients in this cohort maintained response.

The phase 1/2 ZUMA-3 study evaluated KTE-X19 in adults with relapsed/refractory B-cell acute lymphoblastic leukemia. The drug’s efficacy, speed of manufacture, and ease of safety management were found to be sufficient to provide long-term clinical benefit.

Another study focused on the efficacy and safety of aspacytarabine (BST-236) for patients with acute myeloid leukemia (AML) who were unfit for chemotherapy. The rate of complete remission was 39% among the AML population, and 63% of the population in complete remission had minimal residual disease.

Dr. Grunwald closes with a study of ponatinib and blinatumomab in patients with Philadelphia chromosome–positive acute lymphoblastic leukemia. The combination of both drugs was proven to be a safe and effective chemotherapy-free regimen in both newly diagnosed patients and patients with relapsed/refractory disease.
 

--

Michael R. Grunwald, MD, Chief, Leukemia Division. Department of Hematologic Oncology and Blood Disorders. Levine Cancer Institute, Atrium Health. Charlotte, North Carolina.

Michael R. Grunwald, MD, has disclosed the following relevant financial relationships:
Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: AbbVie; Agios; Amgen; Astellas Pharma; Blueprint Medicines; Bristol Myers Squibb; Cardinal Health; Daiichi Sankyo; Gilead Sciences; Incyte; Karius; Pfizer; Premier Pharmaceuticals; Sierra Oncology; Stemline Therapeutics.
Received research grant from: Incyte; Janssen.
 

For adults with Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ALL), frontline therapy with the chemotherapy-free combination of ponatinib (Iclusig) and blinatumomab (Blincyto) shows promise as an alternative to early hematopoietic stem cell transplantation (HSCT), investigators in a single-arm phase 2 study reported.

In an interim analysis of the combination in patients with newly diagnosed or relapsed/refractory Ph+ALL or lymphoid accelerated or blast phase chronic myeloid leukemia (CML), 20 patients who received it as frontline therapy had a rate of complete responses (CR) or complete responses with partial recovery of blood counts (CRp) of 100% and a complete molecular remission (CMR) rate of 85%, reported Nicholas Short, MD, of the University of Texas MD Anderson Cancer Center in Houston.

“This translated into an estimated 2-year overall survival of 93%, with no patients undergoing transplant in first remission, and none having relapse at last follow-up,” he said in an oral abstract presented during the European Hematology Association annual congress.

Among patients with relapsed/refractory Ph+ALL, the CR/CRp rate was 89%, the CMR rate was 88%, and the estimated 2-year overall survival rate was 53%, he said.
 

Transplants on hold

“The big selling point is the ability to avoid stem cell transplant, which is not always the first thing you do in Ph-positive ALL, but it’s always on your mind,” said Gwen Nichols, MD, chief medical officer of the Leukemia and Lymphoma Society, who was not involved in the study.

“It looks, albeit with very limited follow-up, that patients haven’t relapsed yet such that transplant would be necessary. Anything we can do to avoid people having long-term complications that go along with an allogeneic transplant is a step in the right direction,” she said in an interview.
 

One combination, three cohorts

Ph+ALL comprises about 25% of all adult ALL. The standard of care in newly diagnosed patients is chemotherapy plus a tyrosine kinase inhibitor (TKI) targeted against the BCR-ABL transcript.

Ponatinib is a pan-BCR-ABL TKI that has been shown to have activity against ALL with T315I mutations, which are present in about 75% of the cases of relapsed disease, Dr. Short said.

Blinatumomab is a bi-specific T-cell engager (BiTe) that has been shown to be effective as monotherapy against relapsed/refractory Ph+ALL as monotherapy and in combination with dasatinib.

Dr. Short and colleagues enrolled patients with newly diagnosed or relapsed/refractory Ph+ALL or lymphoid accelerated or blast phase CML. Patients in the frontline cohort could have received one or two prior lines of chemotherapy with or without a TKI.

The patients all had Eastern Cooperative Oncology Group performance status of 0-2, and adequate liver function.

Patients with clinically significant cardiovascular disease or central nervous system disease pathology were excluded, except that patients with CNS leukemia could be enrolled.

The induction phase consisted of 30 mg ponatinib daily plus blinatumomab standard dosing on a 4-week-on, 2-week-off schedule. Patients in CMR, defined for frontline patients as undetectable BCR-ABL transcripts by polymerase chain reaction, then received up to four consolidation cycles of the regimen with ponatinib at a 15-mg dose, followed by 5 years of ponatinib 15-mg maintenance. All patients also received CNS prophylaxis with 12 cycles of intrathecal chemotherapy with alternating administration of methotrexate and cytarabine.

Of the 35 patients treated to date with the combination, 20 with Ph+ALL received it as frontline therapy and 10 received it for relapsed/refractory disease; 5 patients with CML in lymphoid blast phase also were treated.
 

High CMR, CR rates

As noted before, the CMR rate, the primary endpoint among patients with newly diagnosed Ph+ALL, was 85%, with a CR/CRp rate of 100%. Six of the patients in the frontline group and one in the salvage therapy group had CRs but were positive for minimal residual disease (MRD) at study outset.

The CR/CRp rate for the entire cohort of 28 patients (excluding those with a CR at start) was 96%, with only 1 patient who had relapsed/refractory disease not having a CR. This patient had received ponatinib in a prior salvage regimen.

The CMR rate among the entire cohort was 79%, with 85% of patients in the frontline ALL cohort having a CMR, 88% in the relapsed/refractory cohort, and 40% in the CML cohort. There were no early deaths among any patients.

“After one cycle of ponatinib plus blinatumomab, 84% of frontline patients had achieved at least a major molecular response, and 58% had achieved a CMR. Among those with relapsed/refractory Ph+ALL, 75% achieved CMR after one cycle of therapy,” Dr. Short said.

Of the 20 frontline patients in CR, one patient experienced visual changes and possible stroke that were considered possibly related to the study medication. This patient was taken off study. During a later maintenance regimen this patient developed a non-ST elevation myocardial infarction and died from postprocedural bleeding and hypovolemic shock following a cardiac catheterization procedure.

The remainder of patients in the frontline cohort had ongoing responses without the need for HSCT at last follow-up. There were no relapses, with a median duration of CR of 6 months,

Among the 10 with relapsed/refractory Ph+ALL, one did not have a response, and the remaining 9 had CR/CRps.

Of the latter groups, four went on to allogeneic HSCT and three were still alive; one patient who underwent a transplant experienced a relapse and died. One additional patient was alive with relapsed disease with T315I and E255V mutations at the time of relapse, one patient in CR who went off study due to insurance issues died from an unknown cause, and the three remaining patients had ongoing responses without transplant.

Among the five patients with CML in lymphoid blast phase, two had relapses, but both are still alive and currently in remission, and three have ongoing responses without transplant.

After a median follow-up of 12 months the 1-year event-free survival (EFS) rate for the entire 35-patient group was 76%, and the 2-year EFS was 70%.

The 1-year overall survival rate was 93%, and the 2-year OS rate was 80%.

Among patients in the frontline group, the 1-year and 2-year EFS and OS rates were all 93%.

For the relapsed/refractory cohort, the estimated 2-year EFS was 41% and OS was 53%. For the CML cohort, the 2-year EFS was 60%, with all patients still alive at last follow-up.

There were no grade 4 adverse events on study. Grade 3 adverse events considered at least possibly related to study treatment were elevated lipase, fever/febrile neutropenia, increased alanine aminotransferase, cerebrovascular ischemia, hypertension, pancreatitis, deep vein thrombosis, and encephalopathy. There were no cases of grade 3 cytokine release syndrome or tremor.

The study was sponsored by MD Anderson Cancer Center with collaboration from the National Cancer Institute, Amgen, and Takeda. Dr. Short has disclosed relationships with Amgen and Takeda. Dr. Nichols reported having no conflicts of interest.

For adults with Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ALL), frontline therapy with the chemotherapy-free combination of ponatinib (Iclusig) and blinatumomab (Blincyto) shows promise as an alternative to early hematopoietic stem cell transplantation (HSCT), investigators in a single-arm phase 2 study reported.

In an interim analysis of the combination in patients with newly diagnosed or relapsed/refractory Ph+ALL or lymphoid accelerated or blast phase chronic myeloid leukemia (CML), 20 patients who received it as frontline therapy had a rate of complete responses (CR) or complete responses with partial recovery of blood counts (CRp) of 100% and a complete molecular remission (CMR) rate of 85%, reported Nicholas Short, MD, of the University of Texas MD Anderson Cancer Center in Houston.

“This translated into an estimated 2-year overall survival of 93%, with no patients undergoing transplant in first remission, and none having relapse at last follow-up,” he said in an oral abstract presented during the European Hematology Association annual congress.

Among patients with relapsed/refractory Ph+ALL, the CR/CRp rate was 89%, the CMR rate was 88%, and the estimated 2-year overall survival rate was 53%, he said.
 

Transplants on hold

“The big selling point is the ability to avoid stem cell transplant, which is not always the first thing you do in Ph-positive ALL, but it’s always on your mind,” said Gwen Nichols, MD, chief medical officer of the Leukemia and Lymphoma Society, who was not involved in the study.

“It looks, albeit with very limited follow-up, that patients haven’t relapsed yet such that transplant would be necessary. Anything we can do to avoid people having long-term complications that go along with an allogeneic transplant is a step in the right direction,” she said in an interview.
 

One combination, three cohorts

Ph+ALL comprises about 25% of all adult ALL. The standard of care in newly diagnosed patients is chemotherapy plus a tyrosine kinase inhibitor (TKI) targeted against the BCR-ABL transcript.

Ponatinib is a pan-BCR-ABL TKI that has been shown to have activity against ALL with T315I mutations, which are present in about 75% of the cases of relapsed disease, Dr. Short said.

Blinatumomab is a bi-specific T-cell engager (BiTe) that has been shown to be effective as monotherapy against relapsed/refractory Ph+ALL as monotherapy and in combination with dasatinib.

Dr. Short and colleagues enrolled patients with newly diagnosed or relapsed/refractory Ph+ALL or lymphoid accelerated or blast phase CML. Patients in the frontline cohort could have received one or two prior lines of chemotherapy with or without a TKI.

The patients all had Eastern Cooperative Oncology Group performance status of 0-2, and adequate liver function.

Patients with clinically significant cardiovascular disease or central nervous system disease pathology were excluded, except that patients with CNS leukemia could be enrolled.

The induction phase consisted of 30 mg ponatinib daily plus blinatumomab standard dosing on a 4-week-on, 2-week-off schedule. Patients in CMR, defined for frontline patients as undetectable BCR-ABL transcripts by polymerase chain reaction, then received up to four consolidation cycles of the regimen with ponatinib at a 15-mg dose, followed by 5 years of ponatinib 15-mg maintenance. All patients also received CNS prophylaxis with 12 cycles of intrathecal chemotherapy with alternating administration of methotrexate and cytarabine.

Of the 35 patients treated to date with the combination, 20 with Ph+ALL received it as frontline therapy and 10 received it for relapsed/refractory disease; 5 patients with CML in lymphoid blast phase also were treated.
 

High CMR, CR rates

As noted before, the CMR rate, the primary endpoint among patients with newly diagnosed Ph+ALL, was 85%, with a CR/CRp rate of 100%. Six of the patients in the frontline group and one in the salvage therapy group had CRs but were positive for minimal residual disease (MRD) at study outset.

The CR/CRp rate for the entire cohort of 28 patients (excluding those with a CR at start) was 96%, with only 1 patient who had relapsed/refractory disease not having a CR. This patient had received ponatinib in a prior salvage regimen.

The CMR rate among the entire cohort was 79%, with 85% of patients in the frontline ALL cohort having a CMR, 88% in the relapsed/refractory cohort, and 40% in the CML cohort. There were no early deaths among any patients.

“After one cycle of ponatinib plus blinatumomab, 84% of frontline patients had achieved at least a major molecular response, and 58% had achieved a CMR. Among those with relapsed/refractory Ph+ALL, 75% achieved CMR after one cycle of therapy,” Dr. Short said.

Of the 20 frontline patients in CR, one patient experienced visual changes and possible stroke that were considered possibly related to the study medication. This patient was taken off study. During a later maintenance regimen this patient developed a non-ST elevation myocardial infarction and died from postprocedural bleeding and hypovolemic shock following a cardiac catheterization procedure.

The remainder of patients in the frontline cohort had ongoing responses without the need for HSCT at last follow-up. There were no relapses, with a median duration of CR of 6 months,

Among the 10 with relapsed/refractory Ph+ALL, one did not have a response, and the remaining 9 had CR/CRps.

Of the latter groups, four went on to allogeneic HSCT and three were still alive; one patient who underwent a transplant experienced a relapse and died. One additional patient was alive with relapsed disease with T315I and E255V mutations at the time of relapse, one patient in CR who went off study due to insurance issues died from an unknown cause, and the three remaining patients had ongoing responses without transplant.

Among the five patients with CML in lymphoid blast phase, two had relapses, but both are still alive and currently in remission, and three have ongoing responses without transplant.

After a median follow-up of 12 months the 1-year event-free survival (EFS) rate for the entire 35-patient group was 76%, and the 2-year EFS was 70%.

The 1-year overall survival rate was 93%, and the 2-year OS rate was 80%.

Among patients in the frontline group, the 1-year and 2-year EFS and OS rates were all 93%.

For the relapsed/refractory cohort, the estimated 2-year EFS was 41% and OS was 53%. For the CML cohort, the 2-year EFS was 60%, with all patients still alive at last follow-up.

There were no grade 4 adverse events on study. Grade 3 adverse events considered at least possibly related to study treatment were elevated lipase, fever/febrile neutropenia, increased alanine aminotransferase, cerebrovascular ischemia, hypertension, pancreatitis, deep vein thrombosis, and encephalopathy. There were no cases of grade 3 cytokine release syndrome or tremor.

The study was sponsored by MD Anderson Cancer Center with collaboration from the National Cancer Institute, Amgen, and Takeda. Dr. Short has disclosed relationships with Amgen and Takeda. Dr. Nichols reported having no conflicts of interest.

For adults with Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ALL), frontline therapy with the chemotherapy-free combination of ponatinib (Iclusig) and blinatumomab (Blincyto) shows promise as an alternative to early hematopoietic stem cell transplantation (HSCT), investigators in a single-arm phase 2 study reported.

In an interim analysis of the combination in patients with newly diagnosed or relapsed/refractory Ph+ALL or lymphoid accelerated or blast phase chronic myeloid leukemia (CML), 20 patients who received it as frontline therapy had a rate of complete responses (CR) or complete responses with partial recovery of blood counts (CRp) of 100% and a complete molecular remission (CMR) rate of 85%, reported Nicholas Short, MD, of the University of Texas MD Anderson Cancer Center in Houston.

“This translated into an estimated 2-year overall survival of 93%, with no patients undergoing transplant in first remission, and none having relapse at last follow-up,” he said in an oral abstract presented during the European Hematology Association annual congress.

Among patients with relapsed/refractory Ph+ALL, the CR/CRp rate was 89%, the CMR rate was 88%, and the estimated 2-year overall survival rate was 53%, he said.
 

Transplants on hold

“The big selling point is the ability to avoid stem cell transplant, which is not always the first thing you do in Ph-positive ALL, but it’s always on your mind,” said Gwen Nichols, MD, chief medical officer of the Leukemia and Lymphoma Society, who was not involved in the study.

“It looks, albeit with very limited follow-up, that patients haven’t relapsed yet such that transplant would be necessary. Anything we can do to avoid people having long-term complications that go along with an allogeneic transplant is a step in the right direction,” she said in an interview.
 

One combination, three cohorts

Ph+ALL comprises about 25% of all adult ALL. The standard of care in newly diagnosed patients is chemotherapy plus a tyrosine kinase inhibitor (TKI) targeted against the BCR-ABL transcript.

Ponatinib is a pan-BCR-ABL TKI that has been shown to have activity against ALL with T315I mutations, which are present in about 75% of the cases of relapsed disease, Dr. Short said.

Blinatumomab is a bi-specific T-cell engager (BiTe) that has been shown to be effective as monotherapy against relapsed/refractory Ph+ALL as monotherapy and in combination with dasatinib.

Dr. Short and colleagues enrolled patients with newly diagnosed or relapsed/refractory Ph+ALL or lymphoid accelerated or blast phase CML. Patients in the frontline cohort could have received one or two prior lines of chemotherapy with or without a TKI.

The patients all had Eastern Cooperative Oncology Group performance status of 0-2, and adequate liver function.

Patients with clinically significant cardiovascular disease or central nervous system disease pathology were excluded, except that patients with CNS leukemia could be enrolled.

The induction phase consisted of 30 mg ponatinib daily plus blinatumomab standard dosing on a 4-week-on, 2-week-off schedule. Patients in CMR, defined for frontline patients as undetectable BCR-ABL transcripts by polymerase chain reaction, then received up to four consolidation cycles of the regimen with ponatinib at a 15-mg dose, followed by 5 years of ponatinib 15-mg maintenance. All patients also received CNS prophylaxis with 12 cycles of intrathecal chemotherapy with alternating administration of methotrexate and cytarabine.

Of the 35 patients treated to date with the combination, 20 with Ph+ALL received it as frontline therapy and 10 received it for relapsed/refractory disease; 5 patients with CML in lymphoid blast phase also were treated.
 

High CMR, CR rates

As noted before, the CMR rate, the primary endpoint among patients with newly diagnosed Ph+ALL, was 85%, with a CR/CRp rate of 100%. Six of the patients in the frontline group and one in the salvage therapy group had CRs but were positive for minimal residual disease (MRD) at study outset.

The CR/CRp rate for the entire cohort of 28 patients (excluding those with a CR at start) was 96%, with only 1 patient who had relapsed/refractory disease not having a CR. This patient had received ponatinib in a prior salvage regimen.

The CMR rate among the entire cohort was 79%, with 85% of patients in the frontline ALL cohort having a CMR, 88% in the relapsed/refractory cohort, and 40% in the CML cohort. There were no early deaths among any patients.

“After one cycle of ponatinib plus blinatumomab, 84% of frontline patients had achieved at least a major molecular response, and 58% had achieved a CMR. Among those with relapsed/refractory Ph+ALL, 75% achieved CMR after one cycle of therapy,” Dr. Short said.

Of the 20 frontline patients in CR, one patient experienced visual changes and possible stroke that were considered possibly related to the study medication. This patient was taken off study. During a later maintenance regimen this patient developed a non-ST elevation myocardial infarction and died from postprocedural bleeding and hypovolemic shock following a cardiac catheterization procedure.

The remainder of patients in the frontline cohort had ongoing responses without the need for HSCT at last follow-up. There were no relapses, with a median duration of CR of 6 months,

Among the 10 with relapsed/refractory Ph+ALL, one did not have a response, and the remaining 9 had CR/CRps.

Of the latter groups, four went on to allogeneic HSCT and three were still alive; one patient who underwent a transplant experienced a relapse and died. One additional patient was alive with relapsed disease with T315I and E255V mutations at the time of relapse, one patient in CR who went off study due to insurance issues died from an unknown cause, and the three remaining patients had ongoing responses without transplant.

Among the five patients with CML in lymphoid blast phase, two had relapses, but both are still alive and currently in remission, and three have ongoing responses without transplant.

After a median follow-up of 12 months the 1-year event-free survival (EFS) rate for the entire 35-patient group was 76%, and the 2-year EFS was 70%.

The 1-year overall survival rate was 93%, and the 2-year OS rate was 80%.

Among patients in the frontline group, the 1-year and 2-year EFS and OS rates were all 93%.

For the relapsed/refractory cohort, the estimated 2-year EFS was 41% and OS was 53%. For the CML cohort, the 2-year EFS was 60%, with all patients still alive at last follow-up.

There were no grade 4 adverse events on study. Grade 3 adverse events considered at least possibly related to study treatment were elevated lipase, fever/febrile neutropenia, increased alanine aminotransferase, cerebrovascular ischemia, hypertension, pancreatitis, deep vein thrombosis, and encephalopathy. There were no cases of grade 3 cytokine release syndrome or tremor.

The study was sponsored by MD Anderson Cancer Center with collaboration from the National Cancer Institute, Amgen, and Takeda. Dr. Short has disclosed relationships with Amgen and Takeda. Dr. Nichols reported having no conflicts of interest.

Hypomethylating agents are generally considered to be agents of choice for older adults with acute myeloid leukemia who cannot tolerate the rigors of more intensive therapies, but HMAs also can serve as a bridge to transplant for children and young adults with relapsed or refractory acute myeloid leukemia.

That’s according to Himalee S. Sabnis, MD, MSc and colleagues at Emory University and the Aflac Cancer and Blood Disorders Center at Children’s Healthcare of Atlanta.

In a scientific poster presented during the annual meeting of the American Society of Pediatric Hematology/Oncology, the investigators reported results of a retrospective study of HMA use in patients with relapsed or refractory pediatric AML treated in their center.
 

Curative intent and palliation

They identified 25 patients (15 boys) with a median age of 8.3 years (range 1.4 to 21 years) with relapsed/refractory AML who received HMAs for curative intent prior to hematopoietic stem cell transplant (HSCT), palliation, or in combination with donor leukocyte infusion (DLI).

Of the 21 patients with relapsed disease, 16 were in first relapse and 5 were in second relapse or greater. Four of the patients had primary refractory disease. The cytogenetic and molecular features were KMT2A rearrangements in six patients, monosomy 7/deletion 7 q in four patients, 8;21 translocation in three patients, and FLT3-ITD mutations in four patients.

The patients received a median of 5.3 HMA cycles each. Of the 133 total HMA cycles, 87 were with azacitidine, and 46 were with decitabine.

HMAs were used as monotherapy in 62% of cycles, and in combination with other therapies in 38%. Of the combinations, 16 were with donor leukocyte infusion, and 9 were gemtuzumab ozogamicin (Mylotarg).

Of the 13 patients for whom HMAs were used as part of treatment plan with curative intent, 5 proceeded to HSCT, and 8 did not. Of the 5 patients, 1 died from transplant-related causes, and 4 were alive post transplant. Of the 8 patients who did not undergo transplant, 1 had chimeric antigen receptor T- cell (CAR T) therapy, and 7 experienced disease progression.

The mean duration of palliative care was 144 days, with patients receiving from one to nine cycles with an HMA, and no treatment interruptions due to toxicity.

Of 5 patients who received donor leukocyte infusions, 3 reached minimal residual disease negativity; all 3 of these patients had late relapses but remained long-term survivors, the investigators reported.

They concluded that “hypomethylating agents can be used effectively as a bridge to transplantation in relapsed and refractory AML with gemtuzumab ozogamicin being the most common agent for combination therapy. Palliation with HMAs is associated with low toxicity and high tolerability in relapsed/refractory AML. Use of HMAs with DLI can induce sustained remissions in some patients.”

The authors propose prospective clinical trials using HMAs in the relapsed/refractory pediatric AML setting in combination with gemtuzumab ozogamicin, alternative targeted agents, and chemotherapy.

HMAs in treatment-related AML

Shilpa Shahani, MD, a pediatric oncologist and assistant clinical professor of pediatrics at City of Hope in Duarte, Calif., who was not involved in the study, has experience administering HMAs primarily in the adolescent and young adult population with AML.

“Azacitidine and decitabine are good for treatment-related leukemias,” she said in an interview. “They can be used otherwise for people who have relapsed disease and are trying to navigate other options.”

Although they are not standard first-line agents in younger patients, HMAs can play a useful role in therapy for relapsed or refractory disease, she said.

The authors and Dr. Shahani reported having no conflicts of interest to disclose.

Hypomethylating agents are generally considered to be agents of choice for older adults with acute myeloid leukemia who cannot tolerate the rigors of more intensive therapies, but HMAs also can serve as a bridge to transplant for children and young adults with relapsed or refractory acute myeloid leukemia.

That’s according to Himalee S. Sabnis, MD, MSc and colleagues at Emory University and the Aflac Cancer and Blood Disorders Center at Children’s Healthcare of Atlanta.

In a scientific poster presented during the annual meeting of the American Society of Pediatric Hematology/Oncology, the investigators reported results of a retrospective study of HMA use in patients with relapsed or refractory pediatric AML treated in their center.
 

Curative intent and palliation

They identified 25 patients (15 boys) with a median age of 8.3 years (range 1.4 to 21 years) with relapsed/refractory AML who received HMAs for curative intent prior to hematopoietic stem cell transplant (HSCT), palliation, or in combination with donor leukocyte infusion (DLI).

Of the 21 patients with relapsed disease, 16 were in first relapse and 5 were in second relapse or greater. Four of the patients had primary refractory disease. The cytogenetic and molecular features were KMT2A rearrangements in six patients, monosomy 7/deletion 7 q in four patients, 8;21 translocation in three patients, and FLT3-ITD mutations in four patients.

The patients received a median of 5.3 HMA cycles each. Of the 133 total HMA cycles, 87 were with azacitidine, and 46 were with decitabine.

HMAs were used as monotherapy in 62% of cycles, and in combination with other therapies in 38%. Of the combinations, 16 were with donor leukocyte infusion, and 9 were gemtuzumab ozogamicin (Mylotarg).

Of the 13 patients for whom HMAs were used as part of treatment plan with curative intent, 5 proceeded to HSCT, and 8 did not. Of the 5 patients, 1 died from transplant-related causes, and 4 were alive post transplant. Of the 8 patients who did not undergo transplant, 1 had chimeric antigen receptor T- cell (CAR T) therapy, and 7 experienced disease progression.

The mean duration of palliative care was 144 days, with patients receiving from one to nine cycles with an HMA, and no treatment interruptions due to toxicity.

Of 5 patients who received donor leukocyte infusions, 3 reached minimal residual disease negativity; all 3 of these patients had late relapses but remained long-term survivors, the investigators reported.

They concluded that “hypomethylating agents can be used effectively as a bridge to transplantation in relapsed and refractory AML with gemtuzumab ozogamicin being the most common agent for combination therapy. Palliation with HMAs is associated with low toxicity and high tolerability in relapsed/refractory AML. Use of HMAs with DLI can induce sustained remissions in some patients.”

The authors propose prospective clinical trials using HMAs in the relapsed/refractory pediatric AML setting in combination with gemtuzumab ozogamicin, alternative targeted agents, and chemotherapy.

HMAs in treatment-related AML

Shilpa Shahani, MD, a pediatric oncologist and assistant clinical professor of pediatrics at City of Hope in Duarte, Calif., who was not involved in the study, has experience administering HMAs primarily in the adolescent and young adult population with AML.

“Azacitidine and decitabine are good for treatment-related leukemias,” she said in an interview. “They can be used otherwise for people who have relapsed disease and are trying to navigate other options.”

Although they are not standard first-line agents in younger patients, HMAs can play a useful role in therapy for relapsed or refractory disease, she said.

The authors and Dr. Shahani reported having no conflicts of interest to disclose.

Hypomethylating agents are generally considered to be agents of choice for older adults with acute myeloid leukemia who cannot tolerate the rigors of more intensive therapies, but HMAs also can serve as a bridge to transplant for children and young adults with relapsed or refractory acute myeloid leukemia.

That’s according to Himalee S. Sabnis, MD, MSc and colleagues at Emory University and the Aflac Cancer and Blood Disorders Center at Children’s Healthcare of Atlanta.

In a scientific poster presented during the annual meeting of the American Society of Pediatric Hematology/Oncology, the investigators reported results of a retrospective study of HMA use in patients with relapsed or refractory pediatric AML treated in their center.
 

Curative intent and palliation

They identified 25 patients (15 boys) with a median age of 8.3 years (range 1.4 to 21 years) with relapsed/refractory AML who received HMAs for curative intent prior to hematopoietic stem cell transplant (HSCT), palliation, or in combination with donor leukocyte infusion (DLI).

Of the 21 patients with relapsed disease, 16 were in first relapse and 5 were in second relapse or greater. Four of the patients had primary refractory disease. The cytogenetic and molecular features were KMT2A rearrangements in six patients, monosomy 7/deletion 7 q in four patients, 8;21 translocation in three patients, and FLT3-ITD mutations in four patients.

The patients received a median of 5.3 HMA cycles each. Of the 133 total HMA cycles, 87 were with azacitidine, and 46 were with decitabine.

HMAs were used as monotherapy in 62% of cycles, and in combination with other therapies in 38%. Of the combinations, 16 were with donor leukocyte infusion, and 9 were gemtuzumab ozogamicin (Mylotarg).

Of the 13 patients for whom HMAs were used as part of treatment plan with curative intent, 5 proceeded to HSCT, and 8 did not. Of the 5 patients, 1 died from transplant-related causes, and 4 were alive post transplant. Of the 8 patients who did not undergo transplant, 1 had chimeric antigen receptor T- cell (CAR T) therapy, and 7 experienced disease progression.

The mean duration of palliative care was 144 days, with patients receiving from one to nine cycles with an HMA, and no treatment interruptions due to toxicity.

Of 5 patients who received donor leukocyte infusions, 3 reached minimal residual disease negativity; all 3 of these patients had late relapses but remained long-term survivors, the investigators reported.

They concluded that “hypomethylating agents can be used effectively as a bridge to transplantation in relapsed and refractory AML with gemtuzumab ozogamicin being the most common agent for combination therapy. Palliation with HMAs is associated with low toxicity and high tolerability in relapsed/refractory AML. Use of HMAs with DLI can induce sustained remissions in some patients.”

The authors propose prospective clinical trials using HMAs in the relapsed/refractory pediatric AML setting in combination with gemtuzumab ozogamicin, alternative targeted agents, and chemotherapy.

HMAs in treatment-related AML

Shilpa Shahani, MD, a pediatric oncologist and assistant clinical professor of pediatrics at City of Hope in Duarte, Calif., who was not involved in the study, has experience administering HMAs primarily in the adolescent and young adult population with AML.

“Azacitidine and decitabine are good for treatment-related leukemias,” she said in an interview. “They can be used otherwise for people who have relapsed disease and are trying to navigate other options.”

Although they are not standard first-line agents in younger patients, HMAs can play a useful role in therapy for relapsed or refractory disease, she said.

The authors and Dr. Shahani reported having no conflicts of interest to disclose.

Among older patients with acute myeloid leukemia (AML), survival is significantly better when they undergo reduced-intensity conditioning (RIC) before receiving an allogeneic hematopoietic cell transplant (HCT) at first remission. This improvement in survival is seen regardless of key factors such as genotype and the status of minimal residual disease (MRD) after initial chemotherapy, results from two large randomized trials show.

“Two consecutive trials of more than 1,500 older AML patients above 60 years of age demonstrate a consistent benefit for RIC transplant in first remission,” said first author Nigel Russell, MD, of Guy’s Hospital, London, and Nottingham University, England. “This benefit is seen independent of their post-course 1 MRD status,” he added.

Dr. Russell presented the new data at the European Hematology Association (EHA) 2021 Annual Meeting.

Commenting on the study, Charles Craddock, MD, said in an interview that the results “confirm the growing importance of RIC transplantation as a central treatment management strategy in high-risk AML and in this population high risk patients over 60.”

“[These findings] reinforce the evolving treatment paradigm that, in fit adults over 60 with AML, hematopoietic cell transplantation should be considered an essential component of their management plan,” said Dr. Craddock, academic director of the Center for Clinical Haematology, Queen Elizabeth Hospital, Birmingham, England.

Patients with AML who are older than 60 years can achieve complete remission with intensive chemotherapy alone; however, relapse is common, and only about 20% survive for 5 years, Dr. Russell explained.

HCT significantly improves survival outcomes, and the development of RIC has made transplantation accessible to high-risk patients by making the procedure more tolerable with lower toxicity in comparison with conventional conditioning regimens.

However, there is ongoing debate over the prognostic effect of key factors in pretransplant conditioning that may be predictive of the risk for post-transplant relapse – in particular, the presence of MRD after the first course of conditioning, he explained.

To more closely investigate those factors and the rate of survival of older patients with AML who undergo RIC transplant, Dr. Russell and his colleagues evaluated results from the National Cancer Research Institute’s (NCRI) AML16 trial, which was conducted from 2006 to 2012, and interim results from the NCRI AML18 trial, which started in 2015 and is ongoing.

Both trials employed double induction of daunorubicin and clofarabine or, in the AML16 trial, AraC ± gemtuzumab, and in the AML18 trial, daunorubicin and AraC (DA) + gemtuzumab.

In AML18, patients who were MRD positive after course 1 were randomly assigned to undergo either an intensification randomization after either FLAG-Ida or DA+cladribine or DA alone.

In AML16, of 983 patients in first complete response, 144 (15%) subsequently underwent RIC transplant. The median follow-up for survival from complete response was 45 months.

In the AML18 trial, of 847 patients, 648 patients achieved complete response. Among them, 201 (31%) underwent transplant. The median follow-up of survival was 45 months.

The results of both trials showed greater benefit with RIC transplant versus chemotherapy alone.

In the AML16 trial, among patients aged 60 to 70 who received RIC, survival at 5 years was significantly improved compared with chemotherapy alone (37% vs. 19%; hazard ratio, 0.65; 95% confidence interval, 0.52-0.82; P < .001).

In AML16, the higher survival benefit in comparison with chemotherapy alone was observed in the RIC group across subgroups of risk level, as stratified according to in the multivariate Wheatley risk group score. Subgroup stratification was based on age, cytogenics, and other factors (HR, 0.66; 95% CI, 0.53-0.83; P < .001).

Importantly, the survival benefits were significantly greater with RIC transplant regardless of MRD-negative or MRD-positive status after course 1 (HR, 0.68; 95% CI, 0.54-0.85; P < .001).

Allograft transplant was also more favorable regardless of FLT3 ITD or NPM1 mutation status (P for heterogeneity by genetic subgroups, 0.61).

In AML16, no groups were found to have benefited more with RIC. Consequently, the criteria for transplant in AML18 trial were based on patients’ health status and donor availability.

An interim analysis of the ongoing AML 18 trial further underscored an overall benefit of RIC transplant. Rates of 3-year survival from remission were 48% with RIC transplant, versus 37.4% with chemotherapy alone (P = .027). The benefit was independent of MRD status after conditioning course 1, similar to the AML16 results (HR, 0.71; 95% CI, 0.54-0.95; P = .02).

Although the rate of transplantation in the AML18 trial was higher among patients who were MRD positive in comparison with those who were MRD negative (36% vs. 24.8%), the rates of post-transplant survival were not significantly different between those who were MRD positive and those who were MRD negative after course 1 (51.1% vs. 46.6% at 3 years; P = .84).

The authors evaluated the effects of a second conditioning course on transplant outcomes among patients who did not initially achieve an MRD-negative complete remission.

They found that 60% of patients did convert from MRD-positive to MRD-negative status after course 2. Among those patients, the survival versus chemotherapy alone was substantially higher (HR, 0.32; 95% CI, 0.11-0.92) compared to those who remained MRD-negative (HR 0.74; 95% CI, 0.32-1.72).

However, the authors note that, owing to a lack of heterogeneity, the results don’t necessarily mean that the patients who remained MRD positive did not also benefit from transplant.

“There was a significant benefit for transplant in those who converted to MRD negativity,” Dr. Russell said.

“With a hazard ratio of .32, this was far superior to those who remained MRD-positive post course 2,” he said.

“These results show that MRD status after course 1 is important information in terms of response to therapy and can alter your treatment strategy if you’re considering a transplant as an option for these patients,” Dr. Russell told this news organization.

In further commenting, Dr. Craddock said the research highlights the importance of randomized trials with regard to whether patients who are MRD-positive before transplant will benefit from an additional course of therapy to reduce the MRD load.

“Most get two courses, but the question is, if they are still MRD positive, should they get a third course, and if so, what should that look like?” he said.

“There are currently no randomized controlled trials to address that ongoing question, and they need to be done,” he added.

Dr. Russell has relationships with Pfizer, Astellas, and Jazz Pharma. Dr. Craddock has a relationship with Bristol-Myers Squibb.

A version of this article first appeared on Medscape.com.

Among older patients with acute myeloid leukemia (AML), survival is significantly better when they undergo reduced-intensity conditioning (RIC) before receiving an allogeneic hematopoietic cell transplant (HCT) at first remission. This improvement in survival is seen regardless of key factors such as genotype and the status of minimal residual disease (MRD) after initial chemotherapy, results from two large randomized trials show.

“Two consecutive trials of more than 1,500 older AML patients above 60 years of age demonstrate a consistent benefit for RIC transplant in first remission,” said first author Nigel Russell, MD, of Guy’s Hospital, London, and Nottingham University, England. “This benefit is seen independent of their post-course 1 MRD status,” he added.

Dr. Russell presented the new data at the European Hematology Association (EHA) 2021 Annual Meeting.

Commenting on the study, Charles Craddock, MD, said in an interview that the results “confirm the growing importance of RIC transplantation as a central treatment management strategy in high-risk AML and in this population high risk patients over 60.”

“[These findings] reinforce the evolving treatment paradigm that, in fit adults over 60 with AML, hematopoietic cell transplantation should be considered an essential component of their management plan,” said Dr. Craddock, academic director of the Center for Clinical Haematology, Queen Elizabeth Hospital, Birmingham, England.

Patients with AML who are older than 60 years can achieve complete remission with intensive chemotherapy alone; however, relapse is common, and only about 20% survive for 5 years, Dr. Russell explained.

HCT significantly improves survival outcomes, and the development of RIC has made transplantation accessible to high-risk patients by making the procedure more tolerable with lower toxicity in comparison with conventional conditioning regimens.

However, there is ongoing debate over the prognostic effect of key factors in pretransplant conditioning that may be predictive of the risk for post-transplant relapse – in particular, the presence of MRD after the first course of conditioning, he explained.

To more closely investigate those factors and the rate of survival of older patients with AML who undergo RIC transplant, Dr. Russell and his colleagues evaluated results from the National Cancer Research Institute’s (NCRI) AML16 trial, which was conducted from 2006 to 2012, and interim results from the NCRI AML18 trial, which started in 2015 and is ongoing.

Both trials employed double induction of daunorubicin and clofarabine or, in the AML16 trial, AraC ± gemtuzumab, and in the AML18 trial, daunorubicin and AraC (DA) + gemtuzumab.

In AML18, patients who were MRD positive after course 1 were randomly assigned to undergo either an intensification randomization after either FLAG-Ida or DA+cladribine or DA alone.

In AML16, of 983 patients in first complete response, 144 (15%) subsequently underwent RIC transplant. The median follow-up for survival from complete response was 45 months.

In the AML18 trial, of 847 patients, 648 patients achieved complete response. Among them, 201 (31%) underwent transplant. The median follow-up of survival was 45 months.

The results of both trials showed greater benefit with RIC transplant versus chemotherapy alone.

In the AML16 trial, among patients aged 60 to 70 who received RIC, survival at 5 years was significantly improved compared with chemotherapy alone (37% vs. 19%; hazard ratio, 0.65; 95% confidence interval, 0.52-0.82; P < .001).

In AML16, the higher survival benefit in comparison with chemotherapy alone was observed in the RIC group across subgroups of risk level, as stratified according to in the multivariate Wheatley risk group score. Subgroup stratification was based on age, cytogenics, and other factors (HR, 0.66; 95% CI, 0.53-0.83; P < .001).

Importantly, the survival benefits were significantly greater with RIC transplant regardless of MRD-negative or MRD-positive status after course 1 (HR, 0.68; 95% CI, 0.54-0.85; P < .001).

Allograft transplant was also more favorable regardless of FLT3 ITD or NPM1 mutation status (P for heterogeneity by genetic subgroups, 0.61).

In AML16, no groups were found to have benefited more with RIC. Consequently, the criteria for transplant in AML18 trial were based on patients’ health status and donor availability.

An interim analysis of the ongoing AML 18 trial further underscored an overall benefit of RIC transplant. Rates of 3-year survival from remission were 48% with RIC transplant, versus 37.4% with chemotherapy alone (P = .027). The benefit was independent of MRD status after conditioning course 1, similar to the AML16 results (HR, 0.71; 95% CI, 0.54-0.95; P = .02).

Although the rate of transplantation in the AML18 trial was higher among patients who were MRD positive in comparison with those who were MRD negative (36% vs. 24.8%), the rates of post-transplant survival were not significantly different between those who were MRD positive and those who were MRD negative after course 1 (51.1% vs. 46.6% at 3 years; P = .84).

The authors evaluated the effects of a second conditioning course on transplant outcomes among patients who did not initially achieve an MRD-negative complete remission.

They found that 60% of patients did convert from MRD-positive to MRD-negative status after course 2. Among those patients, the survival versus chemotherapy alone was substantially higher (HR, 0.32; 95% CI, 0.11-0.92) compared to those who remained MRD-negative (HR 0.74; 95% CI, 0.32-1.72).

However, the authors note that, owing to a lack of heterogeneity, the results don’t necessarily mean that the patients who remained MRD positive did not also benefit from transplant.

“There was a significant benefit for transplant in those who converted to MRD negativity,” Dr. Russell said.

“With a hazard ratio of .32, this was far superior to those who remained MRD-positive post course 2,” he said.

“These results show that MRD status after course 1 is important information in terms of response to therapy and can alter your treatment strategy if you’re considering a transplant as an option for these patients,” Dr. Russell told this news organization.

In further commenting, Dr. Craddock said the research highlights the importance of randomized trials with regard to whether patients who are MRD-positive before transplant will benefit from an additional course of therapy to reduce the MRD load.

“Most get two courses, but the question is, if they are still MRD positive, should they get a third course, and if so, what should that look like?” he said.

“There are currently no randomized controlled trials to address that ongoing question, and they need to be done,” he added.

Dr. Russell has relationships with Pfizer, Astellas, and Jazz Pharma. Dr. Craddock has a relationship with Bristol-Myers Squibb.

A version of this article first appeared on Medscape.com.

Among older patients with acute myeloid leukemia (AML), survival is significantly better when they undergo reduced-intensity conditioning (RIC) before receiving an allogeneic hematopoietic cell transplant (HCT) at first remission. This improvement in survival is seen regardless of key factors such as genotype and the status of minimal residual disease (MRD) after initial chemotherapy, results from two large randomized trials show.

“Two consecutive trials of more than 1,500 older AML patients above 60 years of age demonstrate a consistent benefit for RIC transplant in first remission,” said first author Nigel Russell, MD, of Guy’s Hospital, London, and Nottingham University, England. “This benefit is seen independent of their post-course 1 MRD status,” he added.

Dr. Russell presented the new data at the European Hematology Association (EHA) 2021 Annual Meeting.

Commenting on the study, Charles Craddock, MD, said in an interview that the results “confirm the growing importance of RIC transplantation as a central treatment management strategy in high-risk AML and in this population high risk patients over 60.”

“[These findings] reinforce the evolving treatment paradigm that, in fit adults over 60 with AML, hematopoietic cell transplantation should be considered an essential component of their management plan,” said Dr. Craddock, academic director of the Center for Clinical Haematology, Queen Elizabeth Hospital, Birmingham, England.

Patients with AML who are older than 60 years can achieve complete remission with intensive chemotherapy alone; however, relapse is common, and only about 20% survive for 5 years, Dr. Russell explained.

HCT significantly improves survival outcomes, and the development of RIC has made transplantation accessible to high-risk patients by making the procedure more tolerable with lower toxicity in comparison with conventional conditioning regimens.

However, there is ongoing debate over the prognostic effect of key factors in pretransplant conditioning that may be predictive of the risk for post-transplant relapse – in particular, the presence of MRD after the first course of conditioning, he explained.

To more closely investigate those factors and the rate of survival of older patients with AML who undergo RIC transplant, Dr. Russell and his colleagues evaluated results from the National Cancer Research Institute’s (NCRI) AML16 trial, which was conducted from 2006 to 2012, and interim results from the NCRI AML18 trial, which started in 2015 and is ongoing.

Both trials employed double induction of daunorubicin and clofarabine or, in the AML16 trial, AraC ± gemtuzumab, and in the AML18 trial, daunorubicin and AraC (DA) + gemtuzumab.

In AML18, patients who were MRD positive after course 1 were randomly assigned to undergo either an intensification randomization after either FLAG-Ida or DA+cladribine or DA alone.

In AML16, of 983 patients in first complete response, 144 (15%) subsequently underwent RIC transplant. The median follow-up for survival from complete response was 45 months.

In the AML18 trial, of 847 patients, 648 patients achieved complete response. Among them, 201 (31%) underwent transplant. The median follow-up of survival was 45 months.

The results of both trials showed greater benefit with RIC transplant versus chemotherapy alone.

In the AML16 trial, among patients aged 60 to 70 who received RIC, survival at 5 years was significantly improved compared with chemotherapy alone (37% vs. 19%; hazard ratio, 0.65; 95% confidence interval, 0.52-0.82; P < .001).

In AML16, the higher survival benefit in comparison with chemotherapy alone was observed in the RIC group across subgroups of risk level, as stratified according to in the multivariate Wheatley risk group score. Subgroup stratification was based on age, cytogenics, and other factors (HR, 0.66; 95% CI, 0.53-0.83; P < .001).

Importantly, the survival benefits were significantly greater with RIC transplant regardless of MRD-negative or MRD-positive status after course 1 (HR, 0.68; 95% CI, 0.54-0.85; P < .001).

Allograft transplant was also more favorable regardless of FLT3 ITD or NPM1 mutation status (P for heterogeneity by genetic subgroups, 0.61).

In AML16, no groups were found to have benefited more with RIC. Consequently, the criteria for transplant in AML18 trial were based on patients’ health status and donor availability.

An interim analysis of the ongoing AML 18 trial further underscored an overall benefit of RIC transplant. Rates of 3-year survival from remission were 48% with RIC transplant, versus 37.4% with chemotherapy alone (P = .027). The benefit was independent of MRD status after conditioning course 1, similar to the AML16 results (HR, 0.71; 95% CI, 0.54-0.95; P = .02).

Although the rate of transplantation in the AML18 trial was higher among patients who were MRD positive in comparison with those who were MRD negative (36% vs. 24.8%), the rates of post-transplant survival were not significantly different between those who were MRD positive and those who were MRD negative after course 1 (51.1% vs. 46.6% at 3 years; P = .84).

The authors evaluated the effects of a second conditioning course on transplant outcomes among patients who did not initially achieve an MRD-negative complete remission.

They found that 60% of patients did convert from MRD-positive to MRD-negative status after course 2. Among those patients, the survival versus chemotherapy alone was substantially higher (HR, 0.32; 95% CI, 0.11-0.92) compared to those who remained MRD-negative (HR 0.74; 95% CI, 0.32-1.72).

However, the authors note that, owing to a lack of heterogeneity, the results don’t necessarily mean that the patients who remained MRD positive did not also benefit from transplant.

“There was a significant benefit for transplant in those who converted to MRD negativity,” Dr. Russell said.

“With a hazard ratio of .32, this was far superior to those who remained MRD-positive post course 2,” he said.

“These results show that MRD status after course 1 is important information in terms of response to therapy and can alter your treatment strategy if you’re considering a transplant as an option for these patients,” Dr. Russell told this news organization.

In further commenting, Dr. Craddock said the research highlights the importance of randomized trials with regard to whether patients who are MRD-positive before transplant will benefit from an additional course of therapy to reduce the MRD load.

“Most get two courses, but the question is, if they are still MRD positive, should they get a third course, and if so, what should that look like?” he said.

“There are currently no randomized controlled trials to address that ongoing question, and they need to be done,” he added.

Dr. Russell has relationships with Pfizer, Astellas, and Jazz Pharma. Dr. Craddock has a relationship with Bristol-Myers Squibb.

A version of this article first appeared on Medscape.com.

Even the youngest patients with relapsed or refractory B-lineage acute lymphoblastic leukemia (B-ALL) may be able to benefit from chimeric antigen reception T-cell (CAR T) therapy, investigators in an international consortium say.

Among 30 children aged under 2 years at the time of (B-ALL diagnosis, manufacturing of the CAR T product tisagenlecleucel (Kymriah) was feasible in 28 patients, and treatment resulted in high rates of minimal residual disease (MRD) negativity, complete responses, event-free survival, and overall survival, reported Sara Ghorashian, MD from the University College London Great Ormond Street Institute of Child Health, on behalf of the International BFM Resistant Disease Committee.

“The disease-related outcomes noted in this cohort of younger children predominantly with relapsed/refractory infant [mixed lineage leukemia]–rearranged ALL were at least as good as for the ELIANA study,” she said in an oral abstract presented during the European Hematology Association annual congress (Abstract S116).

The international, single-arm, open-label, ELIANA study was a phase 2 trial that included 97 patients aged 3-24 years with relapsed or refractory B-cell ALL, most of whom had previously undergone a hematopoietic stem cell transplant. Of those patients, 79 patients went on to receive a single infusion of the CAR T therapy.

“It’s fantastic data,” said Kevin J. Curran, MD, a pediatric hematologist/oncologist specializing in stem cell transplants and cellular therapy at Memorial Sloan Kettering Cancer Center, New York.

“Pediatric leukemia, while it’s the most common malignancy that happens in children, when you get down to this really small group, this under 3-year-old group, it’s hard to get a cohort, and for them to put together 30 patients, and show these great results is groundbreaking,” he said in an interview.

“Most importantly, it gives hope to parents who have young children who have really difficult to treat leukemia,” he said.

Dr. Curran was not involved in the study.
 

Scarce data on ALL in infants

“Children under 3 years of age were excluded from the ELIANA study, yet in terms of having often highly aggressive disease, with traditionally poor outcomes with conventional therapy, the need for novel forms of therapy for children with relapsed infant ALL is important,” Dr. Ghorashian said.

Because there is a paucity of data on outcomes in the youngest children, some health authorities will not support the use of tisagenlecleucel in this age group, and there are concerns about difficulties with performing leukapheresis in children weighing less than 10 kg, she noted.

To gain a better understanding of outcomes, members of the International BFM (Berlin-Frankfurt-Munster) Study Group conducted a retrospective analysis of data on all patients assessed for tisagenlecleucel for B-ALL who were aged under 3 years at screening at 1 of 15 centers in Europe and Israel.

A total of 30 patients were screened and had T cells harvested. Of this group, three patients did not receive CAR T infusions, two because of manufacturing failures, and one because of progressive disease.

Of the 27 patients who received CAR T infusions, 26 were evaluable for disease outcomes (1 had yet to reach the 30-day post infusion at the time of data cutoff).

The median age at diagnosis was 4.4 months, and the median age at infusion was 17.4 months; 19 of the 30 children in the entire cohort were boys. Mixed lineage leukemia rearrangements were found in 24 children, and 21 had undergone a stem cell transplant.

The children had a median of two prior lines of therapy, not including transplant. Seven of the children had received inotuzumab (Besponsa) and 11 had received blinotumumab (Blincyto).
 

High success rate

Of the 27 patients infused, 17 had sufficient cells harvested in a single day, and the remainder required 2-4 days. As noted, the CAR T product was successfully manufactured in 28 patients, with a median dose of 2.3 x 10⁶/kg of patient weight.

The treatment failed for 2 of the 26 efficacy-evaluable patients, resulting in an MRD-negative rate of 92%.

Event-free survival at 6 months was 67%, similar to that in ELIANA (73%), and the 12-month event-free survival was 58%, which was superior to that in ELIANA (50%).

The 6-month and 12-month overall survival rates among the younger children were identical at 88%, compared with 90% and 76%, respectively, in ELIANA.

The 6- and 12-month probability of ongoing B-cell depletion, indicating CAR T persistence, were 77% and 68%, respectively. In ELIANA, the 6-month probability of B-cell depletion was 83%.

A total of 10 of the 27 patients received further therapy, including 3 who were given maintenance therapy for poor CAR T persistence, 2 who underwent chemotherapy for relapse, and 5 who underwent allogeneic stem cell transplant.

Of six patients who experienced a relapse after having a complete response, two had CD19 relapse.
 

Low rate of serious CRS

At 30 days post infusion, grade 3 or greater cytokine release syndrome (CRS) had occurred in two patients, severe neurotoxicity occurred in one, and grade 3 or greater prolonged cytopenias occurred in eight patients.

The toxicity profile in this study was generally favorable in comparison with ELIANA, with shorter median duration of CRS, shorter median duration of CRS-related ICU stay, and a lower frequency of tocilizumab use. It should be noted, however, that the I-BFM investigators used American Society for Transplantation and Cellular Therapy CRS consenus criteria, whereas the ELIANA investigators used University of Pennsylvania criteria.

“If the longer-term follow-up data are encouraging, it might suggest that the outcomes from tisagenlecleucel therapy are comparable to that of stem cell transplantation in high-risk relapsed infant ALL, without the associated late effects, and possibly supports CAR T-cell therapy eventually replace stem cell transplantation in this setting,” Dr. Ghorashian said.

Dr. Curran, who leads the CAR T effort at MSK Kids, the children’s division of MSKCC, agreed that the goal is for CAR T to replace stem cell transplants.

“I hope I put my clinical practice out of business with my research practice,” he said, but added that “I think we need to do more research in figuring out how to best use CAR T cells, either earlier, or as some data suggest, by treating patients with lower disease burden we would get better durability.

“Because obviously in kids’ cancer one relapse is too much, and we want to be able to raise that bar and provide hope and a cure for all of our children,” he said.

The study was sponsored by the I-BFM Resistant Disease Committee and member institutions. Dr. Ghorashian disclosed advisory board activity for Novartis, maker of tisagenlecleucel, and patents and royalties from UCL Business. Dr. Curran research funding and consulting fees from Novartis.

Even the youngest patients with relapsed or refractory B-lineage acute lymphoblastic leukemia (B-ALL) may be able to benefit from chimeric antigen reception T-cell (CAR T) therapy, investigators in an international consortium say.

Among 30 children aged under 2 years at the time of (B-ALL diagnosis, manufacturing of the CAR T product tisagenlecleucel (Kymriah) was feasible in 28 patients, and treatment resulted in high rates of minimal residual disease (MRD) negativity, complete responses, event-free survival, and overall survival, reported Sara Ghorashian, MD from the University College London Great Ormond Street Institute of Child Health, on behalf of the International BFM Resistant Disease Committee.

“The disease-related outcomes noted in this cohort of younger children predominantly with relapsed/refractory infant [mixed lineage leukemia]–rearranged ALL were at least as good as for the ELIANA study,” she said in an oral abstract presented during the European Hematology Association annual congress (Abstract S116).

The international, single-arm, open-label, ELIANA study was a phase 2 trial that included 97 patients aged 3-24 years with relapsed or refractory B-cell ALL, most of whom had previously undergone a hematopoietic stem cell transplant. Of those patients, 79 patients went on to receive a single infusion of the CAR T therapy.

“It’s fantastic data,” said Kevin J. Curran, MD, a pediatric hematologist/oncologist specializing in stem cell transplants and cellular therapy at Memorial Sloan Kettering Cancer Center, New York.

“Pediatric leukemia, while it’s the most common malignancy that happens in children, when you get down to this really small group, this under 3-year-old group, it’s hard to get a cohort, and for them to put together 30 patients, and show these great results is groundbreaking,” he said in an interview.

“Most importantly, it gives hope to parents who have young children who have really difficult to treat leukemia,” he said.

Dr. Curran was not involved in the study.
 

Scarce data on ALL in infants

“Children under 3 years of age were excluded from the ELIANA study, yet in terms of having often highly aggressive disease, with traditionally poor outcomes with conventional therapy, the need for novel forms of therapy for children with relapsed infant ALL is important,” Dr. Ghorashian said.

Because there is a paucity of data on outcomes in the youngest children, some health authorities will not support the use of tisagenlecleucel in this age group, and there are concerns about difficulties with performing leukapheresis in children weighing less than 10 kg, she noted.

To gain a better understanding of outcomes, members of the International BFM (Berlin-Frankfurt-Munster) Study Group conducted a retrospective analysis of data on all patients assessed for tisagenlecleucel for B-ALL who were aged under 3 years at screening at 1 of 15 centers in Europe and Israel.

A total of 30 patients were screened and had T cells harvested. Of this group, three patients did not receive CAR T infusions, two because of manufacturing failures, and one because of progressive disease.

Of the 27 patients who received CAR T infusions, 26 were evaluable for disease outcomes (1 had yet to reach the 30-day post infusion at the time of data cutoff).

The median age at diagnosis was 4.4 months, and the median age at infusion was 17.4 months; 19 of the 30 children in the entire cohort were boys. Mixed lineage leukemia rearrangements were found in 24 children, and 21 had undergone a stem cell transplant.

The children had a median of two prior lines of therapy, not including transplant. Seven of the children had received inotuzumab (Besponsa) and 11 had received blinotumumab (Blincyto).
 

High success rate

Of the 27 patients infused, 17 had sufficient cells harvested in a single day, and the remainder required 2-4 days. As noted, the CAR T product was successfully manufactured in 28 patients, with a median dose of 2.3 x 10⁶/kg of patient weight.

The treatment failed for 2 of the 26 efficacy-evaluable patients, resulting in an MRD-negative rate of 92%.

Event-free survival at 6 months was 67%, similar to that in ELIANA (73%), and the 12-month event-free survival was 58%, which was superior to that in ELIANA (50%).

The 6-month and 12-month overall survival rates among the younger children were identical at 88%, compared with 90% and 76%, respectively, in ELIANA.

The 6- and 12-month probability of ongoing B-cell depletion, indicating CAR T persistence, were 77% and 68%, respectively. In ELIANA, the 6-month probability of B-cell depletion was 83%.

A total of 10 of the 27 patients received further therapy, including 3 who were given maintenance therapy for poor CAR T persistence, 2 who underwent chemotherapy for relapse, and 5 who underwent allogeneic stem cell transplant.

Of six patients who experienced a relapse after having a complete response, two had CD19 relapse.
 

Low rate of serious CRS

At 30 days post infusion, grade 3 or greater cytokine release syndrome (CRS) had occurred in two patients, severe neurotoxicity occurred in one, and grade 3 or greater prolonged cytopenias occurred in eight patients.

The toxicity profile in this study was generally favorable in comparison with ELIANA, with shorter median duration of CRS, shorter median duration of CRS-related ICU stay, and a lower frequency of tocilizumab use. It should be noted, however, that the I-BFM investigators used American Society for Transplantation and Cellular Therapy CRS consenus criteria, whereas the ELIANA investigators used University of Pennsylvania criteria.

“If the longer-term follow-up data are encouraging, it might suggest that the outcomes from tisagenlecleucel therapy are comparable to that of stem cell transplantation in high-risk relapsed infant ALL, without the associated late effects, and possibly supports CAR T-cell therapy eventually replace stem cell transplantation in this setting,” Dr. Ghorashian said.

Dr. Curran, who leads the CAR T effort at MSK Kids, the children’s division of MSKCC, agreed that the goal is for CAR T to replace stem cell transplants.

“I hope I put my clinical practice out of business with my research practice,” he said, but added that “I think we need to do more research in figuring out how to best use CAR T cells, either earlier, or as some data suggest, by treating patients with lower disease burden we would get better durability.

“Because obviously in kids’ cancer one relapse is too much, and we want to be able to raise that bar and provide hope and a cure for all of our children,” he said.

The study was sponsored by the I-BFM Resistant Disease Committee and member institutions. Dr. Ghorashian disclosed advisory board activity for Novartis, maker of tisagenlecleucel, and patents and royalties from UCL Business. Dr. Curran research funding and consulting fees from Novartis.

Even the youngest patients with relapsed or refractory B-lineage acute lymphoblastic leukemia (B-ALL) may be able to benefit from chimeric antigen reception T-cell (CAR T) therapy, investigators in an international consortium say.

Among 30 children aged under 2 years at the time of (B-ALL diagnosis, manufacturing of the CAR T product tisagenlecleucel (Kymriah) was feasible in 28 patients, and treatment resulted in high rates of minimal residual disease (MRD) negativity, complete responses, event-free survival, and overall survival, reported Sara Ghorashian, MD from the University College London Great Ormond Street Institute of Child Health, on behalf of the International BFM Resistant Disease Committee.

“The disease-related outcomes noted in this cohort of younger children predominantly with relapsed/refractory infant [mixed lineage leukemia]–rearranged ALL were at least as good as for the ELIANA study,” she said in an oral abstract presented during the European Hematology Association annual congress (Abstract S116).

The international, single-arm, open-label, ELIANA study was a phase 2 trial that included 97 patients aged 3-24 years with relapsed or refractory B-cell ALL, most of whom had previously undergone a hematopoietic stem cell transplant. Of those patients, 79 patients went on to receive a single infusion of the CAR T therapy.

“It’s fantastic data,” said Kevin J. Curran, MD, a pediatric hematologist/oncologist specializing in stem cell transplants and cellular therapy at Memorial Sloan Kettering Cancer Center, New York.

“Pediatric leukemia, while it’s the most common malignancy that happens in children, when you get down to this really small group, this under 3-year-old group, it’s hard to get a cohort, and for them to put together 30 patients, and show these great results is groundbreaking,” he said in an interview.

“Most importantly, it gives hope to parents who have young children who have really difficult to treat leukemia,” he said.

Dr. Curran was not involved in the study.
 

Scarce data on ALL in infants

“Children under 3 years of age were excluded from the ELIANA study, yet in terms of having often highly aggressive disease, with traditionally poor outcomes with conventional therapy, the need for novel forms of therapy for children with relapsed infant ALL is important,” Dr. Ghorashian said.

Because there is a paucity of data on outcomes in the youngest children, some health authorities will not support the use of tisagenlecleucel in this age group, and there are concerns about difficulties with performing leukapheresis in children weighing less than 10 kg, she noted.

To gain a better understanding of outcomes, members of the International BFM (Berlin-Frankfurt-Munster) Study Group conducted a retrospective analysis of data on all patients assessed for tisagenlecleucel for B-ALL who were aged under 3 years at screening at 1 of 15 centers in Europe and Israel.

A total of 30 patients were screened and had T cells harvested. Of this group, three patients did not receive CAR T infusions, two because of manufacturing failures, and one because of progressive disease.

Of the 27 patients who received CAR T infusions, 26 were evaluable for disease outcomes (1 had yet to reach the 30-day post infusion at the time of data cutoff).

The median age at diagnosis was 4.4 months, and the median age at infusion was 17.4 months; 19 of the 30 children in the entire cohort were boys. Mixed lineage leukemia rearrangements were found in 24 children, and 21 had undergone a stem cell transplant.

The children had a median of two prior lines of therapy, not including transplant. Seven of the children had received inotuzumab (Besponsa) and 11 had received blinotumumab (Blincyto).
 

High success rate

Of the 27 patients infused, 17 had sufficient cells harvested in a single day, and the remainder required 2-4 days. As noted, the CAR T product was successfully manufactured in 28 patients, with a median dose of 2.3 x 10⁶/kg of patient weight.

The treatment failed for 2 of the 26 efficacy-evaluable patients, resulting in an MRD-negative rate of 92%.

Event-free survival at 6 months was 67%, similar to that in ELIANA (73%), and the 12-month event-free survival was 58%, which was superior to that in ELIANA (50%).

The 6-month and 12-month overall survival rates among the younger children were identical at 88%, compared with 90% and 76%, respectively, in ELIANA.

The 6- and 12-month probability of ongoing B-cell depletion, indicating CAR T persistence, were 77% and 68%, respectively. In ELIANA, the 6-month probability of B-cell depletion was 83%.

A total of 10 of the 27 patients received further therapy, including 3 who were given maintenance therapy for poor CAR T persistence, 2 who underwent chemotherapy for relapse, and 5 who underwent allogeneic stem cell transplant.

Of six patients who experienced a relapse after having a complete response, two had CD19 relapse.
 

Low rate of serious CRS

At 30 days post infusion, grade 3 or greater cytokine release syndrome (CRS) had occurred in two patients, severe neurotoxicity occurred in one, and grade 3 or greater prolonged cytopenias occurred in eight patients.

The toxicity profile in this study was generally favorable in comparison with ELIANA, with shorter median duration of CRS, shorter median duration of CRS-related ICU stay, and a lower frequency of tocilizumab use. It should be noted, however, that the I-BFM investigators used American Society for Transplantation and Cellular Therapy CRS consenus criteria, whereas the ELIANA investigators used University of Pennsylvania criteria.

“If the longer-term follow-up data are encouraging, it might suggest that the outcomes from tisagenlecleucel therapy are comparable to that of stem cell transplantation in high-risk relapsed infant ALL, without the associated late effects, and possibly supports CAR T-cell therapy eventually replace stem cell transplantation in this setting,” Dr. Ghorashian said.

Dr. Curran, who leads the CAR T effort at MSK Kids, the children’s division of MSKCC, agreed that the goal is for CAR T to replace stem cell transplants.

“I hope I put my clinical practice out of business with my research practice,” he said, but added that “I think we need to do more research in figuring out how to best use CAR T cells, either earlier, or as some data suggest, by treating patients with lower disease burden we would get better durability.

“Because obviously in kids’ cancer one relapse is too much, and we want to be able to raise that bar and provide hope and a cure for all of our children,” he said.

The study was sponsored by the I-BFM Resistant Disease Committee and member institutions. Dr. Ghorashian disclosed advisory board activity for Novartis, maker of tisagenlecleucel, and patents and royalties from UCL Business. Dr. Curran research funding and consulting fees from Novartis.

For older, unfit patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), first-line treatment with the all-oral combination of ibrutinib (Imbruvica) and venetoclax (Venclexta) was associated with superior progression-free survival, compared with chlorambucil and obinutuzumab (Gazyva), results of the phase 3 GLOW trial showed.

Among 211 patients with CLL/SLL who were 65 or older, or younger patients with a high comorbidity burden, the median progression-free survival (PFS) after 27.7 months of follow-up was not reached for patients treated with a fixed duration combination of ibrutinib plus venetoclax (I+V), compared with 21 months for patients who received chlorambucil plus obinutuzumab (Clb+O), reported Arnon P. Kater, MD, PhD, from Amsterdam University Medical Centers.

The oral combination was also associated with a higher rate of undetectable minimal residual disease (MRD) 3 months after the end of treatment, at 51.9% vs. 17.1% with Clb+O, he said in a late-breaking abstract presented during the European Hematology Association annual meeting (Abstract LB1902).

“Overall, the results from GLOW support a positive clinical profile of I+V as an all-oral, once-daily, fixed-duration regimen in older patients with newly diagnosed CLL,” he said.
 

A low bar

But the bar for success in the GLOW trial may have been set low, with the older combination of chlorambucil plus obinutuzumab used as the comparator, rather than a more contemporary regimen, said Clive S. Zent , MD, from the Wilmot Cancer Institute at the University of Rochester (New York) Medical Center, who was not involved in the study.

“Really, nobody in this country that I’m aware of, certainly not in academic medicine, would be using chlorambucil and obinutuzumab or rituximab for standard of care,” Dr. Zent said in an interview.

“This is like comparing a mule cart to a Tesla,” he said.

Apart from possibly providing a rationale for using ibrutinib and venetoclax in this population, the GLOW results do not add much beyond that already in the CAPTIVE MRD trial, he added.

“What we’re really interested in, is ibrutinib and venetoclax better than ibrutinib alone or venetoclax alone? And that has not been asked or answered yet,” he said.

Dr. Zent acknowledged that the combination works very well and is well tolerated, and the idea of fixed duration therapy is attractive, as are the long-term outcomes for many patients following cessation of therapy.

“But remember, if you take ibrutinib, you’ve got a 90% chance of going into remission, and an over 80% chance of being in remission 5 years later, so that’s pretty good as well,” he said.

Paolo P. Ghia, MD, from Univerista Vita-Salute San Raffaele in Milan, who has studied fixed-duration I+V in younger patients with CLL in the CAPTIVATE trial agreed that “in general, there is very little role for chemoimmunotherapy in CLL.”

But Dr. Ghia, who was not involved in the GLOW study, said in an interview that the results add to the growing body of evidence of the efficacy and safety of ibrutinib -venetoclax in a wide range of patients.

“Overall between the two studies [CAPTIVATE and GLOW] we have now over 400 patients who have been treated with the combination, and the message is rather similar in the two studies: you have a high frequency of undetectable MRD in peripheral blood and in the bone marrow, with a high concordance between the two tissues, and in particular we have a durability of the response,” he said.
 

GLOW details

Dr. Kater noted that ibrutinib and venetoclax have distinct and complementary modes of action, with ibrutinib mobilizing CLL cells out of their “protective lymphoid niches” and inhibiting their proliferation, as well as accelerating apoptosis by sensitizing cells to inhibition by the anti–B-cell lymphoma 2 (BCL-2) agent venetoclax. The combination leads to high levels of MRD negative by eliminating subpopulations of resting and dividing CLL cells.

The GLOW investigators enrolled 211 patients who were 65 or older, or were younger than 65 with a cumulative illness rating scale (CIRS) score of greater than 6, or creatinine clearance rate of less than 70 mL/min, and no known deletion 17p (del17p) or TP53 mutation.

The patients all had Eastern Cooperative Oncology Group performance status scores of 0-2.

After stratification by immunoglobulin heavy chain variable (IGHV) region genes and presence of deletion 11q (del11q), the patients were randomly assigned to either a three cycle run-in with ibrutinib 420 mg daily followed by ibrutinib plus venetoclax ramped up from 20 to 400 mg, or to chlorambucil 0.5 mg/kg on days and 15 for six cycles, and obinutuzumab 1,000 mg on days 1,2, 8, and 15 of cycle 1, and day 1 of cycles 2-6.

About one-third of patients in each study arm were 75 or older. Baseline characteristics were generally similar between the arms, except for a higher frequency of CIRS scores above 6 in the I+V arm, and a higher frequency of elevated lactate dehydrogenase in the Clb+O arm.
 

Superior PFS

As noted, the primary endpoint of PFS as assessed by independent review committee (IRC) after 27.7 months of follow-up had not been reached in I+V arm, compared with 21 months in the Clb+O arm, translating into a hazard ratio or progression with I+V of 0.21 (P < .0001). Investigator-assessed PFS was similar, with an HR of 2.07 (P < .0001).

PFS was superior with I+V across all subgroups, including age, baseline performance status. CIRS total score, Rai stage, bulky disease, elevated LDH at baseline, IGHV mutated or unmutated, and presence or absence of del(11q).

IRC-assessed combined complete response (CR) or CR with incomplete recovery of blood counts (CRi) rates were 38.7% with I+V vs. 11.4% with Clb+O (P < .0001).

Responses were also more durable with the oral combination, with 90% of patients having a sustained IRC-assessed response at 24 months, compared with 41% in the chemoimmunotherapy arm.

Rates of undetectable MRD by next-generation sequencing 3 months after the end of treatment were also significantly higher with I+V in both bone marrow (51.9% vs. 17.1%, respectively, P < .0001) and peripheral blood (54.7% vs. 39%, P = .0259). ­

One year post treatment 49% of patients assigned to I+V had undetectable MRD in peripheral blood, compared with 12% of patients assigned to Clb+O).
 

Safety

In all, 11 patients assigned to I+V discontinued treatment because of adverse events, compared with 2 in the Clb+O arm. Two patients in the I+V arm (1.9%) discontinued ibrutinib because of atrial fibrillation (AF). Serious adverse events in 5% or more of patients that were more frequent with I+V include infections (12.3% vs. 8.6% and AF (6.6% vs. o%). The tumor lysis syndrome (TLS) was not seen in the I+V arm, but occurred in 5.7% of patients in the Clb+O arm.

There were a total of 11 deaths in the I+V arm and 12 in the Clb+O arm during treatment or follow-up.

Causes of death were generally similar between the arms, with infections and cardiac events being the most common causes, Dr. Kater said.

Of the four deaths that occurred during ibrutinib lead-in, one was due to infection, one to metastatic carcinoma, and two due to cardiac disorders. Of the three that occurred in the I+V arm during treatment, two were from sudden death, and one from a nervous system disorder. Four patients in this arm died during follow-up, two from infections, one from sudden death, and one from progressive disease with Richter transformation.

In the Clb+O arm, one patient died during treatment from an infection and one died from hepatobiliary disease. Of the 10 that died during follow-up, 6 died from infections/infestations, 2 from cardiac disorders, and 1 each from nervous system and respiratory/thoracic/mediastinal disorder.

The study was supported by Janssen Research & Development. Dr. Kater disclosed advisory board activity, research committee, and steering committee participation for Janssen, and similar relationships with others. Dr. Zent disclosed research funding to the University of Rochester from AstraZenca/Acerta and TG Therpeutics. Dr. Ghia disclosed consultancy, honoraria, travel expenses, and research funding from Janssen and others.

For older, unfit patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), first-line treatment with the all-oral combination of ibrutinib (Imbruvica) and venetoclax (Venclexta) was associated with superior progression-free survival, compared with chlorambucil and obinutuzumab (Gazyva), results of the phase 3 GLOW trial showed.

Among 211 patients with CLL/SLL who were 65 or older, or younger patients with a high comorbidity burden, the median progression-free survival (PFS) after 27.7 months of follow-up was not reached for patients treated with a fixed duration combination of ibrutinib plus venetoclax (I+V), compared with 21 months for patients who received chlorambucil plus obinutuzumab (Clb+O), reported Arnon P. Kater, MD, PhD, from Amsterdam University Medical Centers.

The oral combination was also associated with a higher rate of undetectable minimal residual disease (MRD) 3 months after the end of treatment, at 51.9% vs. 17.1% with Clb+O, he said in a late-breaking abstract presented during the European Hematology Association annual meeting (Abstract LB1902).

“Overall, the results from GLOW support a positive clinical profile of I+V as an all-oral, once-daily, fixed-duration regimen in older patients with newly diagnosed CLL,” he said.
 

A low bar

But the bar for success in the GLOW trial may have been set low, with the older combination of chlorambucil plus obinutuzumab used as the comparator, rather than a more contemporary regimen, said Clive S. Zent , MD, from the Wilmot Cancer Institute at the University of Rochester (New York) Medical Center, who was not involved in the study.

“Really, nobody in this country that I’m aware of, certainly not in academic medicine, would be using chlorambucil and obinutuzumab or rituximab for standard of care,” Dr. Zent said in an interview.

“This is like comparing a mule cart to a Tesla,” he said.

Apart from possibly providing a rationale for using ibrutinib and venetoclax in this population, the GLOW results do not add much beyond that already in the CAPTIVE MRD trial, he added.

“What we’re really interested in, is ibrutinib and venetoclax better than ibrutinib alone or venetoclax alone? And that has not been asked or answered yet,” he said.

Dr. Zent acknowledged that the combination works very well and is well tolerated, and the idea of fixed duration therapy is attractive, as are the long-term outcomes for many patients following cessation of therapy.

“But remember, if you take ibrutinib, you’ve got a 90% chance of going into remission, and an over 80% chance of being in remission 5 years later, so that’s pretty good as well,” he said.

Paolo P. Ghia, MD, from Univerista Vita-Salute San Raffaele in Milan, who has studied fixed-duration I+V in younger patients with CLL in the CAPTIVATE trial agreed that “in general, there is very little role for chemoimmunotherapy in CLL.”

But Dr. Ghia, who was not involved in the GLOW study, said in an interview that the results add to the growing body of evidence of the efficacy and safety of ibrutinib -venetoclax in a wide range of patients.

“Overall between the two studies [CAPTIVATE and GLOW] we have now over 400 patients who have been treated with the combination, and the message is rather similar in the two studies: you have a high frequency of undetectable MRD in peripheral blood and in the bone marrow, with a high concordance between the two tissues, and in particular we have a durability of the response,” he said.
 

GLOW details

Dr. Kater noted that ibrutinib and venetoclax have distinct and complementary modes of action, with ibrutinib mobilizing CLL cells out of their “protective lymphoid niches” and inhibiting their proliferation, as well as accelerating apoptosis by sensitizing cells to inhibition by the anti–B-cell lymphoma 2 (BCL-2) agent venetoclax. The combination leads to high levels of MRD negative by eliminating subpopulations of resting and dividing CLL cells.

The GLOW investigators enrolled 211 patients who were 65 or older, or were younger than 65 with a cumulative illness rating scale (CIRS) score of greater than 6, or creatinine clearance rate of less than 70 mL/min, and no known deletion 17p (del17p) or TP53 mutation.

The patients all had Eastern Cooperative Oncology Group performance status scores of 0-2.

After stratification by immunoglobulin heavy chain variable (IGHV) region genes and presence of deletion 11q (del11q), the patients were randomly assigned to either a three cycle run-in with ibrutinib 420 mg daily followed by ibrutinib plus venetoclax ramped up from 20 to 400 mg, or to chlorambucil 0.5 mg/kg on days and 15 for six cycles, and obinutuzumab 1,000 mg on days 1,2, 8, and 15 of cycle 1, and day 1 of cycles 2-6.

About one-third of patients in each study arm were 75 or older. Baseline characteristics were generally similar between the arms, except for a higher frequency of CIRS scores above 6 in the I+V arm, and a higher frequency of elevated lactate dehydrogenase in the Clb+O arm.
 

Superior PFS

As noted, the primary endpoint of PFS as assessed by independent review committee (IRC) after 27.7 months of follow-up had not been reached in I+V arm, compared with 21 months in the Clb+O arm, translating into a hazard ratio or progression with I+V of 0.21 (P < .0001). Investigator-assessed PFS was similar, with an HR of 2.07 (P < .0001).

PFS was superior with I+V across all subgroups, including age, baseline performance status. CIRS total score, Rai stage, bulky disease, elevated LDH at baseline, IGHV mutated or unmutated, and presence or absence of del(11q).

IRC-assessed combined complete response (CR) or CR with incomplete recovery of blood counts (CRi) rates were 38.7% with I+V vs. 11.4% with Clb+O (P < .0001).

Responses were also more durable with the oral combination, with 90% of patients having a sustained IRC-assessed response at 24 months, compared with 41% in the chemoimmunotherapy arm.

Rates of undetectable MRD by next-generation sequencing 3 months after the end of treatment were also significantly higher with I+V in both bone marrow (51.9% vs. 17.1%, respectively, P < .0001) and peripheral blood (54.7% vs. 39%, P = .0259). ­

One year post treatment 49% of patients assigned to I+V had undetectable MRD in peripheral blood, compared with 12% of patients assigned to Clb+O).
 

Safety

In all, 11 patients assigned to I+V discontinued treatment because of adverse events, compared with 2 in the Clb+O arm. Two patients in the I+V arm (1.9%) discontinued ibrutinib because of atrial fibrillation (AF). Serious adverse events in 5% or more of patients that were more frequent with I+V include infections (12.3% vs. 8.6% and AF (6.6% vs. o%). The tumor lysis syndrome (TLS) was not seen in the I+V arm, but occurred in 5.7% of patients in the Clb+O arm.

There were a total of 11 deaths in the I+V arm and 12 in the Clb+O arm during treatment or follow-up.

Causes of death were generally similar between the arms, with infections and cardiac events being the most common causes, Dr. Kater said.

Of the four deaths that occurred during ibrutinib lead-in, one was due to infection, one to metastatic carcinoma, and two due to cardiac disorders. Of the three that occurred in the I+V arm during treatment, two were from sudden death, and one from a nervous system disorder. Four patients in this arm died during follow-up, two from infections, one from sudden death, and one from progressive disease with Richter transformation.

In the Clb+O arm, one patient died during treatment from an infection and one died from hepatobiliary disease. Of the 10 that died during follow-up, 6 died from infections/infestations, 2 from cardiac disorders, and 1 each from nervous system and respiratory/thoracic/mediastinal disorder.

The study was supported by Janssen Research & Development. Dr. Kater disclosed advisory board activity, research committee, and steering committee participation for Janssen, and similar relationships with others. Dr. Zent disclosed research funding to the University of Rochester from AstraZenca/Acerta and TG Therpeutics. Dr. Ghia disclosed consultancy, honoraria, travel expenses, and research funding from Janssen and others.

For older, unfit patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), first-line treatment with the all-oral combination of ibrutinib (Imbruvica) and venetoclax (Venclexta) was associated with superior progression-free survival, compared with chlorambucil and obinutuzumab (Gazyva), results of the phase 3 GLOW trial showed.

Among 211 patients with CLL/SLL who were 65 or older, or younger patients with a high comorbidity burden, the median progression-free survival (PFS) after 27.7 months of follow-up was not reached for patients treated with a fixed duration combination of ibrutinib plus venetoclax (I+V), compared with 21 months for patients who received chlorambucil plus obinutuzumab (Clb+O), reported Arnon P. Kater, MD, PhD, from Amsterdam University Medical Centers.

The oral combination was also associated with a higher rate of undetectable minimal residual disease (MRD) 3 months after the end of treatment, at 51.9% vs. 17.1% with Clb+O, he said in a late-breaking abstract presented during the European Hematology Association annual meeting (Abstract LB1902).

“Overall, the results from GLOW support a positive clinical profile of I+V as an all-oral, once-daily, fixed-duration regimen in older patients with newly diagnosed CLL,” he said.
 

A low bar

But the bar for success in the GLOW trial may have been set low, with the older combination of chlorambucil plus obinutuzumab used as the comparator, rather than a more contemporary regimen, said Clive S. Zent , MD, from the Wilmot Cancer Institute at the University of Rochester (New York) Medical Center, who was not involved in the study.

“Really, nobody in this country that I’m aware of, certainly not in academic medicine, would be using chlorambucil and obinutuzumab or rituximab for standard of care,” Dr. Zent said in an interview.

“This is like comparing a mule cart to a Tesla,” he said.

Apart from possibly providing a rationale for using ibrutinib and venetoclax in this population, the GLOW results do not add much beyond that already in the CAPTIVE MRD trial, he added.

“What we’re really interested in, is ibrutinib and venetoclax better than ibrutinib alone or venetoclax alone? And that has not been asked or answered yet,” he said.

Dr. Zent acknowledged that the combination works very well and is well tolerated, and the idea of fixed duration therapy is attractive, as are the long-term outcomes for many patients following cessation of therapy.

“But remember, if you take ibrutinib, you’ve got a 90% chance of going into remission, and an over 80% chance of being in remission 5 years later, so that’s pretty good as well,” he said.

Paolo P. Ghia, MD, from Univerista Vita-Salute San Raffaele in Milan, who has studied fixed-duration I+V in younger patients with CLL in the CAPTIVATE trial agreed that “in general, there is very little role for chemoimmunotherapy in CLL.”

But Dr. Ghia, who was not involved in the GLOW study, said in an interview that the results add to the growing body of evidence of the efficacy and safety of ibrutinib -venetoclax in a wide range of patients.

“Overall between the two studies [CAPTIVATE and GLOW] we have now over 400 patients who have been treated with the combination, and the message is rather similar in the two studies: you have a high frequency of undetectable MRD in peripheral blood and in the bone marrow, with a high concordance between the two tissues, and in particular we have a durability of the response,” he said.
 

GLOW details

Dr. Kater noted that ibrutinib and venetoclax have distinct and complementary modes of action, with ibrutinib mobilizing CLL cells out of their “protective lymphoid niches” and inhibiting their proliferation, as well as accelerating apoptosis by sensitizing cells to inhibition by the anti–B-cell lymphoma 2 (BCL-2) agent venetoclax. The combination leads to high levels of MRD negative by eliminating subpopulations of resting and dividing CLL cells.

The GLOW investigators enrolled 211 patients who were 65 or older, or were younger than 65 with a cumulative illness rating scale (CIRS) score of greater than 6, or creatinine clearance rate of less than 70 mL/min, and no known deletion 17p (del17p) or TP53 mutation.

The patients all had Eastern Cooperative Oncology Group performance status scores of 0-2.

After stratification by immunoglobulin heavy chain variable (IGHV) region genes and presence of deletion 11q (del11q), the patients were randomly assigned to either a three cycle run-in with ibrutinib 420 mg daily followed by ibrutinib plus venetoclax ramped up from 20 to 400 mg, or to chlorambucil 0.5 mg/kg on days and 15 for six cycles, and obinutuzumab 1,000 mg on days 1,2, 8, and 15 of cycle 1, and day 1 of cycles 2-6.

About one-third of patients in each study arm were 75 or older. Baseline characteristics were generally similar between the arms, except for a higher frequency of CIRS scores above 6 in the I+V arm, and a higher frequency of elevated lactate dehydrogenase in the Clb+O arm.
 

Superior PFS

As noted, the primary endpoint of PFS as assessed by independent review committee (IRC) after 27.7 months of follow-up had not been reached in I+V arm, compared with 21 months in the Clb+O arm, translating into a hazard ratio or progression with I+V of 0.21 (P < .0001). Investigator-assessed PFS was similar, with an HR of 2.07 (P < .0001).

PFS was superior with I+V across all subgroups, including age, baseline performance status. CIRS total score, Rai stage, bulky disease, elevated LDH at baseline, IGHV mutated or unmutated, and presence or absence of del(11q).

IRC-assessed combined complete response (CR) or CR with incomplete recovery of blood counts (CRi) rates were 38.7% with I+V vs. 11.4% with Clb+O (P < .0001).

Responses were also more durable with the oral combination, with 90% of patients having a sustained IRC-assessed response at 24 months, compared with 41% in the chemoimmunotherapy arm.

Rates of undetectable MRD by next-generation sequencing 3 months after the end of treatment were also significantly higher with I+V in both bone marrow (51.9% vs. 17.1%, respectively, P < .0001) and peripheral blood (54.7% vs. 39%, P = .0259). ­

One year post treatment 49% of patients assigned to I+V had undetectable MRD in peripheral blood, compared with 12% of patients assigned to Clb+O).
 

Safety

In all, 11 patients assigned to I+V discontinued treatment because of adverse events, compared with 2 in the Clb+O arm. Two patients in the I+V arm (1.9%) discontinued ibrutinib because of atrial fibrillation (AF). Serious adverse events in 5% or more of patients that were more frequent with I+V include infections (12.3% vs. 8.6% and AF (6.6% vs. o%). The tumor lysis syndrome (TLS) was not seen in the I+V arm, but occurred in 5.7% of patients in the Clb+O arm.

There were a total of 11 deaths in the I+V arm and 12 in the Clb+O arm during treatment or follow-up.

Causes of death were generally similar between the arms, with infections and cardiac events being the most common causes, Dr. Kater said.

Of the four deaths that occurred during ibrutinib lead-in, one was due to infection, one to metastatic carcinoma, and two due to cardiac disorders. Of the three that occurred in the I+V arm during treatment, two were from sudden death, and one from a nervous system disorder. Four patients in this arm died during follow-up, two from infections, one from sudden death, and one from progressive disease with Richter transformation.

In the Clb+O arm, one patient died during treatment from an infection and one died from hepatobiliary disease. Of the 10 that died during follow-up, 6 died from infections/infestations, 2 from cardiac disorders, and 1 each from nervous system and respiratory/thoracic/mediastinal disorder.

The study was supported by Janssen Research & Development. Dr. Kater disclosed advisory board activity, research committee, and steering committee participation for Janssen, and similar relationships with others. Dr. Zent disclosed research funding to the University of Rochester from AstraZenca/Acerta and TG Therpeutics. Dr. Ghia disclosed consultancy, honoraria, travel expenses, and research funding from Janssen and others.

Data from a small retrospective study suggest that venetoclax-based regimens may have activity against relapsed or refractory T-lineage acute lymphoblastic leukemia (T-ALL) in children and young adults.

Among seven patients with T-ALL treated with venetoclax (Venclexta) in combination with chemotherapy, four had complete remissions and one had a CR with incomplete recovery of blood counts (CRi), and all four patients had undetectable minimal residual disease (MRD), reported pediatric hematology/oncology fellow Amber Gibson, MD, and colleagues from the University of Texas MD Anderson Cancer Center Children’s Cancer Hospital in Houston.

“This single-institution retrospective review found that venetoclax was safe and well tolerated in combination chemotherapy regimens, thrombocytopenia and neutropenia were the most common toxicities identified, [and] venetoclax should be considered for patients with refractory T-cell ALL and investigated as up-front therapy for this patient population,” they wrote in the abstract accompanying a poster presentation at the annual meeting of the American Society of Pediatric Hematology/Oncology.

Children with relapsed T-ALL and T-lymphoblastic lymphoma (T-LL) have a dismal prognosis, with a 3-year event-free survival rate less than 10%, according to the researchers.

To see whether venetoclax, an inhibitor of the antiapoptotic protein B-cell lymphoma-2 (BCL-2), could improve outcomes for children with ALL, the investigators conducted a retrospective chart review of the safety and efficacy of venetoclax in young patients with relapsed/refractory ALL/LL who received the drug at their center.

They identified 10 patients aged 6-21 years (median, 18), 5 of whom had T-ALL (1 with early T-cell precursor ALL), 2 with T-LL, and 3 with B-lineage ALL (B-ALL).

The median number of prior lines of therapy was 3.5. Three of the 10 patients had received hematopoietic stem cell transplants, and the 3 patients with B-ALL had all received prior CD19-directed chimeric antigen receptor T-cell (CAR T) therapy. One of these patients received a dual CD19/CD22 CAR T product, one received CD19-directed blinotumumab.

There were no new safety signals with venetoclax, no treatment-related deaths, and no deaths within 30 days of starting venetoclax.

All 10 patients had grade 4 thrombocytopenias, 6 had grade 4 neutropenia, 3 had grade 4 febrile neutropenia, 2 had grade 4 anemia, and 1 each had grade 4 sepsis, pneumonia, or coagulopathy.

As noted, there were three CRs and one CRi, all in patients with T-ALL. All four of these patients were MRD negative by flow cytometry at a median of 22 days. The median duration of response was 17.4 months (range, 2-18 months).

At the most recent follow-up five patients were still alive, three without disease, one was still undergoing treatment, and one was alive following an allogeneic HSCT.
 

Early studies

Shilpa Shahani, MD, a pediatric oncologist and assistant clinical professor of pediatrics at City of Hope in Duarte, Calif., who was not involved in the study, said that there are early studies exploring the use of venetoclax in infants with ALL.

“Venetoclax is a BCL-2 inhibitor that is pretty well tolerated, but you can also have cytopenias with it,” she said.

She noted that it is not typically used in the frontline setting in pediatric populations, but may be considered for patients with difficult-to-treat disease or for whom the relatively good toxicity profile might be appropriate.

The MD Anderson investigators did not report a funding source. The authors and Dr. Shahani reported no relevant conflicts of interest.

Data from a small retrospective study suggest that venetoclax-based regimens may have activity against relapsed or refractory T-lineage acute lymphoblastic leukemia (T-ALL) in children and young adults.

Among seven patients with T-ALL treated with venetoclax (Venclexta) in combination with chemotherapy, four had complete remissions and one had a CR with incomplete recovery of blood counts (CRi), and all four patients had undetectable minimal residual disease (MRD), reported pediatric hematology/oncology fellow Amber Gibson, MD, and colleagues from the University of Texas MD Anderson Cancer Center Children’s Cancer Hospital in Houston.

“This single-institution retrospective review found that venetoclax was safe and well tolerated in combination chemotherapy regimens, thrombocytopenia and neutropenia were the most common toxicities identified, [and] venetoclax should be considered for patients with refractory T-cell ALL and investigated as up-front therapy for this patient population,” they wrote in the abstract accompanying a poster presentation at the annual meeting of the American Society of Pediatric Hematology/Oncology.

Children with relapsed T-ALL and T-lymphoblastic lymphoma (T-LL) have a dismal prognosis, with a 3-year event-free survival rate less than 10%, according to the researchers.

To see whether venetoclax, an inhibitor of the antiapoptotic protein B-cell lymphoma-2 (BCL-2), could improve outcomes for children with ALL, the investigators conducted a retrospective chart review of the safety and efficacy of venetoclax in young patients with relapsed/refractory ALL/LL who received the drug at their center.

They identified 10 patients aged 6-21 years (median, 18), 5 of whom had T-ALL (1 with early T-cell precursor ALL), 2 with T-LL, and 3 with B-lineage ALL (B-ALL).

The median number of prior lines of therapy was 3.5. Three of the 10 patients had received hematopoietic stem cell transplants, and the 3 patients with B-ALL had all received prior CD19-directed chimeric antigen receptor T-cell (CAR T) therapy. One of these patients received a dual CD19/CD22 CAR T product, one received CD19-directed blinotumumab.

There were no new safety signals with venetoclax, no treatment-related deaths, and no deaths within 30 days of starting venetoclax.

All 10 patients had grade 4 thrombocytopenias, 6 had grade 4 neutropenia, 3 had grade 4 febrile neutropenia, 2 had grade 4 anemia, and 1 each had grade 4 sepsis, pneumonia, or coagulopathy.

As noted, there were three CRs and one CRi, all in patients with T-ALL. All four of these patients were MRD negative by flow cytometry at a median of 22 days. The median duration of response was 17.4 months (range, 2-18 months).

At the most recent follow-up five patients were still alive, three without disease, one was still undergoing treatment, and one was alive following an allogeneic HSCT.
 

Early studies

Shilpa Shahani, MD, a pediatric oncologist and assistant clinical professor of pediatrics at City of Hope in Duarte, Calif., who was not involved in the study, said that there are early studies exploring the use of venetoclax in infants with ALL.

“Venetoclax is a BCL-2 inhibitor that is pretty well tolerated, but you can also have cytopenias with it,” she said.

She noted that it is not typically used in the frontline setting in pediatric populations, but may be considered for patients with difficult-to-treat disease or for whom the relatively good toxicity profile might be appropriate.

The MD Anderson investigators did not report a funding source. The authors and Dr. Shahani reported no relevant conflicts of interest.

Data from a small retrospective study suggest that venetoclax-based regimens may have activity against relapsed or refractory T-lineage acute lymphoblastic leukemia (T-ALL) in children and young adults.

Among seven patients with T-ALL treated with venetoclax (Venclexta) in combination with chemotherapy, four had complete remissions and one had a CR with incomplete recovery of blood counts (CRi), and all four patients had undetectable minimal residual disease (MRD), reported pediatric hematology/oncology fellow Amber Gibson, MD, and colleagues from the University of Texas MD Anderson Cancer Center Children’s Cancer Hospital in Houston.

“This single-institution retrospective review found that venetoclax was safe and well tolerated in combination chemotherapy regimens, thrombocytopenia and neutropenia were the most common toxicities identified, [and] venetoclax should be considered for patients with refractory T-cell ALL and investigated as up-front therapy for this patient population,” they wrote in the abstract accompanying a poster presentation at the annual meeting of the American Society of Pediatric Hematology/Oncology.

Children with relapsed T-ALL and T-lymphoblastic lymphoma (T-LL) have a dismal prognosis, with a 3-year event-free survival rate less than 10%, according to the researchers.

To see whether venetoclax, an inhibitor of the antiapoptotic protein B-cell lymphoma-2 (BCL-2), could improve outcomes for children with ALL, the investigators conducted a retrospective chart review of the safety and efficacy of venetoclax in young patients with relapsed/refractory ALL/LL who received the drug at their center.

They identified 10 patients aged 6-21 years (median, 18), 5 of whom had T-ALL (1 with early T-cell precursor ALL), 2 with T-LL, and 3 with B-lineage ALL (B-ALL).

The median number of prior lines of therapy was 3.5. Three of the 10 patients had received hematopoietic stem cell transplants, and the 3 patients with B-ALL had all received prior CD19-directed chimeric antigen receptor T-cell (CAR T) therapy. One of these patients received a dual CD19/CD22 CAR T product, one received CD19-directed blinotumumab.

There were no new safety signals with venetoclax, no treatment-related deaths, and no deaths within 30 days of starting venetoclax.

All 10 patients had grade 4 thrombocytopenias, 6 had grade 4 neutropenia, 3 had grade 4 febrile neutropenia, 2 had grade 4 anemia, and 1 each had grade 4 sepsis, pneumonia, or coagulopathy.

As noted, there were three CRs and one CRi, all in patients with T-ALL. All four of these patients were MRD negative by flow cytometry at a median of 22 days. The median duration of response was 17.4 months (range, 2-18 months).

At the most recent follow-up five patients were still alive, three without disease, one was still undergoing treatment, and one was alive following an allogeneic HSCT.
 

Early studies

Shilpa Shahani, MD, a pediatric oncologist and assistant clinical professor of pediatrics at City of Hope in Duarte, Calif., who was not involved in the study, said that there are early studies exploring the use of venetoclax in infants with ALL.

“Venetoclax is a BCL-2 inhibitor that is pretty well tolerated, but you can also have cytopenias with it,” she said.

She noted that it is not typically used in the frontline setting in pediatric populations, but may be considered for patients with difficult-to-treat disease or for whom the relatively good toxicity profile might be appropriate.

The MD Anderson investigators did not report a funding source. The authors and Dr. Shahani reported no relevant conflicts of interest.

Even in the age of intensive therapy and extensive risk stratification, there are small but significant differences in outcomes between boys and girls with B-lineage acute lymphoblastic leukemia (B-ALL).

This finding comes from a review of 10 years of clinical trials by the Children’s Oncology Group (COG), which showed that, among patients with B-ALL, 5-year event-free survival (EFS) and overall survival (OS) were inferior with boys, compared with girls, even when adjusted for prognostic factors, reported Sumit Gupta, MD, PhD, FRCPC, from the Hospital for Sick Children in Toronto.

“Inferior outcomes, although small in absolute terms, continue to exist among boys versus girls despite modern therapy and after adjusting for other risk factors. These persist also despite the longer duration of therapy among boys,” he said in an oral abstract presentation during the annual meeting of the American Society of Pediatric Hematology/Oncology. (Abstract 2025).

Among pediatric patients with T-cell lineage ALL (T-ALL), however, there were no significant sex-based differences in either EFS or OS, he said.

Although survival for children with ALL has continued to improve, previous studies found inferior survival outcomes in boys, and suggested that the difference might be explained by imbalances in risk factors.

To see whether sex-based disparities persist with modern intensive therapy protocols after adjustment for risk factors, and to determine whether there are sex-based differences in toxicities or patterns of treatment failure, Dr. Gupta and colleagues created a cohort of all patients age 1-30 years enrolled in frontline COG trial for B-ALL and T-ALL from 2004 to 2014.

During this period, boys received an extra year of maintenance. Cranial radiation was limited to B-ALL patients with slow treatment responses and central nervous system status 3, signifying definite CNS involvement. Among patients with T-ALL, cranial radiation was given to all intermediate- and high-risk patients.
 

Sex differences small, but significant

The investigators identified a total of 8,202 patients (4,463 males and 3,739 females) with B-ALL, and 1,562 (1,161 males and 401 females) with T-ALL. Boys were likely to be older (P < .0001), and to have a small but significantly greater likelihood of having unfavorable B-ALL cytogenetics, compared with girls (P = .05).

Boys with B-ALL were less likely to be negative for minimal residual disease (76.1% vs. 78.1%, P = .04), but the opposite was true for those with T-ALL (59% vs. 56.8%, P = .01).

As noted before, among pediatric patients with B-ALL, EFS and OS were both inferior for males, with a hazard ratio for higher EFS rates in girls of 1.19 (P = .001) and a HR for OS of 1.17 (P = .046).

Both EFS and OS were similar between the sexes among patients with T-ALL.

The differences in EFS in patients with B-ALL was attributable to higher CNS relapses among boys (4.2% vs. 2.5%, P < .0001). The CNS relapses occurred at a median of 2.5 years in boys versus 2.1 years in girls, although most relapses occurred during therapy.

There were no differences in cumulative isolated bone marrow relapses, however.

Treatment-related mortality rates were the same, but osteonecrosis rates were significantly lower for boys, with a 5-year cumulative incidence of 5.2% versus 6.7% for girls (P = .001).
 

Possible explanations

Dr. Gupta noted that the inferior outcomes among boys may be attributable to extramedullary relapses among patients with B-ALL.

In addition, the lack of sex-based differences in T-ALL may be caused in part by the increased use of CNS radiation in this population. Previous studies in which CNS radiation was omitted showed an increase in CNS relapsed rates among boys but not girls, he pointed out.

“This does imply that in the more recent generation of T-lineage ALL treatment trials that we’ll need to monitor sex-based differences in outcome, as fewer and fewer patients with T-ALL disease received cranial radiation in these more recent trials and in contemporary therapy,” he said.

One possible mechanism for sex-based outcome differences might be differences in steroid metabolism, as suggested by the higher osteonecrosis rate among girls, he added.

In the question-and-answer following the presentation, William G. Woods, MD, from Emory University, Atlanta, asked what role testicular relapse played in outcomes.

Dr. Gupta replied that the investigators had considered that the excess risk for extramedullary relapse in boys might be accounted for by testicular relapse, but “when you take away testicular relapse from those numbers and really just concentrate on CNS, it’s still that substantial difference when you’re talking about B-lineage disease.”

In patients with T-ALL as well, CNS relapse was more common in boys after controlling for testicular relapse, he said.

Another audience member asked whether the data suggest a benefit to treating boys with CNS-penetrating drugs such as dexamethasone or high-dose methotrexate,

Dr. Gupta said that it’s still uncertain whether it is clinically sound to subject a boy with otherwise–standard-risk disease to more intensive high-risk therapy, given the relatively small absolute differences in outcomes between the sexes.

The study was supported by grants from the National Cancer Institute and the St. Baldrick’s Foundation. Dr. Gupta, Dr. Woods, and Dr. Meret had no relevant conflicts of interest to report.

Even in the age of intensive therapy and extensive risk stratification, there are small but significant differences in outcomes between boys and girls with B-lineage acute lymphoblastic leukemia (B-ALL).

This finding comes from a review of 10 years of clinical trials by the Children’s Oncology Group (COG), which showed that, among patients with B-ALL, 5-year event-free survival (EFS) and overall survival (OS) were inferior with boys, compared with girls, even when adjusted for prognostic factors, reported Sumit Gupta, MD, PhD, FRCPC, from the Hospital for Sick Children in Toronto.

“Inferior outcomes, although small in absolute terms, continue to exist among boys versus girls despite modern therapy and after adjusting for other risk factors. These persist also despite the longer duration of therapy among boys,” he said in an oral abstract presentation during the annual meeting of the American Society of Pediatric Hematology/Oncology. (Abstract 2025).

Among pediatric patients with T-cell lineage ALL (T-ALL), however, there were no significant sex-based differences in either EFS or OS, he said.

Although survival for children with ALL has continued to improve, previous studies found inferior survival outcomes in boys, and suggested that the difference might be explained by imbalances in risk factors.

To see whether sex-based disparities persist with modern intensive therapy protocols after adjustment for risk factors, and to determine whether there are sex-based differences in toxicities or patterns of treatment failure, Dr. Gupta and colleagues created a cohort of all patients age 1-30 years enrolled in frontline COG trial for B-ALL and T-ALL from 2004 to 2014.

During this period, boys received an extra year of maintenance. Cranial radiation was limited to B-ALL patients with slow treatment responses and central nervous system status 3, signifying definite CNS involvement. Among patients with T-ALL, cranial radiation was given to all intermediate- and high-risk patients.
 

Sex differences small, but significant

The investigators identified a total of 8,202 patients (4,463 males and 3,739 females) with B-ALL, and 1,562 (1,161 males and 401 females) with T-ALL. Boys were likely to be older (P < .0001), and to have a small but significantly greater likelihood of having unfavorable B-ALL cytogenetics, compared with girls (P = .05).

Boys with B-ALL were less likely to be negative for minimal residual disease (76.1% vs. 78.1%, P = .04), but the opposite was true for those with T-ALL (59% vs. 56.8%, P = .01).

As noted before, among pediatric patients with B-ALL, EFS and OS were both inferior for males, with a hazard ratio for higher EFS rates in girls of 1.19 (P = .001) and a HR for OS of 1.17 (P = .046).

Both EFS and OS were similar between the sexes among patients with T-ALL.

The differences in EFS in patients with B-ALL was attributable to higher CNS relapses among boys (4.2% vs. 2.5%, P < .0001). The CNS relapses occurred at a median of 2.5 years in boys versus 2.1 years in girls, although most relapses occurred during therapy.

There were no differences in cumulative isolated bone marrow relapses, however.

Treatment-related mortality rates were the same, but osteonecrosis rates were significantly lower for boys, with a 5-year cumulative incidence of 5.2% versus 6.7% for girls (P = .001).
 

Possible explanations

Dr. Gupta noted that the inferior outcomes among boys may be attributable to extramedullary relapses among patients with B-ALL.

In addition, the lack of sex-based differences in T-ALL may be caused in part by the increased use of CNS radiation in this population. Previous studies in which CNS radiation was omitted showed an increase in CNS relapsed rates among boys but not girls, he pointed out.

“This does imply that in the more recent generation of T-lineage ALL treatment trials that we’ll need to monitor sex-based differences in outcome, as fewer and fewer patients with T-ALL disease received cranial radiation in these more recent trials and in contemporary therapy,” he said.

One possible mechanism for sex-based outcome differences might be differences in steroid metabolism, as suggested by the higher osteonecrosis rate among girls, he added.

In the question-and-answer following the presentation, William G. Woods, MD, from Emory University, Atlanta, asked what role testicular relapse played in outcomes.

Dr. Gupta replied that the investigators had considered that the excess risk for extramedullary relapse in boys might be accounted for by testicular relapse, but “when you take away testicular relapse from those numbers and really just concentrate on CNS, it’s still that substantial difference when you’re talking about B-lineage disease.”

In patients with T-ALL as well, CNS relapse was more common in boys after controlling for testicular relapse, he said.

Another audience member asked whether the data suggest a benefit to treating boys with CNS-penetrating drugs such as dexamethasone or high-dose methotrexate,

Dr. Gupta said that it’s still uncertain whether it is clinically sound to subject a boy with otherwise–standard-risk disease to more intensive high-risk therapy, given the relatively small absolute differences in outcomes between the sexes.

The study was supported by grants from the National Cancer Institute and the St. Baldrick’s Foundation. Dr. Gupta, Dr. Woods, and Dr. Meret had no relevant conflicts of interest to report.

Even in the age of intensive therapy and extensive risk stratification, there are small but significant differences in outcomes between boys and girls with B-lineage acute lymphoblastic leukemia (B-ALL).

This finding comes from a review of 10 years of clinical trials by the Children’s Oncology Group (COG), which showed that, among patients with B-ALL, 5-year event-free survival (EFS) and overall survival (OS) were inferior with boys, compared with girls, even when adjusted for prognostic factors, reported Sumit Gupta, MD, PhD, FRCPC, from the Hospital for Sick Children in Toronto.

“Inferior outcomes, although small in absolute terms, continue to exist among boys versus girls despite modern therapy and after adjusting for other risk factors. These persist also despite the longer duration of therapy among boys,” he said in an oral abstract presentation during the annual meeting of the American Society of Pediatric Hematology/Oncology. (Abstract 2025).

Among pediatric patients with T-cell lineage ALL (T-ALL), however, there were no significant sex-based differences in either EFS or OS, he said.

Although survival for children with ALL has continued to improve, previous studies found inferior survival outcomes in boys, and suggested that the difference might be explained by imbalances in risk factors.

To see whether sex-based disparities persist with modern intensive therapy protocols after adjustment for risk factors, and to determine whether there are sex-based differences in toxicities or patterns of treatment failure, Dr. Gupta and colleagues created a cohort of all patients age 1-30 years enrolled in frontline COG trial for B-ALL and T-ALL from 2004 to 2014.

During this period, boys received an extra year of maintenance. Cranial radiation was limited to B-ALL patients with slow treatment responses and central nervous system status 3, signifying definite CNS involvement. Among patients with T-ALL, cranial radiation was given to all intermediate- and high-risk patients.
 

Sex differences small, but significant

The investigators identified a total of 8,202 patients (4,463 males and 3,739 females) with B-ALL, and 1,562 (1,161 males and 401 females) with T-ALL. Boys were likely to be older (P < .0001), and to have a small but significantly greater likelihood of having unfavorable B-ALL cytogenetics, compared with girls (P = .05).

Boys with B-ALL were less likely to be negative for minimal residual disease (76.1% vs. 78.1%, P = .04), but the opposite was true for those with T-ALL (59% vs. 56.8%, P = .01).

As noted before, among pediatric patients with B-ALL, EFS and OS were both inferior for males, with a hazard ratio for higher EFS rates in girls of 1.19 (P = .001) and a HR for OS of 1.17 (P = .046).

Both EFS and OS were similar between the sexes among patients with T-ALL.

The differences in EFS in patients with B-ALL was attributable to higher CNS relapses among boys (4.2% vs. 2.5%, P < .0001). The CNS relapses occurred at a median of 2.5 years in boys versus 2.1 years in girls, although most relapses occurred during therapy.

There were no differences in cumulative isolated bone marrow relapses, however.

Treatment-related mortality rates were the same, but osteonecrosis rates were significantly lower for boys, with a 5-year cumulative incidence of 5.2% versus 6.7% for girls (P = .001).
 

Possible explanations

Dr. Gupta noted that the inferior outcomes among boys may be attributable to extramedullary relapses among patients with B-ALL.

In addition, the lack of sex-based differences in T-ALL may be caused in part by the increased use of CNS radiation in this population. Previous studies in which CNS radiation was omitted showed an increase in CNS relapsed rates among boys but not girls, he pointed out.

“This does imply that in the more recent generation of T-lineage ALL treatment trials that we’ll need to monitor sex-based differences in outcome, as fewer and fewer patients with T-ALL disease received cranial radiation in these more recent trials and in contemporary therapy,” he said.

One possible mechanism for sex-based outcome differences might be differences in steroid metabolism, as suggested by the higher osteonecrosis rate among girls, he added.

In the question-and-answer following the presentation, William G. Woods, MD, from Emory University, Atlanta, asked what role testicular relapse played in outcomes.

Dr. Gupta replied that the investigators had considered that the excess risk for extramedullary relapse in boys might be accounted for by testicular relapse, but “when you take away testicular relapse from those numbers and really just concentrate on CNS, it’s still that substantial difference when you’re talking about B-lineage disease.”

In patients with T-ALL as well, CNS relapse was more common in boys after controlling for testicular relapse, he said.

Another audience member asked whether the data suggest a benefit to treating boys with CNS-penetrating drugs such as dexamethasone or high-dose methotrexate,

Dr. Gupta said that it’s still uncertain whether it is clinically sound to subject a boy with otherwise–standard-risk disease to more intensive high-risk therapy, given the relatively small absolute differences in outcomes between the sexes.

The study was supported by grants from the National Cancer Institute and the St. Baldrick’s Foundation. Dr. Gupta, Dr. Woods, and Dr. Meret had no relevant conflicts of interest to report.

Survivors of childhood cancers are at increased risk for prescription opioid misuse compared with their peers, a review of a claims database revealed.

Among more than 8,000 patients age 21 or younger who had completed treatment for hematologic, central nervous system, bone, or gonadal cancers, survivors were significantly more likely than were their peers to have an opioid prescription, longer duration of prescription, and higher daily doses of opioids, and to have opioid prescriptions overlapping for a week or more, reported Xu Ji, PhD, of Emory University in Atlanta.

Teenage and young adult patients were at higher risk than were patients younger than 12, and the risk was highest among patients who had been treated for bone malignancies, as well as those who had undergone any hematopoietic stem cell transplant.

“These findings suggest that health care providers who regularly see survivors should explore nonopioid options to help prevent opioid misuse, and screen for potential misuse in those who actually receive opioids,” she said in an oral abstract presented during the annual meeting of the American Society of Pediatric Hematology/Oncology.

“This is a really important topic, and something that’s probably been underinvestigated and underexplored in our patient population,” said session comoderator Sheri Spunt, MD, Endowed Professor of Pediatric Cancer at Stanford (Calif.) University.
 

Database review

Dr. Ji and colleagues used the IBM MarketScan Commercial Claims and Encounters database from 2009 to 2018 to examine prescription opioid use, potential misuse, and substance use disorders in pediatric cancer survivors in the first year after completion of therapy, and to identify factors associated with risk for misuse or substance use disorders. Specifically, the period of interest was the first year after completion of all treatments, including surgery, chemotherapy, radiation, and stem cell transplant (Abstract 2015).

They looked at deidentified records on any opioid prescription and for treatment of any opioid use or substance use disorder (alcohol, psychotherapeutic drugs, marijuana, or illicit drug use disorders).

They defined indicators of potential misuse as either prescriptions for long-acting or extended-release opioids for acute pain conditions; opioid and benzodiazepine prescriptions overlapping by a week or more; opioid prescriptions overlapping by a week or more; high daily opioid dosage (prescribed daily dose of 100 or greater morphine milligram equivalent [MME]; and/or opioid dose escalation (an increase of at least 50% in mean MMEs per month twice consecutively within 1 year).

They compared outcomes between a total of 8,635 survivors and 44,175 controls, matched on a 1:5 basis with survivors by age, sex, and region, and continuous enrollment during the 1-year posttherapy period.

In each of three age categories – 0 to 11 years, 12 to 17 years, and 18 years and older – survivors were significantly more likely to have received an opioid prescription, at 15% for the youngest survivors vs. 2% of controls, 25% vs. 8% for 12- to 17-year-olds, and 28% vs. 12% for those 18 and older (P < .01 for all three comparisons).

Survivors were also significantly more likely to have any indicator of potential misuse (1.6% vs. 0.1%, 4.6% vs. 0.5%, and 7.4% vs. 1.2%, respectively, P < .001 for all) and both the youngest and oldest groups (but not 12- to 17-year-olds) were significantly more like to have opioid or substance use disorder (0.4% vs. 0% for 0-11 years, 5.76% vs. 4.2% for 18 years and older, P < .001 for both).

Among patients with any opioid prescription, survivors were significantly more likely than were controls of any age to have indicators for potential misuse. For example, 13% of survivors aged 18 years and older had prescriptions for high opioid doses, compared with 5% of controls, and 12% had prescription overlap, vs. 2%.

Compared with patients with leukemia, patients treated for bone malignancies had a 6% greater risk for having any indicator of misuse, while patients with other malignancies were at slightly lower risk for misuse than those who completed leukemia therapy.

Patients who received any stem cell transplant had an 8.4% greater risk for misuse compared with patients who had surgery only.
 

Opioids pre- and posttreatment?

“Being someone who takes care of a lot of bone cancer patients, I do see patients with these issues,” Dr. Spunt said.

Audience member Jack H. Staddon, MD, PhD, of the Billings (Montana) Clinic, noted the possibility that opioid use during treatment may have been carried on into the posttreatment period, and asked whether use of narcotics during treatment was an independent risk factor for posttreatment narcotic use or misuse.

The researchers plan to investigate this question in future studies, Dr. Ji replied.

They did not report a study funding source. Dr. Ji and coauthors and Dr. Staddon reported no relevant disclosures.

Survivors of childhood cancers are at increased risk for prescription opioid misuse compared with their peers, a review of a claims database revealed.

Among more than 8,000 patients age 21 or younger who had completed treatment for hematologic, central nervous system, bone, or gonadal cancers, survivors were significantly more likely than were their peers to have an opioid prescription, longer duration of prescription, and higher daily doses of opioids, and to have opioid prescriptions overlapping for a week or more, reported Xu Ji, PhD, of Emory University in Atlanta.

Teenage and young adult patients were at higher risk than were patients younger than 12, and the risk was highest among patients who had been treated for bone malignancies, as well as those who had undergone any hematopoietic stem cell transplant.

“These findings suggest that health care providers who regularly see survivors should explore nonopioid options to help prevent opioid misuse, and screen for potential misuse in those who actually receive opioids,” she said in an oral abstract presented during the annual meeting of the American Society of Pediatric Hematology/Oncology.

“This is a really important topic, and something that’s probably been underinvestigated and underexplored in our patient population,” said session comoderator Sheri Spunt, MD, Endowed Professor of Pediatric Cancer at Stanford (Calif.) University.
 

Database review

Dr. Ji and colleagues used the IBM MarketScan Commercial Claims and Encounters database from 2009 to 2018 to examine prescription opioid use, potential misuse, and substance use disorders in pediatric cancer survivors in the first year after completion of therapy, and to identify factors associated with risk for misuse or substance use disorders. Specifically, the period of interest was the first year after completion of all treatments, including surgery, chemotherapy, radiation, and stem cell transplant (Abstract 2015).

They looked at deidentified records on any opioid prescription and for treatment of any opioid use or substance use disorder (alcohol, psychotherapeutic drugs, marijuana, or illicit drug use disorders).

They defined indicators of potential misuse as either prescriptions for long-acting or extended-release opioids for acute pain conditions; opioid and benzodiazepine prescriptions overlapping by a week or more; opioid prescriptions overlapping by a week or more; high daily opioid dosage (prescribed daily dose of 100 or greater morphine milligram equivalent [MME]; and/or opioid dose escalation (an increase of at least 50% in mean MMEs per month twice consecutively within 1 year).

They compared outcomes between a total of 8,635 survivors and 44,175 controls, matched on a 1:5 basis with survivors by age, sex, and region, and continuous enrollment during the 1-year posttherapy period.

In each of three age categories – 0 to 11 years, 12 to 17 years, and 18 years and older – survivors were significantly more likely to have received an opioid prescription, at 15% for the youngest survivors vs. 2% of controls, 25% vs. 8% for 12- to 17-year-olds, and 28% vs. 12% for those 18 and older (P < .01 for all three comparisons).

Survivors were also significantly more likely to have any indicator of potential misuse (1.6% vs. 0.1%, 4.6% vs. 0.5%, and 7.4% vs. 1.2%, respectively, P < .001 for all) and both the youngest and oldest groups (but not 12- to 17-year-olds) were significantly more like to have opioid or substance use disorder (0.4% vs. 0% for 0-11 years, 5.76% vs. 4.2% for 18 years and older, P < .001 for both).

Among patients with any opioid prescription, survivors were significantly more likely than were controls of any age to have indicators for potential misuse. For example, 13% of survivors aged 18 years and older had prescriptions for high opioid doses, compared with 5% of controls, and 12% had prescription overlap, vs. 2%.

Compared with patients with leukemia, patients treated for bone malignancies had a 6% greater risk for having any indicator of misuse, while patients with other malignancies were at slightly lower risk for misuse than those who completed leukemia therapy.

Patients who received any stem cell transplant had an 8.4% greater risk for misuse compared with patients who had surgery only.
 

Opioids pre- and posttreatment?

“Being someone who takes care of a lot of bone cancer patients, I do see patients with these issues,” Dr. Spunt said.

Audience member Jack H. Staddon, MD, PhD, of the Billings (Montana) Clinic, noted the possibility that opioid use during treatment may have been carried on into the posttreatment period, and asked whether use of narcotics during treatment was an independent risk factor for posttreatment narcotic use or misuse.

The researchers plan to investigate this question in future studies, Dr. Ji replied.

They did not report a study funding source. Dr. Ji and coauthors and Dr. Staddon reported no relevant disclosures.

Survivors of childhood cancers are at increased risk for prescription opioid misuse compared with their peers, a review of a claims database revealed.

Among more than 8,000 patients age 21 or younger who had completed treatment for hematologic, central nervous system, bone, or gonadal cancers, survivors were significantly more likely than were their peers to have an opioid prescription, longer duration of prescription, and higher daily doses of opioids, and to have opioid prescriptions overlapping for a week or more, reported Xu Ji, PhD, of Emory University in Atlanta.

Teenage and young adult patients were at higher risk than were patients younger than 12, and the risk was highest among patients who had been treated for bone malignancies, as well as those who had undergone any hematopoietic stem cell transplant.

“These findings suggest that health care providers who regularly see survivors should explore nonopioid options to help prevent opioid misuse, and screen for potential misuse in those who actually receive opioids,” she said in an oral abstract presented during the annual meeting of the American Society of Pediatric Hematology/Oncology.

“This is a really important topic, and something that’s probably been underinvestigated and underexplored in our patient population,” said session comoderator Sheri Spunt, MD, Endowed Professor of Pediatric Cancer at Stanford (Calif.) University.
 

Database review

Dr. Ji and colleagues used the IBM MarketScan Commercial Claims and Encounters database from 2009 to 2018 to examine prescription opioid use, potential misuse, and substance use disorders in pediatric cancer survivors in the first year after completion of therapy, and to identify factors associated with risk for misuse or substance use disorders. Specifically, the period of interest was the first year after completion of all treatments, including surgery, chemotherapy, radiation, and stem cell transplant (Abstract 2015).

They looked at deidentified records on any opioid prescription and for treatment of any opioid use or substance use disorder (alcohol, psychotherapeutic drugs, marijuana, or illicit drug use disorders).

They defined indicators of potential misuse as either prescriptions for long-acting or extended-release opioids for acute pain conditions; opioid and benzodiazepine prescriptions overlapping by a week or more; opioid prescriptions overlapping by a week or more; high daily opioid dosage (prescribed daily dose of 100 or greater morphine milligram equivalent [MME]; and/or opioid dose escalation (an increase of at least 50% in mean MMEs per month twice consecutively within 1 year).

They compared outcomes between a total of 8,635 survivors and 44,175 controls, matched on a 1:5 basis with survivors by age, sex, and region, and continuous enrollment during the 1-year posttherapy period.

In each of three age categories – 0 to 11 years, 12 to 17 years, and 18 years and older – survivors were significantly more likely to have received an opioid prescription, at 15% for the youngest survivors vs. 2% of controls, 25% vs. 8% for 12- to 17-year-olds, and 28% vs. 12% for those 18 and older (P < .01 for all three comparisons).

Survivors were also significantly more likely to have any indicator of potential misuse (1.6% vs. 0.1%, 4.6% vs. 0.5%, and 7.4% vs. 1.2%, respectively, P < .001 for all) and both the youngest and oldest groups (but not 12- to 17-year-olds) were significantly more like to have opioid or substance use disorder (0.4% vs. 0% for 0-11 years, 5.76% vs. 4.2% for 18 years and older, P < .001 for both).

Among patients with any opioid prescription, survivors were significantly more likely than were controls of any age to have indicators for potential misuse. For example, 13% of survivors aged 18 years and older had prescriptions for high opioid doses, compared with 5% of controls, and 12% had prescription overlap, vs. 2%.

Compared with patients with leukemia, patients treated for bone malignancies had a 6% greater risk for having any indicator of misuse, while patients with other malignancies were at slightly lower risk for misuse than those who completed leukemia therapy.

Patients who received any stem cell transplant had an 8.4% greater risk for misuse compared with patients who had surgery only.
 

Opioids pre- and posttreatment?

“Being someone who takes care of a lot of bone cancer patients, I do see patients with these issues,” Dr. Spunt said.

Audience member Jack H. Staddon, MD, PhD, of the Billings (Montana) Clinic, noted the possibility that opioid use during treatment may have been carried on into the posttreatment period, and asked whether use of narcotics during treatment was an independent risk factor for posttreatment narcotic use or misuse.

The researchers plan to investigate this question in future studies, Dr. Ji replied.

They did not report a study funding source. Dr. Ji and coauthors and Dr. Staddon reported no relevant disclosures.