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FDA approves first CAR T-cell for adult ALL: For patients with R/R B-cell disease
The therapy is the first chimeric antigen receptor (CAR) T-cell treatment approved for adults with ALL.
This is a “meaningful advance,” because “roughly half of all adults with B-ALL will relapse on currently available therapies,” said Bijal Shah, MD, of Moffitt Cancer Center, Tampa, Fla., in a press statement from the manufacturer, Kite.
“A single infusion of Tecartus has demonstrated durable responses, suggesting the potential for long-term remission and a new approach to care,” he added.
“Roughly half of all cases actually occur in adults, and unlike pediatric ALL, adult ALL has historically had a poor prognosis,” said Lee Greenberger, PhD, chief scientific officer at the Leukemia & Lymphoma Society, in the statement. The median overall survival (OS) is only about 8 months in this setting with current treatments, according to the company.
The new FDA approval, which is the fourth indication for brexucabtagene autoleucel, is based on results from ZUMA-3, a multicenter, single-arm study of 71 patients, with 54 efficacy-evaluable patients.
Efficacy was established on the basis of complete remission (CR) rate within 3 months after infusion and the duration of CR (DOCR). Twenty-eight (51.9%) of evaluable patients achieved CR, with a median follow-up for responders of 7.1 months. The median DOCR was not reached.
The median time to CR was 56 days. All 54 efficacy-evaluable patients had potential follow-up for 10 or more months with a median actual follow-up time of 12.3 months.
Among the 54 patients, the median time from leukapheresis to product delivery was 16 days and the median time from leukapheresis to infusion was 29 days.
Of the 17 study patients who did reach efficacy evaluation, 6 did not receive the agent because of manufacturing failure, 8 were not treated because of adverse events following leukapheresis, 2 underwent leukapheresis and received lymphodepleting chemotherapy but were not treated with the drug, and 1 treated patient was not evaluable for efficacy, per the prescribing information.
Among all patients treated with brexucabtagene autoleucel at its target dose, grade 3 or higher cytokine release syndrome (CRS) and neurologic events occurred in 26% and 35% of patients, respectively, and were generally well managed, according to the company.
The most common adverse reactions (≥20%) among ALL patients are fever, CRS, hypotension, encephalopathy, tachycardia, nausea, chills, headache, fatigue, febrile neutropenia, diarrhea, musculoskeletal pain, hypoxia, rash, edema, tremor, infection with pathogen unspecified, constipation, decreased appetite, and vomiting.
The prescribing information includes a boxed warning about the risks of CRS and neurologic toxicities; the drug is approved with a Risk Evaluation and Mitigation Strategy (REMS) because of these risks.
A version of this article first appeared on Medscape.com.
The therapy is the first chimeric antigen receptor (CAR) T-cell treatment approved for adults with ALL.
This is a “meaningful advance,” because “roughly half of all adults with B-ALL will relapse on currently available therapies,” said Bijal Shah, MD, of Moffitt Cancer Center, Tampa, Fla., in a press statement from the manufacturer, Kite.
“A single infusion of Tecartus has demonstrated durable responses, suggesting the potential for long-term remission and a new approach to care,” he added.
“Roughly half of all cases actually occur in adults, and unlike pediatric ALL, adult ALL has historically had a poor prognosis,” said Lee Greenberger, PhD, chief scientific officer at the Leukemia & Lymphoma Society, in the statement. The median overall survival (OS) is only about 8 months in this setting with current treatments, according to the company.
The new FDA approval, which is the fourth indication for brexucabtagene autoleucel, is based on results from ZUMA-3, a multicenter, single-arm study of 71 patients, with 54 efficacy-evaluable patients.
Efficacy was established on the basis of complete remission (CR) rate within 3 months after infusion and the duration of CR (DOCR). Twenty-eight (51.9%) of evaluable patients achieved CR, with a median follow-up for responders of 7.1 months. The median DOCR was not reached.
The median time to CR was 56 days. All 54 efficacy-evaluable patients had potential follow-up for 10 or more months with a median actual follow-up time of 12.3 months.
Among the 54 patients, the median time from leukapheresis to product delivery was 16 days and the median time from leukapheresis to infusion was 29 days.
Of the 17 study patients who did reach efficacy evaluation, 6 did not receive the agent because of manufacturing failure, 8 were not treated because of adverse events following leukapheresis, 2 underwent leukapheresis and received lymphodepleting chemotherapy but were not treated with the drug, and 1 treated patient was not evaluable for efficacy, per the prescribing information.
Among all patients treated with brexucabtagene autoleucel at its target dose, grade 3 or higher cytokine release syndrome (CRS) and neurologic events occurred in 26% and 35% of patients, respectively, and were generally well managed, according to the company.
The most common adverse reactions (≥20%) among ALL patients are fever, CRS, hypotension, encephalopathy, tachycardia, nausea, chills, headache, fatigue, febrile neutropenia, diarrhea, musculoskeletal pain, hypoxia, rash, edema, tremor, infection with pathogen unspecified, constipation, decreased appetite, and vomiting.
The prescribing information includes a boxed warning about the risks of CRS and neurologic toxicities; the drug is approved with a Risk Evaluation and Mitigation Strategy (REMS) because of these risks.
A version of this article first appeared on Medscape.com.
The therapy is the first chimeric antigen receptor (CAR) T-cell treatment approved for adults with ALL.
This is a “meaningful advance,” because “roughly half of all adults with B-ALL will relapse on currently available therapies,” said Bijal Shah, MD, of Moffitt Cancer Center, Tampa, Fla., in a press statement from the manufacturer, Kite.
“A single infusion of Tecartus has demonstrated durable responses, suggesting the potential for long-term remission and a new approach to care,” he added.
“Roughly half of all cases actually occur in adults, and unlike pediatric ALL, adult ALL has historically had a poor prognosis,” said Lee Greenberger, PhD, chief scientific officer at the Leukemia & Lymphoma Society, in the statement. The median overall survival (OS) is only about 8 months in this setting with current treatments, according to the company.
The new FDA approval, which is the fourth indication for brexucabtagene autoleucel, is based on results from ZUMA-3, a multicenter, single-arm study of 71 patients, with 54 efficacy-evaluable patients.
Efficacy was established on the basis of complete remission (CR) rate within 3 months after infusion and the duration of CR (DOCR). Twenty-eight (51.9%) of evaluable patients achieved CR, with a median follow-up for responders of 7.1 months. The median DOCR was not reached.
The median time to CR was 56 days. All 54 efficacy-evaluable patients had potential follow-up for 10 or more months with a median actual follow-up time of 12.3 months.
Among the 54 patients, the median time from leukapheresis to product delivery was 16 days and the median time from leukapheresis to infusion was 29 days.
Of the 17 study patients who did reach efficacy evaluation, 6 did not receive the agent because of manufacturing failure, 8 were not treated because of adverse events following leukapheresis, 2 underwent leukapheresis and received lymphodepleting chemotherapy but were not treated with the drug, and 1 treated patient was not evaluable for efficacy, per the prescribing information.
Among all patients treated with brexucabtagene autoleucel at its target dose, grade 3 or higher cytokine release syndrome (CRS) and neurologic events occurred in 26% and 35% of patients, respectively, and were generally well managed, according to the company.
The most common adverse reactions (≥20%) among ALL patients are fever, CRS, hypotension, encephalopathy, tachycardia, nausea, chills, headache, fatigue, febrile neutropenia, diarrhea, musculoskeletal pain, hypoxia, rash, edema, tremor, infection with pathogen unspecified, constipation, decreased appetite, and vomiting.
The prescribing information includes a boxed warning about the risks of CRS and neurologic toxicities; the drug is approved with a Risk Evaluation and Mitigation Strategy (REMS) because of these risks.
A version of this article first appeared on Medscape.com.
Methylation patterns correlate with prognosis in children with T-ALL
In childhood patients with T-cell acute lymphoblastic leukemia (T-ALL) the hypomethylation status of the arginine synthetase (ASNS) gene was significantly associated with poor therapeutic outcome, according to the results of a Japanese cohort study published online in Blood Advances.
Researchers Koshi Akahane, PHD, of the University of Yamanashi, Kofu, Japan, and colleagues conducted a comprehensive genetic analysis of diagnostic samples of 22 cell lines from childhood patients with T-ALL in Japan.
They also correlated known methylation status with outcomes in two large patient cohorts of Japanese children with T-ALL: the Tokyo Children’s Cancer Study Group (n = 57) and the Japan Association of Childhood Leukemia Study Group (n = 20).
Methylation results
For the 22 cell lines tested, sequencing technology revealed a stepwise allele-specific methylation of the ASNS gene. Mean ASNS gene expression level was significantly upregulated in 14 weakly methylated cell lines (P = .0001), but not significantly upregulated in 3 intermediately methylated cell lines (P = .25) or in 5 highly methylated cell lines (P = .063).
Among the 77 patient cohorts, 20 (26%) samples showed high methylation (> 66.7%), while 15 (19%) samples and 42 (55%) samples showed intermediate (33.3%-66.7%) and weak (< 33.3%) methylation status, respectively.
For the 75 patients where information was provided on outcomes, 25 patients (33%) showed induction failure or disease relapse. A highly methylated status of the ASNS gene was significantly more common in non-refractory/relapse cases (18/50 cases, 36%), while intermediately or weakly methylated status was more common in refractory/relapsed cases (23/25 cases, 92 %; P = .0001). In a log-rank test, the patients with weakly methylated status of the ASNS gene showed significantly shorter event-free survival and overall survival than the patients with an intermediate or highly methylated status (P = .00012 and P = .00016, respectively).
Asparaginase sensitivity
Asparaginase treatment is a key component of chemotherapy for patients with T-ALL, according to the researchers. Asparaginase depletes serum asparagine by deamination into aspartic acid. While normal hematopoietic cells can survive due to ASNS activity, leukemia cells are expected to undergo apoptosis due to silencing of the ASNS gene.
ASNS hypomethylation status was significantly associated with poor therapeutic outcome, and all cases with the poor prognostic SPI1 fusion exclusively showed ASNS hypomethylation status. These observations demonstrate that ASNS hypomethylation status is associated with asparaginase resistance, the researchers stated.
“ASNS methylation status may be a clinically useful biomarker to predict sensitivity to asparaginase therapy in T-ALL patients. Considering the severe complications of asparaginase therapy particularly in adolescents and adults, stratifying prospective asparaginase therapy according to ASNS methylation status may be beneficial for safer and more effective treatment of T-ALL patients,” the researchers concluded.
The authors reported that they had no conflicts of interest.
In childhood patients with T-cell acute lymphoblastic leukemia (T-ALL) the hypomethylation status of the arginine synthetase (ASNS) gene was significantly associated with poor therapeutic outcome, according to the results of a Japanese cohort study published online in Blood Advances.
Researchers Koshi Akahane, PHD, of the University of Yamanashi, Kofu, Japan, and colleagues conducted a comprehensive genetic analysis of diagnostic samples of 22 cell lines from childhood patients with T-ALL in Japan.
They also correlated known methylation status with outcomes in two large patient cohorts of Japanese children with T-ALL: the Tokyo Children’s Cancer Study Group (n = 57) and the Japan Association of Childhood Leukemia Study Group (n = 20).
Methylation results
For the 22 cell lines tested, sequencing technology revealed a stepwise allele-specific methylation of the ASNS gene. Mean ASNS gene expression level was significantly upregulated in 14 weakly methylated cell lines (P = .0001), but not significantly upregulated in 3 intermediately methylated cell lines (P = .25) or in 5 highly methylated cell lines (P = .063).
Among the 77 patient cohorts, 20 (26%) samples showed high methylation (> 66.7%), while 15 (19%) samples and 42 (55%) samples showed intermediate (33.3%-66.7%) and weak (< 33.3%) methylation status, respectively.
For the 75 patients where information was provided on outcomes, 25 patients (33%) showed induction failure or disease relapse. A highly methylated status of the ASNS gene was significantly more common in non-refractory/relapse cases (18/50 cases, 36%), while intermediately or weakly methylated status was more common in refractory/relapsed cases (23/25 cases, 92 %; P = .0001). In a log-rank test, the patients with weakly methylated status of the ASNS gene showed significantly shorter event-free survival and overall survival than the patients with an intermediate or highly methylated status (P = .00012 and P = .00016, respectively).
Asparaginase sensitivity
Asparaginase treatment is a key component of chemotherapy for patients with T-ALL, according to the researchers. Asparaginase depletes serum asparagine by deamination into aspartic acid. While normal hematopoietic cells can survive due to ASNS activity, leukemia cells are expected to undergo apoptosis due to silencing of the ASNS gene.
ASNS hypomethylation status was significantly associated with poor therapeutic outcome, and all cases with the poor prognostic SPI1 fusion exclusively showed ASNS hypomethylation status. These observations demonstrate that ASNS hypomethylation status is associated with asparaginase resistance, the researchers stated.
“ASNS methylation status may be a clinically useful biomarker to predict sensitivity to asparaginase therapy in T-ALL patients. Considering the severe complications of asparaginase therapy particularly in adolescents and adults, stratifying prospective asparaginase therapy according to ASNS methylation status may be beneficial for safer and more effective treatment of T-ALL patients,” the researchers concluded.
The authors reported that they had no conflicts of interest.
In childhood patients with T-cell acute lymphoblastic leukemia (T-ALL) the hypomethylation status of the arginine synthetase (ASNS) gene was significantly associated with poor therapeutic outcome, according to the results of a Japanese cohort study published online in Blood Advances.
Researchers Koshi Akahane, PHD, of the University of Yamanashi, Kofu, Japan, and colleagues conducted a comprehensive genetic analysis of diagnostic samples of 22 cell lines from childhood patients with T-ALL in Japan.
They also correlated known methylation status with outcomes in two large patient cohorts of Japanese children with T-ALL: the Tokyo Children’s Cancer Study Group (n = 57) and the Japan Association of Childhood Leukemia Study Group (n = 20).
Methylation results
For the 22 cell lines tested, sequencing technology revealed a stepwise allele-specific methylation of the ASNS gene. Mean ASNS gene expression level was significantly upregulated in 14 weakly methylated cell lines (P = .0001), but not significantly upregulated in 3 intermediately methylated cell lines (P = .25) or in 5 highly methylated cell lines (P = .063).
Among the 77 patient cohorts, 20 (26%) samples showed high methylation (> 66.7%), while 15 (19%) samples and 42 (55%) samples showed intermediate (33.3%-66.7%) and weak (< 33.3%) methylation status, respectively.
For the 75 patients where information was provided on outcomes, 25 patients (33%) showed induction failure or disease relapse. A highly methylated status of the ASNS gene was significantly more common in non-refractory/relapse cases (18/50 cases, 36%), while intermediately or weakly methylated status was more common in refractory/relapsed cases (23/25 cases, 92 %; P = .0001). In a log-rank test, the patients with weakly methylated status of the ASNS gene showed significantly shorter event-free survival and overall survival than the patients with an intermediate or highly methylated status (P = .00012 and P = .00016, respectively).
Asparaginase sensitivity
Asparaginase treatment is a key component of chemotherapy for patients with T-ALL, according to the researchers. Asparaginase depletes serum asparagine by deamination into aspartic acid. While normal hematopoietic cells can survive due to ASNS activity, leukemia cells are expected to undergo apoptosis due to silencing of the ASNS gene.
ASNS hypomethylation status was significantly associated with poor therapeutic outcome, and all cases with the poor prognostic SPI1 fusion exclusively showed ASNS hypomethylation status. These observations demonstrate that ASNS hypomethylation status is associated with asparaginase resistance, the researchers stated.
“ASNS methylation status may be a clinically useful biomarker to predict sensitivity to asparaginase therapy in T-ALL patients. Considering the severe complications of asparaginase therapy particularly in adolescents and adults, stratifying prospective asparaginase therapy according to ASNS methylation status may be beneficial for safer and more effective treatment of T-ALL patients,” the researchers concluded.
The authors reported that they had no conflicts of interest.
FROM BLOOD ADVANCES
Genetic shift increases susceptibility to childhood ALL
A genetically induced shift toward higher lymphocyte counts was found to increase susceptibility to childhood acute lymphoblastic leukemia, according to the results of a large genome-wide association study of 2,666 childhood patients with ALL as compared with 60,272 control individuals.
The development of ALL is thought to follow a two-hit model of leukemogenesis; in utero formation of a preleukemic clone and subsequent postnatal acquisition of secondary somatic mutations that leads to overt leukemia, according to Linda Kachuri, PhD, of the department of epidemiology and biostatistics, University of California, San Francisco, and colleagues.
The development of ALL is thought to follow a two-hit model of leukemogenesis; in utero formation of a preleukemic clone and subsequent postnatal acquisition of secondary somatic mutations that leads to overt leukemia, according to Linda Kachuri, PhD, of the Department of Epidemiology and Biostatistics, University of California San Francisco, and colleagues.
Previous research has shown that several childhood-ALL–risk regions have also been associated with variation in blood-cell traits and a recent phenome-wide association study of childhood ALL identified platelet count as the most enriched trait among known ALL-risk loci. To further explore this issue, the researchers conducted their comprehensive study of the role of blood-cell-trait variation in the etiology of childhood ALL.
The researchers identified 3,000 blood-cell-trait–associated variants, which accounted for 4.0% to 23.9% of trait variation and included 115 loci associated with blood-cell ratios: lymphocyte-to-monocyte ratio (LMR); neutrophil-to-lymphocyte ratio (NLR); and platelet-to-lymphocyte ratio (PLR), according to a report published online in The American Journal of Human Genetics.
Lymphocyte risk
The researchers found that ALL susceptibility was genetically correlated with lymphocyte counts (rg = 0.088, P = .0004) and PLR (rg = 0.072, P = .0017).
Using Mendelian randomization analyses, a genetically predicted increase in lymphocyte counts was found to be associated with increased ALL risk (odds ratio [OR] = 1.16, P = .031). This correlation was strengthened after the researchers accounted for other cell types (OR = 1.43, P = .0009).
The researchers observed positive associations with increasing LMR (OR = 1.22, P = .0017) as well as inverse effects for NLR (OR = 0.67, P = .0003) and PLR (OR = 0.80, P = .002).
“We identified the cell-type ratios LMR, NLR, and PLR as independent risk factors for ALL and found evidence that these ratios have distinct genetic mechanisms that are not captured by their component traits. In multivariable MR analyses that concurrently modeled the effects of lymphocyte, monocyte, neutrophil, and platelet counts on ALL, lymphocytes remained as the only independent risk factor and this association with ALL strengthened compared to univariate analyses,” the researchers stated.
They reported that they had no competing interests.
A genetically induced shift toward higher lymphocyte counts was found to increase susceptibility to childhood acute lymphoblastic leukemia, according to the results of a large genome-wide association study of 2,666 childhood patients with ALL as compared with 60,272 control individuals.
The development of ALL is thought to follow a two-hit model of leukemogenesis; in utero formation of a preleukemic clone and subsequent postnatal acquisition of secondary somatic mutations that leads to overt leukemia, according to Linda Kachuri, PhD, of the department of epidemiology and biostatistics, University of California, San Francisco, and colleagues.
The development of ALL is thought to follow a two-hit model of leukemogenesis; in utero formation of a preleukemic clone and subsequent postnatal acquisition of secondary somatic mutations that leads to overt leukemia, according to Linda Kachuri, PhD, of the Department of Epidemiology and Biostatistics, University of California San Francisco, and colleagues.
Previous research has shown that several childhood-ALL–risk regions have also been associated with variation in blood-cell traits and a recent phenome-wide association study of childhood ALL identified platelet count as the most enriched trait among known ALL-risk loci. To further explore this issue, the researchers conducted their comprehensive study of the role of blood-cell-trait variation in the etiology of childhood ALL.
The researchers identified 3,000 blood-cell-trait–associated variants, which accounted for 4.0% to 23.9% of trait variation and included 115 loci associated with blood-cell ratios: lymphocyte-to-monocyte ratio (LMR); neutrophil-to-lymphocyte ratio (NLR); and platelet-to-lymphocyte ratio (PLR), according to a report published online in The American Journal of Human Genetics.
Lymphocyte risk
The researchers found that ALL susceptibility was genetically correlated with lymphocyte counts (rg = 0.088, P = .0004) and PLR (rg = 0.072, P = .0017).
Using Mendelian randomization analyses, a genetically predicted increase in lymphocyte counts was found to be associated with increased ALL risk (odds ratio [OR] = 1.16, P = .031). This correlation was strengthened after the researchers accounted for other cell types (OR = 1.43, P = .0009).
The researchers observed positive associations with increasing LMR (OR = 1.22, P = .0017) as well as inverse effects for NLR (OR = 0.67, P = .0003) and PLR (OR = 0.80, P = .002).
“We identified the cell-type ratios LMR, NLR, and PLR as independent risk factors for ALL and found evidence that these ratios have distinct genetic mechanisms that are not captured by their component traits. In multivariable MR analyses that concurrently modeled the effects of lymphocyte, monocyte, neutrophil, and platelet counts on ALL, lymphocytes remained as the only independent risk factor and this association with ALL strengthened compared to univariate analyses,” the researchers stated.
They reported that they had no competing interests.
A genetically induced shift toward higher lymphocyte counts was found to increase susceptibility to childhood acute lymphoblastic leukemia, according to the results of a large genome-wide association study of 2,666 childhood patients with ALL as compared with 60,272 control individuals.
The development of ALL is thought to follow a two-hit model of leukemogenesis; in utero formation of a preleukemic clone and subsequent postnatal acquisition of secondary somatic mutations that leads to overt leukemia, according to Linda Kachuri, PhD, of the department of epidemiology and biostatistics, University of California, San Francisco, and colleagues.
The development of ALL is thought to follow a two-hit model of leukemogenesis; in utero formation of a preleukemic clone and subsequent postnatal acquisition of secondary somatic mutations that leads to overt leukemia, according to Linda Kachuri, PhD, of the Department of Epidemiology and Biostatistics, University of California San Francisco, and colleagues.
Previous research has shown that several childhood-ALL–risk regions have also been associated with variation in blood-cell traits and a recent phenome-wide association study of childhood ALL identified platelet count as the most enriched trait among known ALL-risk loci. To further explore this issue, the researchers conducted their comprehensive study of the role of blood-cell-trait variation in the etiology of childhood ALL.
The researchers identified 3,000 blood-cell-trait–associated variants, which accounted for 4.0% to 23.9% of trait variation and included 115 loci associated with blood-cell ratios: lymphocyte-to-monocyte ratio (LMR); neutrophil-to-lymphocyte ratio (NLR); and platelet-to-lymphocyte ratio (PLR), according to a report published online in The American Journal of Human Genetics.
Lymphocyte risk
The researchers found that ALL susceptibility was genetically correlated with lymphocyte counts (rg = 0.088, P = .0004) and PLR (rg = 0.072, P = .0017).
Using Mendelian randomization analyses, a genetically predicted increase in lymphocyte counts was found to be associated with increased ALL risk (odds ratio [OR] = 1.16, P = .031). This correlation was strengthened after the researchers accounted for other cell types (OR = 1.43, P = .0009).
The researchers observed positive associations with increasing LMR (OR = 1.22, P = .0017) as well as inverse effects for NLR (OR = 0.67, P = .0003) and PLR (OR = 0.80, P = .002).
“We identified the cell-type ratios LMR, NLR, and PLR as independent risk factors for ALL and found evidence that these ratios have distinct genetic mechanisms that are not captured by their component traits. In multivariable MR analyses that concurrently modeled the effects of lymphocyte, monocyte, neutrophil, and platelet counts on ALL, lymphocytes remained as the only independent risk factor and this association with ALL strengthened compared to univariate analyses,” the researchers stated.
They reported that they had no competing interests.
FROM THE AMERICAN JOURNAL OF HUMAN GENETICS
New treatments have transformed Ph+ acute lymphoblastic leukemia care
The use of novel, chemotherapy-free regimens in Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ ALL) is poised to become the new standard of care, according to a review assessment by Nicholas Short, MD, of the University of Texas MD Anderson Cancer Center, Houston, and colleagues.
Since the introduction of highly potent BCR-ABL–mutation tyrosine kinase inhibitors (TKIs), Ph+ ALL in adults has been transformed from an historically poor prognosis disease to a relatively favorable–risk acute leukemia, according to their report published online in Clinical Lymphoma, Myeloma and Leukemia.
Dr. Short and colleagues reviewed the state of the art in Ph+ ALL care, comparing historically intensive with the more modern nonintensive treatments as part of the SOHO (Society of Hematologic Oncology) State of the Art Updates & Next Questions.
Treatment comparisons
Ph+ ALL outcomes have dramatically improved in the past 20 years, first with the addition of BCR-ABL TKIs to chemotherapy backbones and, more recently, with the development of more potent later-generation TKIs and the use of chemotherapy-free regimens.
Since the introduction of TKIs, most studies have evaluated them in combination with intensive chemotherapy such as hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone alternating with high-dose methotrexate and cytarabine) or similar regimens, according to Dr. Short and colleagues. However, the role of intensive chemotherapy in treating patients with Ph+ ALL has been increasingly questioned with the development of more active, broader spectrum TKIs such as ponatinib and effective novel monoclonal antibody constructs such as blinatumomab.
In particular, encouraging early results have been observed with blinatumomab-based, chemotherapy-free regimens, challenging previous notions that all patients with Ph+ ALL should undergo allogeneic hematopoietic stem cell transplantation (HSCT) in first remission, according to Dr. Short and colleagues. These regimens are capable of achieving deep and durable remissions without need for transplant in the vast majority of patients, particularly when combined with ponatinib.
“Given the multiple recent advances in the management of Ph+ ALL, we can reasonably envision a future in which what was once one of the most aggressive forms of leukemia is now considered nearly universally curable without either need for either chemotherapy or HSCT,” the authors concluded.
Disclosures for the authors were not reported in the review article.
The use of novel, chemotherapy-free regimens in Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ ALL) is poised to become the new standard of care, according to a review assessment by Nicholas Short, MD, of the University of Texas MD Anderson Cancer Center, Houston, and colleagues.
Since the introduction of highly potent BCR-ABL–mutation tyrosine kinase inhibitors (TKIs), Ph+ ALL in adults has been transformed from an historically poor prognosis disease to a relatively favorable–risk acute leukemia, according to their report published online in Clinical Lymphoma, Myeloma and Leukemia.
Dr. Short and colleagues reviewed the state of the art in Ph+ ALL care, comparing historically intensive with the more modern nonintensive treatments as part of the SOHO (Society of Hematologic Oncology) State of the Art Updates & Next Questions.
Treatment comparisons
Ph+ ALL outcomes have dramatically improved in the past 20 years, first with the addition of BCR-ABL TKIs to chemotherapy backbones and, more recently, with the development of more potent later-generation TKIs and the use of chemotherapy-free regimens.
Since the introduction of TKIs, most studies have evaluated them in combination with intensive chemotherapy such as hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone alternating with high-dose methotrexate and cytarabine) or similar regimens, according to Dr. Short and colleagues. However, the role of intensive chemotherapy in treating patients with Ph+ ALL has been increasingly questioned with the development of more active, broader spectrum TKIs such as ponatinib and effective novel monoclonal antibody constructs such as blinatumomab.
In particular, encouraging early results have been observed with blinatumomab-based, chemotherapy-free regimens, challenging previous notions that all patients with Ph+ ALL should undergo allogeneic hematopoietic stem cell transplantation (HSCT) in first remission, according to Dr. Short and colleagues. These regimens are capable of achieving deep and durable remissions without need for transplant in the vast majority of patients, particularly when combined with ponatinib.
“Given the multiple recent advances in the management of Ph+ ALL, we can reasonably envision a future in which what was once one of the most aggressive forms of leukemia is now considered nearly universally curable without either need for either chemotherapy or HSCT,” the authors concluded.
Disclosures for the authors were not reported in the review article.
The use of novel, chemotherapy-free regimens in Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ ALL) is poised to become the new standard of care, according to a review assessment by Nicholas Short, MD, of the University of Texas MD Anderson Cancer Center, Houston, and colleagues.
Since the introduction of highly potent BCR-ABL–mutation tyrosine kinase inhibitors (TKIs), Ph+ ALL in adults has been transformed from an historically poor prognosis disease to a relatively favorable–risk acute leukemia, according to their report published online in Clinical Lymphoma, Myeloma and Leukemia.
Dr. Short and colleagues reviewed the state of the art in Ph+ ALL care, comparing historically intensive with the more modern nonintensive treatments as part of the SOHO (Society of Hematologic Oncology) State of the Art Updates & Next Questions.
Treatment comparisons
Ph+ ALL outcomes have dramatically improved in the past 20 years, first with the addition of BCR-ABL TKIs to chemotherapy backbones and, more recently, with the development of more potent later-generation TKIs and the use of chemotherapy-free regimens.
Since the introduction of TKIs, most studies have evaluated them in combination with intensive chemotherapy such as hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone alternating with high-dose methotrexate and cytarabine) or similar regimens, according to Dr. Short and colleagues. However, the role of intensive chemotherapy in treating patients with Ph+ ALL has been increasingly questioned with the development of more active, broader spectrum TKIs such as ponatinib and effective novel monoclonal antibody constructs such as blinatumomab.
In particular, encouraging early results have been observed with blinatumomab-based, chemotherapy-free regimens, challenging previous notions that all patients with Ph+ ALL should undergo allogeneic hematopoietic stem cell transplantation (HSCT) in first remission, according to Dr. Short and colleagues. These regimens are capable of achieving deep and durable remissions without need for transplant in the vast majority of patients, particularly when combined with ponatinib.
“Given the multiple recent advances in the management of Ph+ ALL, we can reasonably envision a future in which what was once one of the most aggressive forms of leukemia is now considered nearly universally curable without either need for either chemotherapy or HSCT,” the authors concluded.
Disclosures for the authors were not reported in the review article.
FROM CLINICAL LYMPHOMA, MYELOMA AND LEUKEMIA
Better CNS control in children with ALL: ‘Goldilocks’ approach
Treatment of central nervous system involvement in pediatric acute lymphoblastic leukemia (ALL) needs to be based on risk, and should no longer be applied in a one-size-fits all approach, say experts writing in an editorial published July 29 in the journal Blood.
“Because cure rates now exceed 90%, using neurotoxic drugs in non–risk-adapted protocols is unacceptable and a paradigm shift in treating CNS ALL is required,” write pediatric leukemia researchers Christina Halsey, PhD, of the University of Glasgow and Gabriele Escherich, MD, of the University Medical Center Hamburg-Eppendorf (Germany).
“We want to reach a Goldilocks point: not too much, not too little, but just right for every child,” they write.
The problem is that “the absence of clinically useful biomarkers prevents accurate risk stratification, resulting in universal use of intensive CNS-directed therapy. This therapy is likely to overtreat many children, exposing them to an unnecessary risk of toxicity,” including long-term cognitive deficits in 20%-40% of them, they point out.
The editorial accompanied a new study in which investigators in China focused on improving CNS control in children with ALL, which the editorialists said was step in the right direction.
In the Chinese Children’s Cancer Group ALL-2015 trial, investigators found that prephase dexamethasone, delayed intrathecal therapy, intravenous anesthesia to reduce traumatic lumbar punctures, and flow cytometry to accurately ascertain initial CNS involvement may improve CNS control.
The trial included 7,640 consecutive children up to age 18 treated from 2015 to 2019 across 20 major medical centers in China. Children received conventional remission induction and subsequent risk-directed therapy, including 16-22 triple intrathecal treatments. Prophylactic cranial irradiation was not used.
The 5-year event-free survival was 80.3% and overall survival 91.1%. The cumulative risk of isolated CNS relapse was 1.9% and of any CNS relapse 2.7%, comparable to reports from other major study groups, both with and without cranial radiation.
“We attributed our relatively good CNS control to the prephase treatment with dexamethasone, which reduced leukemia cells in blood and the CNS, and to the delayed intrathecal therapy until all (or a large proportion) of circulating leukemic blasts were cleared, thus reducing the consequence of traumatic lumbar puncture with blasts,” said the investigators, led by Jingyan Tang, MD, a hematologist/oncologist at the Shanghai (China) Children’s Medical Center.
“This approach of delayed administration of initial intrathecal therapy after prephase steroid treatment, if confirmed successful by additional studies, can be adopted readily,” they say.
The editorialists concur. The low rates of CNS relapse, despite omission of radiotherapy and inclusion of high-risk subgroups, “might suggest a potential protective effect of steroids before diagnostic lumbar puncture,” they said.
“However, flow cytometry is not sensitive enough to track disease response over time. In the bone marrow, minimal residual disease (MRD) is used to identify children at high or low risk of relapse and modify therapy accordingly. We desperately need a minimal residual disease equivalent for CNS leukemia to allow us to tailor therapy,” Dr. Halsey and Dr. Escherich say.
It’s not surprising that the use of anesthesia led to fewer traumatic lumbar punctures than in “frightened child[ren] undergoing such a painful procedure without anesthesia,” the study team notes. Its correlation with lower CNS relapses is probably because drug delivery was more accurate in sedated children, the editorialists add.
Female sex was also protective against relapse in cases where general anesthesia wasn’t used for lumbar puncture. “One could speculate that it is more difficult to restrict male patients than female patients for successful intrathecal therapy if they were not undergoing anesthesia during the procedure,” the investigators write.
“Unfortunately,” the editorialists add, rapid adoption of anesthesia for lumbar punctures “is tempered by the recent observation that repeated general anesthesia in children with ALL is associated with increased neurotoxicity.”
The work was supported by grants from the National Natural Science Foundation of China, National Cancer Institute, and others. The study authors and editorialists have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Treatment of central nervous system involvement in pediatric acute lymphoblastic leukemia (ALL) needs to be based on risk, and should no longer be applied in a one-size-fits all approach, say experts writing in an editorial published July 29 in the journal Blood.
“Because cure rates now exceed 90%, using neurotoxic drugs in non–risk-adapted protocols is unacceptable and a paradigm shift in treating CNS ALL is required,” write pediatric leukemia researchers Christina Halsey, PhD, of the University of Glasgow and Gabriele Escherich, MD, of the University Medical Center Hamburg-Eppendorf (Germany).
“We want to reach a Goldilocks point: not too much, not too little, but just right for every child,” they write.
The problem is that “the absence of clinically useful biomarkers prevents accurate risk stratification, resulting in universal use of intensive CNS-directed therapy. This therapy is likely to overtreat many children, exposing them to an unnecessary risk of toxicity,” including long-term cognitive deficits in 20%-40% of them, they point out.
The editorial accompanied a new study in which investigators in China focused on improving CNS control in children with ALL, which the editorialists said was step in the right direction.
In the Chinese Children’s Cancer Group ALL-2015 trial, investigators found that prephase dexamethasone, delayed intrathecal therapy, intravenous anesthesia to reduce traumatic lumbar punctures, and flow cytometry to accurately ascertain initial CNS involvement may improve CNS control.
The trial included 7,640 consecutive children up to age 18 treated from 2015 to 2019 across 20 major medical centers in China. Children received conventional remission induction and subsequent risk-directed therapy, including 16-22 triple intrathecal treatments. Prophylactic cranial irradiation was not used.
The 5-year event-free survival was 80.3% and overall survival 91.1%. The cumulative risk of isolated CNS relapse was 1.9% and of any CNS relapse 2.7%, comparable to reports from other major study groups, both with and without cranial radiation.
“We attributed our relatively good CNS control to the prephase treatment with dexamethasone, which reduced leukemia cells in blood and the CNS, and to the delayed intrathecal therapy until all (or a large proportion) of circulating leukemic blasts were cleared, thus reducing the consequence of traumatic lumbar puncture with blasts,” said the investigators, led by Jingyan Tang, MD, a hematologist/oncologist at the Shanghai (China) Children’s Medical Center.
“This approach of delayed administration of initial intrathecal therapy after prephase steroid treatment, if confirmed successful by additional studies, can be adopted readily,” they say.
The editorialists concur. The low rates of CNS relapse, despite omission of radiotherapy and inclusion of high-risk subgroups, “might suggest a potential protective effect of steroids before diagnostic lumbar puncture,” they said.
“However, flow cytometry is not sensitive enough to track disease response over time. In the bone marrow, minimal residual disease (MRD) is used to identify children at high or low risk of relapse and modify therapy accordingly. We desperately need a minimal residual disease equivalent for CNS leukemia to allow us to tailor therapy,” Dr. Halsey and Dr. Escherich say.
It’s not surprising that the use of anesthesia led to fewer traumatic lumbar punctures than in “frightened child[ren] undergoing such a painful procedure without anesthesia,” the study team notes. Its correlation with lower CNS relapses is probably because drug delivery was more accurate in sedated children, the editorialists add.
Female sex was also protective against relapse in cases where general anesthesia wasn’t used for lumbar puncture. “One could speculate that it is more difficult to restrict male patients than female patients for successful intrathecal therapy if they were not undergoing anesthesia during the procedure,” the investigators write.
“Unfortunately,” the editorialists add, rapid adoption of anesthesia for lumbar punctures “is tempered by the recent observation that repeated general anesthesia in children with ALL is associated with increased neurotoxicity.”
The work was supported by grants from the National Natural Science Foundation of China, National Cancer Institute, and others. The study authors and editorialists have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Treatment of central nervous system involvement in pediatric acute lymphoblastic leukemia (ALL) needs to be based on risk, and should no longer be applied in a one-size-fits all approach, say experts writing in an editorial published July 29 in the journal Blood.
“Because cure rates now exceed 90%, using neurotoxic drugs in non–risk-adapted protocols is unacceptable and a paradigm shift in treating CNS ALL is required,” write pediatric leukemia researchers Christina Halsey, PhD, of the University of Glasgow and Gabriele Escherich, MD, of the University Medical Center Hamburg-Eppendorf (Germany).
“We want to reach a Goldilocks point: not too much, not too little, but just right for every child,” they write.
The problem is that “the absence of clinically useful biomarkers prevents accurate risk stratification, resulting in universal use of intensive CNS-directed therapy. This therapy is likely to overtreat many children, exposing them to an unnecessary risk of toxicity,” including long-term cognitive deficits in 20%-40% of them, they point out.
The editorial accompanied a new study in which investigators in China focused on improving CNS control in children with ALL, which the editorialists said was step in the right direction.
In the Chinese Children’s Cancer Group ALL-2015 trial, investigators found that prephase dexamethasone, delayed intrathecal therapy, intravenous anesthesia to reduce traumatic lumbar punctures, and flow cytometry to accurately ascertain initial CNS involvement may improve CNS control.
The trial included 7,640 consecutive children up to age 18 treated from 2015 to 2019 across 20 major medical centers in China. Children received conventional remission induction and subsequent risk-directed therapy, including 16-22 triple intrathecal treatments. Prophylactic cranial irradiation was not used.
The 5-year event-free survival was 80.3% and overall survival 91.1%. The cumulative risk of isolated CNS relapse was 1.9% and of any CNS relapse 2.7%, comparable to reports from other major study groups, both with and without cranial radiation.
“We attributed our relatively good CNS control to the prephase treatment with dexamethasone, which reduced leukemia cells in blood and the CNS, and to the delayed intrathecal therapy until all (or a large proportion) of circulating leukemic blasts were cleared, thus reducing the consequence of traumatic lumbar puncture with blasts,” said the investigators, led by Jingyan Tang, MD, a hematologist/oncologist at the Shanghai (China) Children’s Medical Center.
“This approach of delayed administration of initial intrathecal therapy after prephase steroid treatment, if confirmed successful by additional studies, can be adopted readily,” they say.
The editorialists concur. The low rates of CNS relapse, despite omission of radiotherapy and inclusion of high-risk subgroups, “might suggest a potential protective effect of steroids before diagnostic lumbar puncture,” they said.
“However, flow cytometry is not sensitive enough to track disease response over time. In the bone marrow, minimal residual disease (MRD) is used to identify children at high or low risk of relapse and modify therapy accordingly. We desperately need a minimal residual disease equivalent for CNS leukemia to allow us to tailor therapy,” Dr. Halsey and Dr. Escherich say.
It’s not surprising that the use of anesthesia led to fewer traumatic lumbar punctures than in “frightened child[ren] undergoing such a painful procedure without anesthesia,” the study team notes. Its correlation with lower CNS relapses is probably because drug delivery was more accurate in sedated children, the editorialists add.
Female sex was also protective against relapse in cases where general anesthesia wasn’t used for lumbar puncture. “One could speculate that it is more difficult to restrict male patients than female patients for successful intrathecal therapy if they were not undergoing anesthesia during the procedure,” the investigators write.
“Unfortunately,” the editorialists add, rapid adoption of anesthesia for lumbar punctures “is tempered by the recent observation that repeated general anesthesia in children with ALL is associated with increased neurotoxicity.”
The work was supported by grants from the National Natural Science Foundation of China, National Cancer Institute, and others. The study authors and editorialists have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FDA approves new asparaginase product for leukemia
The new product is Jazz Pharmaceutical’s Rylaze (asparaginase erwinia chrysanthemi [recombinant]-rywn), and it is approved for use in the treatment of acute lymphoblastic leukemia and lymphoblastic lymphoma.
Asparaginase, an enzyme that helps kill blood cancer cells, is a key component of chemotherapy for both conditions.
The problem is that about 20% of patients become allergic to the standard option, asparaginase derived from Escherichia coli.
The only alternative until now has been Erwinaze (also distributed by Jazz Pharmaceuticals), which, like Rylaze, is derived from Erwinia chrysanthemi, a plant pathogen related to Escherichia coli.
However, Erwinaze has been bedeviled by manufacturing problems and has been in short supply since 2016.
The situation has been “extremely disconcerting to patients, families and providers,” and the hope is that Rylaze will “provide a consistently sourced alternative,” Gregory Reaman, MD, the FDA’s associate director of pediatric oncology, said in a press release.
Rylaze will hit the U.S. market in mid-July. Jazz has been a distributor of Erwinaze as well, but it released its last batch in May, according to a spokesperson.
The key difference between the two products is that the asparaginase in Erwinaze is derived directly from Erwinia chrysanthemi, whereas the asparaginase in Rylaze is a recombinant product produced by different bacteria that have been genetically altered with Erwinia chrysanthemi DNA.
The approval for Rylaze was based on a study involving 102 patients (median age, 10 years) who developed hypersensitivity to Escherichia coli–derived enzyme or “silent inactivation” from neutralizing antibodies. In the study, almost 94% of patients achieved asparaginase target activity levels at the approved dosage of 25 mg/m2 IM every 48 hours. The study is ongoing, and investigators are currently evaluating intravenous dosing.
The most common side effects are hypersensitivity reactions, blood clots, hemorrhage, and pancreatic and liver toxicity. There is also a risk for fetal harm, so labeling advises women to use effective nonhormonal contraception during treatment and for 3 months afterward.
A version of this article first appeared on Medscape.com.
The new product is Jazz Pharmaceutical’s Rylaze (asparaginase erwinia chrysanthemi [recombinant]-rywn), and it is approved for use in the treatment of acute lymphoblastic leukemia and lymphoblastic lymphoma.
Asparaginase, an enzyme that helps kill blood cancer cells, is a key component of chemotherapy for both conditions.
The problem is that about 20% of patients become allergic to the standard option, asparaginase derived from Escherichia coli.
The only alternative until now has been Erwinaze (also distributed by Jazz Pharmaceuticals), which, like Rylaze, is derived from Erwinia chrysanthemi, a plant pathogen related to Escherichia coli.
However, Erwinaze has been bedeviled by manufacturing problems and has been in short supply since 2016.
The situation has been “extremely disconcerting to patients, families and providers,” and the hope is that Rylaze will “provide a consistently sourced alternative,” Gregory Reaman, MD, the FDA’s associate director of pediatric oncology, said in a press release.
Rylaze will hit the U.S. market in mid-July. Jazz has been a distributor of Erwinaze as well, but it released its last batch in May, according to a spokesperson.
The key difference between the two products is that the asparaginase in Erwinaze is derived directly from Erwinia chrysanthemi, whereas the asparaginase in Rylaze is a recombinant product produced by different bacteria that have been genetically altered with Erwinia chrysanthemi DNA.
The approval for Rylaze was based on a study involving 102 patients (median age, 10 years) who developed hypersensitivity to Escherichia coli–derived enzyme or “silent inactivation” from neutralizing antibodies. In the study, almost 94% of patients achieved asparaginase target activity levels at the approved dosage of 25 mg/m2 IM every 48 hours. The study is ongoing, and investigators are currently evaluating intravenous dosing.
The most common side effects are hypersensitivity reactions, blood clots, hemorrhage, and pancreatic and liver toxicity. There is also a risk for fetal harm, so labeling advises women to use effective nonhormonal contraception during treatment and for 3 months afterward.
A version of this article first appeared on Medscape.com.
The new product is Jazz Pharmaceutical’s Rylaze (asparaginase erwinia chrysanthemi [recombinant]-rywn), and it is approved for use in the treatment of acute lymphoblastic leukemia and lymphoblastic lymphoma.
Asparaginase, an enzyme that helps kill blood cancer cells, is a key component of chemotherapy for both conditions.
The problem is that about 20% of patients become allergic to the standard option, asparaginase derived from Escherichia coli.
The only alternative until now has been Erwinaze (also distributed by Jazz Pharmaceuticals), which, like Rylaze, is derived from Erwinia chrysanthemi, a plant pathogen related to Escherichia coli.
However, Erwinaze has been bedeviled by manufacturing problems and has been in short supply since 2016.
The situation has been “extremely disconcerting to patients, families and providers,” and the hope is that Rylaze will “provide a consistently sourced alternative,” Gregory Reaman, MD, the FDA’s associate director of pediatric oncology, said in a press release.
Rylaze will hit the U.S. market in mid-July. Jazz has been a distributor of Erwinaze as well, but it released its last batch in May, according to a spokesperson.
The key difference between the two products is that the asparaginase in Erwinaze is derived directly from Erwinia chrysanthemi, whereas the asparaginase in Rylaze is a recombinant product produced by different bacteria that have been genetically altered with Erwinia chrysanthemi DNA.
The approval for Rylaze was based on a study involving 102 patients (median age, 10 years) who developed hypersensitivity to Escherichia coli–derived enzyme or “silent inactivation” from neutralizing antibodies. In the study, almost 94% of patients achieved asparaginase target activity levels at the approved dosage of 25 mg/m2 IM every 48 hours. The study is ongoing, and investigators are currently evaluating intravenous dosing.
The most common side effects are hypersensitivity reactions, blood clots, hemorrhage, and pancreatic and liver toxicity. There is also a risk for fetal harm, so labeling advises women to use effective nonhormonal contraception during treatment and for 3 months afterward.
A version of this article first appeared on Medscape.com.
Ponatinib/blinatumomab start strong against Ph+ALL
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.
FROM EHA 2021
CAR T cells rescue younger children with relapsed/refractory ALL
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.
FROM EHA 2021
Venetoclax shows activity against T-ALL in children
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.
FROM ASPHO 2021
Sex differences in pediatric B-ALL outcomes persist
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.
FROM ASPHO 2021