ALL

The bispecific T-cell engager (BiTE®) antibody blinatumomab can produce complete responses (CRs) in pediatric patients with relapsed/refractory B-cell precursor acute lymphoblastic leukemia (ALL), according to a phase 1/2 study published in the Journal of Clinical Oncology.

Of the patients who received the recommended dosage of blinatumomab, 39% achieved a CR within the first 2 treatment cycles.

And 52% of these patients achieved a complete minimal residual disease (MRD) response.

“This study showed that [blinatumomab] can induce deep molecular remissions in children with highly refractory, multiply relapsed ALL,” said study author Lia Gore, MD, of University of Colorado Anschutz Medical Campus in Aurora, Colorado.

However, most of these remissions did not last. Although a few of the complete responders were still alive and in CR at the study’s 2-year follow-up, more than half had relapsed, and two-thirds had died.

This trial, known as Study ‘205, was supported by Amgen.

Study ‘205 included 93 pediatric patients with relapsed or refractory B-cell precursor ALL. Patients received blinatumomab as a continuous intravenous infusion—49 patients in the phase 1 portion of the trial and 44 in phase 2. The patients were followed for 2 years.

Toxicities and recommended dose

There were 4 dose-limiting toxicities during the phase 1 portion of the trial, and 2 of these events were fatal. One patient treated at 15 μg/m²/day developed grade 4 cytokine release syndrome (CRS), which was deemed related to grade 4 gastrointestinal hemorrhage.

Two patients treated at 30 μg/m²/day had grade 4 CRS. One case was attributed to grade 5 cardiac failure, and the other was treated successfully with tocilizumab.

One patient treated at 15 μg/m²/day had grade 5 respiratory failure with cardiac arrest after hypotonia and muscle weakness after 7 days of infusion with blinatumomab. This patient experienced febrile neutropenia and pneumonia shortly before the start of the infusion.

Based on these toxicities, the maximum-tolerated dose of blinatumomab was 15 μg/m²/day, but a step-wise dosage was recommended to reduce the risk of CRS.

So the recommended dose was 5 μg/m²/day on days 1-7 and 15 μg/m²/day on days 8-28 for cycle 1, and 15 μg/m²/day on days 1-28 for subsequent cycles.

Dose adjustment was possible in case of adverse events. Patients who responded to blinatumomab but later relapsed had the option to be retreated with blinatumomab.

Treatment at recommended dose

Seventy patients received at least 1 infusion of blinatumomab at the recommended dose. The median number of treatment cycles was 1 (range, 1 to 5).

The patients’ median age was 8 years (range, 7 months to 17 years). Forty patients (57%) had undergone allogeneic transplant prior to receiving blinatumomab, and 39 (56%) had refractory disease. Four patients had less than the 25% bone marrow blasts required for protocol entry but had more than 5% blasts.

Adverse events

The most common adverse events among the patients who received the recommended dose of blinatumomab were pyrexia (80%), anemia (41%), nausea (33%), and headache (30%).

The most frequent grade 3 or higher events were anemia (36%), thrombocytopenia (21%), febrile neutropenia (17%), hypokalemia (17%), and neutropenia (17%).

Eight patients developed CRS. Three had grade 3 and 1 had grade 4 CRS. Two of these patients had treatment interruptions, and 2 discontinued treatment permanently. All 4 patients achieved a CR.

Ten patients (14%) had treatment interruptions due to adverse events, and 4 (6%) discontinued treatment permanently because of adverse events.

Six patients had fatal adverse events. Three died after they went on to allogeneic transplant—1 of multiorgan failure, 1 of sepsis, and 1 of respiratory failure. The 3 other deaths were due to fungal infection, multiorgan failure, and thrombocytopenia.

Response and follow-up

Among the 70 patients who received the recommended dose of blinatumomab, 27 (39%) achieved a CR within the first 2 cycles. Fourteen of these patients (52%) achieved complete MRD response.

CRs were achieved across subgroups, and complete MRD response rates were similar across subgroups.

Thirteen of the 27 patients (48%) who achieved a CR went on to receive an allogeneic transplant.

At the end of the 2-year follow-up, 4 of the 27 complete responders were still in remission.

Two of the patients had relapsed but were still alive, 3 had withdrawn consent (1 in CR and 2 after relapse), 3 had died in CR after transplant, and 15 had relapsed and died.

Of the 43 patients who did not achieve a CR within the first 2 treatment cycles, 8 were still alive at the end of the 2-year follow-up.

The bispecific T-cell engager (BiTE®) antibody blinatumomab can produce complete responses (CRs) in pediatric patients with relapsed/refractory B-cell precursor acute lymphoblastic leukemia (ALL), according to a phase 1/2 study published in the Journal of Clinical Oncology.

Of the patients who received the recommended dosage of blinatumomab, 39% achieved a CR within the first 2 treatment cycles.

And 52% of these patients achieved a complete minimal residual disease (MRD) response.

“This study showed that [blinatumomab] can induce deep molecular remissions in children with highly refractory, multiply relapsed ALL,” said study author Lia Gore, MD, of University of Colorado Anschutz Medical Campus in Aurora, Colorado.

However, most of these remissions did not last. Although a few of the complete responders were still alive and in CR at the study’s 2-year follow-up, more than half had relapsed, and two-thirds had died.

This trial, known as Study ‘205, was supported by Amgen.

Study ‘205 included 93 pediatric patients with relapsed or refractory B-cell precursor ALL. Patients received blinatumomab as a continuous intravenous infusion—49 patients in the phase 1 portion of the trial and 44 in phase 2. The patients were followed for 2 years.

Toxicities and recommended dose

There were 4 dose-limiting toxicities during the phase 1 portion of the trial, and 2 of these events were fatal. One patient treated at 15 μg/m²/day developed grade 4 cytokine release syndrome (CRS), which was deemed related to grade 4 gastrointestinal hemorrhage.

Two patients treated at 30 μg/m²/day had grade 4 CRS. One case was attributed to grade 5 cardiac failure, and the other was treated successfully with tocilizumab.

One patient treated at 15 μg/m²/day had grade 5 respiratory failure with cardiac arrest after hypotonia and muscle weakness after 7 days of infusion with blinatumomab. This patient experienced febrile neutropenia and pneumonia shortly before the start of the infusion.

Based on these toxicities, the maximum-tolerated dose of blinatumomab was 15 μg/m²/day, but a step-wise dosage was recommended to reduce the risk of CRS.

So the recommended dose was 5 μg/m²/day on days 1-7 and 15 μg/m²/day on days 8-28 for cycle 1, and 15 μg/m²/day on days 1-28 for subsequent cycles.

Dose adjustment was possible in case of adverse events. Patients who responded to blinatumomab but later relapsed had the option to be retreated with blinatumomab.

Treatment at recommended dose

Seventy patients received at least 1 infusion of blinatumomab at the recommended dose. The median number of treatment cycles was 1 (range, 1 to 5).

The patients’ median age was 8 years (range, 7 months to 17 years). Forty patients (57%) had undergone allogeneic transplant prior to receiving blinatumomab, and 39 (56%) had refractory disease. Four patients had less than the 25% bone marrow blasts required for protocol entry but had more than 5% blasts.

Adverse events

The most common adverse events among the patients who received the recommended dose of blinatumomab were pyrexia (80%), anemia (41%), nausea (33%), and headache (30%).

The most frequent grade 3 or higher events were anemia (36%), thrombocytopenia (21%), febrile neutropenia (17%), hypokalemia (17%), and neutropenia (17%).

Eight patients developed CRS. Three had grade 3 and 1 had grade 4 CRS. Two of these patients had treatment interruptions, and 2 discontinued treatment permanently. All 4 patients achieved a CR.

Ten patients (14%) had treatment interruptions due to adverse events, and 4 (6%) discontinued treatment permanently because of adverse events.

Six patients had fatal adverse events. Three died after they went on to allogeneic transplant—1 of multiorgan failure, 1 of sepsis, and 1 of respiratory failure. The 3 other deaths were due to fungal infection, multiorgan failure, and thrombocytopenia.

Response and follow-up

Among the 70 patients who received the recommended dose of blinatumomab, 27 (39%) achieved a CR within the first 2 cycles. Fourteen of these patients (52%) achieved complete MRD response.

CRs were achieved across subgroups, and complete MRD response rates were similar across subgroups.

Thirteen of the 27 patients (48%) who achieved a CR went on to receive an allogeneic transplant.

At the end of the 2-year follow-up, 4 of the 27 complete responders were still in remission.

Two of the patients had relapsed but were still alive, 3 had withdrawn consent (1 in CR and 2 after relapse), 3 had died in CR after transplant, and 15 had relapsed and died.

Of the 43 patients who did not achieve a CR within the first 2 treatment cycles, 8 were still alive at the end of the 2-year follow-up.

The bispecific T-cell engager (BiTE®) antibody blinatumomab can produce complete responses (CRs) in pediatric patients with relapsed/refractory B-cell precursor acute lymphoblastic leukemia (ALL), according to a phase 1/2 study published in the Journal of Clinical Oncology.

Of the patients who received the recommended dosage of blinatumomab, 39% achieved a CR within the first 2 treatment cycles.

And 52% of these patients achieved a complete minimal residual disease (MRD) response.

“This study showed that [blinatumomab] can induce deep molecular remissions in children with highly refractory, multiply relapsed ALL,” said study author Lia Gore, MD, of University of Colorado Anschutz Medical Campus in Aurora, Colorado.

However, most of these remissions did not last. Although a few of the complete responders were still alive and in CR at the study’s 2-year follow-up, more than half had relapsed, and two-thirds had died.

This trial, known as Study ‘205, was supported by Amgen.

Study ‘205 included 93 pediatric patients with relapsed or refractory B-cell precursor ALL. Patients received blinatumomab as a continuous intravenous infusion—49 patients in the phase 1 portion of the trial and 44 in phase 2. The patients were followed for 2 years.

Toxicities and recommended dose

There were 4 dose-limiting toxicities during the phase 1 portion of the trial, and 2 of these events were fatal. One patient treated at 15 μg/m²/day developed grade 4 cytokine release syndrome (CRS), which was deemed related to grade 4 gastrointestinal hemorrhage.

Two patients treated at 30 μg/m²/day had grade 4 CRS. One case was attributed to grade 5 cardiac failure, and the other was treated successfully with tocilizumab.

One patient treated at 15 μg/m²/day had grade 5 respiratory failure with cardiac arrest after hypotonia and muscle weakness after 7 days of infusion with blinatumomab. This patient experienced febrile neutropenia and pneumonia shortly before the start of the infusion.

Based on these toxicities, the maximum-tolerated dose of blinatumomab was 15 μg/m²/day, but a step-wise dosage was recommended to reduce the risk of CRS.

So the recommended dose was 5 μg/m²/day on days 1-7 and 15 μg/m²/day on days 8-28 for cycle 1, and 15 μg/m²/day on days 1-28 for subsequent cycles.

Dose adjustment was possible in case of adverse events. Patients who responded to blinatumomab but later relapsed had the option to be retreated with blinatumomab.

Treatment at recommended dose

Seventy patients received at least 1 infusion of blinatumomab at the recommended dose. The median number of treatment cycles was 1 (range, 1 to 5).

The patients’ median age was 8 years (range, 7 months to 17 years). Forty patients (57%) had undergone allogeneic transplant prior to receiving blinatumomab, and 39 (56%) had refractory disease. Four patients had less than the 25% bone marrow blasts required for protocol entry but had more than 5% blasts.

Adverse events

The most common adverse events among the patients who received the recommended dose of blinatumomab were pyrexia (80%), anemia (41%), nausea (33%), and headache (30%).

The most frequent grade 3 or higher events were anemia (36%), thrombocytopenia (21%), febrile neutropenia (17%), hypokalemia (17%), and neutropenia (17%).

Eight patients developed CRS. Three had grade 3 and 1 had grade 4 CRS. Two of these patients had treatment interruptions, and 2 discontinued treatment permanently. All 4 patients achieved a CR.

Ten patients (14%) had treatment interruptions due to adverse events, and 4 (6%) discontinued treatment permanently because of adverse events.

Six patients had fatal adverse events. Three died after they went on to allogeneic transplant—1 of multiorgan failure, 1 of sepsis, and 1 of respiratory failure. The 3 other deaths were due to fungal infection, multiorgan failure, and thrombocytopenia.

Response and follow-up

Among the 70 patients who received the recommended dose of blinatumomab, 27 (39%) achieved a CR within the first 2 cycles. Fourteen of these patients (52%) achieved complete MRD response.

CRs were achieved across subgroups, and complete MRD response rates were similar across subgroups.

Thirteen of the 27 patients (48%) who achieved a CR went on to receive an allogeneic transplant.

At the end of the 2-year follow-up, 4 of the 27 complete responders were still in remission.

Two of the patients had relapsed but were still alive, 3 had withdrawn consent (1 in CR and 2 after relapse), 3 had died in CR after transplant, and 15 had relapsed and died.

Of the 43 patients who did not achieve a CR within the first 2 treatment cycles, 8 were still alive at the end of the 2-year follow-up.

CML cells

Image from UCSD

The Japanese Pharmaceuticals and Medical Devices Agency (PMDA) has approved 2 uses of the tyrosine kinase inhibitor (TKI) ponatinib (Iclusig®).

The drug is now approved to treat recurrent or refractory Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) and chronic myeloid leukemia (CML) that was resistant to or intolerant of prior treatment.

Ponatinib will be manufactured and sold by Otsuka Pharmaceutical Co., Ltd.

Due to the limited existing treatment options for patients in Japan, Otsuka said it will provide access to ponatinib free of charge as soon as procedures are in place from an ethical standpoint.

This program will be offered at medical institutions where clinical trials of ponatinib were performed and which are amenable to accepting the drug access program until the product is listed on the Japan National Health Insurance price list.

About ponatinib

Ponatinib is a TKI discovered by ARIAD Pharmaceuticals, Inc. The drug has demonstrated activity against native and mutated BCR-ABL and other kinases.

The PMDA’s approval of ponatinib for CML and Ph+ ALL is based on data from a phase 1/2 trial of Japanese patients, a phase 1 trial, and the phase 2 PACE trial.

Extended follow-up data from the PACE trial, collected in 2013, suggested ponatinib can increase the risk of thrombotic events. When these data came to light, officials in the European Union and the US, where ponatinib had already been approved, began to investigate the drug.

Ponatinib was pulled from the US market for a little over 2 months, and trials of the TKI were placed on partial hold while the US Food and Drug Administration evaluated the drug’s safety. Ponatinib went back on the market in January 2014, with new safety measures in place.

Ponatinib was not pulled from the market in the European Union, but the European Medicine’s Agency released recommendations for safer use of the TKI. The Committee for Medicinal Products for Human Use reviewed data on ponatinib and decided its benefits outweigh its risks.

In addition to the European Union and the US, ponatinib has been approved in Australia, Canada, Israel, and Switzerland.

CML cells

Image from UCSD

The Japanese Pharmaceuticals and Medical Devices Agency (PMDA) has approved 2 uses of the tyrosine kinase inhibitor (TKI) ponatinib (Iclusig®).

The drug is now approved to treat recurrent or refractory Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) and chronic myeloid leukemia (CML) that was resistant to or intolerant of prior treatment.

Ponatinib will be manufactured and sold by Otsuka Pharmaceutical Co., Ltd.

Due to the limited existing treatment options for patients in Japan, Otsuka said it will provide access to ponatinib free of charge as soon as procedures are in place from an ethical standpoint.

This program will be offered at medical institutions where clinical trials of ponatinib were performed and which are amenable to accepting the drug access program until the product is listed on the Japan National Health Insurance price list.

About ponatinib

Ponatinib is a TKI discovered by ARIAD Pharmaceuticals, Inc. The drug has demonstrated activity against native and mutated BCR-ABL and other kinases.

The PMDA’s approval of ponatinib for CML and Ph+ ALL is based on data from a phase 1/2 trial of Japanese patients, a phase 1 trial, and the phase 2 PACE trial.

Extended follow-up data from the PACE trial, collected in 2013, suggested ponatinib can increase the risk of thrombotic events. When these data came to light, officials in the European Union and the US, where ponatinib had already been approved, began to investigate the drug.

Ponatinib was pulled from the US market for a little over 2 months, and trials of the TKI were placed on partial hold while the US Food and Drug Administration evaluated the drug’s safety. Ponatinib went back on the market in January 2014, with new safety measures in place.

Ponatinib was not pulled from the market in the European Union, but the European Medicine’s Agency released recommendations for safer use of the TKI. The Committee for Medicinal Products for Human Use reviewed data on ponatinib and decided its benefits outweigh its risks.

In addition to the European Union and the US, ponatinib has been approved in Australia, Canada, Israel, and Switzerland.

CML cells

Image from UCSD

The Japanese Pharmaceuticals and Medical Devices Agency (PMDA) has approved 2 uses of the tyrosine kinase inhibitor (TKI) ponatinib (Iclusig®).

The drug is now approved to treat recurrent or refractory Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) and chronic myeloid leukemia (CML) that was resistant to or intolerant of prior treatment.

Ponatinib will be manufactured and sold by Otsuka Pharmaceutical Co., Ltd.

Due to the limited existing treatment options for patients in Japan, Otsuka said it will provide access to ponatinib free of charge as soon as procedures are in place from an ethical standpoint.

This program will be offered at medical institutions where clinical trials of ponatinib were performed and which are amenable to accepting the drug access program until the product is listed on the Japan National Health Insurance price list.

About ponatinib

Ponatinib is a TKI discovered by ARIAD Pharmaceuticals, Inc. The drug has demonstrated activity against native and mutated BCR-ABL and other kinases.

The PMDA’s approval of ponatinib for CML and Ph+ ALL is based on data from a phase 1/2 trial of Japanese patients, a phase 1 trial, and the phase 2 PACE trial.

Extended follow-up data from the PACE trial, collected in 2013, suggested ponatinib can increase the risk of thrombotic events. When these data came to light, officials in the European Union and the US, where ponatinib had already been approved, began to investigate the drug.

Ponatinib was pulled from the US market for a little over 2 months, and trials of the TKI were placed on partial hold while the US Food and Drug Administration evaluated the drug’s safety. Ponatinib went back on the market in January 2014, with new safety measures in place.

Ponatinib was not pulled from the market in the European Union, but the European Medicine’s Agency released recommendations for safer use of the TKI. The Committee for Medicinal Products for Human Use reviewed data on ponatinib and decided its benefits outweigh its risks.

In addition to the European Union and the US, ponatinib has been approved in Australia, Canada, Israel, and Switzerland.

Hossein Khiabanian, PhD

Photo by Debbie Vogel

New research has revealed relapse-specific mutations in pediatric acute lymphoblastic leukemia (ALL) and suggests that mutations in the RAS family may drive both resistance and sensitivity to treatment.

Specifically, the study showed that KRAS-mutant ALL cells were resistant to methotrexate but exhibited increased sensitivity to vincristine.

Hossein Khiabanian, PhD, of Rutgers Cancer Institute of New Jersey, and his colleagues reported these findings in PNAS.

The researchers performed whole-exome and whole-genome sequencing on samples from 55 pediatric patients with relapsed ALL, identified specific genomic changes, and validated these findings in 279 additional samples.

“We found that ALL relapse emerges from small, often clinically undetectable populations of cancer cells that are only partially genetically similar to the dominant leukemic population at diagnosis,” Dr Khiabanian said. “We also identified numerous new mutations in genes involved in drug resistance that are specific to relapsed ALL.”

In the first 55 patients (33 T-cell ALLs and 22 B-cell precursor ALLs), the researchers identified 27 recurrently mutated genes whose mutations were preferentially selected or retained at the time of relapse.

The team said 23 (85%) of these mutated genes were not previously implicated in ALL relapse—HTR3A, MED12, USP9X, CACNA1H, TENM3, AACS, SAMD4A, ANO5, PAPPA, NAALADL2, HIST3H2A, FZD7, TBX15, NEB, GREB1L, PLXNA4, SGK223, TSC1, PTPRG, FGF10, SYCP2, TRPM3, and EYS.

The researchers found mutations in the same genes when they analyzed 49 paired diagnosis and relapse B-cell precursor ALL samples as well as an additional 230 relapsed B-cell precursor ALL samples. In addition, the analyses revealed mutations in NT5C2, NR3C1, CREBBP, KMT2D, JAK2, JAK3, and TP53.

The team also noted that some patient samples showed retention or emergence of RAS mutant clones at relapse. In other patients, RAS mutant clones that were present at diagnosis were replaced by RAS wild-type populations at relapse.

The researchers said this suggests a role for both positive and negative selection evolutionary pressures in clonal evolution of RAS-mutant leukemia.

To investigate this further, they analyzed mouse and human wild-type and mutant RAS isogenic leukemia cells. In these experiments, KRAS-mutant cells showed increased sensitivity to vincristine and increased resistance to methotrexate.

“These results highlight how drug therapy can impact the evolution of leukemia and show a previously unrecognized role of RAS mutations as causes of both sensitivity and resistance to chemotherapy,” Dr Khiabanian said.

“Early identification of these mutations, as well as other genetic alterations that have been shown to induce therapeutic resistance in leukemia patients, is pertinent in guiding precision medicine treatment strategies and prevention of relapsed disease—a goal that is now being pursued in my lab at Rutgers.”

Hossein Khiabanian, PhD

Photo by Debbie Vogel

New research has revealed relapse-specific mutations in pediatric acute lymphoblastic leukemia (ALL) and suggests that mutations in the RAS family may drive both resistance and sensitivity to treatment.

Specifically, the study showed that KRAS-mutant ALL cells were resistant to methotrexate but exhibited increased sensitivity to vincristine.

Hossein Khiabanian, PhD, of Rutgers Cancer Institute of New Jersey, and his colleagues reported these findings in PNAS.

The researchers performed whole-exome and whole-genome sequencing on samples from 55 pediatric patients with relapsed ALL, identified specific genomic changes, and validated these findings in 279 additional samples.

“We found that ALL relapse emerges from small, often clinically undetectable populations of cancer cells that are only partially genetically similar to the dominant leukemic population at diagnosis,” Dr Khiabanian said. “We also identified numerous new mutations in genes involved in drug resistance that are specific to relapsed ALL.”

In the first 55 patients (33 T-cell ALLs and 22 B-cell precursor ALLs), the researchers identified 27 recurrently mutated genes whose mutations were preferentially selected or retained at the time of relapse.

The team said 23 (85%) of these mutated genes were not previously implicated in ALL relapse—HTR3A, MED12, USP9X, CACNA1H, TENM3, AACS, SAMD4A, ANO5, PAPPA, NAALADL2, HIST3H2A, FZD7, TBX15, NEB, GREB1L, PLXNA4, SGK223, TSC1, PTPRG, FGF10, SYCP2, TRPM3, and EYS.

The researchers found mutations in the same genes when they analyzed 49 paired diagnosis and relapse B-cell precursor ALL samples as well as an additional 230 relapsed B-cell precursor ALL samples. In addition, the analyses revealed mutations in NT5C2, NR3C1, CREBBP, KMT2D, JAK2, JAK3, and TP53.

The team also noted that some patient samples showed retention or emergence of RAS mutant clones at relapse. In other patients, RAS mutant clones that were present at diagnosis were replaced by RAS wild-type populations at relapse.

The researchers said this suggests a role for both positive and negative selection evolutionary pressures in clonal evolution of RAS-mutant leukemia.

To investigate this further, they analyzed mouse and human wild-type and mutant RAS isogenic leukemia cells. In these experiments, KRAS-mutant cells showed increased sensitivity to vincristine and increased resistance to methotrexate.

“These results highlight how drug therapy can impact the evolution of leukemia and show a previously unrecognized role of RAS mutations as causes of both sensitivity and resistance to chemotherapy,” Dr Khiabanian said.

“Early identification of these mutations, as well as other genetic alterations that have been shown to induce therapeutic resistance in leukemia patients, is pertinent in guiding precision medicine treatment strategies and prevention of relapsed disease—a goal that is now being pursued in my lab at Rutgers.”

Hossein Khiabanian, PhD

Photo by Debbie Vogel

New research has revealed relapse-specific mutations in pediatric acute lymphoblastic leukemia (ALL) and suggests that mutations in the RAS family may drive both resistance and sensitivity to treatment.

Specifically, the study showed that KRAS-mutant ALL cells were resistant to methotrexate but exhibited increased sensitivity to vincristine.

Hossein Khiabanian, PhD, of Rutgers Cancer Institute of New Jersey, and his colleagues reported these findings in PNAS.

The researchers performed whole-exome and whole-genome sequencing on samples from 55 pediatric patients with relapsed ALL, identified specific genomic changes, and validated these findings in 279 additional samples.

“We found that ALL relapse emerges from small, often clinically undetectable populations of cancer cells that are only partially genetically similar to the dominant leukemic population at diagnosis,” Dr Khiabanian said. “We also identified numerous new mutations in genes involved in drug resistance that are specific to relapsed ALL.”

In the first 55 patients (33 T-cell ALLs and 22 B-cell precursor ALLs), the researchers identified 27 recurrently mutated genes whose mutations were preferentially selected or retained at the time of relapse.

The team said 23 (85%) of these mutated genes were not previously implicated in ALL relapse—HTR3A, MED12, USP9X, CACNA1H, TENM3, AACS, SAMD4A, ANO5, PAPPA, NAALADL2, HIST3H2A, FZD7, TBX15, NEB, GREB1L, PLXNA4, SGK223, TSC1, PTPRG, FGF10, SYCP2, TRPM3, and EYS.

The researchers found mutations in the same genes when they analyzed 49 paired diagnosis and relapse B-cell precursor ALL samples as well as an additional 230 relapsed B-cell precursor ALL samples. In addition, the analyses revealed mutations in NT5C2, NR3C1, CREBBP, KMT2D, JAK2, JAK3, and TP53.

The team also noted that some patient samples showed retention or emergence of RAS mutant clones at relapse. In other patients, RAS mutant clones that were present at diagnosis were replaced by RAS wild-type populations at relapse.

The researchers said this suggests a role for both positive and negative selection evolutionary pressures in clonal evolution of RAS-mutant leukemia.

To investigate this further, they analyzed mouse and human wild-type and mutant RAS isogenic leukemia cells. In these experiments, KRAS-mutant cells showed increased sensitivity to vincristine and increased resistance to methotrexate.

“These results highlight how drug therapy can impact the evolution of leukemia and show a previously unrecognized role of RAS mutations as causes of both sensitivity and resistance to chemotherapy,” Dr Khiabanian said.

“Early identification of these mutations, as well as other genetic alterations that have been shown to induce therapeutic resistance in leukemia patients, is pertinent in guiding precision medicine treatment strategies and prevention of relapsed disease—a goal that is now being pursued in my lab at Rutgers.”

B-cell precursor ALL

Image by Vashi Donsk

Adding rituximab to a chemotherapy regimen can improve event-free survival (EFS) in adults with newly diagnosed, CD20-positive acute lymphoblastic leukemia (ALL), according to the GRAALL-2005/R study.

The 2-year EFS was significantly higher for patients who received rituximab than for those who received chemotherapy alone.

However, there was no significant difference between the groups in 2-year overall survival.

Sébastien Maury, MD, PhD, of Hȏpital Hénri Mondor in Creteil, France, and his colleagues reported these results in NEJM. Results from this study were previously presented at the 2015 ASH Annual Meeting.

The study included 209 patients with newly diagnosed, Ph-negative, B-cell precursor ALL with 20% or more CD20-positive leukemic blasts.

The patients’ median age was 40.2 (range, 24.5–52.6), 13% had an ECOG performance status greater than 1, 6% had CNS involvement, and 21% had a white blood cell count of 30 x 10⁹/L or higher.

Half of the patients (n=104) were randomized to receive the GRAALL-2005 regimen, and the other half (n=105) were randomized to receive the same regimen plus rituximab. Details on the regimens are available in the supplementary material published with the NEJM paper.

Baseline patient characteristics were well-balanced between the treatment groups.

Results

At a median follow-up of 30 months, 101 patients (48%) had at least 1 event, including 44 (42%) in the rituximab group and 57 (55%) in the control group.

There were 17 induction failures (8 in the rituximab group and 9 in the control group), 57 relapses (22 and 35, respectively), and 27 deaths during remission (14 and 13, respectively). Two patients in the rituximab group were lost to follow-up during the first 12 months.

The 2-year EFS was significantly higher in the rituximab group than the control group—65% and 52%, respectively (hazard ratio [HR]=0.66, P=0.04).

However, the EFS benefit did not translate into a significant improvement in overall survival. The 2-year overall survival was 71% in the rituximab group and 64% in the control group (HR=0.70, P=0.10).

Similarly, the cumulative incidence of death during first remission was not significantly different between the treatment groups—12% for both (HR=0.98, P=0.96).

The researchers said the difference in EFS was mostly due to a lower incidence of relapse in the rituximab group. The 2-year incidence of relapse was 18% in the rituximab group and 32% in the control group (HR=0.52, P=0.02).

In a multivariate analysis, receiving the control treatment, older age, higher white blood cell count at baseline, and CNS involvement were all significantly associated with poor EFS.

There were 245 severe adverse events (AEs) reported in 124 patients—67 patients with 1 event, 26 with 2 events, 13 with 3 events, and 18 with 4 or more events.

The overall incidence of severe AEs did not differ significantly between the treatment groups—96% in the rituximab group and 92% in the control group.

Severe AEs included infection, laboratory abnormalities, allergic reactions, neurologic events, pulmonary events, coagulopathy, cardiac events, gastrointestinal events, and “other” events.

The only severe AE for which there was a significant difference between the treatment groups was allergic reactions. There were 2 severe allergic events in the rituximab group and 14 in the control group (P=0.002). Of these 16 events, all but 1 were due to asparaginase.

The researchers therefore theorized that rituximab might inhibit B-cell protection of antibodies against asparaginase, although they could not confirm this hypothesis.

B-cell precursor ALL

Image by Vashi Donsk

Adding rituximab to a chemotherapy regimen can improve event-free survival (EFS) in adults with newly diagnosed, CD20-positive acute lymphoblastic leukemia (ALL), according to the GRAALL-2005/R study.

The 2-year EFS was significantly higher for patients who received rituximab than for those who received chemotherapy alone.

However, there was no significant difference between the groups in 2-year overall survival.

Sébastien Maury, MD, PhD, of Hȏpital Hénri Mondor in Creteil, France, and his colleagues reported these results in NEJM. Results from this study were previously presented at the 2015 ASH Annual Meeting.

The study included 209 patients with newly diagnosed, Ph-negative, B-cell precursor ALL with 20% or more CD20-positive leukemic blasts.

The patients’ median age was 40.2 (range, 24.5–52.6), 13% had an ECOG performance status greater than 1, 6% had CNS involvement, and 21% had a white blood cell count of 30 x 10⁹/L or higher.

Half of the patients (n=104) were randomized to receive the GRAALL-2005 regimen, and the other half (n=105) were randomized to receive the same regimen plus rituximab. Details on the regimens are available in the supplementary material published with the NEJM paper.

Baseline patient characteristics were well-balanced between the treatment groups.

Results

At a median follow-up of 30 months, 101 patients (48%) had at least 1 event, including 44 (42%) in the rituximab group and 57 (55%) in the control group.

There were 17 induction failures (8 in the rituximab group and 9 in the control group), 57 relapses (22 and 35, respectively), and 27 deaths during remission (14 and 13, respectively). Two patients in the rituximab group were lost to follow-up during the first 12 months.

The 2-year EFS was significantly higher in the rituximab group than the control group—65% and 52%, respectively (hazard ratio [HR]=0.66, P=0.04).

However, the EFS benefit did not translate into a significant improvement in overall survival. The 2-year overall survival was 71% in the rituximab group and 64% in the control group (HR=0.70, P=0.10).

Similarly, the cumulative incidence of death during first remission was not significantly different between the treatment groups—12% for both (HR=0.98, P=0.96).

The researchers said the difference in EFS was mostly due to a lower incidence of relapse in the rituximab group. The 2-year incidence of relapse was 18% in the rituximab group and 32% in the control group (HR=0.52, P=0.02).

In a multivariate analysis, receiving the control treatment, older age, higher white blood cell count at baseline, and CNS involvement were all significantly associated with poor EFS.

There were 245 severe adverse events (AEs) reported in 124 patients—67 patients with 1 event, 26 with 2 events, 13 with 3 events, and 18 with 4 or more events.

The overall incidence of severe AEs did not differ significantly between the treatment groups—96% in the rituximab group and 92% in the control group.

Severe AEs included infection, laboratory abnormalities, allergic reactions, neurologic events, pulmonary events, coagulopathy, cardiac events, gastrointestinal events, and “other” events.

The only severe AE for which there was a significant difference between the treatment groups was allergic reactions. There were 2 severe allergic events in the rituximab group and 14 in the control group (P=0.002). Of these 16 events, all but 1 were due to asparaginase.

The researchers therefore theorized that rituximab might inhibit B-cell protection of antibodies against asparaginase, although they could not confirm this hypothesis.

B-cell precursor ALL

Image by Vashi Donsk

Adding rituximab to a chemotherapy regimen can improve event-free survival (EFS) in adults with newly diagnosed, CD20-positive acute lymphoblastic leukemia (ALL), according to the GRAALL-2005/R study.

The 2-year EFS was significantly higher for patients who received rituximab than for those who received chemotherapy alone.

However, there was no significant difference between the groups in 2-year overall survival.

Sébastien Maury, MD, PhD, of Hȏpital Hénri Mondor in Creteil, France, and his colleagues reported these results in NEJM. Results from this study were previously presented at the 2015 ASH Annual Meeting.

The study included 209 patients with newly diagnosed, Ph-negative, B-cell precursor ALL with 20% or more CD20-positive leukemic blasts.

The patients’ median age was 40.2 (range, 24.5–52.6), 13% had an ECOG performance status greater than 1, 6% had CNS involvement, and 21% had a white blood cell count of 30 x 10⁹/L or higher.

Half of the patients (n=104) were randomized to receive the GRAALL-2005 regimen, and the other half (n=105) were randomized to receive the same regimen plus rituximab. Details on the regimens are available in the supplementary material published with the NEJM paper.

Baseline patient characteristics were well-balanced between the treatment groups.

Results

At a median follow-up of 30 months, 101 patients (48%) had at least 1 event, including 44 (42%) in the rituximab group and 57 (55%) in the control group.

There were 17 induction failures (8 in the rituximab group and 9 in the control group), 57 relapses (22 and 35, respectively), and 27 deaths during remission (14 and 13, respectively). Two patients in the rituximab group were lost to follow-up during the first 12 months.

The 2-year EFS was significantly higher in the rituximab group than the control group—65% and 52%, respectively (hazard ratio [HR]=0.66, P=0.04).

However, the EFS benefit did not translate into a significant improvement in overall survival. The 2-year overall survival was 71% in the rituximab group and 64% in the control group (HR=0.70, P=0.10).

Similarly, the cumulative incidence of death during first remission was not significantly different between the treatment groups—12% for both (HR=0.98, P=0.96).

The researchers said the difference in EFS was mostly due to a lower incidence of relapse in the rituximab group. The 2-year incidence of relapse was 18% in the rituximab group and 32% in the control group (HR=0.52, P=0.02).

In a multivariate analysis, receiving the control treatment, older age, higher white blood cell count at baseline, and CNS involvement were all significantly associated with poor EFS.

There were 245 severe adverse events (AEs) reported in 124 patients—67 patients with 1 event, 26 with 2 events, 13 with 3 events, and 18 with 4 or more events.

The overall incidence of severe AEs did not differ significantly between the treatment groups—96% in the rituximab group and 92% in the control group.

Severe AEs included infection, laboratory abnormalities, allergic reactions, neurologic events, pulmonary events, coagulopathy, cardiac events, gastrointestinal events, and “other” events.

The only severe AE for which there was a significant difference between the treatment groups was allergic reactions. There were 2 severe allergic events in the rituximab group and 14 in the control group (P=0.002). Of these 16 events, all but 1 were due to asparaginase.

The researchers therefore theorized that rituximab might inhibit B-cell protection of antibodies against asparaginase, although they could not confirm this hypothesis.

Lab mice

Photo by Aaron Logan

Preclinical research suggests that combining a BCL2 inhibitor with a tyrosine kinase inhibitor (TKI) could overcome resistance in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL).

Investigators found that combining venetoclax and dasatinib increased antitumor activity (when compared to either agent alone) against Ph+ ALL cells in vitro and in a mouse model of the disease.

Jessica Leonard, MD, of Oregon Health & Science University in Portland, and her colleagues reported these findings in Science Translational Medicine.

The researchers said venetoclax and dasatinib demonstrated synergy in vitro, and the combination resulted in a greater degree of apoptosis in Ph+ ALL cells than either agent alone.

The team also observed synergy between venetoclax and cytarabine, dexamethasone, doxorubicin, and vincristine. They said this suggests venetoclax could potentially be used in combination with standard chemotherapy in patients with Ph+ ALL.

The investigators then assessed synergy between venetoclax and other TKIs. Venetoclax demonstrated synergy with imatinib and nilotinib, but the researchers said they saw the most robust synergy when venetoclax was combined with dasatinib or ponatinib.

Further investigation revealed that ponatinib and dasatinib inhibit LYN activity, which impedes STAT5 phosphorylation, which inhibits upregulation of MCL-1.

As upregulation of MCL-1 is a known mechanism of resistance to venetoclax, the researchers believe the addition of either TKI could potentially overcome the development of venetoclax resistance.

Results in a mouse model of Ph+ ALL seemed to support this theory. The researchers injected NSG mice with mononuclear cells from a patient with Ph+ ALL and found that combination treatment with venetoclax and dasatinib prevented engraftment within 90 days in all mice that received the therapy.

In comparison, mice in the control group and those that received single-agent venetoclax engrafted within 60 days. Two of the 5 mice that received dasatinib alone engrafted within 90 days.

In another mouse model, the investigators injected NSG mice with a primary Ph+ ALL sample and found the combination of venetoclax and dasatinib reduced spleen size when compared to no treatment.

In addition, all of the mice that received the combination remained alive during the 4-week treatment period, whereas untreated mice became moribund and were euthanized.

The researchers said these results suggest the combination of dasatinib and venetoclax has the potential to improve the treatment of Ph+ ALL and should be further evaluated for patient care.

Lab mice

Photo by Aaron Logan

Preclinical research suggests that combining a BCL2 inhibitor with a tyrosine kinase inhibitor (TKI) could overcome resistance in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL).

Investigators found that combining venetoclax and dasatinib increased antitumor activity (when compared to either agent alone) against Ph+ ALL cells in vitro and in a mouse model of the disease.

Jessica Leonard, MD, of Oregon Health & Science University in Portland, and her colleagues reported these findings in Science Translational Medicine.

The researchers said venetoclax and dasatinib demonstrated synergy in vitro, and the combination resulted in a greater degree of apoptosis in Ph+ ALL cells than either agent alone.

The team also observed synergy between venetoclax and cytarabine, dexamethasone, doxorubicin, and vincristine. They said this suggests venetoclax could potentially be used in combination with standard chemotherapy in patients with Ph+ ALL.

The investigators then assessed synergy between venetoclax and other TKIs. Venetoclax demonstrated synergy with imatinib and nilotinib, but the researchers said they saw the most robust synergy when venetoclax was combined with dasatinib or ponatinib.

Further investigation revealed that ponatinib and dasatinib inhibit LYN activity, which impedes STAT5 phosphorylation, which inhibits upregulation of MCL-1.

As upregulation of MCL-1 is a known mechanism of resistance to venetoclax, the researchers believe the addition of either TKI could potentially overcome the development of venetoclax resistance.

Results in a mouse model of Ph+ ALL seemed to support this theory. The researchers injected NSG mice with mononuclear cells from a patient with Ph+ ALL and found that combination treatment with venetoclax and dasatinib prevented engraftment within 90 days in all mice that received the therapy.

In comparison, mice in the control group and those that received single-agent venetoclax engrafted within 60 days. Two of the 5 mice that received dasatinib alone engrafted within 90 days.

In another mouse model, the investigators injected NSG mice with a primary Ph+ ALL sample and found the combination of venetoclax and dasatinib reduced spleen size when compared to no treatment.

In addition, all of the mice that received the combination remained alive during the 4-week treatment period, whereas untreated mice became moribund and were euthanized.

The researchers said these results suggest the combination of dasatinib and venetoclax has the potential to improve the treatment of Ph+ ALL and should be further evaluated for patient care.

Lab mice

Photo by Aaron Logan

Preclinical research suggests that combining a BCL2 inhibitor with a tyrosine kinase inhibitor (TKI) could overcome resistance in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL).

Investigators found that combining venetoclax and dasatinib increased antitumor activity (when compared to either agent alone) against Ph+ ALL cells in vitro and in a mouse model of the disease.

Jessica Leonard, MD, of Oregon Health & Science University in Portland, and her colleagues reported these findings in Science Translational Medicine.

The researchers said venetoclax and dasatinib demonstrated synergy in vitro, and the combination resulted in a greater degree of apoptosis in Ph+ ALL cells than either agent alone.

The team also observed synergy between venetoclax and cytarabine, dexamethasone, doxorubicin, and vincristine. They said this suggests venetoclax could potentially be used in combination with standard chemotherapy in patients with Ph+ ALL.

The investigators then assessed synergy between venetoclax and other TKIs. Venetoclax demonstrated synergy with imatinib and nilotinib, but the researchers said they saw the most robust synergy when venetoclax was combined with dasatinib or ponatinib.

Further investigation revealed that ponatinib and dasatinib inhibit LYN activity, which impedes STAT5 phosphorylation, which inhibits upregulation of MCL-1.

As upregulation of MCL-1 is a known mechanism of resistance to venetoclax, the researchers believe the addition of either TKI could potentially overcome the development of venetoclax resistance.

Results in a mouse model of Ph+ ALL seemed to support this theory. The researchers injected NSG mice with mononuclear cells from a patient with Ph+ ALL and found that combination treatment with venetoclax and dasatinib prevented engraftment within 90 days in all mice that received the therapy.

In comparison, mice in the control group and those that received single-agent venetoclax engrafted within 60 days. Two of the 5 mice that received dasatinib alone engrafted within 90 days.

In another mouse model, the investigators injected NSG mice with a primary Ph+ ALL sample and found the combination of venetoclax and dasatinib reduced spleen size when compared to no treatment.

In addition, all of the mice that received the combination remained alive during the 4-week treatment period, whereas untreated mice became moribund and were euthanized.

The researchers said these results suggest the combination of dasatinib and venetoclax has the potential to improve the treatment of Ph+ ALL and should be further evaluated for patient care.

Doctor consults with cancer

patient and her father

Photo by Rhoda Baer

Many adolescent females are not being screened for pregnancy before beginning chemotherapy or undergoing computed tomography (CT) scans, according to research published in Cancer.

In this study, pregnancy screening was underused in adolescents with acute lymphoblastic leukemia (ALL), those with acute myeloid leukemia (AML), and those who received CT scans of the abdomen or pelvis during visits to the emergency room (ER).

“We found that adolescent girls are not adequately screened for pregnancy prior to receiving chemotherapy or CT scans that could harm a developing fetus,” said study author Pooja Rao, MD, of Penn State Health’s Milton S. Hershey Medical Center in Hershey, Pennsylvania.

“Adolescents with ALL, the most common childhood cancer, had the lowest rates of pregnancy screening of the patients we studied.”

Dr Rao and her colleagues examined pregnancy screening patterns among adolescent females newly diagnosed with ALL or AML, as well as adolescent females who visited the ER and received CT scans of the abdomen or pelvis. (In emergency medicine, pregnancy screening protocols exist for adolescents prior to receiving radiation due to the known teratogenic risks of radiation.)

The analysis included patients ages 10 to 18 who were admitted to hospitals across the US from 1999 to 2011. There were a total of 35,650 patient visits—127 for AML patients, 889 for ALL patients, and 34,634 ER admissions with CT scans of the abdomen/pelvis.

The proportion of visits with an appropriately timed pregnancy test was 35% for the ALL patients, 64% for the AML patients, and 58% in the ER group.

The researchers noted that ALL patients tended to be younger than the AML patients and the ER patients, and there was substantial variation in pregnancy screening patterns among the different hospitals.

However, in a generalized estimating equation (GEE) model adjusted for hospital clustering and patient age, patients with ALL were significantly less likely to have an appropriately timed pregnancy test when compared to patients in the ER cohort. The adjusted prevalence ratio was 0.71 (95% CI, 0.65-0.78).

And in a GEE model adjusted for hospital clustering, patients with AML were more likely to have an appropriately timed pregnancy test than patients in the ER cohort, but this difference was not statistically significant. The adjusted prevalence ratio was 1.12 (95% CI, 0.99-1.27).

The researchers also found that pregnancy screening continued to increase over time in the ALL cohort but remained “relatively stable” from 2008 onward in the AML and ER cohorts.

“Since nearly all chemotherapy agents used for childhood/adolescent acute leukemia can cause potential harm to a developing fetus, our findings indicate a need for standardized pregnancy screening practices for adolescent patients being treated for cancer,” Dr Rao said.

She also noted that the low rates of pregnancy screening observed in this study may indicate a reluctance on the part of pediatric oncologists to discuss sexual health practices with adolescent patients.

“While sexual health discussions and education may traditionally be thought to be the responsibility of the patient’s primary care provider, adolescents with cancer will often see their oncologist frequently over the course of their cancer treatment and afterwards,” Dr Rao said. “Oncologists therefore are well-positioned to initiate discussions about sexual health with their patients.”

Doctor consults with cancer

patient and her father

Photo by Rhoda Baer

Many adolescent females are not being screened for pregnancy before beginning chemotherapy or undergoing computed tomography (CT) scans, according to research published in Cancer.

In this study, pregnancy screening was underused in adolescents with acute lymphoblastic leukemia (ALL), those with acute myeloid leukemia (AML), and those who received CT scans of the abdomen or pelvis during visits to the emergency room (ER).

“We found that adolescent girls are not adequately screened for pregnancy prior to receiving chemotherapy or CT scans that could harm a developing fetus,” said study author Pooja Rao, MD, of Penn State Health’s Milton S. Hershey Medical Center in Hershey, Pennsylvania.

“Adolescents with ALL, the most common childhood cancer, had the lowest rates of pregnancy screening of the patients we studied.”

Dr Rao and her colleagues examined pregnancy screening patterns among adolescent females newly diagnosed with ALL or AML, as well as adolescent females who visited the ER and received CT scans of the abdomen or pelvis. (In emergency medicine, pregnancy screening protocols exist for adolescents prior to receiving radiation due to the known teratogenic risks of radiation.)

The analysis included patients ages 10 to 18 who were admitted to hospitals across the US from 1999 to 2011. There were a total of 35,650 patient visits—127 for AML patients, 889 for ALL patients, and 34,634 ER admissions with CT scans of the abdomen/pelvis.

The proportion of visits with an appropriately timed pregnancy test was 35% for the ALL patients, 64% for the AML patients, and 58% in the ER group.

The researchers noted that ALL patients tended to be younger than the AML patients and the ER patients, and there was substantial variation in pregnancy screening patterns among the different hospitals.

However, in a generalized estimating equation (GEE) model adjusted for hospital clustering and patient age, patients with ALL were significantly less likely to have an appropriately timed pregnancy test when compared to patients in the ER cohort. The adjusted prevalence ratio was 0.71 (95% CI, 0.65-0.78).

And in a GEE model adjusted for hospital clustering, patients with AML were more likely to have an appropriately timed pregnancy test than patients in the ER cohort, but this difference was not statistically significant. The adjusted prevalence ratio was 1.12 (95% CI, 0.99-1.27).

The researchers also found that pregnancy screening continued to increase over time in the ALL cohort but remained “relatively stable” from 2008 onward in the AML and ER cohorts.

“Since nearly all chemotherapy agents used for childhood/adolescent acute leukemia can cause potential harm to a developing fetus, our findings indicate a need for standardized pregnancy screening practices for adolescent patients being treated for cancer,” Dr Rao said.

She also noted that the low rates of pregnancy screening observed in this study may indicate a reluctance on the part of pediatric oncologists to discuss sexual health practices with adolescent patients.

“While sexual health discussions and education may traditionally be thought to be the responsibility of the patient’s primary care provider, adolescents with cancer will often see their oncologist frequently over the course of their cancer treatment and afterwards,” Dr Rao said. “Oncologists therefore are well-positioned to initiate discussions about sexual health with their patients.”

Doctor consults with cancer

patient and her father

Photo by Rhoda Baer

Many adolescent females are not being screened for pregnancy before beginning chemotherapy or undergoing computed tomography (CT) scans, according to research published in Cancer.

In this study, pregnancy screening was underused in adolescents with acute lymphoblastic leukemia (ALL), those with acute myeloid leukemia (AML), and those who received CT scans of the abdomen or pelvis during visits to the emergency room (ER).

“We found that adolescent girls are not adequately screened for pregnancy prior to receiving chemotherapy or CT scans that could harm a developing fetus,” said study author Pooja Rao, MD, of Penn State Health’s Milton S. Hershey Medical Center in Hershey, Pennsylvania.

“Adolescents with ALL, the most common childhood cancer, had the lowest rates of pregnancy screening of the patients we studied.”

Dr Rao and her colleagues examined pregnancy screening patterns among adolescent females newly diagnosed with ALL or AML, as well as adolescent females who visited the ER and received CT scans of the abdomen or pelvis. (In emergency medicine, pregnancy screening protocols exist for adolescents prior to receiving radiation due to the known teratogenic risks of radiation.)

The analysis included patients ages 10 to 18 who were admitted to hospitals across the US from 1999 to 2011. There were a total of 35,650 patient visits—127 for AML patients, 889 for ALL patients, and 34,634 ER admissions with CT scans of the abdomen/pelvis.

The proportion of visits with an appropriately timed pregnancy test was 35% for the ALL patients, 64% for the AML patients, and 58% in the ER group.

The researchers noted that ALL patients tended to be younger than the AML patients and the ER patients, and there was substantial variation in pregnancy screening patterns among the different hospitals.

However, in a generalized estimating equation (GEE) model adjusted for hospital clustering and patient age, patients with ALL were significantly less likely to have an appropriately timed pregnancy test when compared to patients in the ER cohort. The adjusted prevalence ratio was 0.71 (95% CI, 0.65-0.78).

And in a GEE model adjusted for hospital clustering, patients with AML were more likely to have an appropriately timed pregnancy test than patients in the ER cohort, but this difference was not statistically significant. The adjusted prevalence ratio was 1.12 (95% CI, 0.99-1.27).

The researchers also found that pregnancy screening continued to increase over time in the ALL cohort but remained “relatively stable” from 2008 onward in the AML and ER cohorts.

“Since nearly all chemotherapy agents used for childhood/adolescent acute leukemia can cause potential harm to a developing fetus, our findings indicate a need for standardized pregnancy screening practices for adolescent patients being treated for cancer,” Dr Rao said.

She also noted that the low rates of pregnancy screening observed in this study may indicate a reluctance on the part of pediatric oncologists to discuss sexual health practices with adolescent patients.

“While sexual health discussions and education may traditionally be thought to be the responsibility of the patient’s primary care provider, adolescents with cancer will often see their oncologist frequently over the course of their cancer treatment and afterwards,” Dr Rao said. “Oncologists therefore are well-positioned to initiate discussions about sexual health with their patients.”

Vials of blinatumomab powder

and solution for infusion

Photo courtesy of Amgen

The US Food and Drug Administration (FDA) has granted accelerated approval for blinatumomab (Blincyto®) to treat pediatric patients with Philadelphia chromosome-negative (Ph-) relapsed or refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL).

The approval is based on results from a phase 1/2 study.

Continued approval of blinatumomab for this indication may be contingent upon verification of clinical benefit in subsequent trials.

Blinatumomab is a bispecific, CD19-directed, CD3 T-cell engager (BiTE®) antibody construct that binds specifically to CD19 expressed on the surface of cells of B-lineage origin and CD3 expressed on the surface of T cells.

In 2014, blinatumomab received accelerated approval from the FDA to treat adults with Ph- relapsed or refractory BCP-ALL. The FDA has also granted the drug priority review, breakthrough therapy designation, and orphan drug designation.

Blinatumomab is being developed by Amgen. Full prescribing information is available at www.blincyto.com.

‘205 trial

The latest accelerated approval of blinatumomab is based on results from the phase 1/2 ‘205 trial, in which researchers evaluated blinatumomab in 93 pediatric patients with relapsed or refractory BCP-ALL.

Amgen said treatment in this study has been completed, subjects are being monitored for long-term efficacy, and the data will be submitted for publication.

Initial results from this study were presented at ASH 2014. The abstract included data on 39 patients with relapsed/refractory BCP-ALL and a median age of 9 (range, 2-16).

The patients received blinatumomab at a dose of 5-15 µg/m²/day. Nineteen patients completed 1 cycle of blinatumomab, 4 completed 2 cycles, and 2 completed 3 cycles.

During the first 2 treatment cycles, 12 patients achieved a complete response, 5 of whom were negative for minimal residual disease.

Six of the complete responders went on to transplant. The median relapse-free survival for complete responders was 5.6 months.

At 6 months of follow-up, the median overall survival for all 39 patients was 4.3 months.

All of the patients experienced adverse events. The most common were pyrexia (74%), anemia (33%), nausea (31%), headache (28%), hypertension (26%), increased alanine aminotransferase (23%), and cough (21%).

The most common grade 3 or higher events were anemia (26%), pyrexia (21%), increased alanine aminotransferase (18%), increased aspartate aminotransferase (18%), and febrile neutropenia (15%).

Three patients developed cytokine release syndrome (2 grade 3).

Vials of blinatumomab powder

and solution for infusion

Photo courtesy of Amgen

The US Food and Drug Administration (FDA) has granted accelerated approval for blinatumomab (Blincyto®) to treat pediatric patients with Philadelphia chromosome-negative (Ph-) relapsed or refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL).

The approval is based on results from a phase 1/2 study.

Continued approval of blinatumomab for this indication may be contingent upon verification of clinical benefit in subsequent trials.

Blinatumomab is a bispecific, CD19-directed, CD3 T-cell engager (BiTE®) antibody construct that binds specifically to CD19 expressed on the surface of cells of B-lineage origin and CD3 expressed on the surface of T cells.

In 2014, blinatumomab received accelerated approval from the FDA to treat adults with Ph- relapsed or refractory BCP-ALL. The FDA has also granted the drug priority review, breakthrough therapy designation, and orphan drug designation.

Blinatumomab is being developed by Amgen. Full prescribing information is available at www.blincyto.com.

‘205 trial

The latest accelerated approval of blinatumomab is based on results from the phase 1/2 ‘205 trial, in which researchers evaluated blinatumomab in 93 pediatric patients with relapsed or refractory BCP-ALL.

Amgen said treatment in this study has been completed, subjects are being monitored for long-term efficacy, and the data will be submitted for publication.

Initial results from this study were presented at ASH 2014. The abstract included data on 39 patients with relapsed/refractory BCP-ALL and a median age of 9 (range, 2-16).

The patients received blinatumomab at a dose of 5-15 µg/m²/day. Nineteen patients completed 1 cycle of blinatumomab, 4 completed 2 cycles, and 2 completed 3 cycles.

During the first 2 treatment cycles, 12 patients achieved a complete response, 5 of whom were negative for minimal residual disease.

Six of the complete responders went on to transplant. The median relapse-free survival for complete responders was 5.6 months.

At 6 months of follow-up, the median overall survival for all 39 patients was 4.3 months.

All of the patients experienced adverse events. The most common were pyrexia (74%), anemia (33%), nausea (31%), headache (28%), hypertension (26%), increased alanine aminotransferase (23%), and cough (21%).

The most common grade 3 or higher events were anemia (26%), pyrexia (21%), increased alanine aminotransferase (18%), increased aspartate aminotransferase (18%), and febrile neutropenia (15%).

Three patients developed cytokine release syndrome (2 grade 3).

Vials of blinatumomab powder

and solution for infusion

Photo courtesy of Amgen

The US Food and Drug Administration (FDA) has granted accelerated approval for blinatumomab (Blincyto®) to treat pediatric patients with Philadelphia chromosome-negative (Ph-) relapsed or refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL).

The approval is based on results from a phase 1/2 study.

Continued approval of blinatumomab for this indication may be contingent upon verification of clinical benefit in subsequent trials.

Blinatumomab is a bispecific, CD19-directed, CD3 T-cell engager (BiTE®) antibody construct that binds specifically to CD19 expressed on the surface of cells of B-lineage origin and CD3 expressed on the surface of T cells.

In 2014, blinatumomab received accelerated approval from the FDA to treat adults with Ph- relapsed or refractory BCP-ALL. The FDA has also granted the drug priority review, breakthrough therapy designation, and orphan drug designation.

Blinatumomab is being developed by Amgen. Full prescribing information is available at www.blincyto.com.

‘205 trial

The latest accelerated approval of blinatumomab is based on results from the phase 1/2 ‘205 trial, in which researchers evaluated blinatumomab in 93 pediatric patients with relapsed or refractory BCP-ALL.

Amgen said treatment in this study has been completed, subjects are being monitored for long-term efficacy, and the data will be submitted for publication.

Initial results from this study were presented at ASH 2014. The abstract included data on 39 patients with relapsed/refractory BCP-ALL and a median age of 9 (range, 2-16).

The patients received blinatumomab at a dose of 5-15 µg/m²/day. Nineteen patients completed 1 cycle of blinatumomab, 4 completed 2 cycles, and 2 completed 3 cycles.

During the first 2 treatment cycles, 12 patients achieved a complete response, 5 of whom were negative for minimal residual disease.

Six of the complete responders went on to transplant. The median relapse-free survival for complete responders was 5.6 months.

At 6 months of follow-up, the median overall survival for all 39 patients was 4.3 months.

All of the patients experienced adverse events. The most common were pyrexia (74%), anemia (33%), nausea (31%), headache (28%), hypertension (26%), increased alanine aminotransferase (23%), and cough (21%).

The most common grade 3 or higher events were anemia (26%), pyrexia (21%), increased alanine aminotransferase (18%), increased aspartate aminotransferase (18%), and febrile neutropenia (15%).

Three patients developed cytokine release syndrome (2 grade 3).

The combination of dasatinib and venetoclax had a synergistic effect that was associated with lower toxicity than single-agent therapy, based on responses of primary Philadelphia chromosome–positive acute lymphoblastic leukemia (PH+ALL) samples in xenografted immunodeficient mice, according to Jessica T. Leonard, MD.

Dr. Leonard and her colleagues at Oregon Health and Science University in Portland demonstrated that the combination of venetoclax – a selective inhibitor of B cell lymphoma 2 – was highly synergistic with tyrosine kinase inhibitors in vitro. In the preclinical model of PH+ALL, a stepwise reduction in median inhibitory concentration of dasatinib was observed with increasing doses of venetoclax, as was decreased cell viability and induced apoptosis. Dasatinib – a breakpoint cluster region–Abelson kinase inhibitor – has an additional advantage of potentially overcoming venetoclax resistance by blocking a common mechanism of resistance to the agent, the investigators reported Aug. 31 in Science Translational Medicine (2016; 8[354]:354ra114).

The combination boosted antitumor activity against Ph+ALL cells grown in culture. In the mouse model of Ph+ALL, all of the mice in the combination dosing group remained alive during the 4-week treatment period. The combination therapy was well tolerated, and superior to either agent alone with respect to antileukemic efficacy.

The investigators focused on combining venetoclax with dasatinib because it is “the current backbone for the treatment of adult Ph+ALL ... These results lay the foundation for the testing of this combination in patients with Ph+ALL with the goal of improving treatment,” they concluded.

This study was supported in part by the Leukemia & Lymphoma Society and the Newman’s Own Foundation. Dr. Leonard reported having no other disclosures, but various coauthors reported receiving research support from, and/or serving as a consultant or scientific advisory board member to Genentech, the maker of venetoclax, and Bristol-Myers Squibb, the maker of dasatinib, as well as numerous other drug companies.

sworcester@frontlinemedcom.com

The combination of dasatinib and venetoclax had a synergistic effect that was associated with lower toxicity than single-agent therapy, based on responses of primary Philadelphia chromosome–positive acute lymphoblastic leukemia (PH+ALL) samples in xenografted immunodeficient mice, according to Jessica T. Leonard, MD.

Dr. Leonard and her colleagues at Oregon Health and Science University in Portland demonstrated that the combination of venetoclax – a selective inhibitor of B cell lymphoma 2 – was highly synergistic with tyrosine kinase inhibitors in vitro. In the preclinical model of PH+ALL, a stepwise reduction in median inhibitory concentration of dasatinib was observed with increasing doses of venetoclax, as was decreased cell viability and induced apoptosis. Dasatinib – a breakpoint cluster region–Abelson kinase inhibitor – has an additional advantage of potentially overcoming venetoclax resistance by blocking a common mechanism of resistance to the agent, the investigators reported Aug. 31 in Science Translational Medicine (2016; 8[354]:354ra114).

The combination boosted antitumor activity against Ph+ALL cells grown in culture. In the mouse model of Ph+ALL, all of the mice in the combination dosing group remained alive during the 4-week treatment period. The combination therapy was well tolerated, and superior to either agent alone with respect to antileukemic efficacy.

The investigators focused on combining venetoclax with dasatinib because it is “the current backbone for the treatment of adult Ph+ALL ... These results lay the foundation for the testing of this combination in patients with Ph+ALL with the goal of improving treatment,” they concluded.

This study was supported in part by the Leukemia & Lymphoma Society and the Newman’s Own Foundation. Dr. Leonard reported having no other disclosures, but various coauthors reported receiving research support from, and/or serving as a consultant or scientific advisory board member to Genentech, the maker of venetoclax, and Bristol-Myers Squibb, the maker of dasatinib, as well as numerous other drug companies.

sworcester@frontlinemedcom.com

The combination of dasatinib and venetoclax had a synergistic effect that was associated with lower toxicity than single-agent therapy, based on responses of primary Philadelphia chromosome–positive acute lymphoblastic leukemia (PH+ALL) samples in xenografted immunodeficient mice, according to Jessica T. Leonard, MD.

Dr. Leonard and her colleagues at Oregon Health and Science University in Portland demonstrated that the combination of venetoclax – a selective inhibitor of B cell lymphoma 2 – was highly synergistic with tyrosine kinase inhibitors in vitro. In the preclinical model of PH+ALL, a stepwise reduction in median inhibitory concentration of dasatinib was observed with increasing doses of venetoclax, as was decreased cell viability and induced apoptosis. Dasatinib – a breakpoint cluster region–Abelson kinase inhibitor – has an additional advantage of potentially overcoming venetoclax resistance by blocking a common mechanism of resistance to the agent, the investigators reported Aug. 31 in Science Translational Medicine (2016; 8[354]:354ra114).

The combination boosted antitumor activity against Ph+ALL cells grown in culture. In the mouse model of Ph+ALL, all of the mice in the combination dosing group remained alive during the 4-week treatment period. The combination therapy was well tolerated, and superior to either agent alone with respect to antileukemic efficacy.

The investigators focused on combining venetoclax with dasatinib because it is “the current backbone for the treatment of adult Ph+ALL ... These results lay the foundation for the testing of this combination in patients with Ph+ALL with the goal of improving treatment,” they concluded.

This study was supported in part by the Leukemia & Lymphoma Society and the Newman’s Own Foundation. Dr. Leonard reported having no other disclosures, but various coauthors reported receiving research support from, and/or serving as a consultant or scientific advisory board member to Genentech, the maker of venetoclax, and Bristol-Myers Squibb, the maker of dasatinib, as well as numerous other drug companies.

sworcester@frontlinemedcom.com

A new therapy combining an anti-c-Kit monoclonal antibody with a CD47 blocker allowed hematopoietic stem cell engraftment in immunocompetent mice without the need for toxic preconditioning using radiation or chemotherapy, according to a report published in Science Translational Medicine.

Until now, hematopoietic stem cell transplantation has required rigorous conditioning regimens to clear out the host’s bone marrow, which can cause lifelong complications. So the procedure has been reserved for patients whose life-threatening disorders justified such toxicity. “Safer and more targeted conditioning protocols could both improve the safety of transplantation and extend the existing clinical utility of this powerful form of cell therapy,” said Akanksha Chhabra, PhD, of the department of blood and marrow transplantation, Stanford (Calif.) University, and her associates.

They assessed the new combined treatment in a series of laboratory and mouse studies. The opsonizing anti-c-Kit monoclonal antibodies induced robust depletion of functional hematopoietic stem cells in immunocompetent mice, which allowed donor stem cells to engraft in these hosts. Adding the T-cell–depleting CD47-antagonists further facilitated immune ablation of host stem cells and progenitor cells. Combined, the two agents eliminated more than 99% of host hematopoietic stem cells in the bone marrow and enabled strong engraftment of the donor stem cells, while avoiding radiation- and chemotherapy-related adverse effects.

The main toxicities that occurred in treated mice were, as expected, reductions in hematologic parameters, especially red blood cell indices. This may be related to a factor in mouse physiology that is not present in humans. But if such toxicities do develop in human subjects, they can be mitigated by careful monitoring and occasional supportive transfusions, Dr. Chhabra and her associates said (Sci Transl Med. 2016;8:351ra105).

These two types of antibodies are already being investigated separately in early-phase clinical trials. If the combined treatment proves effective and safe in humans – a question that awaits further clinical studies – hematopoietic stem cell transplantation might be extended to nonmalignant conditions such as inherited immunodeficiency, inborn errors of metabolism, and hemoglobinopathies. It might also be adapted for use in solid-organ transplants, the researchers added.

This work was supported by the Virginia and D.K. Ludwig Fund for Cancer Research and several other nonprofit organizations, the California Institute for Regenerative Medicine, and the National Institutes of Health. Dr. Chhabra is a coinventor on a patent described in this article, and her associates are cofounders of Forty Seven, the company that licensed the technology for radiation- and chemotherapy-free stem-cell transplantation. Two associates also serve as advisors for Alexo Therapeutics, which develops CD47-based treatments.

A new therapy combining an anti-c-Kit monoclonal antibody with a CD47 blocker allowed hematopoietic stem cell engraftment in immunocompetent mice without the need for toxic preconditioning using radiation or chemotherapy, according to a report published in Science Translational Medicine.

Until now, hematopoietic stem cell transplantation has required rigorous conditioning regimens to clear out the host’s bone marrow, which can cause lifelong complications. So the procedure has been reserved for patients whose life-threatening disorders justified such toxicity. “Safer and more targeted conditioning protocols could both improve the safety of transplantation and extend the existing clinical utility of this powerful form of cell therapy,” said Akanksha Chhabra, PhD, of the department of blood and marrow transplantation, Stanford (Calif.) University, and her associates.

They assessed the new combined treatment in a series of laboratory and mouse studies. The opsonizing anti-c-Kit monoclonal antibodies induced robust depletion of functional hematopoietic stem cells in immunocompetent mice, which allowed donor stem cells to engraft in these hosts. Adding the T-cell–depleting CD47-antagonists further facilitated immune ablation of host stem cells and progenitor cells. Combined, the two agents eliminated more than 99% of host hematopoietic stem cells in the bone marrow and enabled strong engraftment of the donor stem cells, while avoiding radiation- and chemotherapy-related adverse effects.

The main toxicities that occurred in treated mice were, as expected, reductions in hematologic parameters, especially red blood cell indices. This may be related to a factor in mouse physiology that is not present in humans. But if such toxicities do develop in human subjects, they can be mitigated by careful monitoring and occasional supportive transfusions, Dr. Chhabra and her associates said (Sci Transl Med. 2016;8:351ra105).

These two types of antibodies are already being investigated separately in early-phase clinical trials. If the combined treatment proves effective and safe in humans – a question that awaits further clinical studies – hematopoietic stem cell transplantation might be extended to nonmalignant conditions such as inherited immunodeficiency, inborn errors of metabolism, and hemoglobinopathies. It might also be adapted for use in solid-organ transplants, the researchers added.

This work was supported by the Virginia and D.K. Ludwig Fund for Cancer Research and several other nonprofit organizations, the California Institute for Regenerative Medicine, and the National Institutes of Health. Dr. Chhabra is a coinventor on a patent described in this article, and her associates are cofounders of Forty Seven, the company that licensed the technology for radiation- and chemotherapy-free stem-cell transplantation. Two associates also serve as advisors for Alexo Therapeutics, which develops CD47-based treatments.

A new therapy combining an anti-c-Kit monoclonal antibody with a CD47 blocker allowed hematopoietic stem cell engraftment in immunocompetent mice without the need for toxic preconditioning using radiation or chemotherapy, according to a report published in Science Translational Medicine.

Until now, hematopoietic stem cell transplantation has required rigorous conditioning regimens to clear out the host’s bone marrow, which can cause lifelong complications. So the procedure has been reserved for patients whose life-threatening disorders justified such toxicity. “Safer and more targeted conditioning protocols could both improve the safety of transplantation and extend the existing clinical utility of this powerful form of cell therapy,” said Akanksha Chhabra, PhD, of the department of blood and marrow transplantation, Stanford (Calif.) University, and her associates.

They assessed the new combined treatment in a series of laboratory and mouse studies. The opsonizing anti-c-Kit monoclonal antibodies induced robust depletion of functional hematopoietic stem cells in immunocompetent mice, which allowed donor stem cells to engraft in these hosts. Adding the T-cell–depleting CD47-antagonists further facilitated immune ablation of host stem cells and progenitor cells. Combined, the two agents eliminated more than 99% of host hematopoietic stem cells in the bone marrow and enabled strong engraftment of the donor stem cells, while avoiding radiation- and chemotherapy-related adverse effects.

The main toxicities that occurred in treated mice were, as expected, reductions in hematologic parameters, especially red blood cell indices. This may be related to a factor in mouse physiology that is not present in humans. But if such toxicities do develop in human subjects, they can be mitigated by careful monitoring and occasional supportive transfusions, Dr. Chhabra and her associates said (Sci Transl Med. 2016;8:351ra105).

These two types of antibodies are already being investigated separately in early-phase clinical trials. If the combined treatment proves effective and safe in humans – a question that awaits further clinical studies – hematopoietic stem cell transplantation might be extended to nonmalignant conditions such as inherited immunodeficiency, inborn errors of metabolism, and hemoglobinopathies. It might also be adapted for use in solid-organ transplants, the researchers added.

This work was supported by the Virginia and D.K. Ludwig Fund for Cancer Research and several other nonprofit organizations, the California Institute for Regenerative Medicine, and the National Institutes of Health. Dr. Chhabra is a coinventor on a patent described in this article, and her associates are cofounders of Forty Seven, the company that licensed the technology for radiation- and chemotherapy-free stem-cell transplantation. Two associates also serve as advisors for Alexo Therapeutics, which develops CD47-based treatments.

Micrograph showing BCP-ALL

Image by Vashi Donsk

Screening for genetic abnormalities can provide a more accurate prediction of outcomes in children with relapsed B-cell precursor acute lymphoblastic leukemia (BCP-ALL), according to a study published in Blood.

Researchers found that mutations or deletions in TP53, NR3C1, BTG1, and NRAS were associated with inferior outcomes in relapsed BCP-ALL.

And screening for these abnormalities could improve upon the predictive accuracy of clinical risk factors.

“Current methods used to guide treatment for relapsed leukemia are not accurate enough, with some children believed to have a good chance of survival actually responding very poorly to chemotherapy,” said study author Anthony Moorman, PhD, of Newcastle University in Newcastle upon Tyne, UK.

“Screening patients at relapse for key genetic abnormalities that influence outcome will ensure that treatment can be personalized, thereby improving their chances of survival.”

For this study, Dr Moorman and his colleagues analyzed cytogenetic data from 427 children with relapsed BCP-ALL and screened 238 patients with a marrow relapse for certain copy number alterations and mutations.

According to univariate analysis, alterations in TP53, NR3C1 deletions, and BTG1 deletions were significantly associated with patient outcomes.

Patients with TP53 alterations had a higher risk of progression (hazard ratio [HR]=2.36, P<0.001) and death (HR=2.56, P<0.001), as did patients with deletions in NR3C1 and BTG1.

Because both NR3C1 and BTG1 are implicated in resistance to glucocorticoids and the deletions are mutually exclusive, the researchers considered the effect of the deletions together. So for patients with NR3C1 and BTG1 deletions, the HR for progression was 2.15 (P=0.002), and the HR for death was 1.91 (P=0.015).

Patients with NRAS mutations had an increased risk of progression and death as well, but this did not reach statistical significance.

The researchers also found that patients who were standard risk according to clinical characteristics but, at the time of relapse, had one or more high-risk genetic abnormalities had poorer outcomes.

Standard-risk patients with a TP53 alteration had an increased risk of death (HR=2.56, P<0.001), as did standard-risk patients with NR3C1 and BTG1 deletions (HR=1.91, P=0.015).

Standard-risk patients with NRAS mutations and high hyperdiploidy had an increased risk of progression (HR=3.17, P=0.026) and death (HR=3.41, P=0.032).

The researchers concluded that the outcomes of clinical standard-risk patients with high-risk cytogenetics were equivalent to outcomes of clinical high-risk patients.

The team therefore believes that screening BCP-ALL patients for the aforementioned genetic abnormalities at relapse will improve patient stratification and outcomes.

Micrograph showing BCP-ALL

Image by Vashi Donsk

Screening for genetic abnormalities can provide a more accurate prediction of outcomes in children with relapsed B-cell precursor acute lymphoblastic leukemia (BCP-ALL), according to a study published in Blood.

Researchers found that mutations or deletions in TP53, NR3C1, BTG1, and NRAS were associated with inferior outcomes in relapsed BCP-ALL.

And screening for these abnormalities could improve upon the predictive accuracy of clinical risk factors.

“Current methods used to guide treatment for relapsed leukemia are not accurate enough, with some children believed to have a good chance of survival actually responding very poorly to chemotherapy,” said study author Anthony Moorman, PhD, of Newcastle University in Newcastle upon Tyne, UK.

“Screening patients at relapse for key genetic abnormalities that influence outcome will ensure that treatment can be personalized, thereby improving their chances of survival.”

For this study, Dr Moorman and his colleagues analyzed cytogenetic data from 427 children with relapsed BCP-ALL and screened 238 patients with a marrow relapse for certain copy number alterations and mutations.

According to univariate analysis, alterations in TP53, NR3C1 deletions, and BTG1 deletions were significantly associated with patient outcomes.

Patients with TP53 alterations had a higher risk of progression (hazard ratio [HR]=2.36, P<0.001) and death (HR=2.56, P<0.001), as did patients with deletions in NR3C1 and BTG1.

Because both NR3C1 and BTG1 are implicated in resistance to glucocorticoids and the deletions are mutually exclusive, the researchers considered the effect of the deletions together. So for patients with NR3C1 and BTG1 deletions, the HR for progression was 2.15 (P=0.002), and the HR for death was 1.91 (P=0.015).

Patients with NRAS mutations had an increased risk of progression and death as well, but this did not reach statistical significance.

The researchers also found that patients who were standard risk according to clinical characteristics but, at the time of relapse, had one or more high-risk genetic abnormalities had poorer outcomes.

Standard-risk patients with a TP53 alteration had an increased risk of death (HR=2.56, P<0.001), as did standard-risk patients with NR3C1 and BTG1 deletions (HR=1.91, P=0.015).

Standard-risk patients with NRAS mutations and high hyperdiploidy had an increased risk of progression (HR=3.17, P=0.026) and death (HR=3.41, P=0.032).

The researchers concluded that the outcomes of clinical standard-risk patients with high-risk cytogenetics were equivalent to outcomes of clinical high-risk patients.

The team therefore believes that screening BCP-ALL patients for the aforementioned genetic abnormalities at relapse will improve patient stratification and outcomes.

Micrograph showing BCP-ALL

Image by Vashi Donsk

Screening for genetic abnormalities can provide a more accurate prediction of outcomes in children with relapsed B-cell precursor acute lymphoblastic leukemia (BCP-ALL), according to a study published in Blood.

Researchers found that mutations or deletions in TP53, NR3C1, BTG1, and NRAS were associated with inferior outcomes in relapsed BCP-ALL.

And screening for these abnormalities could improve upon the predictive accuracy of clinical risk factors.

“Current methods used to guide treatment for relapsed leukemia are not accurate enough, with some children believed to have a good chance of survival actually responding very poorly to chemotherapy,” said study author Anthony Moorman, PhD, of Newcastle University in Newcastle upon Tyne, UK.

“Screening patients at relapse for key genetic abnormalities that influence outcome will ensure that treatment can be personalized, thereby improving their chances of survival.”

For this study, Dr Moorman and his colleagues analyzed cytogenetic data from 427 children with relapsed BCP-ALL and screened 238 patients with a marrow relapse for certain copy number alterations and mutations.

According to univariate analysis, alterations in TP53, NR3C1 deletions, and BTG1 deletions were significantly associated with patient outcomes.

Patients with TP53 alterations had a higher risk of progression (hazard ratio [HR]=2.36, P<0.001) and death (HR=2.56, P<0.001), as did patients with deletions in NR3C1 and BTG1.

Because both NR3C1 and BTG1 are implicated in resistance to glucocorticoids and the deletions are mutually exclusive, the researchers considered the effect of the deletions together. So for patients with NR3C1 and BTG1 deletions, the HR for progression was 2.15 (P=0.002), and the HR for death was 1.91 (P=0.015).

Patients with NRAS mutations had an increased risk of progression and death as well, but this did not reach statistical significance.

The researchers also found that patients who were standard risk according to clinical characteristics but, at the time of relapse, had one or more high-risk genetic abnormalities had poorer outcomes.

Standard-risk patients with a TP53 alteration had an increased risk of death (HR=2.56, P<0.001), as did standard-risk patients with NR3C1 and BTG1 deletions (HR=1.91, P=0.015).

Standard-risk patients with NRAS mutations and high hyperdiploidy had an increased risk of progression (HR=3.17, P=0.026) and death (HR=3.41, P=0.032).

The researchers concluded that the outcomes of clinical standard-risk patients with high-risk cytogenetics were equivalent to outcomes of clinical high-risk patients.

The team therefore believes that screening BCP-ALL patients for the aforementioned genetic abnormalities at relapse will improve patient stratification and outcomes.