ALL

Jae Park, MD

WASHINGTON, DC—Results of a retrospective study suggest pretreatment disease burden impacts the outcome of chimeric antigen receptor (CAR) T-cell therapy in patients with relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL).

Patients who had minimal residual disease (MRD) prior to treatment had superior event-free and overall survival compared to patients who had morphologic disease before treatment.

Patients with MRD were also less likely to experience cytokine release syndrome (CRS) and neurologic toxicity.

Jae Park, MD, of Memorial Sloan Kettering Cancer Center (MSKCC) in New York, New York, presented these results at the AACR Annual Meeting 2017 (abstract CT078).

This study was funded by Juno Therapeutics, the National Cancer Institute, the Terry Fox Foundation, and MSKCC Experimental Therapeutics Center.

“[W]e and other groups have developed and tested CD19-specific [19-28z] CAR T-cell therapy and have reported encouraging results, with high initial complete response rates in patients with B-ALL,” Dr Park said.

“However, relapses are common, even after achieving seemingly deep remission, and severe toxicities have been observed in some patients.”

To gain more insight into these results, Dr Park and his colleagues retrospectively analyzed data from a prospective clinical trial that tested 19-28z CAR T-cell therapy in patients with B-ALL.

All 51 adults in this trial had relapsed after or were refractory to 1 or more conventional multiagent chemotherapy regimens.

The researchers measured disease burden prior to CAR T-cell infusion in all patients and divided them into 2 cohorts:

• 20 patients who had MRD—less than 5% blasts in the bone marrow
• 31 patients who had morphologic disease—5% or more blasts in the bone marrow.

Response and survival

The complete response rate was 95% in the MRD cohort and 77% in the morphologic disease cohort, a difference that was not statistically significant.

At a median follow-up of 18 months, the median event-free survival and overall survival had not been reached for patients in the MRD cohort (because most were still alive and disease-free).

However, for patients in the morphologic disease cohort, the median event-free survival was 6.3 months (P=0.0005), and the median overall survival was 17 months (P=0.0189).

Role of transplant

The researchers found that long-term survival did not improve for patients who proceeded to hematopoietic stem cell transplant (HSCT), regardless of their disease burden at baseline.

“While more patients and longer follow-up will be needed to adequately address the significance of HSCT, the result of this analysis raises a question as to whether 19-28z CAR therapy can be considered as a definitive, curative therapy rather than a bridge to stem cell transplant, at least in a subset of patients,” Dr Park noted.

“Our data suggest that incorporation of 19-28z CAR T cells at the time of MRD following first-line chemotherapy will maximize the durability of CAR T-cell-mediated remissions and survival and can potentially spare these high-risk patients from HSCT, rather than waiting until they relapse morphologically and then trying CAR T-cell therapy when it is less likely to achieve a durable long-term outcome.”

Adverse events and limitations

Patients from the MRD cohort fared better than the morphologic disease cohort in terms of CRS and neurologic toxicity.

Forty-two percent of patients in the morphologic disease cohort developed CRS, compared to 5% of patients in the MRD cohort (P=0.0326).

Neurologic toxicity occurred in 58% of patients in the morphologic disease cohort and 15% of those in the MRD cohort (P=0.0001).

Dr Park noted that a limitation of this study is its retrospective nature, and the findings will need to be validated prospectively.

Furthermore, the analysis on the impact of allogeneic HSCT was limited by a relatively small sample size in each cohort.

Jae Park, MD

WASHINGTON, DC—Results of a retrospective study suggest pretreatment disease burden impacts the outcome of chimeric antigen receptor (CAR) T-cell therapy in patients with relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL).

Patients who had minimal residual disease (MRD) prior to treatment had superior event-free and overall survival compared to patients who had morphologic disease before treatment.

Patients with MRD were also less likely to experience cytokine release syndrome (CRS) and neurologic toxicity.

Jae Park, MD, of Memorial Sloan Kettering Cancer Center (MSKCC) in New York, New York, presented these results at the AACR Annual Meeting 2017 (abstract CT078).

This study was funded by Juno Therapeutics, the National Cancer Institute, the Terry Fox Foundation, and MSKCC Experimental Therapeutics Center.

“[W]e and other groups have developed and tested CD19-specific [19-28z] CAR T-cell therapy and have reported encouraging results, with high initial complete response rates in patients with B-ALL,” Dr Park said.

“However, relapses are common, even after achieving seemingly deep remission, and severe toxicities have been observed in some patients.”

To gain more insight into these results, Dr Park and his colleagues retrospectively analyzed data from a prospective clinical trial that tested 19-28z CAR T-cell therapy in patients with B-ALL.

All 51 adults in this trial had relapsed after or were refractory to 1 or more conventional multiagent chemotherapy regimens.

The researchers measured disease burden prior to CAR T-cell infusion in all patients and divided them into 2 cohorts:

• 20 patients who had MRD—less than 5% blasts in the bone marrow
• 31 patients who had morphologic disease—5% or more blasts in the bone marrow.

Response and survival

The complete response rate was 95% in the MRD cohort and 77% in the morphologic disease cohort, a difference that was not statistically significant.

At a median follow-up of 18 months, the median event-free survival and overall survival had not been reached for patients in the MRD cohort (because most were still alive and disease-free).

However, for patients in the morphologic disease cohort, the median event-free survival was 6.3 months (P=0.0005), and the median overall survival was 17 months (P=0.0189).

Role of transplant

The researchers found that long-term survival did not improve for patients who proceeded to hematopoietic stem cell transplant (HSCT), regardless of their disease burden at baseline.

“While more patients and longer follow-up will be needed to adequately address the significance of HSCT, the result of this analysis raises a question as to whether 19-28z CAR therapy can be considered as a definitive, curative therapy rather than a bridge to stem cell transplant, at least in a subset of patients,” Dr Park noted.

“Our data suggest that incorporation of 19-28z CAR T cells at the time of MRD following first-line chemotherapy will maximize the durability of CAR T-cell-mediated remissions and survival and can potentially spare these high-risk patients from HSCT, rather than waiting until they relapse morphologically and then trying CAR T-cell therapy when it is less likely to achieve a durable long-term outcome.”

Adverse events and limitations

Patients from the MRD cohort fared better than the morphologic disease cohort in terms of CRS and neurologic toxicity.

Forty-two percent of patients in the morphologic disease cohort developed CRS, compared to 5% of patients in the MRD cohort (P=0.0326).

Neurologic toxicity occurred in 58% of patients in the morphologic disease cohort and 15% of those in the MRD cohort (P=0.0001).

Dr Park noted that a limitation of this study is its retrospective nature, and the findings will need to be validated prospectively.

Furthermore, the analysis on the impact of allogeneic HSCT was limited by a relatively small sample size in each cohort.

Jae Park, MD

WASHINGTON, DC—Results of a retrospective study suggest pretreatment disease burden impacts the outcome of chimeric antigen receptor (CAR) T-cell therapy in patients with relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL).

Patients who had minimal residual disease (MRD) prior to treatment had superior event-free and overall survival compared to patients who had morphologic disease before treatment.

Patients with MRD were also less likely to experience cytokine release syndrome (CRS) and neurologic toxicity.

Jae Park, MD, of Memorial Sloan Kettering Cancer Center (MSKCC) in New York, New York, presented these results at the AACR Annual Meeting 2017 (abstract CT078).

This study was funded by Juno Therapeutics, the National Cancer Institute, the Terry Fox Foundation, and MSKCC Experimental Therapeutics Center.

“[W]e and other groups have developed and tested CD19-specific [19-28z] CAR T-cell therapy and have reported encouraging results, with high initial complete response rates in patients with B-ALL,” Dr Park said.

“However, relapses are common, even after achieving seemingly deep remission, and severe toxicities have been observed in some patients.”

To gain more insight into these results, Dr Park and his colleagues retrospectively analyzed data from a prospective clinical trial that tested 19-28z CAR T-cell therapy in patients with B-ALL.

All 51 adults in this trial had relapsed after or were refractory to 1 or more conventional multiagent chemotherapy regimens.

The researchers measured disease burden prior to CAR T-cell infusion in all patients and divided them into 2 cohorts:

• 20 patients who had MRD—less than 5% blasts in the bone marrow
• 31 patients who had morphologic disease—5% or more blasts in the bone marrow.

Response and survival

The complete response rate was 95% in the MRD cohort and 77% in the morphologic disease cohort, a difference that was not statistically significant.

At a median follow-up of 18 months, the median event-free survival and overall survival had not been reached for patients in the MRD cohort (because most were still alive and disease-free).

However, for patients in the morphologic disease cohort, the median event-free survival was 6.3 months (P=0.0005), and the median overall survival was 17 months (P=0.0189).

Role of transplant

The researchers found that long-term survival did not improve for patients who proceeded to hematopoietic stem cell transplant (HSCT), regardless of their disease burden at baseline.

“While more patients and longer follow-up will be needed to adequately address the significance of HSCT, the result of this analysis raises a question as to whether 19-28z CAR therapy can be considered as a definitive, curative therapy rather than a bridge to stem cell transplant, at least in a subset of patients,” Dr Park noted.

“Our data suggest that incorporation of 19-28z CAR T cells at the time of MRD following first-line chemotherapy will maximize the durability of CAR T-cell-mediated remissions and survival and can potentially spare these high-risk patients from HSCT, rather than waiting until they relapse morphologically and then trying CAR T-cell therapy when it is less likely to achieve a durable long-term outcome.”

Adverse events and limitations

Patients from the MRD cohort fared better than the morphologic disease cohort in terms of CRS and neurologic toxicity.

Forty-two percent of patients in the morphologic disease cohort developed CRS, compared to 5% of patients in the MRD cohort (P=0.0326).

Neurologic toxicity occurred in 58% of patients in the morphologic disease cohort and 15% of those in the MRD cohort (P=0.0001).

Dr Park noted that a limitation of this study is its retrospective nature, and the findings will need to be validated prospectively.

Furthermore, the analysis on the impact of allogeneic HSCT was limited by a relatively small sample size in each cohort.

B-cell precursor ALL

Blinatumomab has demonstrated activity in high-risk patients with Philadelphia chromosome-positive (Ph+) B-cell precursor acute lymphoblastic leukemia (BCP-ALL), according to research published in the Journal of Clinical Oncology.

This phase 2 trial enrolled patients with relapsed or refractory Ph+ BCP-ALL who had failed treatment with at least 1 tyrosine kinase inhibitor (TKI).

Blinatumomab produced a complete response (CR) in 31% of these patients, the median relapse-free survival was 6.7 months, and the median overall survival was 7.1 months.

The most common adverse events (AEs) were pyrexia, neurologic events, febrile neutropenia, and headache.

“Patients with Ph+ relapsed or refractory B-cell precursor ALL typically have lower remission rates, poor long-term prognosis, and shorter duration of remission than patients with Philadelphia chromosome-negative disease, and are especially in need of new treatment options beyond TKIs,” said study author Anthony Stein, MD, of City of Hope in Duarte, California.

“Results from this phase 2 study showed blinatumomab induced complete remission in these high-risk patients, regardless of prior TKI therapy or mutational status . . . .”

This study was supported by Amgen, the company developing and marketing blinatumomab.

The trial enrolled 45 patients with relapsed or refractory Ph+ BCP-ALL. Fifty-nine percent of patients had additional cytogenetic abnormalities. Forty-six percent had ABL1 kinase domain mutations, and 27% had the T315I mutation.

The patients’ median age was 55 (range, 23-78), and 55% were male. The median baseline bone marrow blast percentage was 80% (range, 6% to 98%).

Eighty-four percent of patients had received at least 2 prior TKIs. All patients were refractory to (56%), had relapsed on (33%), or progressed after (11%) TKI therapy. Forty-four percent of patients had undergone an allogeneic hematopoietic stem cell transplant (allo-HSCT).

The patients received blinatumomab in 28-day cycles by continuous intravenous infusion. The median number of cycles received was 2 (range, 1-5).

Efficacy

Thirty-six percent of patients (n=16) had a CR or CR with partial hematologic recovery (CRh) during the first 2 cycles of treatment. For 31% of patients (n=14), their best response was a CR.

Eighty-eight percent of patients who achieved a CR/CRh (n=14) achieved minimal residual disease (MRD) negativity.

Forty percent of patients with a T315I mutation had a CR/CRh (4/10), and all of these responders were MRD negative.

Seven responders (44%) went on to allo-HSCT, 6 of whom were transplant-naïve.

Eight of the 16 responders (50%) ultimately relapsed. Their median time to relapse was 6.7 months. Three patients relapsed during treatment, 2 relapsed without undergoing allo-HSCT, and 3 relapsed after allo-HSCT.

Seven responders (44%) were still alive and had not relapsed at last follow-up. The remaining responder died in CR after allo-HSCT.

The median relapse-free survival was 6.7 months, with or without censoring for allo-HSCT. And the median overall survival was 7.1 months, with or without censoring for allo-HSCT.

Safety

The most common AEs were pyrexia (58%), febrile neutropenia (40%), and headache (31%). Nearly half of patients (47%) had neurologic events.

Eighty-two percent of patients had grade 3 or higher treatment-emergent AEs. The most common were febrile neutropenia (27%), thrombocytopenia (22%), and anemia (16%).

Forty-four percent of patients had grade 3 or higher AEs that were considered possibly related to blinatumomab. The most common were febrile neutropenia and increased levels of alanine aminotransferase (11% each).

Five patients had fatal AEs—multiorgan failure, sepsis, septic shock, cerebral hemorrhage, and respiratory failure. The case of septic shock was considered related to treatment with blinatumomab.

Three patients developed cytokine release syndrome (all grade 1 or 2), but none of them had their treatment interrupted or discontinued as a result.

Three patients had grade 3 neurologic events, and 1 of these events (aphasia) required temporary treatment interruption. There were no grade 4 or 5 neurologic events.

B-cell precursor ALL

Blinatumomab has demonstrated activity in high-risk patients with Philadelphia chromosome-positive (Ph+) B-cell precursor acute lymphoblastic leukemia (BCP-ALL), according to research published in the Journal of Clinical Oncology.

This phase 2 trial enrolled patients with relapsed or refractory Ph+ BCP-ALL who had failed treatment with at least 1 tyrosine kinase inhibitor (TKI).

Blinatumomab produced a complete response (CR) in 31% of these patients, the median relapse-free survival was 6.7 months, and the median overall survival was 7.1 months.

The most common adverse events (AEs) were pyrexia, neurologic events, febrile neutropenia, and headache.

“Patients with Ph+ relapsed or refractory B-cell precursor ALL typically have lower remission rates, poor long-term prognosis, and shorter duration of remission than patients with Philadelphia chromosome-negative disease, and are especially in need of new treatment options beyond TKIs,” said study author Anthony Stein, MD, of City of Hope in Duarte, California.

“Results from this phase 2 study showed blinatumomab induced complete remission in these high-risk patients, regardless of prior TKI therapy or mutational status . . . .”

This study was supported by Amgen, the company developing and marketing blinatumomab.

The trial enrolled 45 patients with relapsed or refractory Ph+ BCP-ALL. Fifty-nine percent of patients had additional cytogenetic abnormalities. Forty-six percent had ABL1 kinase domain mutations, and 27% had the T315I mutation.

The patients’ median age was 55 (range, 23-78), and 55% were male. The median baseline bone marrow blast percentage was 80% (range, 6% to 98%).

Eighty-four percent of patients had received at least 2 prior TKIs. All patients were refractory to (56%), had relapsed on (33%), or progressed after (11%) TKI therapy. Forty-four percent of patients had undergone an allogeneic hematopoietic stem cell transplant (allo-HSCT).

The patients received blinatumomab in 28-day cycles by continuous intravenous infusion. The median number of cycles received was 2 (range, 1-5).

Efficacy

Thirty-six percent of patients (n=16) had a CR or CR with partial hematologic recovery (CRh) during the first 2 cycles of treatment. For 31% of patients (n=14), their best response was a CR.

Eighty-eight percent of patients who achieved a CR/CRh (n=14) achieved minimal residual disease (MRD) negativity.

Forty percent of patients with a T315I mutation had a CR/CRh (4/10), and all of these responders were MRD negative.

Seven responders (44%) went on to allo-HSCT, 6 of whom were transplant-naïve.

Eight of the 16 responders (50%) ultimately relapsed. Their median time to relapse was 6.7 months. Three patients relapsed during treatment, 2 relapsed without undergoing allo-HSCT, and 3 relapsed after allo-HSCT.

Seven responders (44%) were still alive and had not relapsed at last follow-up. The remaining responder died in CR after allo-HSCT.

The median relapse-free survival was 6.7 months, with or without censoring for allo-HSCT. And the median overall survival was 7.1 months, with or without censoring for allo-HSCT.

Safety

The most common AEs were pyrexia (58%), febrile neutropenia (40%), and headache (31%). Nearly half of patients (47%) had neurologic events.

Eighty-two percent of patients had grade 3 or higher treatment-emergent AEs. The most common were febrile neutropenia (27%), thrombocytopenia (22%), and anemia (16%).

Forty-four percent of patients had grade 3 or higher AEs that were considered possibly related to blinatumomab. The most common were febrile neutropenia and increased levels of alanine aminotransferase (11% each).

Five patients had fatal AEs—multiorgan failure, sepsis, septic shock, cerebral hemorrhage, and respiratory failure. The case of septic shock was considered related to treatment with blinatumomab.

Three patients developed cytokine release syndrome (all grade 1 or 2), but none of them had their treatment interrupted or discontinued as a result.

Three patients had grade 3 neurologic events, and 1 of these events (aphasia) required temporary treatment interruption. There were no grade 4 or 5 neurologic events.

B-cell precursor ALL

Blinatumomab has demonstrated activity in high-risk patients with Philadelphia chromosome-positive (Ph+) B-cell precursor acute lymphoblastic leukemia (BCP-ALL), according to research published in the Journal of Clinical Oncology.

This phase 2 trial enrolled patients with relapsed or refractory Ph+ BCP-ALL who had failed treatment with at least 1 tyrosine kinase inhibitor (TKI).

Blinatumomab produced a complete response (CR) in 31% of these patients, the median relapse-free survival was 6.7 months, and the median overall survival was 7.1 months.

The most common adverse events (AEs) were pyrexia, neurologic events, febrile neutropenia, and headache.

“Patients with Ph+ relapsed or refractory B-cell precursor ALL typically have lower remission rates, poor long-term prognosis, and shorter duration of remission than patients with Philadelphia chromosome-negative disease, and are especially in need of new treatment options beyond TKIs,” said study author Anthony Stein, MD, of City of Hope in Duarte, California.

“Results from this phase 2 study showed blinatumomab induced complete remission in these high-risk patients, regardless of prior TKI therapy or mutational status . . . .”

This study was supported by Amgen, the company developing and marketing blinatumomab.

The trial enrolled 45 patients with relapsed or refractory Ph+ BCP-ALL. Fifty-nine percent of patients had additional cytogenetic abnormalities. Forty-six percent had ABL1 kinase domain mutations, and 27% had the T315I mutation.

The patients’ median age was 55 (range, 23-78), and 55% were male. The median baseline bone marrow blast percentage was 80% (range, 6% to 98%).

Eighty-four percent of patients had received at least 2 prior TKIs. All patients were refractory to (56%), had relapsed on (33%), or progressed after (11%) TKI therapy. Forty-four percent of patients had undergone an allogeneic hematopoietic stem cell transplant (allo-HSCT).

The patients received blinatumomab in 28-day cycles by continuous intravenous infusion. The median number of cycles received was 2 (range, 1-5).

Efficacy

Thirty-six percent of patients (n=16) had a CR or CR with partial hematologic recovery (CRh) during the first 2 cycles of treatment. For 31% of patients (n=14), their best response was a CR.

Eighty-eight percent of patients who achieved a CR/CRh (n=14) achieved minimal residual disease (MRD) negativity.

Forty percent of patients with a T315I mutation had a CR/CRh (4/10), and all of these responders were MRD negative.

Seven responders (44%) went on to allo-HSCT, 6 of whom were transplant-naïve.

Eight of the 16 responders (50%) ultimately relapsed. Their median time to relapse was 6.7 months. Three patients relapsed during treatment, 2 relapsed without undergoing allo-HSCT, and 3 relapsed after allo-HSCT.

Seven responders (44%) were still alive and had not relapsed at last follow-up. The remaining responder died in CR after allo-HSCT.

The median relapse-free survival was 6.7 months, with or without censoring for allo-HSCT. And the median overall survival was 7.1 months, with or without censoring for allo-HSCT.

Safety

The most common AEs were pyrexia (58%), febrile neutropenia (40%), and headache (31%). Nearly half of patients (47%) had neurologic events.

Eighty-two percent of patients had grade 3 or higher treatment-emergent AEs. The most common were febrile neutropenia (27%), thrombocytopenia (22%), and anemia (16%).

Forty-four percent of patients had grade 3 or higher AEs that were considered possibly related to blinatumomab. The most common were febrile neutropenia and increased levels of alanine aminotransferase (11% each).

Five patients had fatal AEs—multiorgan failure, sepsis, septic shock, cerebral hemorrhage, and respiratory failure. The case of septic shock was considered related to treatment with blinatumomab.

Three patients developed cytokine release syndrome (all grade 1 or 2), but none of them had their treatment interrupted or discontinued as a result.

Three patients had grade 3 neurologic events, and 1 of these events (aphasia) required temporary treatment interruption. There were no grade 4 or 5 neurologic events.

Photo courtesy of Amgen

The US Food and Drug Administration (FDA) has accepted for priority review the supplemental biologics license application (sBLA) for blinatumomab (Blincyto®).

The aim of this application is to expand the indication for blinatumomab to include all patients with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL) and to convert blinatumomab’s current accelerated approval to a full approval.

The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.

The agency’s goal is to take action on a priority review application within 6 months of receiving it, rather than the standard 10 months.

The Prescription Drug User Fee Act target action date for the blinatumomab sBLA is August 14, 2017.

About blinatumomab

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.

Blinatumomab currently has accelerated approval in the US as a treatment for adult and pediatric patients with Philadelphia chromosome-negative (Ph-) relapsed or refractory BCP-ALL.

The FDA-approved prescribing information for blinatumomab includes a boxed warning detailing the risk of cytokine release syndrome and neurologic toxicities.

Blinatumomab is also under a Risk Evaluation and Mitigation Strategy program in the US intended to inform healthcare providers about these risks.

Blinatumomab is being developed and marketed by Amgen.

About the sBLA

With this sBLA, Amgen is seeking to make blinatumomab available as a treatment for patients with Philadelphia chromosome-positive (Ph+) relapsed/refractory BCP-ALL (as well as Ph-).

To this end, the application includes data from the ALCANTARA study, which were just published in the Journal of Clinical Oncology.

In this trial, researchers evaluated blinatumomab in adults with Ph+ relapsed/refractory BCP-ALL who had failed treatment with at least 1 tyrosine kinase inhibitor.

Thirty-six percent of patients achieved a complete response or complete response with partial hematologic recovery within the first 2 cycles of blinatumomab treatment. Of these patients, 88% were minimal residual disease negative.

The most frequent adverse events (AEs) in this trial were pyrexia (58%), neurologic events (47%), febrile neutropenia (40%), and headache (31%). Three patients had grade 1/2 cytokine release syndrome, and 3 patients had grade 3 neurologic AEs.

The sBLA also includes overall survival (OS) data from the phase 3 TOWER trial, which is intended to support the conversion of blinatumomab’s accelerated approval to a full approval.

Results from the TOWER trial were recently published in NEJM.

In this study, researchers compared blinatumomab to standard of care (SOC) chemotherapy (4 different regimens) in adults with Ph- relapsed/refractory BCP-ALL.

Blinatumomab produced higher response rates and nearly doubled OS compared to SOC. The median OS was 7.7 months in the blinatumomab arm and 4 months in the SOC arm. The hazard ratio for death was 0.71 (P=0.012).

The incidence of grade 3 or higher AEs was higher in the SOC arm, but the incidence of serious AEs was higher in the blinatumomab arm.

Photo courtesy of Amgen

The US Food and Drug Administration (FDA) has accepted for priority review the supplemental biologics license application (sBLA) for blinatumomab (Blincyto®).

The aim of this application is to expand the indication for blinatumomab to include all patients with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL) and to convert blinatumomab’s current accelerated approval to a full approval.

The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.

The agency’s goal is to take action on a priority review application within 6 months of receiving it, rather than the standard 10 months.

The Prescription Drug User Fee Act target action date for the blinatumomab sBLA is August 14, 2017.

About blinatumomab

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.

Blinatumomab currently has accelerated approval in the US as a treatment for adult and pediatric patients with Philadelphia chromosome-negative (Ph-) relapsed or refractory BCP-ALL.

The FDA-approved prescribing information for blinatumomab includes a boxed warning detailing the risk of cytokine release syndrome and neurologic toxicities.

Blinatumomab is also under a Risk Evaluation and Mitigation Strategy program in the US intended to inform healthcare providers about these risks.

Blinatumomab is being developed and marketed by Amgen.

About the sBLA

With this sBLA, Amgen is seeking to make blinatumomab available as a treatment for patients with Philadelphia chromosome-positive (Ph+) relapsed/refractory BCP-ALL (as well as Ph-).

To this end, the application includes data from the ALCANTARA study, which were just published in the Journal of Clinical Oncology.

In this trial, researchers evaluated blinatumomab in adults with Ph+ relapsed/refractory BCP-ALL who had failed treatment with at least 1 tyrosine kinase inhibitor.

Thirty-six percent of patients achieved a complete response or complete response with partial hematologic recovery within the first 2 cycles of blinatumomab treatment. Of these patients, 88% were minimal residual disease negative.

The most frequent adverse events (AEs) in this trial were pyrexia (58%), neurologic events (47%), febrile neutropenia (40%), and headache (31%). Three patients had grade 1/2 cytokine release syndrome, and 3 patients had grade 3 neurologic AEs.

The sBLA also includes overall survival (OS) data from the phase 3 TOWER trial, which is intended to support the conversion of blinatumomab’s accelerated approval to a full approval.

Results from the TOWER trial were recently published in NEJM.

In this study, researchers compared blinatumomab to standard of care (SOC) chemotherapy (4 different regimens) in adults with Ph- relapsed/refractory BCP-ALL.

Blinatumomab produced higher response rates and nearly doubled OS compared to SOC. The median OS was 7.7 months in the blinatumomab arm and 4 months in the SOC arm. The hazard ratio for death was 0.71 (P=0.012).

The incidence of grade 3 or higher AEs was higher in the SOC arm, but the incidence of serious AEs was higher in the blinatumomab arm.

Photo courtesy of Amgen

The US Food and Drug Administration (FDA) has accepted for priority review the supplemental biologics license application (sBLA) for blinatumomab (Blincyto®).

The aim of this application is to expand the indication for blinatumomab to include all patients with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL) and to convert blinatumomab’s current accelerated approval to a full approval.

The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.

The agency’s goal is to take action on a priority review application within 6 months of receiving it, rather than the standard 10 months.

The Prescription Drug User Fee Act target action date for the blinatumomab sBLA is August 14, 2017.

About blinatumomab

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.

Blinatumomab currently has accelerated approval in the US as a treatment for adult and pediatric patients with Philadelphia chromosome-negative (Ph-) relapsed or refractory BCP-ALL.

The FDA-approved prescribing information for blinatumomab includes a boxed warning detailing the risk of cytokine release syndrome and neurologic toxicities.

Blinatumomab is also under a Risk Evaluation and Mitigation Strategy program in the US intended to inform healthcare providers about these risks.

Blinatumomab is being developed and marketed by Amgen.

About the sBLA

With this sBLA, Amgen is seeking to make blinatumomab available as a treatment for patients with Philadelphia chromosome-positive (Ph+) relapsed/refractory BCP-ALL (as well as Ph-).

To this end, the application includes data from the ALCANTARA study, which were just published in the Journal of Clinical Oncology.

In this trial, researchers evaluated blinatumomab in adults with Ph+ relapsed/refractory BCP-ALL who had failed treatment with at least 1 tyrosine kinase inhibitor.

Thirty-six percent of patients achieved a complete response or complete response with partial hematologic recovery within the first 2 cycles of blinatumomab treatment. Of these patients, 88% were minimal residual disease negative.

The most frequent adverse events (AEs) in this trial were pyrexia (58%), neurologic events (47%), febrile neutropenia (40%), and headache (31%). Three patients had grade 1/2 cytokine release syndrome, and 3 patients had grade 3 neurologic AEs.

The sBLA also includes overall survival (OS) data from the phase 3 TOWER trial, which is intended to support the conversion of blinatumomab’s accelerated approval to a full approval.

Results from the TOWER trial were recently published in NEJM.

In this study, researchers compared blinatumomab to standard of care (SOC) chemotherapy (4 different regimens) in adults with Ph- relapsed/refractory BCP-ALL.

Blinatumomab produced higher response rates and nearly doubled OS compared to SOC. The median OS was 7.7 months in the blinatumomab arm and 4 months in the SOC arm. The hazard ratio for death was 0.71 (P=0.012).

The incidence of grade 3 or higher AEs was higher in the SOC arm, but the incidence of serious AEs was higher in the blinatumomab arm.

Photo from Penn Medicine

The US Food and Drug Administration (FDA) has granted priority review for a biologics license application (BLA) for CTL019 (tisagenlecleucel-T), an investigational chimeric antigen receptor (CAR) T-cell therapy.

The BLA is for CTL019 as a treatment for pediatric patients and young adults with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL).

The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.

The agency’s goal is to take action on a priority review application within 6 months of receiving it, rather than the standard 10 months.

The FDA accepted the BLA for CTL019 yesterday, according to Novartis.

About CTL019

CTL019 consists of autologous T cells expressing a CD19-specific CAR. The therapy was first developed by the University of Pennsylvania.

In 2012, the university and Novartis entered into a global collaboration to further research, develop, and commercialize CAR-T cell therapies, including CTL019. Novartis holds the worldwide rights to CARs developed through the collaboration.

CTL019 already has breakthrough therapy designation for the treatment of adults and children with relapsed/refractory ALL.

Novartis said it is planning additional filings for CTL019 in the US and European Union later this year, including a BLA with the FDA for the treatment of adults with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) and applications for marketing authorization with the European Medicines Agency in relapsed/refractory B-cell ALL and relapsed/refractory DLBCL.

Trials of CTL019 in ALL

The priority review designation for CTL019 is based on results from the Novartis-sponsored ELIANA study (NCT02435849). Results from this international, phase 2 trial were presented at ASH 2016.

The trial enrolled patients who had CD19-positive B-ALL with morphologic marrow tumor involvement at registration (>5% blasts) and were primary refractory, were chemo-refractory after first relapse, had relapsed after second-line therapy, or were ineligible for allogeneic hematopoietic stem cell transplant.

Most patients received fludarabine/cyclophosphamide lymphodepleting chemotherapy followed by a single dose of CTL019.

Three months post-infusion, 82% of patients (41/50) had achieved a complete response or complete response with incomplete blood count recovery.

Nearly half of the patients in the trial (48%) experienced grade 3/4 cytokine release syndrome (CRS), though there were no deaths due to CRS. Fifteen percent of patients experienced grade 3 neurological and psychiatric events, including confusion, delirium, encephalopathy, agitation, and seizure.

The BLA for CTL019 is also supported by results from the phase 2 ENSIGN trial, which were presented at ASH 2016, and results of a pilot study in patients with relapsed/refractory ALL, which were presented at ASH 2015.

Photo from Penn Medicine

The US Food and Drug Administration (FDA) has granted priority review for a biologics license application (BLA) for CTL019 (tisagenlecleucel-T), an investigational chimeric antigen receptor (CAR) T-cell therapy.

The BLA is for CTL019 as a treatment for pediatric patients and young adults with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL).

The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.

The agency’s goal is to take action on a priority review application within 6 months of receiving it, rather than the standard 10 months.

The FDA accepted the BLA for CTL019 yesterday, according to Novartis.

About CTL019

CTL019 consists of autologous T cells expressing a CD19-specific CAR. The therapy was first developed by the University of Pennsylvania.

In 2012, the university and Novartis entered into a global collaboration to further research, develop, and commercialize CAR-T cell therapies, including CTL019. Novartis holds the worldwide rights to CARs developed through the collaboration.

CTL019 already has breakthrough therapy designation for the treatment of adults and children with relapsed/refractory ALL.

Novartis said it is planning additional filings for CTL019 in the US and European Union later this year, including a BLA with the FDA for the treatment of adults with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) and applications for marketing authorization with the European Medicines Agency in relapsed/refractory B-cell ALL and relapsed/refractory DLBCL.

Trials of CTL019 in ALL

The priority review designation for CTL019 is based on results from the Novartis-sponsored ELIANA study (NCT02435849). Results from this international, phase 2 trial were presented at ASH 2016.

The trial enrolled patients who had CD19-positive B-ALL with morphologic marrow tumor involvement at registration (>5% blasts) and were primary refractory, were chemo-refractory after first relapse, had relapsed after second-line therapy, or were ineligible for allogeneic hematopoietic stem cell transplant.

Most patients received fludarabine/cyclophosphamide lymphodepleting chemotherapy followed by a single dose of CTL019.

Three months post-infusion, 82% of patients (41/50) had achieved a complete response or complete response with incomplete blood count recovery.

Nearly half of the patients in the trial (48%) experienced grade 3/4 cytokine release syndrome (CRS), though there were no deaths due to CRS. Fifteen percent of patients experienced grade 3 neurological and psychiatric events, including confusion, delirium, encephalopathy, agitation, and seizure.

The BLA for CTL019 is also supported by results from the phase 2 ENSIGN trial, which were presented at ASH 2016, and results of a pilot study in patients with relapsed/refractory ALL, which were presented at ASH 2015.

Photo from Penn Medicine

The US Food and Drug Administration (FDA) has granted priority review for a biologics license application (BLA) for CTL019 (tisagenlecleucel-T), an investigational chimeric antigen receptor (CAR) T-cell therapy.

The BLA is for CTL019 as a treatment for pediatric patients and young adults with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL).

The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.

The agency’s goal is to take action on a priority review application within 6 months of receiving it, rather than the standard 10 months.

The FDA accepted the BLA for CTL019 yesterday, according to Novartis.

About CTL019

CTL019 consists of autologous T cells expressing a CD19-specific CAR. The therapy was first developed by the University of Pennsylvania.

In 2012, the university and Novartis entered into a global collaboration to further research, develop, and commercialize CAR-T cell therapies, including CTL019. Novartis holds the worldwide rights to CARs developed through the collaboration.

CTL019 already has breakthrough therapy designation for the treatment of adults and children with relapsed/refractory ALL.

Novartis said it is planning additional filings for CTL019 in the US and European Union later this year, including a BLA with the FDA for the treatment of adults with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) and applications for marketing authorization with the European Medicines Agency in relapsed/refractory B-cell ALL and relapsed/refractory DLBCL.

Trials of CTL019 in ALL

The priority review designation for CTL019 is based on results from the Novartis-sponsored ELIANA study (NCT02435849). Results from this international, phase 2 trial were presented at ASH 2016.

The trial enrolled patients who had CD19-positive B-ALL with morphologic marrow tumor involvement at registration (>5% blasts) and were primary refractory, were chemo-refractory after first relapse, had relapsed after second-line therapy, or were ineligible for allogeneic hematopoietic stem cell transplant.

Most patients received fludarabine/cyclophosphamide lymphodepleting chemotherapy followed by a single dose of CTL019.

Three months post-infusion, 82% of patients (41/50) had achieved a complete response or complete response with incomplete blood count recovery.

Nearly half of the patients in the trial (48%) experienced grade 3/4 cytokine release syndrome (CRS), though there were no deaths due to CRS. Fifteen percent of patients experienced grade 3 neurological and psychiatric events, including confusion, delirium, encephalopathy, agitation, and seizure.

The BLA for CTL019 is also supported by results from the phase 2 ENSIGN trial, which were presented at ASH 2016, and results of a pilot study in patients with relapsed/refractory ALL, which were presented at ASH 2015.

Hospital Medical Center

Researchers say they have identified 2 signaling proteins that enable resistance to tyrosine kinase inhibitors (TKIs) and could be therapeutic targets for acute lymphoblastic leukemia (ALL) and chronic myeloid leukemia (CML).

The team found that by deleting these proteins—c-Fos and Dusp1—they could eradicate BCR-ABL-induced B-cell ALL in mice.

And treatment combining c-Fos and Dusp1 inhibitors with the TKI imatinib was able to cure mice with BCR-ABL-driven CML.

The researchers reported these findings in Nature Medicine.

“We think that, within the next 5 years, our data will change the way people think about cancer development and targeted therapy,” said study author Mohammad Azam, PhD, of Cincinnati Children’s Hospital Medical Center in Ohio.

“This study identifies a potential Achilles’ heel of kinase-driven cancers, and what we propose is intended to be curative, not just treatment.”

The potential Achilles’ heel is a common point of passage in cells—a signaling node—that appears to be required to generate cancer cells. The node is formed by the signaling proteins c-Fos and Dusp1, according to the researchers.

The team identified c-Fos and Dusp1 by conducting global gene-expression analysis of mouse leukemia cells and human CML cells. Analysis of the human cells revealed extremely high levels of c-FOS and DUSP1 in BCR-ABL-positive, TKI-resistant cells.

Dr Azam and his colleagues found that signaling from tyrosine kinase and growth factor proteins that support cell expansion (such as IL-3 and IL-6) converge to elevate c-Fos and Dusp1 levels in leukemia cells.

Working together, these molecules maintain the survival of leukemia stem cells (LSCs), which translates to minimal residual disease (MRD) after treatment.

Dr Azam said Dusp1 and c-Fos support the survival of LSCs by increasing the toxic threshold needed to kill them. This means imatinib and other TKIs cannot eliminate the residual LSCs.

After describing the roles of c-Fos and Dusp1, Dr Azam and his colleagues put their ideas to the test in mouse models of CML.

The team tested several treatments in these mice, including:

• monotherapy with imatinib
• inhibitors of c-Fos and Dusp1
• treatment with imatinib and inhibitors of c-Fos and Dusp1.

As suspected, treatment with imatinib alone initially stopped CML progression, but mice ultimately relapsed.

Treatment with c-Fos and Dusp1 inhibitors significantly slowed CML progression and prolonged survival in a majority of mice, but this treatment wasn’t curative.

However, a month of treatment with c-Fos and Dusp1 inhibitors as well as imatinib cured about 90% of mice with CML, and there were no signs of MRD.

The researchers also found that simply deleting c-Fos and Dusp1 was sufficient to block the development of B-cell ALL in mice.

The team said they are following up this study by testing c-Fos and Dusp1 as treatment targets for different kinase-fueled cancers.

Hospital Medical Center

Researchers say they have identified 2 signaling proteins that enable resistance to tyrosine kinase inhibitors (TKIs) and could be therapeutic targets for acute lymphoblastic leukemia (ALL) and chronic myeloid leukemia (CML).

The team found that by deleting these proteins—c-Fos and Dusp1—they could eradicate BCR-ABL-induced B-cell ALL in mice.

And treatment combining c-Fos and Dusp1 inhibitors with the TKI imatinib was able to cure mice with BCR-ABL-driven CML.

The researchers reported these findings in Nature Medicine.

“We think that, within the next 5 years, our data will change the way people think about cancer development and targeted therapy,” said study author Mohammad Azam, PhD, of Cincinnati Children’s Hospital Medical Center in Ohio.

“This study identifies a potential Achilles’ heel of kinase-driven cancers, and what we propose is intended to be curative, not just treatment.”

The potential Achilles’ heel is a common point of passage in cells—a signaling node—that appears to be required to generate cancer cells. The node is formed by the signaling proteins c-Fos and Dusp1, according to the researchers.

The team identified c-Fos and Dusp1 by conducting global gene-expression analysis of mouse leukemia cells and human CML cells. Analysis of the human cells revealed extremely high levels of c-FOS and DUSP1 in BCR-ABL-positive, TKI-resistant cells.

Dr Azam and his colleagues found that signaling from tyrosine kinase and growth factor proteins that support cell expansion (such as IL-3 and IL-6) converge to elevate c-Fos and Dusp1 levels in leukemia cells.

Working together, these molecules maintain the survival of leukemia stem cells (LSCs), which translates to minimal residual disease (MRD) after treatment.

Dr Azam said Dusp1 and c-Fos support the survival of LSCs by increasing the toxic threshold needed to kill them. This means imatinib and other TKIs cannot eliminate the residual LSCs.

After describing the roles of c-Fos and Dusp1, Dr Azam and his colleagues put their ideas to the test in mouse models of CML.

The team tested several treatments in these mice, including:

• monotherapy with imatinib
• inhibitors of c-Fos and Dusp1
• treatment with imatinib and inhibitors of c-Fos and Dusp1.

As suspected, treatment with imatinib alone initially stopped CML progression, but mice ultimately relapsed.

Treatment with c-Fos and Dusp1 inhibitors significantly slowed CML progression and prolonged survival in a majority of mice, but this treatment wasn’t curative.

However, a month of treatment with c-Fos and Dusp1 inhibitors as well as imatinib cured about 90% of mice with CML, and there were no signs of MRD.

The researchers also found that simply deleting c-Fos and Dusp1 was sufficient to block the development of B-cell ALL in mice.

The team said they are following up this study by testing c-Fos and Dusp1 as treatment targets for different kinase-fueled cancers.

Hospital Medical Center

Researchers say they have identified 2 signaling proteins that enable resistance to tyrosine kinase inhibitors (TKIs) and could be therapeutic targets for acute lymphoblastic leukemia (ALL) and chronic myeloid leukemia (CML).

The team found that by deleting these proteins—c-Fos and Dusp1—they could eradicate BCR-ABL-induced B-cell ALL in mice.

And treatment combining c-Fos and Dusp1 inhibitors with the TKI imatinib was able to cure mice with BCR-ABL-driven CML.

The researchers reported these findings in Nature Medicine.

“We think that, within the next 5 years, our data will change the way people think about cancer development and targeted therapy,” said study author Mohammad Azam, PhD, of Cincinnati Children’s Hospital Medical Center in Ohio.

“This study identifies a potential Achilles’ heel of kinase-driven cancers, and what we propose is intended to be curative, not just treatment.”

The potential Achilles’ heel is a common point of passage in cells—a signaling node—that appears to be required to generate cancer cells. The node is formed by the signaling proteins c-Fos and Dusp1, according to the researchers.

The team identified c-Fos and Dusp1 by conducting global gene-expression analysis of mouse leukemia cells and human CML cells. Analysis of the human cells revealed extremely high levels of c-FOS and DUSP1 in BCR-ABL-positive, TKI-resistant cells.

Dr Azam and his colleagues found that signaling from tyrosine kinase and growth factor proteins that support cell expansion (such as IL-3 and IL-6) converge to elevate c-Fos and Dusp1 levels in leukemia cells.

Working together, these molecules maintain the survival of leukemia stem cells (LSCs), which translates to minimal residual disease (MRD) after treatment.

Dr Azam said Dusp1 and c-Fos support the survival of LSCs by increasing the toxic threshold needed to kill them. This means imatinib and other TKIs cannot eliminate the residual LSCs.

After describing the roles of c-Fos and Dusp1, Dr Azam and his colleagues put their ideas to the test in mouse models of CML.

The team tested several treatments in these mice, including:

• monotherapy with imatinib
• inhibitors of c-Fos and Dusp1
• treatment with imatinib and inhibitors of c-Fos and Dusp1.

As suspected, treatment with imatinib alone initially stopped CML progression, but mice ultimately relapsed.

Treatment with c-Fos and Dusp1 inhibitors significantly slowed CML progression and prolonged survival in a majority of mice, but this treatment wasn’t curative.

However, a month of treatment with c-Fos and Dusp1 inhibitors as well as imatinib cured about 90% of mice with CML, and there were no signs of MRD.

The researchers also found that simply deleting c-Fos and Dusp1 was sufficient to block the development of B-cell ALL in mice.

The team said they are following up this study by testing c-Fos and Dusp1 as treatment targets for different kinase-fueled cancers.

Image by Spencer Phillips

New research appears to explain how 10q21.2 influences the risk of high-hyperdiploid acute lymphoblastic leukemia (HD-ALL).

Previous research indicated that variation in the gene ARID5B at 10q21.2 is associated with HD-ALL.

Now, researchers have reported that the 10q21.2 risk locus for HD-ALL is mediated through the single nucleotide polymorphism (SNP) rs7090445, which disrupts RUNX3 transcription factor binding.

Specifically, the rs7090445-C allele confers an increased risk of HD-ALL through reduced RUNX3-mediated expression of ARID5B.

The researchers described these findings in Nature Communications.

“This study expands our understanding of how genetic risk factors can influence the development of acute lymphoblastic leukemia . . .,” said study author Richard Houlston, MD, PhD, of The Institute of Cancer Research in London, UK.

Dr Houlston and his colleagues focused this research on 10q21.2 because it had previously been implicated in HD-ALL, but it wasn’t clear how the region affects the risk of HD-ALL.

The team said they found that a SNP in the region, rs7090445, is “highly associated” with HD-ALL.

Further investigation revealed that variation at rs7090445 disrupts RUNX3 binding and reduces the expression of ARID5B, as RUNX3 regulates ARID5B expression.

The researchers also discovered that the rs7090445-C risk allele, which is associated with reduced ARID5B expression, is amplified in HD-ALL. The risk allele is “preferentially retained” on additional copies of chromosome 10 in HD-ALL blasts.

“We implicate reduced expression of a gene called ARID5B in the production and release of the immature ‘blast’ cells that characterize [HD-ALL],” Dr Houlston said. “Our study gives a new insight into the causes of the disease and may open up new strategies for prevention.”

Image by Spencer Phillips

New research appears to explain how 10q21.2 influences the risk of high-hyperdiploid acute lymphoblastic leukemia (HD-ALL).

Previous research indicated that variation in the gene ARID5B at 10q21.2 is associated with HD-ALL.

Now, researchers have reported that the 10q21.2 risk locus for HD-ALL is mediated through the single nucleotide polymorphism (SNP) rs7090445, which disrupts RUNX3 transcription factor binding.

Specifically, the rs7090445-C allele confers an increased risk of HD-ALL through reduced RUNX3-mediated expression of ARID5B.

The researchers described these findings in Nature Communications.

“This study expands our understanding of how genetic risk factors can influence the development of acute lymphoblastic leukemia . . .,” said study author Richard Houlston, MD, PhD, of The Institute of Cancer Research in London, UK.

Dr Houlston and his colleagues focused this research on 10q21.2 because it had previously been implicated in HD-ALL, but it wasn’t clear how the region affects the risk of HD-ALL.

The team said they found that a SNP in the region, rs7090445, is “highly associated” with HD-ALL.

Further investigation revealed that variation at rs7090445 disrupts RUNX3 binding and reduces the expression of ARID5B, as RUNX3 regulates ARID5B expression.

The researchers also discovered that the rs7090445-C risk allele, which is associated with reduced ARID5B expression, is amplified in HD-ALL. The risk allele is “preferentially retained” on additional copies of chromosome 10 in HD-ALL blasts.

“We implicate reduced expression of a gene called ARID5B in the production and release of the immature ‘blast’ cells that characterize [HD-ALL],” Dr Houlston said. “Our study gives a new insight into the causes of the disease and may open up new strategies for prevention.”

Image by Spencer Phillips

New research appears to explain how 10q21.2 influences the risk of high-hyperdiploid acute lymphoblastic leukemia (HD-ALL).

Previous research indicated that variation in the gene ARID5B at 10q21.2 is associated with HD-ALL.

Now, researchers have reported that the 10q21.2 risk locus for HD-ALL is mediated through the single nucleotide polymorphism (SNP) rs7090445, which disrupts RUNX3 transcription factor binding.

Specifically, the rs7090445-C allele confers an increased risk of HD-ALL through reduced RUNX3-mediated expression of ARID5B.

The researchers described these findings in Nature Communications.

“This study expands our understanding of how genetic risk factors can influence the development of acute lymphoblastic leukemia . . .,” said study author Richard Houlston, MD, PhD, of The Institute of Cancer Research in London, UK.

Dr Houlston and his colleagues focused this research on 10q21.2 because it had previously been implicated in HD-ALL, but it wasn’t clear how the region affects the risk of HD-ALL.

The team said they found that a SNP in the region, rs7090445, is “highly associated” with HD-ALL.

Further investigation revealed that variation at rs7090445 disrupts RUNX3 binding and reduces the expression of ARID5B, as RUNX3 regulates ARID5B expression.

The researchers also discovered that the rs7090445-C risk allele, which is associated with reduced ARID5B expression, is amplified in HD-ALL. The risk allele is “preferentially retained” on additional copies of chromosome 10 in HD-ALL blasts.

“We implicate reduced expression of a gene called ARID5B in the production and release of the immature ‘blast’ cells that characterize [HD-ALL],” Dr Houlston said. “Our study gives a new insight into the causes of the disease and may open up new strategies for prevention.”

Photo by Chad McNeeley

ORLANDO, FL—Minimal residual disease (MRD) measurements before and after hematopoietic stem cell transplant (HSCT) can help predict outcomes in patients with childhood acute lymphoblastic leukemia (ALL), according to researchers.

Their work also suggests several other factors can be used to predict event-free survival (EFS) in this patient population, and the team developed risk scores incorporating these factors.

Michael A. Pulsipher, MD, of Children’s Hospital Los Angeles in California, presented this work as one of the “Best Abstracts” at the 2017 BMT Tandem Meetings (abstract 4*).

“The new risk scores that we were able to develop very nicely predict outcomes post-transplant and can guide study planning,” Dr Pulsipher said.

“MRD pre-transplant was a very powerful predictor of outcome, and MRD post-transplant highlights individual patients at risk.”

For this study, Dr Pulsipher and his colleagues retrospectively analyzed 747 patients treated in Europe, North America, and Australia. The patients received transplants between September 1999 and May 2015.

Most patients had pre-B ALL (78%, n=586), 19% (n=145) had T-cell ALL, 2% had “other” ALLs (n=8) or no data on ALL type (n=8). Sixty-two percent (n=466) were male.

Nearly half of patients were between the ages of 2 and 10 (49%, n=365), 47% (n=351) were older than 10, and 4% (n=31) were younger than 2.

Transplant details

Patients received grafts from matched unrelated donors (42%, n=314), matched sibling donors (30%, n=227), mismatched donors (10%, n=75), and cord blood from unrelated donors (17%, n=128). There was no data on donor type for 3 patients.

Most patients received bone marrow transplants (61%, n=458), 20% (n=147) received cord blood, and 18% (n=131) received peripheral blood stem cells. Eight patients received “other” types of transplants, and 3 patients had no data on stem cell source.

More than half of the patients (55%, n=410) were in their second complete remission (CR) at transplant. Thirty-seven percent were in their first CR (n=275), 7% were in their third or greater CR (n=53), and 1% were not in remission (n=7). Two patients had no data on remission status.

MRD

MRD was assessed before HSCT as well as after—on or near days 30, 60, 90, 180, 365, and beyond.

There were 4 MRD categories:

• MRD negative: No signal
• MRD low: >0 to <10^-4 (<0.01%)
• MRD high: ≥10^-4 to <10^-3 (0.01 to 0.1%)
• MRD very high: ≥10^-3 to <10^-2 (>0.1%).

Dr Pulsipher noted that, when analyzing MRD pre-HSCT or at 30 days after HSCT, the estimated 5-year EFS was similar for patients in the MRD-negative and MRD-low groups. However, as time went on (at days 90, 180, and 365), any detectable level of MRD was associated with a poor prognosis.

“And patients arriving at day 365 with no detectable MRD had an exceptional prognosis, with survival approaching 90%,” Dr Pulsipher said.

He also pointed out an interaction between acute graft-vs-host disease (aGVHD) and MRD post-HSCT. He and his colleagues observed better survival for MRD-positive patients with aGVHD (grade 1-2) than for MRD-positive patients without aGVHD.

Pre-HSCT risk score

Via an adjusted Cox regression analysis, the researchers identified several pre-transplant factors that predicted EFS at 18 months.

These included remission status, donor type, immunophenotype, and MRD. The researchers assigned points to each of these factors to create a risk score.

Compared to patients in first CR, the hazard ratio (HR) for patients in early second CR was 2.53, and the score was 3. For patients in third CR or greater, the HR was 1.95, and the score was 2.

Compared to patients with a matched sibling donor, the HR for patients with a mismatched donor was 1.41, and the score was 1. For patients who received cord blood from an unrelated donor, the HR was 1.48, and the score was 1.

Compared to patients with T-cell ALL, the HR for patients with pre-B ALL was 1.35, and the score was 1.

Compared to patients with MRD <10^-4, the HR for patients with MRD ≥10^-4 was 2.32, and the score was 2.

The probability of EFS at 18 months was 78% ± 2% for patients with 0 to 1 points, 54% ± 3% for those with 2 to 3 points, and 46% ± 5% for patients with 4 or more points.

Day 30 post-HSCT risk score

When considering patients at day 30 post-HSCT, factors that predicted 18-month EFS included remission status, donor type, immunophenotype, aGVHD status, and MRD.

The HR for patients in early second CR was 2.51, and the score was 3. For patients in third CR or greater, the HR was 2.09, and the score was 2.

The HR for patients with a mismatched donor was 1.75, and the score was 2. The HR for patients with pre-B ALL was 1.40, and the score was 1.

Compared to patients with grade 1-2 aGVHD, the HR was 2.02 for patients with grade 0 aGVHD, and the score was 2. For patients with grade 3 aGVHD, the HR was 1.44, and the score was 1. For patients with grade 4 aGVHD, the HR was 7.12, and the score was 7.

The researchers evaluated MRD prior to HSCT and MRD at day 30, using a reference of MRD <10^-4 at both time points. For patients with MRD <10^-4 pre-HSCT and ≥10^-4 at day 30, the HR was 2.29, and the score was 2.

For patients with MRD ≥10^-4 pre-HSCT and <10^-4 at day 30, the HR was 3.17, and the score was 3. For patients with MRD ≥10^-4 pre-HSCT and at day 30, the HR was 3.63, and the score was 4.

The probability of EFS at 18 months was 80% ± 2% for patients with 0 to 3 points, 54% ± 4% for those with 4 to 6 points, and 25% ± 6% for those with 7 or more points.

Day 90 post-HSCT risk score

When considering patients at day 90 post-HSCT, factors that predicted 18-month EFS included remission status, aGVHD status, and MRD.

For patients in early second CR, the HR was 2.81, and the score was 3. For those in third CR or greater, the HR was 1.85, and the score was 2.

Compared to patients with grade 1-2 aGVHD, the HR was 1.60 for patients with grade 0 aGVHD, and the score was 2. For patients with grade 4 aGVHD, the HR was 2.49, and the score was 2.

The researchers assessed MRD prior to HSCT and MRD at day 90, using a reference of MRD <10^-4 at both time points. For patients with MRD <10^-4 pre-HSCT and ≥10^-4 at day 90, the HR was 6.03, and the score was 6.

For patients with MRD ≥10^-4 pre-HSCT and <10^-4 at day 90, the HR was 3.11, and the score was 3. For patients with MRD ≥10^-4 pre-HSCT and at day 90, the HR was 4.59, and the score was 5.

The probability of EFS at 18 months was 83% ± 2% for patients with 0 to 2 points, 60% ± 4% for those with 3 to 5 points, and 17% ± 11 for those with 6 or more points.

*Information in the abstract differs from the presentation.

Photo by Chad McNeeley

ORLANDO, FL—Minimal residual disease (MRD) measurements before and after hematopoietic stem cell transplant (HSCT) can help predict outcomes in patients with childhood acute lymphoblastic leukemia (ALL), according to researchers.

Their work also suggests several other factors can be used to predict event-free survival (EFS) in this patient population, and the team developed risk scores incorporating these factors.

Michael A. Pulsipher, MD, of Children’s Hospital Los Angeles in California, presented this work as one of the “Best Abstracts” at the 2017 BMT Tandem Meetings (abstract 4*).

“The new risk scores that we were able to develop very nicely predict outcomes post-transplant and can guide study planning,” Dr Pulsipher said.

“MRD pre-transplant was a very powerful predictor of outcome, and MRD post-transplant highlights individual patients at risk.”

For this study, Dr Pulsipher and his colleagues retrospectively analyzed 747 patients treated in Europe, North America, and Australia. The patients received transplants between September 1999 and May 2015.

Most patients had pre-B ALL (78%, n=586), 19% (n=145) had T-cell ALL, 2% had “other” ALLs (n=8) or no data on ALL type (n=8). Sixty-two percent (n=466) were male.

Nearly half of patients were between the ages of 2 and 10 (49%, n=365), 47% (n=351) were older than 10, and 4% (n=31) were younger than 2.

Transplant details

Patients received grafts from matched unrelated donors (42%, n=314), matched sibling donors (30%, n=227), mismatched donors (10%, n=75), and cord blood from unrelated donors (17%, n=128). There was no data on donor type for 3 patients.

Most patients received bone marrow transplants (61%, n=458), 20% (n=147) received cord blood, and 18% (n=131) received peripheral blood stem cells. Eight patients received “other” types of transplants, and 3 patients had no data on stem cell source.

More than half of the patients (55%, n=410) were in their second complete remission (CR) at transplant. Thirty-seven percent were in their first CR (n=275), 7% were in their third or greater CR (n=53), and 1% were not in remission (n=7). Two patients had no data on remission status.

MRD

MRD was assessed before HSCT as well as after—on or near days 30, 60, 90, 180, 365, and beyond.

There were 4 MRD categories:

• MRD negative: No signal
• MRD low: >0 to <10^-4 (<0.01%)
• MRD high: ≥10^-4 to <10^-3 (0.01 to 0.1%)
• MRD very high: ≥10^-3 to <10^-2 (>0.1%).

Dr Pulsipher noted that, when analyzing MRD pre-HSCT or at 30 days after HSCT, the estimated 5-year EFS was similar for patients in the MRD-negative and MRD-low groups. However, as time went on (at days 90, 180, and 365), any detectable level of MRD was associated with a poor prognosis.

“And patients arriving at day 365 with no detectable MRD had an exceptional prognosis, with survival approaching 90%,” Dr Pulsipher said.

He also pointed out an interaction between acute graft-vs-host disease (aGVHD) and MRD post-HSCT. He and his colleagues observed better survival for MRD-positive patients with aGVHD (grade 1-2) than for MRD-positive patients without aGVHD.

Pre-HSCT risk score

Via an adjusted Cox regression analysis, the researchers identified several pre-transplant factors that predicted EFS at 18 months.

These included remission status, donor type, immunophenotype, and MRD. The researchers assigned points to each of these factors to create a risk score.

Compared to patients in first CR, the hazard ratio (HR) for patients in early second CR was 2.53, and the score was 3. For patients in third CR or greater, the HR was 1.95, and the score was 2.

Compared to patients with a matched sibling donor, the HR for patients with a mismatched donor was 1.41, and the score was 1. For patients who received cord blood from an unrelated donor, the HR was 1.48, and the score was 1.

Compared to patients with T-cell ALL, the HR for patients with pre-B ALL was 1.35, and the score was 1.

Compared to patients with MRD <10^-4, the HR for patients with MRD ≥10^-4 was 2.32, and the score was 2.

The probability of EFS at 18 months was 78% ± 2% for patients with 0 to 1 points, 54% ± 3% for those with 2 to 3 points, and 46% ± 5% for patients with 4 or more points.

Day 30 post-HSCT risk score

When considering patients at day 30 post-HSCT, factors that predicted 18-month EFS included remission status, donor type, immunophenotype, aGVHD status, and MRD.

The HR for patients in early second CR was 2.51, and the score was 3. For patients in third CR or greater, the HR was 2.09, and the score was 2.

The HR for patients with a mismatched donor was 1.75, and the score was 2. The HR for patients with pre-B ALL was 1.40, and the score was 1.

Compared to patients with grade 1-2 aGVHD, the HR was 2.02 for patients with grade 0 aGVHD, and the score was 2. For patients with grade 3 aGVHD, the HR was 1.44, and the score was 1. For patients with grade 4 aGVHD, the HR was 7.12, and the score was 7.

The researchers evaluated MRD prior to HSCT and MRD at day 30, using a reference of MRD <10^-4 at both time points. For patients with MRD <10^-4 pre-HSCT and ≥10^-4 at day 30, the HR was 2.29, and the score was 2.

For patients with MRD ≥10^-4 pre-HSCT and <10^-4 at day 30, the HR was 3.17, and the score was 3. For patients with MRD ≥10^-4 pre-HSCT and at day 30, the HR was 3.63, and the score was 4.

The probability of EFS at 18 months was 80% ± 2% for patients with 0 to 3 points, 54% ± 4% for those with 4 to 6 points, and 25% ± 6% for those with 7 or more points.

Day 90 post-HSCT risk score

When considering patients at day 90 post-HSCT, factors that predicted 18-month EFS included remission status, aGVHD status, and MRD.

For patients in early second CR, the HR was 2.81, and the score was 3. For those in third CR or greater, the HR was 1.85, and the score was 2.

Compared to patients with grade 1-2 aGVHD, the HR was 1.60 for patients with grade 0 aGVHD, and the score was 2. For patients with grade 4 aGVHD, the HR was 2.49, and the score was 2.

The researchers assessed MRD prior to HSCT and MRD at day 90, using a reference of MRD <10^-4 at both time points. For patients with MRD <10^-4 pre-HSCT and ≥10^-4 at day 90, the HR was 6.03, and the score was 6.

For patients with MRD ≥10^-4 pre-HSCT and <10^-4 at day 90, the HR was 3.11, and the score was 3. For patients with MRD ≥10^-4 pre-HSCT and at day 90, the HR was 4.59, and the score was 5.

The probability of EFS at 18 months was 83% ± 2% for patients with 0 to 2 points, 60% ± 4% for those with 3 to 5 points, and 17% ± 11 for those with 6 or more points.

*Information in the abstract differs from the presentation.

Photo by Chad McNeeley

ORLANDO, FL—Minimal residual disease (MRD) measurements before and after hematopoietic stem cell transplant (HSCT) can help predict outcomes in patients with childhood acute lymphoblastic leukemia (ALL), according to researchers.

Their work also suggests several other factors can be used to predict event-free survival (EFS) in this patient population, and the team developed risk scores incorporating these factors.

Michael A. Pulsipher, MD, of Children’s Hospital Los Angeles in California, presented this work as one of the “Best Abstracts” at the 2017 BMT Tandem Meetings (abstract 4*).

“The new risk scores that we were able to develop very nicely predict outcomes post-transplant and can guide study planning,” Dr Pulsipher said.

“MRD pre-transplant was a very powerful predictor of outcome, and MRD post-transplant highlights individual patients at risk.”

For this study, Dr Pulsipher and his colleagues retrospectively analyzed 747 patients treated in Europe, North America, and Australia. The patients received transplants between September 1999 and May 2015.

Most patients had pre-B ALL (78%, n=586), 19% (n=145) had T-cell ALL, 2% had “other” ALLs (n=8) or no data on ALL type (n=8). Sixty-two percent (n=466) were male.

Nearly half of patients were between the ages of 2 and 10 (49%, n=365), 47% (n=351) were older than 10, and 4% (n=31) were younger than 2.

Transplant details

Patients received grafts from matched unrelated donors (42%, n=314), matched sibling donors (30%, n=227), mismatched donors (10%, n=75), and cord blood from unrelated donors (17%, n=128). There was no data on donor type for 3 patients.

Most patients received bone marrow transplants (61%, n=458), 20% (n=147) received cord blood, and 18% (n=131) received peripheral blood stem cells. Eight patients received “other” types of transplants, and 3 patients had no data on stem cell source.

More than half of the patients (55%, n=410) were in their second complete remission (CR) at transplant. Thirty-seven percent were in their first CR (n=275), 7% were in their third or greater CR (n=53), and 1% were not in remission (n=7). Two patients had no data on remission status.

MRD

MRD was assessed before HSCT as well as after—on or near days 30, 60, 90, 180, 365, and beyond.

There were 4 MRD categories:

• MRD negative: No signal
• MRD low: >0 to <10^-4 (<0.01%)
• MRD high: ≥10^-4 to <10^-3 (0.01 to 0.1%)
• MRD very high: ≥10^-3 to <10^-2 (>0.1%).

Dr Pulsipher noted that, when analyzing MRD pre-HSCT or at 30 days after HSCT, the estimated 5-year EFS was similar for patients in the MRD-negative and MRD-low groups. However, as time went on (at days 90, 180, and 365), any detectable level of MRD was associated with a poor prognosis.

“And patients arriving at day 365 with no detectable MRD had an exceptional prognosis, with survival approaching 90%,” Dr Pulsipher said.

He also pointed out an interaction between acute graft-vs-host disease (aGVHD) and MRD post-HSCT. He and his colleagues observed better survival for MRD-positive patients with aGVHD (grade 1-2) than for MRD-positive patients without aGVHD.

Pre-HSCT risk score

Via an adjusted Cox regression analysis, the researchers identified several pre-transplant factors that predicted EFS at 18 months.

These included remission status, donor type, immunophenotype, and MRD. The researchers assigned points to each of these factors to create a risk score.

Compared to patients in first CR, the hazard ratio (HR) for patients in early second CR was 2.53, and the score was 3. For patients in third CR or greater, the HR was 1.95, and the score was 2.

Compared to patients with a matched sibling donor, the HR for patients with a mismatched donor was 1.41, and the score was 1. For patients who received cord blood from an unrelated donor, the HR was 1.48, and the score was 1.

Compared to patients with T-cell ALL, the HR for patients with pre-B ALL was 1.35, and the score was 1.

Compared to patients with MRD <10^-4, the HR for patients with MRD ≥10^-4 was 2.32, and the score was 2.

The probability of EFS at 18 months was 78% ± 2% for patients with 0 to 1 points, 54% ± 3% for those with 2 to 3 points, and 46% ± 5% for patients with 4 or more points.

Day 30 post-HSCT risk score

When considering patients at day 30 post-HSCT, factors that predicted 18-month EFS included remission status, donor type, immunophenotype, aGVHD status, and MRD.

The HR for patients in early second CR was 2.51, and the score was 3. For patients in third CR or greater, the HR was 2.09, and the score was 2.

The HR for patients with a mismatched donor was 1.75, and the score was 2. The HR for patients with pre-B ALL was 1.40, and the score was 1.

Compared to patients with grade 1-2 aGVHD, the HR was 2.02 for patients with grade 0 aGVHD, and the score was 2. For patients with grade 3 aGVHD, the HR was 1.44, and the score was 1. For patients with grade 4 aGVHD, the HR was 7.12, and the score was 7.

The researchers evaluated MRD prior to HSCT and MRD at day 30, using a reference of MRD <10^-4 at both time points. For patients with MRD <10^-4 pre-HSCT and ≥10^-4 at day 30, the HR was 2.29, and the score was 2.

For patients with MRD ≥10^-4 pre-HSCT and <10^-4 at day 30, the HR was 3.17, and the score was 3. For patients with MRD ≥10^-4 pre-HSCT and at day 30, the HR was 3.63, and the score was 4.

The probability of EFS at 18 months was 80% ± 2% for patients with 0 to 3 points, 54% ± 4% for those with 4 to 6 points, and 25% ± 6% for those with 7 or more points.

Day 90 post-HSCT risk score

When considering patients at day 90 post-HSCT, factors that predicted 18-month EFS included remission status, aGVHD status, and MRD.

For patients in early second CR, the HR was 2.81, and the score was 3. For those in third CR or greater, the HR was 1.85, and the score was 2.

Compared to patients with grade 1-2 aGVHD, the HR was 1.60 for patients with grade 0 aGVHD, and the score was 2. For patients with grade 4 aGVHD, the HR was 2.49, and the score was 2.

The researchers assessed MRD prior to HSCT and MRD at day 90, using a reference of MRD <10^-4 at both time points. For patients with MRD <10^-4 pre-HSCT and ≥10^-4 at day 90, the HR was 6.03, and the score was 6.

For patients with MRD ≥10^-4 pre-HSCT and <10^-4 at day 90, the HR was 3.11, and the score was 3. For patients with MRD ≥10^-4 pre-HSCT and at day 90, the HR was 4.59, and the score was 5.

The probability of EFS at 18 months was 83% ± 2% for patients with 0 to 2 points, 60% ± 4% for those with 3 to 5 points, and 17% ± 11 for those with 6 or more points.

*Information in the abstract differs from the presentation.

Image courtesy of the National Institute of General Medical Sciences

ORLANDO, FL—Results of a genome-wide association study suggest that several genetic variants are associated with outcomes of allogeneic hematopoietic stem cell transplant (HSCT) in patients with acute lymphoblastic leukemia (ALL).

Investigators identified several single-nucleotide polymorphisms (SNPs) in ALL patients and their unrelated donors that were associated with disease-related death or progression-free survival (PFS) within 1 year of HSCT.

“We believe that these findings will lead to a better understanding of the biology of this disease,” said investigator Theresa Hahn, PhD, of Roswell Park Cancer Institute in Buffalo, New York.

“Additionally, we expect that this work will eventually help clinical teams to identify unrelated donors with genotypes that yield better survival in transplant patients and enhance the chances for successful blood and marrow transplants.”

Dr Hahn presented this work as a “Best Abstract” at the 2017 BMT Tandem Meetings (abstract 1).

For this study, she and her colleagues analyzed data on patients treated at more than 150 US transplant centers between 2000 and 2011. The investigators evaluated data on more than 3000 patients with acute leukemias or myelodysplastic syndromes, but Dr Hahn only presented findings in the ALL patients and their donors.

The patients and donors were divided into 2 cohorts. Cohort 1 included 483 ALL patients who underwent HSCT from 2000 to 2008 and 466 unrelated donors who were a 10/10 HLA match for the patients.

Cohort 2 included 94 ALL patients who received a transplant from a 10/10 HLA-matched donor between 2009 and 2011 or from an 8/8 HLA-matched donor between 2000 and 2011. There were 92 donors in this cohort.

The investigators sequenced blood samples from the recipients and donors to identify SNPs. The SNPs were then measured for association with disease-related death and PFS using Cox proportional hazards models adjusted for recipient age, disease status at HSCT (early, intermediate, or advanced), graft source (blood or marrow), and year of transplant.

SNPs in donors

The top 2 SNPs in donors that were associated with a significant increase in disease-related death were:

• rs79503405 in LRP2 on chromosome 2.
• rs77618918 in ASIC2 on chromosome 17.

Dr Hahn noted that rs79503405 is in complete linkage disequilibrium (r²=1.0) with a genotyped missense variant (rs17848149) and a synonymous coding variant (rs35114151) in LRP2.

She also pointed out that the other top SNP (rs77618918) associated with disease-related death is not in linkage disequilibrium with other SNPs of functional importance, so the significance of this SNP is unknown.

There were no SNPs in donors that were significantly associated with PFS.

SNPs in recipients

In HSCT recipients, there were 3 linked variants in NRG1 on chromosome 8 (rs79853417, rs6990973, and rs145488394) that were significantly associated with disease-related death.

Another SNP (rs60640657) on chromosome 2 (CTNNA3/LOC101928961/LRRTM3) was also significantly associated with ALL-related death.

In addition, Dr Hahn and her colleagues found that 1 region in recipient genomes contains multiple variants (rs113263921 and others) associated with PFS. The SNPs are located on chromosome 3 in MLH1 and TRANK1.

“The donor and recipient genetic variants contributed independently to death due to ALL,” Dr Hahn said in closing. “Genetic variants for PFS do not overlap with death due to ALL, and this is probably due to the inclusion of both non-fatal disease progression as well as transplant-related mortality in the definition of PFS.”

“Constitutional genetic variants in recipients and donors increase the risk of death due to ALL, and they warrant further study into the impact of these genes on disease and transplant-related biology.”

Image courtesy of the National Institute of General Medical Sciences

ORLANDO, FL—Results of a genome-wide association study suggest that several genetic variants are associated with outcomes of allogeneic hematopoietic stem cell transplant (HSCT) in patients with acute lymphoblastic leukemia (ALL).

Investigators identified several single-nucleotide polymorphisms (SNPs) in ALL patients and their unrelated donors that were associated with disease-related death or progression-free survival (PFS) within 1 year of HSCT.

“We believe that these findings will lead to a better understanding of the biology of this disease,” said investigator Theresa Hahn, PhD, of Roswell Park Cancer Institute in Buffalo, New York.

“Additionally, we expect that this work will eventually help clinical teams to identify unrelated donors with genotypes that yield better survival in transplant patients and enhance the chances for successful blood and marrow transplants.”

Dr Hahn presented this work as a “Best Abstract” at the 2017 BMT Tandem Meetings (abstract 1).

For this study, she and her colleagues analyzed data on patients treated at more than 150 US transplant centers between 2000 and 2011. The investigators evaluated data on more than 3000 patients with acute leukemias or myelodysplastic syndromes, but Dr Hahn only presented findings in the ALL patients and their donors.

The patients and donors were divided into 2 cohorts. Cohort 1 included 483 ALL patients who underwent HSCT from 2000 to 2008 and 466 unrelated donors who were a 10/10 HLA match for the patients.

Cohort 2 included 94 ALL patients who received a transplant from a 10/10 HLA-matched donor between 2009 and 2011 or from an 8/8 HLA-matched donor between 2000 and 2011. There were 92 donors in this cohort.

The investigators sequenced blood samples from the recipients and donors to identify SNPs. The SNPs were then measured for association with disease-related death and PFS using Cox proportional hazards models adjusted for recipient age, disease status at HSCT (early, intermediate, or advanced), graft source (blood or marrow), and year of transplant.

SNPs in donors

The top 2 SNPs in donors that were associated with a significant increase in disease-related death were:

• rs79503405 in LRP2 on chromosome 2.
• rs77618918 in ASIC2 on chromosome 17.

Dr Hahn noted that rs79503405 is in complete linkage disequilibrium (r²=1.0) with a genotyped missense variant (rs17848149) and a synonymous coding variant (rs35114151) in LRP2.

She also pointed out that the other top SNP (rs77618918) associated with disease-related death is not in linkage disequilibrium with other SNPs of functional importance, so the significance of this SNP is unknown.

There were no SNPs in donors that were significantly associated with PFS.

SNPs in recipients

In HSCT recipients, there were 3 linked variants in NRG1 on chromosome 8 (rs79853417, rs6990973, and rs145488394) that were significantly associated with disease-related death.

Another SNP (rs60640657) on chromosome 2 (CTNNA3/LOC101928961/LRRTM3) was also significantly associated with ALL-related death.

In addition, Dr Hahn and her colleagues found that 1 region in recipient genomes contains multiple variants (rs113263921 and others) associated with PFS. The SNPs are located on chromosome 3 in MLH1 and TRANK1.

“The donor and recipient genetic variants contributed independently to death due to ALL,” Dr Hahn said in closing. “Genetic variants for PFS do not overlap with death due to ALL, and this is probably due to the inclusion of both non-fatal disease progression as well as transplant-related mortality in the definition of PFS.”

“Constitutional genetic variants in recipients and donors increase the risk of death due to ALL, and they warrant further study into the impact of these genes on disease and transplant-related biology.”

Image courtesy of the National Institute of General Medical Sciences

ORLANDO, FL—Results of a genome-wide association study suggest that several genetic variants are associated with outcomes of allogeneic hematopoietic stem cell transplant (HSCT) in patients with acute lymphoblastic leukemia (ALL).

Investigators identified several single-nucleotide polymorphisms (SNPs) in ALL patients and their unrelated donors that were associated with disease-related death or progression-free survival (PFS) within 1 year of HSCT.

“We believe that these findings will lead to a better understanding of the biology of this disease,” said investigator Theresa Hahn, PhD, of Roswell Park Cancer Institute in Buffalo, New York.

“Additionally, we expect that this work will eventually help clinical teams to identify unrelated donors with genotypes that yield better survival in transplant patients and enhance the chances for successful blood and marrow transplants.”

Dr Hahn presented this work as a “Best Abstract” at the 2017 BMT Tandem Meetings (abstract 1).

For this study, she and her colleagues analyzed data on patients treated at more than 150 US transplant centers between 2000 and 2011. The investigators evaluated data on more than 3000 patients with acute leukemias or myelodysplastic syndromes, but Dr Hahn only presented findings in the ALL patients and their donors.

The patients and donors were divided into 2 cohorts. Cohort 1 included 483 ALL patients who underwent HSCT from 2000 to 2008 and 466 unrelated donors who were a 10/10 HLA match for the patients.

Cohort 2 included 94 ALL patients who received a transplant from a 10/10 HLA-matched donor between 2009 and 2011 or from an 8/8 HLA-matched donor between 2000 and 2011. There were 92 donors in this cohort.

The investigators sequenced blood samples from the recipients and donors to identify SNPs. The SNPs were then measured for association with disease-related death and PFS using Cox proportional hazards models adjusted for recipient age, disease status at HSCT (early, intermediate, or advanced), graft source (blood or marrow), and year of transplant.

SNPs in donors

The top 2 SNPs in donors that were associated with a significant increase in disease-related death were:

• rs79503405 in LRP2 on chromosome 2.
• rs77618918 in ASIC2 on chromosome 17.

Dr Hahn noted that rs79503405 is in complete linkage disequilibrium (r²=1.0) with a genotyped missense variant (rs17848149) and a synonymous coding variant (rs35114151) in LRP2.

She also pointed out that the other top SNP (rs77618918) associated with disease-related death is not in linkage disequilibrium with other SNPs of functional importance, so the significance of this SNP is unknown.

There were no SNPs in donors that were significantly associated with PFS.

SNPs in recipients

In HSCT recipients, there were 3 linked variants in NRG1 on chromosome 8 (rs79853417, rs6990973, and rs145488394) that were significantly associated with disease-related death.

Another SNP (rs60640657) on chromosome 2 (CTNNA3/LOC101928961/LRRTM3) was also significantly associated with ALL-related death.

In addition, Dr Hahn and her colleagues found that 1 region in recipient genomes contains multiple variants (rs113263921 and others) associated with PFS. The SNPs are located on chromosome 3 in MLH1 and TRANK1.

“The donor and recipient genetic variants contributed independently to death due to ALL,” Dr Hahn said in closing. “Genetic variants for PFS do not overlap with death due to ALL, and this is probably due to the inclusion of both non-fatal disease progression as well as transplant-related mortality in the definition of PFS.”

“Constitutional genetic variants in recipients and donors increase the risk of death due to ALL, and they warrant further study into the impact of these genes on disease and transplant-related biology.”

of Colorado Cancer Center

New research suggests that, in the US, early deaths from childhood cancer may be more common than clinical trials suggest.

Researchers found the rate of death within 1 month of diagnosis was higher among patients included in a large national database than among patients enrolled in phase 3 trials.

The data also indicated that early death is more likely in cancer patients under the age of 1 and those belonging to minority racial and ethnic groups.

Adam Green, MD, of the University of Colorado Anschutz Medical Campus in Aurora, and his colleagues conducted this research and reported the results in the Journal of Clinical Oncology.

The researchers analyzed data from the Surveillance, Epidemiology and End Results (SEER) database, which collects about 15% of all cancer outcomes across the US (representing a geographic and socioeconomic cross-section).

The team identified 36,337 patients with pediatric cancer (ages 0 to 19) diagnosed between 1992 and 2011. Of these patients, 555 (1.5%) died within 1 month of diagnosis.

Young age

Overall, the strongest predictor of early death was age below 1 year. The odds ratio (OR) was 4.36 for these patients (P<0.001), 0.75 for patients age 1 to 4, 0.78 for patients age 5 to 9, 1.00 (reference) for those age 10 to 14, and 1.69 for those age 15 to 19.

For hematologic malignancies, the adjusted OR (adjusted by poverty, unemployment, education, and year of diagnosis) was 4.32 for patients younger than 1 (P<0.001), 0.76 for patients age 1 to 4, 0.79 for patients age 5 to 9, 1.00 for those age 10 to 14, and 1.76 for those age 15 to 19 (P=0.002).

“In general, babies are just challenging, clinically, because they can’t tell you what they’re feeling,” Dr Green noted. “Parents and physicians have to pick the ones with cancer from the ones with a cold, without the patient being able to tell you about symptoms that could be diagnostic.”

“Babies tend to get aggressive cancers, it’s hard to tell when they’re getting sick, and some are even born with cancers that have already progressed. These factors combine to make very young age the strongest predictor of early death in our study.”

Race/ethnicity

Black race and Hispanic ethnicity also predicted early death. The OR was 1.48 for black race, 1.00 for white race (reference), and 1.09 for “other” races (P=0.102). The OR was 1.39 for Hispanic patients and 1.00 (reference) for non-Hispanic patients (P=0.007).

For hematologic malignancies, the adjusted OR was 1.68 for black patients (P=0.01) and 1.44 for patients of other, non-white races. The adjusted OR was 1.48 for Hispanic patients (P=0.009).

Dr Green said he hopes future studies will be able to determine the factors responsible for these disparities.

Higher death rates

Dr Green and his colleagues also found the rate of early death due to pediatric cancers is higher than reported in clinical trials, and this was true for all cancer subtypes assessed.

“Most of what we know about outcomes for cancer patients come from clinical trials, which have much more thorough reporting rules than cancer treated outside trials,” Dr Green said. “However, these kids in our study aren’t surviving long enough to join clinical trials.”

The researchers looked at a phase 3 trial (COG AAML0531) of pediatric patients with acute myeloid leukemia (AML) who were studied from August 2006 to June 2010. The early death rate in this trial was 1.6% (16/1022).

In contrast, the SEER database showed an early death rate for pediatric AML patients of 5.9% (15/256) during the same period as the trial and 6.2% (106/1698) for the period from 1992 to 2011. This is almost 4 times as high as the death rate in the trial.

The same effect was observed for acute lymphoblastic leukemia (ALL).

The early death rate for non-infant ALL was 0.7% (13/1790) in a trial (POG 9900) conducted from April 2000 to April 2005, 1.6% (30/1823) in the SEER data covering the same time period, and 1.3% (94/7353) in the SEER data from 1992 to 2011.

For infant ALL, the rates were 2.0% (3/149) in a trial (COG AALL0631) conducted from January 2008 to June 2014, 5.0% (2/40) in the SEER data during the trial period, and 5.4% (12/223) in the SEER data from 1992 to 2011.

“I had a hunch this was a bigger problem than we thought,” Dr Green said. “Now we see that is indeed the case.”

of Colorado Cancer Center

New research suggests that, in the US, early deaths from childhood cancer may be more common than clinical trials suggest.

Researchers found the rate of death within 1 month of diagnosis was higher among patients included in a large national database than among patients enrolled in phase 3 trials.

The data also indicated that early death is more likely in cancer patients under the age of 1 and those belonging to minority racial and ethnic groups.

Adam Green, MD, of the University of Colorado Anschutz Medical Campus in Aurora, and his colleagues conducted this research and reported the results in the Journal of Clinical Oncology.

The researchers analyzed data from the Surveillance, Epidemiology and End Results (SEER) database, which collects about 15% of all cancer outcomes across the US (representing a geographic and socioeconomic cross-section).

The team identified 36,337 patients with pediatric cancer (ages 0 to 19) diagnosed between 1992 and 2011. Of these patients, 555 (1.5%) died within 1 month of diagnosis.

Young age

Overall, the strongest predictor of early death was age below 1 year. The odds ratio (OR) was 4.36 for these patients (P<0.001), 0.75 for patients age 1 to 4, 0.78 for patients age 5 to 9, 1.00 (reference) for those age 10 to 14, and 1.69 for those age 15 to 19.

For hematologic malignancies, the adjusted OR (adjusted by poverty, unemployment, education, and year of diagnosis) was 4.32 for patients younger than 1 (P<0.001), 0.76 for patients age 1 to 4, 0.79 for patients age 5 to 9, 1.00 for those age 10 to 14, and 1.76 for those age 15 to 19 (P=0.002).

“In general, babies are just challenging, clinically, because they can’t tell you what they’re feeling,” Dr Green noted. “Parents and physicians have to pick the ones with cancer from the ones with a cold, without the patient being able to tell you about symptoms that could be diagnostic.”

“Babies tend to get aggressive cancers, it’s hard to tell when they’re getting sick, and some are even born with cancers that have already progressed. These factors combine to make very young age the strongest predictor of early death in our study.”

Race/ethnicity

Black race and Hispanic ethnicity also predicted early death. The OR was 1.48 for black race, 1.00 for white race (reference), and 1.09 for “other” races (P=0.102). The OR was 1.39 for Hispanic patients and 1.00 (reference) for non-Hispanic patients (P=0.007).

For hematologic malignancies, the adjusted OR was 1.68 for black patients (P=0.01) and 1.44 for patients of other, non-white races. The adjusted OR was 1.48 for Hispanic patients (P=0.009).

Dr Green said he hopes future studies will be able to determine the factors responsible for these disparities.

Higher death rates

Dr Green and his colleagues also found the rate of early death due to pediatric cancers is higher than reported in clinical trials, and this was true for all cancer subtypes assessed.

“Most of what we know about outcomes for cancer patients come from clinical trials, which have much more thorough reporting rules than cancer treated outside trials,” Dr Green said. “However, these kids in our study aren’t surviving long enough to join clinical trials.”

The researchers looked at a phase 3 trial (COG AAML0531) of pediatric patients with acute myeloid leukemia (AML) who were studied from August 2006 to June 2010. The early death rate in this trial was 1.6% (16/1022).

In contrast, the SEER database showed an early death rate for pediatric AML patients of 5.9% (15/256) during the same period as the trial and 6.2% (106/1698) for the period from 1992 to 2011. This is almost 4 times as high as the death rate in the trial.

The same effect was observed for acute lymphoblastic leukemia (ALL).

The early death rate for non-infant ALL was 0.7% (13/1790) in a trial (POG 9900) conducted from April 2000 to April 2005, 1.6% (30/1823) in the SEER data covering the same time period, and 1.3% (94/7353) in the SEER data from 1992 to 2011.

For infant ALL, the rates were 2.0% (3/149) in a trial (COG AALL0631) conducted from January 2008 to June 2014, 5.0% (2/40) in the SEER data during the trial period, and 5.4% (12/223) in the SEER data from 1992 to 2011.

“I had a hunch this was a bigger problem than we thought,” Dr Green said. “Now we see that is indeed the case.”

of Colorado Cancer Center

New research suggests that, in the US, early deaths from childhood cancer may be more common than clinical trials suggest.

Researchers found the rate of death within 1 month of diagnosis was higher among patients included in a large national database than among patients enrolled in phase 3 trials.

The data also indicated that early death is more likely in cancer patients under the age of 1 and those belonging to minority racial and ethnic groups.

Adam Green, MD, of the University of Colorado Anschutz Medical Campus in Aurora, and his colleagues conducted this research and reported the results in the Journal of Clinical Oncology.

The researchers analyzed data from the Surveillance, Epidemiology and End Results (SEER) database, which collects about 15% of all cancer outcomes across the US (representing a geographic and socioeconomic cross-section).

The team identified 36,337 patients with pediatric cancer (ages 0 to 19) diagnosed between 1992 and 2011. Of these patients, 555 (1.5%) died within 1 month of diagnosis.

Young age

Overall, the strongest predictor of early death was age below 1 year. The odds ratio (OR) was 4.36 for these patients (P<0.001), 0.75 for patients age 1 to 4, 0.78 for patients age 5 to 9, 1.00 (reference) for those age 10 to 14, and 1.69 for those age 15 to 19.

For hematologic malignancies, the adjusted OR (adjusted by poverty, unemployment, education, and year of diagnosis) was 4.32 for patients younger than 1 (P<0.001), 0.76 for patients age 1 to 4, 0.79 for patients age 5 to 9, 1.00 for those age 10 to 14, and 1.76 for those age 15 to 19 (P=0.002).

“In general, babies are just challenging, clinically, because they can’t tell you what they’re feeling,” Dr Green noted. “Parents and physicians have to pick the ones with cancer from the ones with a cold, without the patient being able to tell you about symptoms that could be diagnostic.”

“Babies tend to get aggressive cancers, it’s hard to tell when they’re getting sick, and some are even born with cancers that have already progressed. These factors combine to make very young age the strongest predictor of early death in our study.”

Race/ethnicity

Black race and Hispanic ethnicity also predicted early death. The OR was 1.48 for black race, 1.00 for white race (reference), and 1.09 for “other” races (P=0.102). The OR was 1.39 for Hispanic patients and 1.00 (reference) for non-Hispanic patients (P=0.007).

For hematologic malignancies, the adjusted OR was 1.68 for black patients (P=0.01) and 1.44 for patients of other, non-white races. The adjusted OR was 1.48 for Hispanic patients (P=0.009).

Dr Green said he hopes future studies will be able to determine the factors responsible for these disparities.

Higher death rates

Dr Green and his colleagues also found the rate of early death due to pediatric cancers is higher than reported in clinical trials, and this was true for all cancer subtypes assessed.

“Most of what we know about outcomes for cancer patients come from clinical trials, which have much more thorough reporting rules than cancer treated outside trials,” Dr Green said. “However, these kids in our study aren’t surviving long enough to join clinical trials.”

The researchers looked at a phase 3 trial (COG AAML0531) of pediatric patients with acute myeloid leukemia (AML) who were studied from August 2006 to June 2010. The early death rate in this trial was 1.6% (16/1022).

In contrast, the SEER database showed an early death rate for pediatric AML patients of 5.9% (15/256) during the same period as the trial and 6.2% (106/1698) for the period from 1992 to 2011. This is almost 4 times as high as the death rate in the trial.

The same effect was observed for acute lymphoblastic leukemia (ALL).

The early death rate for non-infant ALL was 0.7% (13/1790) in a trial (POG 9900) conducted from April 2000 to April 2005, 1.6% (30/1823) in the SEER data covering the same time period, and 1.3% (94/7353) in the SEER data from 1992 to 2011.

For infant ALL, the rates were 2.0% (3/149) in a trial (COG AALL0631) conducted from January 2008 to June 2014, 5.0% (2/40) in the SEER data during the trial period, and 5.4% (12/223) in the SEER data from 1992 to 2011.

“I had a hunch this was a bigger problem than we thought,” Dr Green said. “Now we see that is indeed the case.”

Photo courtesy of Amgen

Blinatumomab proved more effective than chemotherapy in a phase 3 trial of adults with Ph-negative, relapsed/refractory B-cell precursor acute lymphoblastic leukemia (B-ALL).

Blinatumomab produced higher remission rates and nearly doubled overall survival (OS) when compared to standard care, which encompassed 4 different chemotherapy regimens (investigator’s choice).

The incidence of grade 3 or higher adverse events (AEs) was higher for patients who received chemotherapy, but the incidence of serious AEs was higher in the blinatumomab arm.

These results were published in NEJM. The trial, known as TOWER, was sponsored by Amgen, the company developing blinatumomab.

“Results from the TOWER study reinforce the potential of this single-agent, bispecific T-cell engager immunotherapy, which helped a higher percentage of patients achieve minimal residual disease response versus standard of care chemotherapy, highlighting the depth and quality of remissions achieved,” said study author Hagop M. Kantarjian, MD, of The University of Texas MD Anderson Cancer Center in Houston.

Treatment

TOWER enrolled 405 patients with Ph-negative, relapsed/refractory B-ALL, 376 of whom ultimately received treatment.

The patients received blinatumomab (n=267) or investigator’s choice of 1 of 4 protocol-defined standard chemotherapy regimens (n=109):

• FLAG (fludarabine, high-dose cytarabine arabinoside, and granulocyte-colony stimulating factor), with or without an anthracycline (n=49, 45%)
• A high-dose cytarabine arabinoside-based regimen (n=19, 17%)
• A high-dose methotrexate-based regimen (n=22, 20%)
• A clofarabine-based regimen (n=19, 17%).

Patients who received blinatumomab received it as a continuous infusion, 4 weeks on and 2 weeks off, at 9 µg/day for 7 days, then 28 µg/day on weeks 2-4. They received 2 cycles of induction, which was followed by 3 cycles of consolidation if they had ≤5% blasts.

If patients still had ≤5% blasts after consolidation, they received up to 12 months of blinatumomab maintenance. Maintenance was a continuous infusion, 4 weeks on and 8 weeks off, at 28 µg/day.

Patients in the blinatumomab arm received a median of 2 cycles of therapy (range, 1-9). And patients in the chemotherapy arm received a median of 1 cycle (range, 1 to 4).

Thirty-two percent of patients in the blinatumomab arm received consolidation, as did 3% of patients in the chemotherapy arm.

Patients

Patient characteristics were similar between the treatment arms. The mean age was 41 in both arms (range, 18-80). Nearly 60% of patients in both arms were male.

About 40% of patients in the blinatumomab arm and 50% in the chemotherapy arm had not received any prior salvage regimens.

Thirty-five percent of patients in the blinatumomab arm and 34% in the chemotherapy arm had an allogeneic hematopoietic stem cell transplant (allo-HSCT) prior to study enrollment. Seventeen percent and 20%, respectively, relapsed after HSCT.

Forty-two percent and 40%, respectively, were refractory to primary or salvage therapy. Twenty-eight percent of patients in both arms were in their first relapse, and their first remission had lasted less than 12 months. Twelve percent of patients in both arms had an untreated second or greater relapse.

Remission

Within 12 weeks of treatment initiation, complete remission (CR) rates were significantly higher in the blinatumomab arm than the chemotherapy arm. (This was in the intent-to-treat population, which included 271 patients in the blinatumomab arm and 134 patients in the chemotherapy arm.)

The rate of CR with full hematologic recovery was 34% in the blinatumomab arm and 16% in the chemotherapy arm (P<0.001). The rate of CR with full, partial, or incomplete hematologic recovery was 44% and 25%, respectively (P<0.001).

Among patients who achieved a CR with full, partial, or incomplete hematologic recovery, 76% of those in the blinatumomab arm and 48% of those in the chemotherapy arm were negative for minimal residual disease.

Survival

At a median follow-up of 11.7 months for the blinatumomab arm and 11.8 months for the chemotherapy arm, the OS was significantly longer in the blinatumomab arm.

The median OS was 7.7 months and 4.0 months, respectively (hazard ratio for death=0.71, P=0.01).

The improvement in OS with blinatumomab was consistent across subgroups, regardless of age, prior salvage therapy, or prior allo-HSCT.

The investigators also considered the effect that post-treatment allo-HSCT might have on OS. Sixty-five patients in the blinatumomab arm and 32 in the chemotherapy arm went on to receive an allo-HSCT (24% of patients in both arms).

When the investigators censored for post-treatment allo-HSCT, the median OS was 6.9 months in the blinatumomab arm and 3.9 months in the chemotherapy arm (hazard ratio=0.66, P=0.004).

Safety

Nearly all patients in both arms (99%) experienced AEs. Grade 3 or higher AEs occurred in 87% of patients in the blinatumomab arm and 92% of those in the chemotherapy arm. Serious AEs occurred in 62% and 45%, respectively.

Grade 3 or higher AEs of interest, according to the researchers, were infection (34% with blinatumomab and 52% with chemotherapy), neutropenia (38% and 58%, respectively), elevated liver enzymes (13% and 15%, respectively), neurologic events (9% and 8%, respectively), cytokine release syndrome (5% and 0%, respectively), infusion reactions (3% and 1%, respectively), and lymphopenia (2% and 4%, respectively).

Fatal AEs occurred in 19% of patients in the blinatumomab arm and 17% of those in the chemotherapy arm.

Fatal AEs that occurred in at least 1% of patients in either arm (blinatumomab and chemotherapy, respectively) were sepsis (3% and 4%), septic shock (2% and 0%), multiorgan failure (1% and 0%), respiratory failure (<1% and 2%), and bacteremia (0% and 2%). 

Photo courtesy of Amgen

Blinatumomab proved more effective than chemotherapy in a phase 3 trial of adults with Ph-negative, relapsed/refractory B-cell precursor acute lymphoblastic leukemia (B-ALL).

Blinatumomab produced higher remission rates and nearly doubled overall survival (OS) when compared to standard care, which encompassed 4 different chemotherapy regimens (investigator’s choice).

The incidence of grade 3 or higher adverse events (AEs) was higher for patients who received chemotherapy, but the incidence of serious AEs was higher in the blinatumomab arm.

These results were published in NEJM. The trial, known as TOWER, was sponsored by Amgen, the company developing blinatumomab.

“Results from the TOWER study reinforce the potential of this single-agent, bispecific T-cell engager immunotherapy, which helped a higher percentage of patients achieve minimal residual disease response versus standard of care chemotherapy, highlighting the depth and quality of remissions achieved,” said study author Hagop M. Kantarjian, MD, of The University of Texas MD Anderson Cancer Center in Houston.

Treatment

TOWER enrolled 405 patients with Ph-negative, relapsed/refractory B-ALL, 376 of whom ultimately received treatment.

The patients received blinatumomab (n=267) or investigator’s choice of 1 of 4 protocol-defined standard chemotherapy regimens (n=109):

• FLAG (fludarabine, high-dose cytarabine arabinoside, and granulocyte-colony stimulating factor), with or without an anthracycline (n=49, 45%)
• A high-dose cytarabine arabinoside-based regimen (n=19, 17%)
• A high-dose methotrexate-based regimen (n=22, 20%)
• A clofarabine-based regimen (n=19, 17%).

Patients who received blinatumomab received it as a continuous infusion, 4 weeks on and 2 weeks off, at 9 µg/day for 7 days, then 28 µg/day on weeks 2-4. They received 2 cycles of induction, which was followed by 3 cycles of consolidation if they had ≤5% blasts.

If patients still had ≤5% blasts after consolidation, they received up to 12 months of blinatumomab maintenance. Maintenance was a continuous infusion, 4 weeks on and 8 weeks off, at 28 µg/day.

Patients in the blinatumomab arm received a median of 2 cycles of therapy (range, 1-9). And patients in the chemotherapy arm received a median of 1 cycle (range, 1 to 4).

Thirty-two percent of patients in the blinatumomab arm received consolidation, as did 3% of patients in the chemotherapy arm.

Patients

Patient characteristics were similar between the treatment arms. The mean age was 41 in both arms (range, 18-80). Nearly 60% of patients in both arms were male.

About 40% of patients in the blinatumomab arm and 50% in the chemotherapy arm had not received any prior salvage regimens.

Thirty-five percent of patients in the blinatumomab arm and 34% in the chemotherapy arm had an allogeneic hematopoietic stem cell transplant (allo-HSCT) prior to study enrollment. Seventeen percent and 20%, respectively, relapsed after HSCT.

Forty-two percent and 40%, respectively, were refractory to primary or salvage therapy. Twenty-eight percent of patients in both arms were in their first relapse, and their first remission had lasted less than 12 months. Twelve percent of patients in both arms had an untreated second or greater relapse.

Remission

Within 12 weeks of treatment initiation, complete remission (CR) rates were significantly higher in the blinatumomab arm than the chemotherapy arm. (This was in the intent-to-treat population, which included 271 patients in the blinatumomab arm and 134 patients in the chemotherapy arm.)

The rate of CR with full hematologic recovery was 34% in the blinatumomab arm and 16% in the chemotherapy arm (P<0.001). The rate of CR with full, partial, or incomplete hematologic recovery was 44% and 25%, respectively (P<0.001).

Among patients who achieved a CR with full, partial, or incomplete hematologic recovery, 76% of those in the blinatumomab arm and 48% of those in the chemotherapy arm were negative for minimal residual disease.

Survival

At a median follow-up of 11.7 months for the blinatumomab arm and 11.8 months for the chemotherapy arm, the OS was significantly longer in the blinatumomab arm.

The median OS was 7.7 months and 4.0 months, respectively (hazard ratio for death=0.71, P=0.01).

The improvement in OS with blinatumomab was consistent across subgroups, regardless of age, prior salvage therapy, or prior allo-HSCT.

The investigators also considered the effect that post-treatment allo-HSCT might have on OS. Sixty-five patients in the blinatumomab arm and 32 in the chemotherapy arm went on to receive an allo-HSCT (24% of patients in both arms).

When the investigators censored for post-treatment allo-HSCT, the median OS was 6.9 months in the blinatumomab arm and 3.9 months in the chemotherapy arm (hazard ratio=0.66, P=0.004).

Safety

Nearly all patients in both arms (99%) experienced AEs. Grade 3 or higher AEs occurred in 87% of patients in the blinatumomab arm and 92% of those in the chemotherapy arm. Serious AEs occurred in 62% and 45%, respectively.

Grade 3 or higher AEs of interest, according to the researchers, were infection (34% with blinatumomab and 52% with chemotherapy), neutropenia (38% and 58%, respectively), elevated liver enzymes (13% and 15%, respectively), neurologic events (9% and 8%, respectively), cytokine release syndrome (5% and 0%, respectively), infusion reactions (3% and 1%, respectively), and lymphopenia (2% and 4%, respectively).

Fatal AEs occurred in 19% of patients in the blinatumomab arm and 17% of those in the chemotherapy arm.

Fatal AEs that occurred in at least 1% of patients in either arm (blinatumomab and chemotherapy, respectively) were sepsis (3% and 4%), septic shock (2% and 0%), multiorgan failure (1% and 0%), respiratory failure (<1% and 2%), and bacteremia (0% and 2%). 

Photo courtesy of Amgen

Blinatumomab proved more effective than chemotherapy in a phase 3 trial of adults with Ph-negative, relapsed/refractory B-cell precursor acute lymphoblastic leukemia (B-ALL).

Blinatumomab produced higher remission rates and nearly doubled overall survival (OS) when compared to standard care, which encompassed 4 different chemotherapy regimens (investigator’s choice).

The incidence of grade 3 or higher adverse events (AEs) was higher for patients who received chemotherapy, but the incidence of serious AEs was higher in the blinatumomab arm.

These results were published in NEJM. The trial, known as TOWER, was sponsored by Amgen, the company developing blinatumomab.

“Results from the TOWER study reinforce the potential of this single-agent, bispecific T-cell engager immunotherapy, which helped a higher percentage of patients achieve minimal residual disease response versus standard of care chemotherapy, highlighting the depth and quality of remissions achieved,” said study author Hagop M. Kantarjian, MD, of The University of Texas MD Anderson Cancer Center in Houston.

Treatment

TOWER enrolled 405 patients with Ph-negative, relapsed/refractory B-ALL, 376 of whom ultimately received treatment.

The patients received blinatumomab (n=267) or investigator’s choice of 1 of 4 protocol-defined standard chemotherapy regimens (n=109):

• FLAG (fludarabine, high-dose cytarabine arabinoside, and granulocyte-colony stimulating factor), with or without an anthracycline (n=49, 45%)
• A high-dose cytarabine arabinoside-based regimen (n=19, 17%)
• A high-dose methotrexate-based regimen (n=22, 20%)
• A clofarabine-based regimen (n=19, 17%).

Patients who received blinatumomab received it as a continuous infusion, 4 weeks on and 2 weeks off, at 9 µg/day for 7 days, then 28 µg/day on weeks 2-4. They received 2 cycles of induction, which was followed by 3 cycles of consolidation if they had ≤5% blasts.

If patients still had ≤5% blasts after consolidation, they received up to 12 months of blinatumomab maintenance. Maintenance was a continuous infusion, 4 weeks on and 8 weeks off, at 28 µg/day.

Patients in the blinatumomab arm received a median of 2 cycles of therapy (range, 1-9). And patients in the chemotherapy arm received a median of 1 cycle (range, 1 to 4).

Thirty-two percent of patients in the blinatumomab arm received consolidation, as did 3% of patients in the chemotherapy arm.

Patients

Patient characteristics were similar between the treatment arms. The mean age was 41 in both arms (range, 18-80). Nearly 60% of patients in both arms were male.

About 40% of patients in the blinatumomab arm and 50% in the chemotherapy arm had not received any prior salvage regimens.

Thirty-five percent of patients in the blinatumomab arm and 34% in the chemotherapy arm had an allogeneic hematopoietic stem cell transplant (allo-HSCT) prior to study enrollment. Seventeen percent and 20%, respectively, relapsed after HSCT.

Forty-two percent and 40%, respectively, were refractory to primary or salvage therapy. Twenty-eight percent of patients in both arms were in their first relapse, and their first remission had lasted less than 12 months. Twelve percent of patients in both arms had an untreated second or greater relapse.

Remission

Within 12 weeks of treatment initiation, complete remission (CR) rates were significantly higher in the blinatumomab arm than the chemotherapy arm. (This was in the intent-to-treat population, which included 271 patients in the blinatumomab arm and 134 patients in the chemotherapy arm.)

The rate of CR with full hematologic recovery was 34% in the blinatumomab arm and 16% in the chemotherapy arm (P<0.001). The rate of CR with full, partial, or incomplete hematologic recovery was 44% and 25%, respectively (P<0.001).

Among patients who achieved a CR with full, partial, or incomplete hematologic recovery, 76% of those in the blinatumomab arm and 48% of those in the chemotherapy arm were negative for minimal residual disease.

Survival

At a median follow-up of 11.7 months for the blinatumomab arm and 11.8 months for the chemotherapy arm, the OS was significantly longer in the blinatumomab arm.

The median OS was 7.7 months and 4.0 months, respectively (hazard ratio for death=0.71, P=0.01).

The improvement in OS with blinatumomab was consistent across subgroups, regardless of age, prior salvage therapy, or prior allo-HSCT.

The investigators also considered the effect that post-treatment allo-HSCT might have on OS. Sixty-five patients in the blinatumomab arm and 32 in the chemotherapy arm went on to receive an allo-HSCT (24% of patients in both arms).

When the investigators censored for post-treatment allo-HSCT, the median OS was 6.9 months in the blinatumomab arm and 3.9 months in the chemotherapy arm (hazard ratio=0.66, P=0.004).

Safety

Nearly all patients in both arms (99%) experienced AEs. Grade 3 or higher AEs occurred in 87% of patients in the blinatumomab arm and 92% of those in the chemotherapy arm. Serious AEs occurred in 62% and 45%, respectively.

Grade 3 or higher AEs of interest, according to the researchers, were infection (34% with blinatumomab and 52% with chemotherapy), neutropenia (38% and 58%, respectively), elevated liver enzymes (13% and 15%, respectively), neurologic events (9% and 8%, respectively), cytokine release syndrome (5% and 0%, respectively), infusion reactions (3% and 1%, respectively), and lymphopenia (2% and 4%, respectively).

Fatal AEs occurred in 19% of patients in the blinatumomab arm and 17% of those in the chemotherapy arm.

Fatal AEs that occurred in at least 1% of patients in either arm (blinatumomab and chemotherapy, respectively) were sepsis (3% and 4%), septic shock (2% and 0%), multiorgan failure (1% and 0%), respiratory failure (<1% and 2%), and bacteremia (0% and 2%).