ALL

Photo by Bill Branson

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended expanding the marketing authorization for dasatinib (Sprycel).

The CHMP’s recommendation is to approve dasatinib in combination with chemotherapy to treat pediatric patients with newly diagnosed, Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL).

The CHMP’s recommendation will be reviewed by the European Commission (EC), which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.

The EC usually makes a decision within 67 days of a CHMP recommendation.

Dasatinib is already EC-approved to treat:

• Adults with newly diagnosed, Ph+ chronic myelogenous leukemia (CML) in the chronic phase
• Adults with chronic, accelerated, or blast phase CML with resistance or intolerance to prior therapy including imatinib
• Adults with Ph+ ALL and lymphoid blast CML with resistance or intolerance to prior therapy
• Pediatric patients with newly diagnosed, Ph+ CML in chronic phase
• Pediatric patients with Ph+ CML in chronic phase that is resistant or intolerant to prior therapy including imatinib.

Phase 2 trial

The CHMP’s recommendation to approve dasatinib in pediatric patients with newly diagnosed, Ph+ ALL is based on data from a phase 2 trial (NCT01460160). In this trial, researchers are evaluating dasatinib in combination with a chemotherapy regimen modeled on a Berlin-Frankfurt-Munster high-risk backbone.

Results from the trial were presented at the 2017 ASH Annual Meeting.

At that time, 106 patients had been treated. They received continuous daily dasatinib (60 mg/m²) beginning at day 15 of induction chemotherapy. All treated patients achieved complete remission.

Patients who had evidence of minimal residual disease (MRD) ≥ 0.05% at the end of the first block of treatment (day 78) and those with MRD 0.005% to 0.05% who remained MRD-positive at any detectable level after three additional high-risk chemotherapy blocks were eligible for hematopoietic stem cell transplant (HSCT) in first remission.

Nineteen patients met these criteria, and 15 (14.2%) received HSCT. The remaining 85.8% of patients received dasatinib plus chemotherapy for two years.

The 3-year event-free survival rate was 65.5%, and the 3-year overall survival rate was 91.5%.

Two patients discontinued dasatinib due to toxicity—one due to allergy and one due to prolonged thrombocytopenia.

Grade 3/4 adverse events attributed to dasatinib included elevated alanine aminotransferase (21.7%), elevated aspartate transaminase (10.4%), pleural effusion (3.8%), edema (2.8%), hemorrhage (5.7%), and cardiac failure (0.8%).

Five patients died while receiving chemotherapy (three from sepsis, one due to pneumonia, and one of an unknown cause). Two deaths were HSCT-related.

This trial was sponsored by Bristol-Myers Squibb.

Photo by Bill Branson

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended expanding the marketing authorization for dasatinib (Sprycel).

The CHMP’s recommendation is to approve dasatinib in combination with chemotherapy to treat pediatric patients with newly diagnosed, Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL).

The CHMP’s recommendation will be reviewed by the European Commission (EC), which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.

The EC usually makes a decision within 67 days of a CHMP recommendation.

Dasatinib is already EC-approved to treat:

• Adults with newly diagnosed, Ph+ chronic myelogenous leukemia (CML) in the chronic phase
• Adults with chronic, accelerated, or blast phase CML with resistance or intolerance to prior therapy including imatinib
• Adults with Ph+ ALL and lymphoid blast CML with resistance or intolerance to prior therapy
• Pediatric patients with newly diagnosed, Ph+ CML in chronic phase
• Pediatric patients with Ph+ CML in chronic phase that is resistant or intolerant to prior therapy including imatinib.

Phase 2 trial

The CHMP’s recommendation to approve dasatinib in pediatric patients with newly diagnosed, Ph+ ALL is based on data from a phase 2 trial (NCT01460160). In this trial, researchers are evaluating dasatinib in combination with a chemotherapy regimen modeled on a Berlin-Frankfurt-Munster high-risk backbone.

Results from the trial were presented at the 2017 ASH Annual Meeting.

At that time, 106 patients had been treated. They received continuous daily dasatinib (60 mg/m²) beginning at day 15 of induction chemotherapy. All treated patients achieved complete remission.

Patients who had evidence of minimal residual disease (MRD) ≥ 0.05% at the end of the first block of treatment (day 78) and those with MRD 0.005% to 0.05% who remained MRD-positive at any detectable level after three additional high-risk chemotherapy blocks were eligible for hematopoietic stem cell transplant (HSCT) in first remission.

Nineteen patients met these criteria, and 15 (14.2%) received HSCT. The remaining 85.8% of patients received dasatinib plus chemotherapy for two years.

The 3-year event-free survival rate was 65.5%, and the 3-year overall survival rate was 91.5%.

Two patients discontinued dasatinib due to toxicity—one due to allergy and one due to prolonged thrombocytopenia.

Grade 3/4 adverse events attributed to dasatinib included elevated alanine aminotransferase (21.7%), elevated aspartate transaminase (10.4%), pleural effusion (3.8%), edema (2.8%), hemorrhage (5.7%), and cardiac failure (0.8%).

Five patients died while receiving chemotherapy (three from sepsis, one due to pneumonia, and one of an unknown cause). Two deaths were HSCT-related.

This trial was sponsored by Bristol-Myers Squibb.

Photo by Bill Branson

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended expanding the marketing authorization for dasatinib (Sprycel).

The CHMP’s recommendation is to approve dasatinib in combination with chemotherapy to treat pediatric patients with newly diagnosed, Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL).

The CHMP’s recommendation will be reviewed by the European Commission (EC), which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.

The EC usually makes a decision within 67 days of a CHMP recommendation.

Dasatinib is already EC-approved to treat:

• Adults with newly diagnosed, Ph+ chronic myelogenous leukemia (CML) in the chronic phase
• Adults with chronic, accelerated, or blast phase CML with resistance or intolerance to prior therapy including imatinib
• Adults with Ph+ ALL and lymphoid blast CML with resistance or intolerance to prior therapy
• Pediatric patients with newly diagnosed, Ph+ CML in chronic phase
• Pediatric patients with Ph+ CML in chronic phase that is resistant or intolerant to prior therapy including imatinib.

Phase 2 trial

The CHMP’s recommendation to approve dasatinib in pediatric patients with newly diagnosed, Ph+ ALL is based on data from a phase 2 trial (NCT01460160). In this trial, researchers are evaluating dasatinib in combination with a chemotherapy regimen modeled on a Berlin-Frankfurt-Munster high-risk backbone.

Results from the trial were presented at the 2017 ASH Annual Meeting.

At that time, 106 patients had been treated. They received continuous daily dasatinib (60 mg/m²) beginning at day 15 of induction chemotherapy. All treated patients achieved complete remission.

Patients who had evidence of minimal residual disease (MRD) ≥ 0.05% at the end of the first block of treatment (day 78) and those with MRD 0.005% to 0.05% who remained MRD-positive at any detectable level after three additional high-risk chemotherapy blocks were eligible for hematopoietic stem cell transplant (HSCT) in first remission.

Nineteen patients met these criteria, and 15 (14.2%) received HSCT. The remaining 85.8% of patients received dasatinib plus chemotherapy for two years.

The 3-year event-free survival rate was 65.5%, and the 3-year overall survival rate was 91.5%.

Two patients discontinued dasatinib due to toxicity—one due to allergy and one due to prolonged thrombocytopenia.

Grade 3/4 adverse events attributed to dasatinib included elevated alanine aminotransferase (21.7%), elevated aspartate transaminase (10.4%), pleural effusion (3.8%), edema (2.8%), hemorrhage (5.7%), and cardiac failure (0.8%).

Five patients died while receiving chemotherapy (three from sepsis, one due to pneumonia, and one of an unknown cause). Two deaths were HSCT-related.

This trial was sponsored by Bristol-Myers Squibb.

Photo courtesy of ASH

SAN DIEGO—An update of the ZUMA-3 trial showed that KTE-X19—an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy—can induce high rates of undetectable minimal residual disease (MRD) and durable complete remissions (CRs) in adults with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL).

And this was particularly the case at the middle dose level of 1 x 10⁶ cells/kg.

William G. Wierda, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston, presented the update at the 2018 ASH Annual Meeting (abstract 897*).

Dr. Wierda explained that KTE-X19 is a new name for KTE-C19, also known as axicabtagene ciloleucel (Yescarta™), which is currently approved in the United States for the treatment of relapsed diffuse large B-cell lymphoma in adults and in Europe for diffuse large B-cell lymphoma and primary mediastinal large B-cell lymphoma.

“This approval was based on the ZUMA-1 clinical trial,” he said, “which showed a 54% complete remission rate and 82% overall response rate with durable remissions.”

ZUMA-3 (NCT02614066) is a phase 1/2 study of KTE-X19—a CAR T cell with CD3ζ signaling and CD28 costimulatory domains—for relapsed or refractory adults with ALL.

Dr. Wierda presented the phase 1 data available at the cutoff of August 16.

Study design

Patients underwent leukapheresis to collect their T cells for production and received bridging therapy selected by the treating physician from several prespecified regimens to maintain disease control.

Conditioning chemotherapy included fludarabine at 25 mg/m² on days -4, -3, and -2 and cyclophosphamide at 900 mg/m² on day -2.

Patients received KTE-X19 on day 0. They were monitored and released from the hospital on day 7 or upon resolution of any toxicities.

The investigators assessed response, including bone marrow evaluation, on day 28, week 8, month 3, and every 3 months for the first year as well as every 6 months for the second year of follow-up.

The dose-finding portion of the trial initially enrolled three patients. They received a dose of 2 x 10⁶ CAR T cells/kg and were monitored for dose-limiting toxicities (DLTs).

If there were no DLTs in the first three patients, phase 2 could open or investigators could further expand the 2 x 10⁶ dose level or explore lower doses of the product (1 x 10⁶ cells/kg and 0.5 x 10⁶ cells/kg).

Investigators defined DLTs as:

• KTE-X19-related events in the first 28 days, including grade 4 hematologic toxicity lasting more than 30 days and not attributable to ALL
• Grade 3 nonhematologic toxicities lasting more than 7 days
• Grade 4 nonhematologic toxicities regardless of duration, excluding grade 4 cytokine release syndrome (CRS) events lasting 7 days or less
• Neurologic events that resolve to grade 1 in 2 weeks or to baseline within 4 weeks.

Dr. Wierda said no DLTs occurred among the first 3 patients treated, and all dose levels were explored in phase 1.

Patients

As of the cutoff date, 54 patients were enrolled, confirmed eligible, and underwent leukapheresis. Six patients did not receive conditioning, three patients received conditioning but not KTE-X19, and one patient withdrew from the study after the first failed production of CAR T cells.

So 44 patients received KTE-X19. Six patients received the highest dose of CAR T cells (2 x 10⁶/kg), 22 received the middle dose (1 x 10⁶/kg), and 16 received the lowest dose (0.5 x 10⁶/kg).

The patients’ median age was 46 (range, 18 – 77). Almost half (48%) were male, and 68% had three or more prior treatment regimens. Forty-one percent had prior blinatumomab, and 14% had prior inotuzumab.

Patients had a median bone marrow blast percentage of 59% (n=44; range, 5% - 100%) at screening and 70% (n=40; range, 0 – 97%) prior to conditioning but after bridging therapy.

The safety analysis included all 44 treated patients, and the efficacy analysis included 36 patients.

“[T]he follow-up period was too short from dosing for the most recently treated eight patients,” Dr Wierda explained.

The median follow-up was 15.1 months for the 36 efficacy-evaluable patients.

Safety

All patients had a treatment-emergent adverse events (TEAEs), with 75% having grade 3/4 events.

Grade 5 TEAEs included three due to progressive disease, three due to infections, and one stroke 6 weeks after infusion.

Two patients died of KTE-X19-related AEs. One patient in the 2 x 10⁶ dose group had multiorgan failure secondary to CRS on study day 6. The other patient, in the 0.5 x 10⁶ dose group, had a stroke after infusion in the context of CRS and neurologic events (NEs) on day 7.

Investigators detected a higher incidence of grade 3 and greater CRS for the six patients treated at the highest dose. Half developed CRS of grade 3 or higher, compared with 18% in the 1 x 10⁶ dose cohort and 19% in the 0.5 x 10⁶ dose cohort.

Grade 3 or higher NEs were more common than CRS. The lowest incidence occurred in the lowest dose cohort, at 25%, compared with 45% in the 1 x 10⁶ dose cohort and 50% in the 2 x 10⁶ dose cohort.

Due to the incidence of grade 3 and greater NEs observed in the 1 x 10⁶ dose cohort, investigators revised the management guidelines for AEs. The revisions included using tocilizumab only for CRS—and not for NEs—and initiating steroids for grade 2 NEs instead of waiting for grade 3.

Eight patients were treated under the revised recommendations, and the incidence of grade 3 NEs was 13%, with no grade 4 or 5 NEs.

“This compared favorably with the 14 patients treated at the same dose level but prior to these changes," Dr. Wierda said.

In comparison, 57% developed grade 3 NEs and 7% grade 4 with the original AE management protocol.

The incidence of grade 3 CRS remained low, with no CRS events of grade 4 or greater with the revised recommendations.

Efficacy

The best overall response in the 36 efficacy-evaluable patients was 69% CR and CR with incomplete hematologic recovery (CRi).

Seventy-five percent of these patients had undetectable MRD in the bone marrow at 10^-4 sensitivity at 3 months of follow-up.

All patients in the 1 x 10⁶ dose cohort (n=14) responded. Ninety-three percent achieved a CR/CRi, 7% had a partial response, and all had undetectable MRD in the bone marrow.

The median duration of response was 12.9 months in the 1 x 10⁶ cohort. This was the dose selected for the phase 2 trial, which is now enrolling patients.

ZUMA-3 was sponsored by Kite, a Gilead Company.

Dr. Wierda disclosed research funding from AbbVie and Genentech. 

* Data in the abstract differ from the presentation.

Photo courtesy of ASH

SAN DIEGO—An update of the ZUMA-3 trial showed that KTE-X19—an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy—can induce high rates of undetectable minimal residual disease (MRD) and durable complete remissions (CRs) in adults with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL).

And this was particularly the case at the middle dose level of 1 x 10⁶ cells/kg.

William G. Wierda, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston, presented the update at the 2018 ASH Annual Meeting (abstract 897*).

Dr. Wierda explained that KTE-X19 is a new name for KTE-C19, also known as axicabtagene ciloleucel (Yescarta™), which is currently approved in the United States for the treatment of relapsed diffuse large B-cell lymphoma in adults and in Europe for diffuse large B-cell lymphoma and primary mediastinal large B-cell lymphoma.

“This approval was based on the ZUMA-1 clinical trial,” he said, “which showed a 54% complete remission rate and 82% overall response rate with durable remissions.”

ZUMA-3 (NCT02614066) is a phase 1/2 study of KTE-X19—a CAR T cell with CD3ζ signaling and CD28 costimulatory domains—for relapsed or refractory adults with ALL.

Dr. Wierda presented the phase 1 data available at the cutoff of August 16.

Study design

Patients underwent leukapheresis to collect their T cells for production and received bridging therapy selected by the treating physician from several prespecified regimens to maintain disease control.

Conditioning chemotherapy included fludarabine at 25 mg/m² on days -4, -3, and -2 and cyclophosphamide at 900 mg/m² on day -2.

Patients received KTE-X19 on day 0. They were monitored and released from the hospital on day 7 or upon resolution of any toxicities.

The investigators assessed response, including bone marrow evaluation, on day 28, week 8, month 3, and every 3 months for the first year as well as every 6 months for the second year of follow-up.

The dose-finding portion of the trial initially enrolled three patients. They received a dose of 2 x 10⁶ CAR T cells/kg and were monitored for dose-limiting toxicities (DLTs).

If there were no DLTs in the first three patients, phase 2 could open or investigators could further expand the 2 x 10⁶ dose level or explore lower doses of the product (1 x 10⁶ cells/kg and 0.5 x 10⁶ cells/kg).

Investigators defined DLTs as:

• KTE-X19-related events in the first 28 days, including grade 4 hematologic toxicity lasting more than 30 days and not attributable to ALL
• Grade 3 nonhematologic toxicities lasting more than 7 days
• Grade 4 nonhematologic toxicities regardless of duration, excluding grade 4 cytokine release syndrome (CRS) events lasting 7 days or less
• Neurologic events that resolve to grade 1 in 2 weeks or to baseline within 4 weeks.

Dr. Wierda said no DLTs occurred among the first 3 patients treated, and all dose levels were explored in phase 1.

Patients

As of the cutoff date, 54 patients were enrolled, confirmed eligible, and underwent leukapheresis. Six patients did not receive conditioning, three patients received conditioning but not KTE-X19, and one patient withdrew from the study after the first failed production of CAR T cells.

So 44 patients received KTE-X19. Six patients received the highest dose of CAR T cells (2 x 10⁶/kg), 22 received the middle dose (1 x 10⁶/kg), and 16 received the lowest dose (0.5 x 10⁶/kg).

The patients’ median age was 46 (range, 18 – 77). Almost half (48%) were male, and 68% had three or more prior treatment regimens. Forty-one percent had prior blinatumomab, and 14% had prior inotuzumab.

Patients had a median bone marrow blast percentage of 59% (n=44; range, 5% - 100%) at screening and 70% (n=40; range, 0 – 97%) prior to conditioning but after bridging therapy.

The safety analysis included all 44 treated patients, and the efficacy analysis included 36 patients.

“[T]he follow-up period was too short from dosing for the most recently treated eight patients,” Dr Wierda explained.

The median follow-up was 15.1 months for the 36 efficacy-evaluable patients.

Safety

All patients had a treatment-emergent adverse events (TEAEs), with 75% having grade 3/4 events.

Grade 5 TEAEs included three due to progressive disease, three due to infections, and one stroke 6 weeks after infusion.

Two patients died of KTE-X19-related AEs. One patient in the 2 x 10⁶ dose group had multiorgan failure secondary to CRS on study day 6. The other patient, in the 0.5 x 10⁶ dose group, had a stroke after infusion in the context of CRS and neurologic events (NEs) on day 7.

Investigators detected a higher incidence of grade 3 and greater CRS for the six patients treated at the highest dose. Half developed CRS of grade 3 or higher, compared with 18% in the 1 x 10⁶ dose cohort and 19% in the 0.5 x 10⁶ dose cohort.

Grade 3 or higher NEs were more common than CRS. The lowest incidence occurred in the lowest dose cohort, at 25%, compared with 45% in the 1 x 10⁶ dose cohort and 50% in the 2 x 10⁶ dose cohort.

Due to the incidence of grade 3 and greater NEs observed in the 1 x 10⁶ dose cohort, investigators revised the management guidelines for AEs. The revisions included using tocilizumab only for CRS—and not for NEs—and initiating steroids for grade 2 NEs instead of waiting for grade 3.

Eight patients were treated under the revised recommendations, and the incidence of grade 3 NEs was 13%, with no grade 4 or 5 NEs.

“This compared favorably with the 14 patients treated at the same dose level but prior to these changes," Dr. Wierda said.

In comparison, 57% developed grade 3 NEs and 7% grade 4 with the original AE management protocol.

The incidence of grade 3 CRS remained low, with no CRS events of grade 4 or greater with the revised recommendations.

Efficacy

The best overall response in the 36 efficacy-evaluable patients was 69% CR and CR with incomplete hematologic recovery (CRi).

Seventy-five percent of these patients had undetectable MRD in the bone marrow at 10^-4 sensitivity at 3 months of follow-up.

All patients in the 1 x 10⁶ dose cohort (n=14) responded. Ninety-three percent achieved a CR/CRi, 7% had a partial response, and all had undetectable MRD in the bone marrow.

The median duration of response was 12.9 months in the 1 x 10⁶ cohort. This was the dose selected for the phase 2 trial, which is now enrolling patients.

ZUMA-3 was sponsored by Kite, a Gilead Company.

Dr. Wierda disclosed research funding from AbbVie and Genentech. 

* Data in the abstract differ from the presentation.

Photo courtesy of ASH

SAN DIEGO—An update of the ZUMA-3 trial showed that KTE-X19—an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy—can induce high rates of undetectable minimal residual disease (MRD) and durable complete remissions (CRs) in adults with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL).

And this was particularly the case at the middle dose level of 1 x 10⁶ cells/kg.

William G. Wierda, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston, presented the update at the 2018 ASH Annual Meeting (abstract 897*).

Dr. Wierda explained that KTE-X19 is a new name for KTE-C19, also known as axicabtagene ciloleucel (Yescarta™), which is currently approved in the United States for the treatment of relapsed diffuse large B-cell lymphoma in adults and in Europe for diffuse large B-cell lymphoma and primary mediastinal large B-cell lymphoma.

“This approval was based on the ZUMA-1 clinical trial,” he said, “which showed a 54% complete remission rate and 82% overall response rate with durable remissions.”

ZUMA-3 (NCT02614066) is a phase 1/2 study of KTE-X19—a CAR T cell with CD3ζ signaling and CD28 costimulatory domains—for relapsed or refractory adults with ALL.

Dr. Wierda presented the phase 1 data available at the cutoff of August 16.

Study design

Patients underwent leukapheresis to collect their T cells for production and received bridging therapy selected by the treating physician from several prespecified regimens to maintain disease control.

Conditioning chemotherapy included fludarabine at 25 mg/m² on days -4, -3, and -2 and cyclophosphamide at 900 mg/m² on day -2.

Patients received KTE-X19 on day 0. They were monitored and released from the hospital on day 7 or upon resolution of any toxicities.

The investigators assessed response, including bone marrow evaluation, on day 28, week 8, month 3, and every 3 months for the first year as well as every 6 months for the second year of follow-up.

The dose-finding portion of the trial initially enrolled three patients. They received a dose of 2 x 10⁶ CAR T cells/kg and were monitored for dose-limiting toxicities (DLTs).

If there were no DLTs in the first three patients, phase 2 could open or investigators could further expand the 2 x 10⁶ dose level or explore lower doses of the product (1 x 10⁶ cells/kg and 0.5 x 10⁶ cells/kg).

Investigators defined DLTs as:

• KTE-X19-related events in the first 28 days, including grade 4 hematologic toxicity lasting more than 30 days and not attributable to ALL
• Grade 3 nonhematologic toxicities lasting more than 7 days
• Grade 4 nonhematologic toxicities regardless of duration, excluding grade 4 cytokine release syndrome (CRS) events lasting 7 days or less
• Neurologic events that resolve to grade 1 in 2 weeks or to baseline within 4 weeks.

Dr. Wierda said no DLTs occurred among the first 3 patients treated, and all dose levels were explored in phase 1.

Patients

As of the cutoff date, 54 patients were enrolled, confirmed eligible, and underwent leukapheresis. Six patients did not receive conditioning, three patients received conditioning but not KTE-X19, and one patient withdrew from the study after the first failed production of CAR T cells.

So 44 patients received KTE-X19. Six patients received the highest dose of CAR T cells (2 x 10⁶/kg), 22 received the middle dose (1 x 10⁶/kg), and 16 received the lowest dose (0.5 x 10⁶/kg).

The patients’ median age was 46 (range, 18 – 77). Almost half (48%) were male, and 68% had three or more prior treatment regimens. Forty-one percent had prior blinatumomab, and 14% had prior inotuzumab.

Patients had a median bone marrow blast percentage of 59% (n=44; range, 5% - 100%) at screening and 70% (n=40; range, 0 – 97%) prior to conditioning but after bridging therapy.

The safety analysis included all 44 treated patients, and the efficacy analysis included 36 patients.

“[T]he follow-up period was too short from dosing for the most recently treated eight patients,” Dr Wierda explained.

The median follow-up was 15.1 months for the 36 efficacy-evaluable patients.

Safety

All patients had a treatment-emergent adverse events (TEAEs), with 75% having grade 3/4 events.

Grade 5 TEAEs included three due to progressive disease, three due to infections, and one stroke 6 weeks after infusion.

Two patients died of KTE-X19-related AEs. One patient in the 2 x 10⁶ dose group had multiorgan failure secondary to CRS on study day 6. The other patient, in the 0.5 x 10⁶ dose group, had a stroke after infusion in the context of CRS and neurologic events (NEs) on day 7.

Investigators detected a higher incidence of grade 3 and greater CRS for the six patients treated at the highest dose. Half developed CRS of grade 3 or higher, compared with 18% in the 1 x 10⁶ dose cohort and 19% in the 0.5 x 10⁶ dose cohort.

Grade 3 or higher NEs were more common than CRS. The lowest incidence occurred in the lowest dose cohort, at 25%, compared with 45% in the 1 x 10⁶ dose cohort and 50% in the 2 x 10⁶ dose cohort.

Due to the incidence of grade 3 and greater NEs observed in the 1 x 10⁶ dose cohort, investigators revised the management guidelines for AEs. The revisions included using tocilizumab only for CRS—and not for NEs—and initiating steroids for grade 2 NEs instead of waiting for grade 3.

Eight patients were treated under the revised recommendations, and the incidence of grade 3 NEs was 13%, with no grade 4 or 5 NEs.

“This compared favorably with the 14 patients treated at the same dose level but prior to these changes," Dr. Wierda said.

In comparison, 57% developed grade 3 NEs and 7% grade 4 with the original AE management protocol.

The incidence of grade 3 CRS remained low, with no CRS events of grade 4 or greater with the revised recommendations.

Efficacy

The best overall response in the 36 efficacy-evaluable patients was 69% CR and CR with incomplete hematologic recovery (CRi).

Seventy-five percent of these patients had undetectable MRD in the bone marrow at 10^-4 sensitivity at 3 months of follow-up.

All patients in the 1 x 10⁶ dose cohort (n=14) responded. Ninety-three percent achieved a CR/CRi, 7% had a partial response, and all had undetectable MRD in the bone marrow.

The median duration of response was 12.9 months in the 1 x 10⁶ cohort. This was the dose selected for the phase 2 trial, which is now enrolling patients.

ZUMA-3 was sponsored by Kite, a Gilead Company.

Dr. Wierda disclosed research funding from AbbVie and Genentech. 

* Data in the abstract differ from the presentation.

Photo by Jen Smith

SAN DIEGO—Preliminary data on UCART19—the first off-the-shelf, anti-CD19, allogeneic chimeric antigen receptor (CAR) T-cell therapy—suggest it can produce complete responses (CRs) and minimal residual disease (MRD) negativity, and side effects are manageable.

Investigators pooled data from the phase 1 pediatric (PALL) and adult (CALM) trials of UCART19 in patients with relapsed or refractory acute lymphoblastic leukemia (ALL) and observed a 67% CR rate in the overall population and an 82% CR rate in patients who received a three-drug lymphodepleting regimen.

Additionally, investigators reported no instance of moderate or severe acute graft-versus-host disease (GVHD) with UCART19.

“We’ve been blessed with the new treatments that have emerged in recent years,” said Reuben Benjamin, MD, PhD, “that include BiTEs, antibody-drug conjugates, and most excitingly, the autologous CAR T-cell therapies.”

Nevertheless, some logistical issues with the autologous CAR T cells leave an unmet need in this group of patients, he noted.

“So an off-the-shelf approach using a product like UCART19 may potentially overcome some of these hurdles that we see in the autologous CAR T-cell therapy field,” he said.

Dr. Benjamin, of King’s College Hospital in London, U.K., presented the analysis of PALL and CALM data at the 2018 ASH Annual Meeting as abstract 896.*

UCART19 product

UCART19 is an allogeneic, genetically modified, CAR T-cell product (anti-CD19 scFv- 41BB-CD3ζ) manufactured from healthy donor T cells.

It has a safety switch—RQR8, which is a CD20 mimotope—that allows the CAR T cells to be targeted by rituximab.

“And importantly,” Dr. Benjamin explained, “the T-cell alpha gene has been knocked out using TALEN® gene-editing technology to prevent T-cell receptor-mediated graft-versus-host disease.”

The CD52 gene is also knocked out, which permits an anti-CD52 monoclonal antibody, such as alemtuzumab, to be used in lymphodepletion.

Study design

The primary objective of both the adult (NCT02746952) and pediatric (NCT02808442) studies was to determine the safety and tolerability of UCART19. Also, the adult study was to determine the maximum tolerated dose of UCART19 and the optimal lymphodepleting regimen.

A secondary objective of both studies was to determine the remission rate at day 28.

Eligible patients received a lymphodepleting regimen for 7 days, followed by a single infusion of UCART19.

Lymphodepletion in the pediatric trial consisted of fludarabine (F) at 150 mg/m² and cyclophosphamide (C) at 120 mg/kg, with or without alemtuzumab (A) at 1 mg/kg capped at 40 mg.

Adults received lower doses of each agent—90 mg/m², 1,500 mg/m², and (optionally) 1 mg/kg or 40 mg, respectively.

Investigators included alemtuzumab in the regimen to minimize viral infections.

The UCART19 dose was weight-banded in the pediatric trial and ranged from 1.1 to 2.3 x 10⁶ cells/kg.

The adult trial included three UCART19 dose levels:

• 6 x 10⁶ cells (≈1 x 10⁵ cells/kg)
• 6 or 8 x 10⁷ cells (≈1 x 10⁶ cells/kg)
• 8 or 2.4 x 10⁸ cells (≈3 x 10⁶ cells/kg).

Patients were assessed for safety and response at day 28 and regularly thereafter for up to 12 months. Patients had the option during the follow-up period to receive a second dose if they did not respond or lost their response.

Patient characteristics/status

Twenty-one patients were enrolled in the trials—seven children and 14 adults. Median ages were 2.7 years (PALL; range, 0.8–16.4) and 29.5 years (CALM; range, 18–62).

Both studies included high-risk, heavily pretreated populations, Dr. Benjamin noted.

The pooled population had a median of 4 prior lines of therapy (range, 1–6), and nine patients had a high-risk cytogenetics, including complex karyotypes, MLL rearrangements, and Ph+ disease.

Thirteen patients had prior allogeneic stem cell transplants.

Nine patients had a bone marrow tumor burden of more than 25% blasts prior to lymphodepletion.

As of the cutoff date of October 23, all patients had been treated with UCART19.

Four of the pediatric patients are still on the trial. Two are in remission, one has relapsed, and one is refractory.

Eight adult patients are still on trial. Three are in remission, three are relapsed, and two are refractory.

Safety

“UCART19 appears to show an acceptable safety profile based on the adverse events reported so far,” Dr. Benjamin said.

Nineteen patients experienced cytokine release syndrome (CRS), primarily grades 1 and 2. Eight patients had grade 1 and 2 neurotoxicity events, and two patients had grade 1 acute skin GVHD.

“In keeping with what is seen in some of the autologous CAR T-cell trials,” Dr. Benjamin explained, “prolonged cytopenias were seen, which we defined in these studies as grade 4 neutropenia or thrombocytopenia occurring at 42 days post-UCART infusion.”

Six of 21 patients developed prolonged cytopenia.

There was also an increased incidence of viral infections occurring in eight patients, including cytomegalovirus, adenovirus, BK virus, and metapneumovirus.

“Most of these infections, however, were manageable,” Dr. Benjamin said.

Two patients developed neutropenic sepsis, one grade 5, which was one of the treatment-related deaths in the CALM trial.

No treatment-related deaths occurred in the PALL study, but there were two in the CALM study—one from pulmonary hemorrhage and the other from neutropenic sepsis and grade 4 CRS.

Twelve patients are still alive, five of whom are in CR.

Efficacy

Of the patients who received FCA lymphodepletion, 82% (14/17) achieved CR/CR with incomplete hematologic recovery (CRi), and 71% (10/14) achieved MRD negativity.

An additional patient gained MRD-negative status after the second dose of UCART19.

Of the 14 patients who achieved a CR/CRi, 78% (n=11) went on to receive an allogeneic transplant.

In the entire pooled population, 67% (14/21) achieved CR/CRi.

Three patients received a second UCART19 dose, and five patients remain in CR/CRi.

UCART19 expansion

UCART19 expansion, as measured by quantitative polymerase chain reaction in PALL and flow-based methods in CALM, occurred primarily in the first 28 days in the FCA-treated population.

Investigators observed expansion in 15 of 17 patients treated with FCA. None of the patients who received FC alone (n=4) had expansion detectable in blood or bone marrow, Dr. Benjamin noted.

“The response we’ve seen in the study so far,” Dr. Benjamin clarified, “is linked to the expansion observed within the first 28-day period.”

UCART cells persisted in three patients beyond day 42. In one patient, they persisted up to day 120.

“Of interest is the T-cell recovery seen in the study,” Dr. Benjamin elaborated. “We only have data from the adult study here—14 patients. And you’ll see that, in the FCA-treated arm (n=11), you have a deeper and more sustained lymphodepletion compared to the FC-treated patients (n=3). And this may play a role in the subsequent UCART19 expansion and disease response.”

Re-dosing

Of the three patients who were re-dosed, two achieved MRD negativity.

One patient achieved MRD-negative status at day 28 but relapsed and received a second infusion 3 months after the first dose. The second expansion was not as deep as the first, but the patient nevertheless achieved MRD negativity after the second dose.

The second patient received FC lymphodepletion and was refractory at day 28.

“The second time around, he received FCA, had a slightly better expansion, and achieved molecular remission,” Dr. Benjamin said.

And the third patient had FCA lymphodepletion but was refractory at day 28.

“We elected to give a second dose at 2.4 months later, but unfortunately, there wasn’t very much expansion, even the second time around, and the patient progressed,” Dr. Benjamin said.

FCA lymphodepletion appears to be required for UCART19 expansion. There was no UCART19 expansion and no response in all four patients lymphodepleted with FC.

The evaluation of UCART19 is ongoing in pediatric and adult B-cell ALL, and “there is a plan for moving into the lymphoma space as well,” Dr. Benjamin added.

Dr. Benjamin disclosed honoraria from Amgen, Takeda, Novartis, Gilead, and Celgene, and research funding from Servier and Pfizer.

Servier and Allogene are supporting the UCART19 trials. 

*Data in the abstract differ from the presentation.

Photo by Jen Smith

SAN DIEGO—Preliminary data on UCART19—the first off-the-shelf, anti-CD19, allogeneic chimeric antigen receptor (CAR) T-cell therapy—suggest it can produce complete responses (CRs) and minimal residual disease (MRD) negativity, and side effects are manageable.

Investigators pooled data from the phase 1 pediatric (PALL) and adult (CALM) trials of UCART19 in patients with relapsed or refractory acute lymphoblastic leukemia (ALL) and observed a 67% CR rate in the overall population and an 82% CR rate in patients who received a three-drug lymphodepleting regimen.

Additionally, investigators reported no instance of moderate or severe acute graft-versus-host disease (GVHD) with UCART19.

“We’ve been blessed with the new treatments that have emerged in recent years,” said Reuben Benjamin, MD, PhD, “that include BiTEs, antibody-drug conjugates, and most excitingly, the autologous CAR T-cell therapies.”

Nevertheless, some logistical issues with the autologous CAR T cells leave an unmet need in this group of patients, he noted.

“So an off-the-shelf approach using a product like UCART19 may potentially overcome some of these hurdles that we see in the autologous CAR T-cell therapy field,” he said.

Dr. Benjamin, of King’s College Hospital in London, U.K., presented the analysis of PALL and CALM data at the 2018 ASH Annual Meeting as abstract 896.*

UCART19 product

UCART19 is an allogeneic, genetically modified, CAR T-cell product (anti-CD19 scFv- 41BB-CD3ζ) manufactured from healthy donor T cells.

It has a safety switch—RQR8, which is a CD20 mimotope—that allows the CAR T cells to be targeted by rituximab.

“And importantly,” Dr. Benjamin explained, “the T-cell alpha gene has been knocked out using TALEN® gene-editing technology to prevent T-cell receptor-mediated graft-versus-host disease.”

The CD52 gene is also knocked out, which permits an anti-CD52 monoclonal antibody, such as alemtuzumab, to be used in lymphodepletion.

Study design

The primary objective of both the adult (NCT02746952) and pediatric (NCT02808442) studies was to determine the safety and tolerability of UCART19. Also, the adult study was to determine the maximum tolerated dose of UCART19 and the optimal lymphodepleting regimen.

A secondary objective of both studies was to determine the remission rate at day 28.

Eligible patients received a lymphodepleting regimen for 7 days, followed by a single infusion of UCART19.

Lymphodepletion in the pediatric trial consisted of fludarabine (F) at 150 mg/m² and cyclophosphamide (C) at 120 mg/kg, with or without alemtuzumab (A) at 1 mg/kg capped at 40 mg.

Adults received lower doses of each agent—90 mg/m², 1,500 mg/m², and (optionally) 1 mg/kg or 40 mg, respectively.

Investigators included alemtuzumab in the regimen to minimize viral infections.

The UCART19 dose was weight-banded in the pediatric trial and ranged from 1.1 to 2.3 x 10⁶ cells/kg.

The adult trial included three UCART19 dose levels:

• 6 x 10⁶ cells (≈1 x 10⁵ cells/kg)
• 6 or 8 x 10⁷ cells (≈1 x 10⁶ cells/kg)
• 8 or 2.4 x 10⁸ cells (≈3 x 10⁶ cells/kg).

Patients were assessed for safety and response at day 28 and regularly thereafter for up to 12 months. Patients had the option during the follow-up period to receive a second dose if they did not respond or lost their response.

Patient characteristics/status

Twenty-one patients were enrolled in the trials—seven children and 14 adults. Median ages were 2.7 years (PALL; range, 0.8–16.4) and 29.5 years (CALM; range, 18–62).

Both studies included high-risk, heavily pretreated populations, Dr. Benjamin noted.

The pooled population had a median of 4 prior lines of therapy (range, 1–6), and nine patients had a high-risk cytogenetics, including complex karyotypes, MLL rearrangements, and Ph+ disease.

Thirteen patients had prior allogeneic stem cell transplants.

Nine patients had a bone marrow tumor burden of more than 25% blasts prior to lymphodepletion.

As of the cutoff date of October 23, all patients had been treated with UCART19.

Four of the pediatric patients are still on the trial. Two are in remission, one has relapsed, and one is refractory.

Eight adult patients are still on trial. Three are in remission, three are relapsed, and two are refractory.

Safety

“UCART19 appears to show an acceptable safety profile based on the adverse events reported so far,” Dr. Benjamin said.

Nineteen patients experienced cytokine release syndrome (CRS), primarily grades 1 and 2. Eight patients had grade 1 and 2 neurotoxicity events, and two patients had grade 1 acute skin GVHD.

“In keeping with what is seen in some of the autologous CAR T-cell trials,” Dr. Benjamin explained, “prolonged cytopenias were seen, which we defined in these studies as grade 4 neutropenia or thrombocytopenia occurring at 42 days post-UCART infusion.”

Six of 21 patients developed prolonged cytopenia.

There was also an increased incidence of viral infections occurring in eight patients, including cytomegalovirus, adenovirus, BK virus, and metapneumovirus.

“Most of these infections, however, were manageable,” Dr. Benjamin said.

Two patients developed neutropenic sepsis, one grade 5, which was one of the treatment-related deaths in the CALM trial.

No treatment-related deaths occurred in the PALL study, but there were two in the CALM study—one from pulmonary hemorrhage and the other from neutropenic sepsis and grade 4 CRS.

Twelve patients are still alive, five of whom are in CR.

Efficacy

Of the patients who received FCA lymphodepletion, 82% (14/17) achieved CR/CR with incomplete hematologic recovery (CRi), and 71% (10/14) achieved MRD negativity.

An additional patient gained MRD-negative status after the second dose of UCART19.

Of the 14 patients who achieved a CR/CRi, 78% (n=11) went on to receive an allogeneic transplant.

In the entire pooled population, 67% (14/21) achieved CR/CRi.

Three patients received a second UCART19 dose, and five patients remain in CR/CRi.

UCART19 expansion

UCART19 expansion, as measured by quantitative polymerase chain reaction in PALL and flow-based methods in CALM, occurred primarily in the first 28 days in the FCA-treated population.

Investigators observed expansion in 15 of 17 patients treated with FCA. None of the patients who received FC alone (n=4) had expansion detectable in blood or bone marrow, Dr. Benjamin noted.

“The response we’ve seen in the study so far,” Dr. Benjamin clarified, “is linked to the expansion observed within the first 28-day period.”

UCART cells persisted in three patients beyond day 42. In one patient, they persisted up to day 120.

“Of interest is the T-cell recovery seen in the study,” Dr. Benjamin elaborated. “We only have data from the adult study here—14 patients. And you’ll see that, in the FCA-treated arm (n=11), you have a deeper and more sustained lymphodepletion compared to the FC-treated patients (n=3). And this may play a role in the subsequent UCART19 expansion and disease response.”

Re-dosing

Of the three patients who were re-dosed, two achieved MRD negativity.

One patient achieved MRD-negative status at day 28 but relapsed and received a second infusion 3 months after the first dose. The second expansion was not as deep as the first, but the patient nevertheless achieved MRD negativity after the second dose.

The second patient received FC lymphodepletion and was refractory at day 28.

“The second time around, he received FCA, had a slightly better expansion, and achieved molecular remission,” Dr. Benjamin said.

And the third patient had FCA lymphodepletion but was refractory at day 28.

“We elected to give a second dose at 2.4 months later, but unfortunately, there wasn’t very much expansion, even the second time around, and the patient progressed,” Dr. Benjamin said.

FCA lymphodepletion appears to be required for UCART19 expansion. There was no UCART19 expansion and no response in all four patients lymphodepleted with FC.

The evaluation of UCART19 is ongoing in pediatric and adult B-cell ALL, and “there is a plan for moving into the lymphoma space as well,” Dr. Benjamin added.

Dr. Benjamin disclosed honoraria from Amgen, Takeda, Novartis, Gilead, and Celgene, and research funding from Servier and Pfizer.

Servier and Allogene are supporting the UCART19 trials. 

*Data in the abstract differ from the presentation.

Photo by Jen Smith

SAN DIEGO—Preliminary data on UCART19—the first off-the-shelf, anti-CD19, allogeneic chimeric antigen receptor (CAR) T-cell therapy—suggest it can produce complete responses (CRs) and minimal residual disease (MRD) negativity, and side effects are manageable.

Investigators pooled data from the phase 1 pediatric (PALL) and adult (CALM) trials of UCART19 in patients with relapsed or refractory acute lymphoblastic leukemia (ALL) and observed a 67% CR rate in the overall population and an 82% CR rate in patients who received a three-drug lymphodepleting regimen.

Additionally, investigators reported no instance of moderate or severe acute graft-versus-host disease (GVHD) with UCART19.

“We’ve been blessed with the new treatments that have emerged in recent years,” said Reuben Benjamin, MD, PhD, “that include BiTEs, antibody-drug conjugates, and most excitingly, the autologous CAR T-cell therapies.”

Nevertheless, some logistical issues with the autologous CAR T cells leave an unmet need in this group of patients, he noted.

“So an off-the-shelf approach using a product like UCART19 may potentially overcome some of these hurdles that we see in the autologous CAR T-cell therapy field,” he said.

Dr. Benjamin, of King’s College Hospital in London, U.K., presented the analysis of PALL and CALM data at the 2018 ASH Annual Meeting as abstract 896.*

UCART19 product

UCART19 is an allogeneic, genetically modified, CAR T-cell product (anti-CD19 scFv- 41BB-CD3ζ) manufactured from healthy donor T cells.

It has a safety switch—RQR8, which is a CD20 mimotope—that allows the CAR T cells to be targeted by rituximab.

“And importantly,” Dr. Benjamin explained, “the T-cell alpha gene has been knocked out using TALEN® gene-editing technology to prevent T-cell receptor-mediated graft-versus-host disease.”

The CD52 gene is also knocked out, which permits an anti-CD52 monoclonal antibody, such as alemtuzumab, to be used in lymphodepletion.

Study design

The primary objective of both the adult (NCT02746952) and pediatric (NCT02808442) studies was to determine the safety and tolerability of UCART19. Also, the adult study was to determine the maximum tolerated dose of UCART19 and the optimal lymphodepleting regimen.

A secondary objective of both studies was to determine the remission rate at day 28.

Eligible patients received a lymphodepleting regimen for 7 days, followed by a single infusion of UCART19.

Lymphodepletion in the pediatric trial consisted of fludarabine (F) at 150 mg/m² and cyclophosphamide (C) at 120 mg/kg, with or without alemtuzumab (A) at 1 mg/kg capped at 40 mg.

Adults received lower doses of each agent—90 mg/m², 1,500 mg/m², and (optionally) 1 mg/kg or 40 mg, respectively.

Investigators included alemtuzumab in the regimen to minimize viral infections.

The UCART19 dose was weight-banded in the pediatric trial and ranged from 1.1 to 2.3 x 10⁶ cells/kg.

The adult trial included three UCART19 dose levels:

• 6 x 10⁶ cells (≈1 x 10⁵ cells/kg)
• 6 or 8 x 10⁷ cells (≈1 x 10⁶ cells/kg)
• 8 or 2.4 x 10⁸ cells (≈3 x 10⁶ cells/kg).

Patients were assessed for safety and response at day 28 and regularly thereafter for up to 12 months. Patients had the option during the follow-up period to receive a second dose if they did not respond or lost their response.

Patient characteristics/status

Twenty-one patients were enrolled in the trials—seven children and 14 adults. Median ages were 2.7 years (PALL; range, 0.8–16.4) and 29.5 years (CALM; range, 18–62).

Both studies included high-risk, heavily pretreated populations, Dr. Benjamin noted.

The pooled population had a median of 4 prior lines of therapy (range, 1–6), and nine patients had a high-risk cytogenetics, including complex karyotypes, MLL rearrangements, and Ph+ disease.

Thirteen patients had prior allogeneic stem cell transplants.

Nine patients had a bone marrow tumor burden of more than 25% blasts prior to lymphodepletion.

As of the cutoff date of October 23, all patients had been treated with UCART19.

Four of the pediatric patients are still on the trial. Two are in remission, one has relapsed, and one is refractory.

Eight adult patients are still on trial. Three are in remission, three are relapsed, and two are refractory.

Safety

“UCART19 appears to show an acceptable safety profile based on the adverse events reported so far,” Dr. Benjamin said.

Nineteen patients experienced cytokine release syndrome (CRS), primarily grades 1 and 2. Eight patients had grade 1 and 2 neurotoxicity events, and two patients had grade 1 acute skin GVHD.

“In keeping with what is seen in some of the autologous CAR T-cell trials,” Dr. Benjamin explained, “prolonged cytopenias were seen, which we defined in these studies as grade 4 neutropenia or thrombocytopenia occurring at 42 days post-UCART infusion.”

Six of 21 patients developed prolonged cytopenia.

There was also an increased incidence of viral infections occurring in eight patients, including cytomegalovirus, adenovirus, BK virus, and metapneumovirus.

“Most of these infections, however, were manageable,” Dr. Benjamin said.

Two patients developed neutropenic sepsis, one grade 5, which was one of the treatment-related deaths in the CALM trial.

No treatment-related deaths occurred in the PALL study, but there were two in the CALM study—one from pulmonary hemorrhage and the other from neutropenic sepsis and grade 4 CRS.

Twelve patients are still alive, five of whom are in CR.

Efficacy

Of the patients who received FCA lymphodepletion, 82% (14/17) achieved CR/CR with incomplete hematologic recovery (CRi), and 71% (10/14) achieved MRD negativity.

An additional patient gained MRD-negative status after the second dose of UCART19.

Of the 14 patients who achieved a CR/CRi, 78% (n=11) went on to receive an allogeneic transplant.

In the entire pooled population, 67% (14/21) achieved CR/CRi.

Three patients received a second UCART19 dose, and five patients remain in CR/CRi.

UCART19 expansion

UCART19 expansion, as measured by quantitative polymerase chain reaction in PALL and flow-based methods in CALM, occurred primarily in the first 28 days in the FCA-treated population.

Investigators observed expansion in 15 of 17 patients treated with FCA. None of the patients who received FC alone (n=4) had expansion detectable in blood or bone marrow, Dr. Benjamin noted.

“The response we’ve seen in the study so far,” Dr. Benjamin clarified, “is linked to the expansion observed within the first 28-day period.”

UCART cells persisted in three patients beyond day 42. In one patient, they persisted up to day 120.

“Of interest is the T-cell recovery seen in the study,” Dr. Benjamin elaborated. “We only have data from the adult study here—14 patients. And you’ll see that, in the FCA-treated arm (n=11), you have a deeper and more sustained lymphodepletion compared to the FC-treated patients (n=3). And this may play a role in the subsequent UCART19 expansion and disease response.”

Re-dosing

Of the three patients who were re-dosed, two achieved MRD negativity.

One patient achieved MRD-negative status at day 28 but relapsed and received a second infusion 3 months after the first dose. The second expansion was not as deep as the first, but the patient nevertheless achieved MRD negativity after the second dose.

The second patient received FC lymphodepletion and was refractory at day 28.

“The second time around, he received FCA, had a slightly better expansion, and achieved molecular remission,” Dr. Benjamin said.

And the third patient had FCA lymphodepletion but was refractory at day 28.

“We elected to give a second dose at 2.4 months later, but unfortunately, there wasn’t very much expansion, even the second time around, and the patient progressed,” Dr. Benjamin said.

FCA lymphodepletion appears to be required for UCART19 expansion. There was no UCART19 expansion and no response in all four patients lymphodepleted with FC.

The evaluation of UCART19 is ongoing in pediatric and adult B-cell ALL, and “there is a plan for moving into the lymphoma space as well,” Dr. Benjamin added.

Dr. Benjamin disclosed honoraria from Amgen, Takeda, Novartis, Gilead, and Celgene, and research funding from Servier and Pfizer.

Servier and Allogene are supporting the UCART19 trials. 

*Data in the abstract differ from the presentation.

Photo by Jen Smith

SAN DIEGO—Pediatric patients with mixed phenotype acute leukemia (MPAL) can achieve minimal residual disease (MRD) negativity with acute lymphoblastic leukemia (ALL)-directed chemotherapy, according to new research.

In a retrospective study, most pediatric MPAL patients who received ALL-directed chemotherapy achieved an MRD-negative complete response (CR).

Ninety-three percent of patients achieved a CR at the end of induction with an ALL regimen, 70% were MRD-negative at the end of induction, and 86% were MRD-negative at the end of induction or consolidation.

Etan Orgel, MD, of the University of Southern California, Los Angeles, presented these findings at the ASH 2018 Annual Meeting (abstract 558*).

The study included 94 patients aged 1-21 years who met World Health Organization MPAL criteria and were treated between 2008 and 2016 at one of six U.S. institutions.

Most patients had B/Myeloid phenotype (89%, n=84), 10% (n=9) had T/Myeloid, and 1% (n=1) had B/T phenotype.

Eighty-seven patients (93%) received ALL induction, and 83 (89%) continued on ALL therapy after induction.

Ninety-three percent (81/87) of patients treated with an ALL induction regimen had a CR at the end of induction. One patient died during induction, and six had induction failures, defined as either disease progression (n=2) or MRD of 5% or greater (n=4).

The MRD-negative rates, defined as MRD less than 0.01%, were 70% (59/84) at the end of induction and 86% (68/79) at the end of induction or consolidation.

Twelve of 14 patients (86%) who were MRD-positive at the end of induction and continued on ALL therapy achieved MRD negativity at the end of consolidation.

Survival

The researchers assessed 5-year survival in patients who received an ALL regimen but did not go on to transplant.

In these patients, the 5-year event-free survival (EFS) was 75%, and the 5-year overall survival (OS) was 89%, “thus demonstrating that, for a majority of patients, transplant in first remission may not be necessary,” Dr. Orgel said.

“[T]his is very different from the approach used at many adult centers and many of the adult recommendations,” he added.

The 5-year EFS rate was 80% in patients who were MRD-negative at the end of induction and 52% in patients who were MRD-positive at the end of induction. Five-year OS rates were 91% and 84%, respectively.

The 5-year EFS rate was 77% in patients who were MRD-negative at the end of consolidation and was unavailable in the three patients who were MRD-positive. The 5-year OS rates were 89% and not available, respectively.

In a multivariable analysis, MRD was the strongest predictor of EFS (hazard ratio [HR]=3.5) and OS (HR=4.6).

There was a trend toward earlier failure and worse OS (HR=4.49, P=0.074) for T-lineage-containing MPAL.

“That indicates that this might be a group that needs careful scrutiny of which form of ALL therapy they receive,” Dr. Orgel said.

In closing, he said this research suggests that ALL therapy without transplant may be sufficient to treat most patients with pediatric MPAL. However, he noted that clinical trials are necessary to prospectively validate MRD thresholds at end of induction and consolidation and to establish the threshold for favorable survival.

“Future research should explore either intensification of therapy or different therapies for patients with persistent MRD,” Dr. Orgel said.

He disclosed no conflicts of interest. 

* Data in the presentation differ from the abstract.

Photo by Jen Smith

SAN DIEGO—Pediatric patients with mixed phenotype acute leukemia (MPAL) can achieve minimal residual disease (MRD) negativity with acute lymphoblastic leukemia (ALL)-directed chemotherapy, according to new research.

In a retrospective study, most pediatric MPAL patients who received ALL-directed chemotherapy achieved an MRD-negative complete response (CR).

Ninety-three percent of patients achieved a CR at the end of induction with an ALL regimen, 70% were MRD-negative at the end of induction, and 86% were MRD-negative at the end of induction or consolidation.

Etan Orgel, MD, of the University of Southern California, Los Angeles, presented these findings at the ASH 2018 Annual Meeting (abstract 558*).

The study included 94 patients aged 1-21 years who met World Health Organization MPAL criteria and were treated between 2008 and 2016 at one of six U.S. institutions.

Most patients had B/Myeloid phenotype (89%, n=84), 10% (n=9) had T/Myeloid, and 1% (n=1) had B/T phenotype.

Eighty-seven patients (93%) received ALL induction, and 83 (89%) continued on ALL therapy after induction.

Ninety-three percent (81/87) of patients treated with an ALL induction regimen had a CR at the end of induction. One patient died during induction, and six had induction failures, defined as either disease progression (n=2) or MRD of 5% or greater (n=4).

The MRD-negative rates, defined as MRD less than 0.01%, were 70% (59/84) at the end of induction and 86% (68/79) at the end of induction or consolidation.

Twelve of 14 patients (86%) who were MRD-positive at the end of induction and continued on ALL therapy achieved MRD negativity at the end of consolidation.

Survival

The researchers assessed 5-year survival in patients who received an ALL regimen but did not go on to transplant.

In these patients, the 5-year event-free survival (EFS) was 75%, and the 5-year overall survival (OS) was 89%, “thus demonstrating that, for a majority of patients, transplant in first remission may not be necessary,” Dr. Orgel said.

“[T]his is very different from the approach used at many adult centers and many of the adult recommendations,” he added.

The 5-year EFS rate was 80% in patients who were MRD-negative at the end of induction and 52% in patients who were MRD-positive at the end of induction. Five-year OS rates were 91% and 84%, respectively.

The 5-year EFS rate was 77% in patients who were MRD-negative at the end of consolidation and was unavailable in the three patients who were MRD-positive. The 5-year OS rates were 89% and not available, respectively.

In a multivariable analysis, MRD was the strongest predictor of EFS (hazard ratio [HR]=3.5) and OS (HR=4.6).

There was a trend toward earlier failure and worse OS (HR=4.49, P=0.074) for T-lineage-containing MPAL.

“That indicates that this might be a group that needs careful scrutiny of which form of ALL therapy they receive,” Dr. Orgel said.

In closing, he said this research suggests that ALL therapy without transplant may be sufficient to treat most patients with pediatric MPAL. However, he noted that clinical trials are necessary to prospectively validate MRD thresholds at end of induction and consolidation and to establish the threshold for favorable survival.

“Future research should explore either intensification of therapy or different therapies for patients with persistent MRD,” Dr. Orgel said.

He disclosed no conflicts of interest. 

* Data in the presentation differ from the abstract.

Photo by Jen Smith

SAN DIEGO—Pediatric patients with mixed phenotype acute leukemia (MPAL) can achieve minimal residual disease (MRD) negativity with acute lymphoblastic leukemia (ALL)-directed chemotherapy, according to new research.

In a retrospective study, most pediatric MPAL patients who received ALL-directed chemotherapy achieved an MRD-negative complete response (CR).

Ninety-three percent of patients achieved a CR at the end of induction with an ALL regimen, 70% were MRD-negative at the end of induction, and 86% were MRD-negative at the end of induction or consolidation.

Etan Orgel, MD, of the University of Southern California, Los Angeles, presented these findings at the ASH 2018 Annual Meeting (abstract 558*).

The study included 94 patients aged 1-21 years who met World Health Organization MPAL criteria and were treated between 2008 and 2016 at one of six U.S. institutions.

Most patients had B/Myeloid phenotype (89%, n=84), 10% (n=9) had T/Myeloid, and 1% (n=1) had B/T phenotype.

Eighty-seven patients (93%) received ALL induction, and 83 (89%) continued on ALL therapy after induction.

Ninety-three percent (81/87) of patients treated with an ALL induction regimen had a CR at the end of induction. One patient died during induction, and six had induction failures, defined as either disease progression (n=2) or MRD of 5% or greater (n=4).

The MRD-negative rates, defined as MRD less than 0.01%, were 70% (59/84) at the end of induction and 86% (68/79) at the end of induction or consolidation.

Twelve of 14 patients (86%) who were MRD-positive at the end of induction and continued on ALL therapy achieved MRD negativity at the end of consolidation.

Survival

The researchers assessed 5-year survival in patients who received an ALL regimen but did not go on to transplant.

In these patients, the 5-year event-free survival (EFS) was 75%, and the 5-year overall survival (OS) was 89%, “thus demonstrating that, for a majority of patients, transplant in first remission may not be necessary,” Dr. Orgel said.

“[T]his is very different from the approach used at many adult centers and many of the adult recommendations,” he added.

The 5-year EFS rate was 80% in patients who were MRD-negative at the end of induction and 52% in patients who were MRD-positive at the end of induction. Five-year OS rates were 91% and 84%, respectively.

The 5-year EFS rate was 77% in patients who were MRD-negative at the end of consolidation and was unavailable in the three patients who were MRD-positive. The 5-year OS rates were 89% and not available, respectively.

In a multivariable analysis, MRD was the strongest predictor of EFS (hazard ratio [HR]=3.5) and OS (HR=4.6).

There was a trend toward earlier failure and worse OS (HR=4.49, P=0.074) for T-lineage-containing MPAL.

“That indicates that this might be a group that needs careful scrutiny of which form of ALL therapy they receive,” Dr. Orgel said.

In closing, he said this research suggests that ALL therapy without transplant may be sufficient to treat most patients with pediatric MPAL. However, he noted that clinical trials are necessary to prospectively validate MRD thresholds at end of induction and consolidation and to establish the threshold for favorable survival.

“Future research should explore either intensification of therapy or different therapies for patients with persistent MRD,” Dr. Orgel said.

He disclosed no conflicts of interest. 

* Data in the presentation differ from the abstract.

SAN DIEGO – A single infusion of tisagenlecleucel (Kymriah) continues to demonstrate high efficacy a year and a half after pediatric and young adult patients with relapsed or refractory acute lymphoblastic leukemia (ALL) were enrolled in the pivotal ELIANA trial, Stephan A. Grupp, MD, PhD, reported at a press conference at the annual meeting of the American Society of Hematology.

Neil Osterweil/MDedge News

Of patients in complete remission after receiving the chimeric antigen receptor (CAR) T-cell therapy, 66% were still in remission at 18 months of follow-up and median survival has yet to be reached.

“We think the efficacy is sustained and excellent,” said Dr. Grupp, of the University of Pennsylvania, Philadelphia. “These are durable complete responses even without further therapy. We haven’t reached median duration of response or overall survival, and we can manage toxicity, so I think this is clearly an opportunity for us to treat our patients both in America and across the world.”

The results of ELIANA were the basis for the approval of tisagenlecleucel (Kymriah) for relapsed/refractory B-cell ALL in the United States, and for subsequent approvals by health authorities in the European Union, Switzerland, and Canada.

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

The rate of overall remission, defined as the rate of complete remission or complete remission with incomplete blood count recovery, was 82% (65 patients). Among those patients, 66% were still in remission at 18 months, while overall survival was “excellent” at 70%, Dr. Grupp said, and the median overall survival was not reached.

Adverse events prevalence remained relatively unchanged since the previous analyses, according to Dr. Grupp, who added that appropriately trained personnel were able to effectively manage those adverse events across study sites. Cytokine release syndrome (CRS) occurred in 77% of patients. All cases were reversible; 39% received tocilizumab for treatment of CRS with or without other anticytokine therapies; 48% required ICU-level care for CRS, with a median ICU stay of 7 days.

The other most common grade 3/4 nonhematologic adverse events were neutropenia with a body temperature exceeding 38.3° C (62% within 8 weeks of infusion), hypoxia (20%), and hypotension (20%). Grade 3 neurologic effects occurred in 13% of patients, and none had cerebral edema. Based on laboratory results, 43% had grade 3/4 thrombocytopenia and 54% had neutropenia not resolved by day 28; most of these events resolved to grade 2 or less by 3 months.

There were 25 postinfusion deaths, with 2 occurring within 30 days (1 because of disease progression, 1 because of cerebral hemorrhage). Of the 23 deaths after 30 days (range, 53-859 days), 18 were caused by disease progression. The other deaths were caused by encephalitis, systemic mycosis, vasoocclusive hepatobiliary disorder related to allogeneic SCT, bacterial lung infection, and an unknown reason after study withdrawal.

Follow-up is ongoing in the ELIANA study, which is supported by Novartis, the maker of Kymriah.

Dr. Grupp reported research funding from Novartis, consultancy with Novartis, Jazz Pharmaceuticals, and Adaptimmune Therapeutics, and patents or royalties with the University of Pennsylvania.

SOURCE: Grupp SA et al. ASH 2018, Abstract 895.

SAN DIEGO – A single infusion of tisagenlecleucel (Kymriah) continues to demonstrate high efficacy a year and a half after pediatric and young adult patients with relapsed or refractory acute lymphoblastic leukemia (ALL) were enrolled in the pivotal ELIANA trial, Stephan A. Grupp, MD, PhD, reported at a press conference at the annual meeting of the American Society of Hematology.

Neil Osterweil/MDedge News

Of patients in complete remission after receiving the chimeric antigen receptor (CAR) T-cell therapy, 66% were still in remission at 18 months of follow-up and median survival has yet to be reached.

“We think the efficacy is sustained and excellent,” said Dr. Grupp, of the University of Pennsylvania, Philadelphia. “These are durable complete responses even without further therapy. We haven’t reached median duration of response or overall survival, and we can manage toxicity, so I think this is clearly an opportunity for us to treat our patients both in America and across the world.”

The results of ELIANA were the basis for the approval of tisagenlecleucel (Kymriah) for relapsed/refractory B-cell ALL in the United States, and for subsequent approvals by health authorities in the European Union, Switzerland, and Canada.

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

The rate of overall remission, defined as the rate of complete remission or complete remission with incomplete blood count recovery, was 82% (65 patients). Among those patients, 66% were still in remission at 18 months, while overall survival was “excellent” at 70%, Dr. Grupp said, and the median overall survival was not reached.

Adverse events prevalence remained relatively unchanged since the previous analyses, according to Dr. Grupp, who added that appropriately trained personnel were able to effectively manage those adverse events across study sites. Cytokine release syndrome (CRS) occurred in 77% of patients. All cases were reversible; 39% received tocilizumab for treatment of CRS with or without other anticytokine therapies; 48% required ICU-level care for CRS, with a median ICU stay of 7 days.

The other most common grade 3/4 nonhematologic adverse events were neutropenia with a body temperature exceeding 38.3° C (62% within 8 weeks of infusion), hypoxia (20%), and hypotension (20%). Grade 3 neurologic effects occurred in 13% of patients, and none had cerebral edema. Based on laboratory results, 43% had grade 3/4 thrombocytopenia and 54% had neutropenia not resolved by day 28; most of these events resolved to grade 2 or less by 3 months.

There were 25 postinfusion deaths, with 2 occurring within 30 days (1 because of disease progression, 1 because of cerebral hemorrhage). Of the 23 deaths after 30 days (range, 53-859 days), 18 were caused by disease progression. The other deaths were caused by encephalitis, systemic mycosis, vasoocclusive hepatobiliary disorder related to allogeneic SCT, bacterial lung infection, and an unknown reason after study withdrawal.

Follow-up is ongoing in the ELIANA study, which is supported by Novartis, the maker of Kymriah.

Dr. Grupp reported research funding from Novartis, consultancy with Novartis, Jazz Pharmaceuticals, and Adaptimmune Therapeutics, and patents or royalties with the University of Pennsylvania.

SOURCE: Grupp SA et al. ASH 2018, Abstract 895.

SAN DIEGO – A single infusion of tisagenlecleucel (Kymriah) continues to demonstrate high efficacy a year and a half after pediatric and young adult patients with relapsed or refractory acute lymphoblastic leukemia (ALL) were enrolled in the pivotal ELIANA trial, Stephan A. Grupp, MD, PhD, reported at a press conference at the annual meeting of the American Society of Hematology.

Neil Osterweil/MDedge News

Of patients in complete remission after receiving the chimeric antigen receptor (CAR) T-cell therapy, 66% were still in remission at 18 months of follow-up and median survival has yet to be reached.

“We think the efficacy is sustained and excellent,” said Dr. Grupp, of the University of Pennsylvania, Philadelphia. “These are durable complete responses even without further therapy. We haven’t reached median duration of response or overall survival, and we can manage toxicity, so I think this is clearly an opportunity for us to treat our patients both in America and across the world.”

The results of ELIANA were the basis for the approval of tisagenlecleucel (Kymriah) for relapsed/refractory B-cell ALL in the United States, and for subsequent approvals by health authorities in the European Union, Switzerland, and Canada.

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

The rate of overall remission, defined as the rate of complete remission or complete remission with incomplete blood count recovery, was 82% (65 patients). Among those patients, 66% were still in remission at 18 months, while overall survival was “excellent” at 70%, Dr. Grupp said, and the median overall survival was not reached.

Adverse events prevalence remained relatively unchanged since the previous analyses, according to Dr. Grupp, who added that appropriately trained personnel were able to effectively manage those adverse events across study sites. Cytokine release syndrome (CRS) occurred in 77% of patients. All cases were reversible; 39% received tocilizumab for treatment of CRS with or without other anticytokine therapies; 48% required ICU-level care for CRS, with a median ICU stay of 7 days.

The other most common grade 3/4 nonhematologic adverse events were neutropenia with a body temperature exceeding 38.3° C (62% within 8 weeks of infusion), hypoxia (20%), and hypotension (20%). Grade 3 neurologic effects occurred in 13% of patients, and none had cerebral edema. Based on laboratory results, 43% had grade 3/4 thrombocytopenia and 54% had neutropenia not resolved by day 28; most of these events resolved to grade 2 or less by 3 months.

There were 25 postinfusion deaths, with 2 occurring within 30 days (1 because of disease progression, 1 because of cerebral hemorrhage). Of the 23 deaths after 30 days (range, 53-859 days), 18 were caused by disease progression. The other deaths were caused by encephalitis, systemic mycosis, vasoocclusive hepatobiliary disorder related to allogeneic SCT, bacterial lung infection, and an unknown reason after study withdrawal.

Follow-up is ongoing in the ELIANA study, which is supported by Novartis, the maker of Kymriah.

Dr. Grupp reported research funding from Novartis, consultancy with Novartis, Jazz Pharmaceuticals, and Adaptimmune Therapeutics, and patents or royalties with the University of Pennsylvania.

SOURCE: Grupp SA et al. ASH 2018, Abstract 895.

SAN DIEGO – A hematopoietic cell transplant following chimeric antigen receptor (CAR) T-cell therapy for B-cell acute lymphocytic leukemia (B-ALL) may reduce late relapse risk in certain patients, a retrospective analysis suggests.

Corinne Summers, MD, of Seattle Children’s Hospital, and her colleagues evaluated the potential benefits of allogeneic hematopoietic cell transplant (HCT) in 50 pediatric and young adult B-ALL patients who had sustained leukemic remission after receiving SCRI-CAR19v1, a CD19-specific CAR T-cell product.

Leukemia-free survival was significantly improved for patients with no history of HCT who received CD19 CAR T-cell therapy followed by consolidative HCT, Dr. Summers reported at the annual meeting of the American Society of Hematology.

However, the benefits of consolidative HCT are unclear for patients with a history of HCT, Dr. Summers said at the meeting, noting that larger studies are needed.

In her video interview at ASH 2018, Dr. Summers talked more about the challenges of late leukemic relapse and the potential role of HCT after CAR T-cell therapy.

Dr. Summers reported no disclosures related to her presentation.

SAN DIEGO – A hematopoietic cell transplant following chimeric antigen receptor (CAR) T-cell therapy for B-cell acute lymphocytic leukemia (B-ALL) may reduce late relapse risk in certain patients, a retrospective analysis suggests.

Corinne Summers, MD, of Seattle Children’s Hospital, and her colleagues evaluated the potential benefits of allogeneic hematopoietic cell transplant (HCT) in 50 pediatric and young adult B-ALL patients who had sustained leukemic remission after receiving SCRI-CAR19v1, a CD19-specific CAR T-cell product.

Leukemia-free survival was significantly improved for patients with no history of HCT who received CD19 CAR T-cell therapy followed by consolidative HCT, Dr. Summers reported at the annual meeting of the American Society of Hematology.

However, the benefits of consolidative HCT are unclear for patients with a history of HCT, Dr. Summers said at the meeting, noting that larger studies are needed.

In her video interview at ASH 2018, Dr. Summers talked more about the challenges of late leukemic relapse and the potential role of HCT after CAR T-cell therapy.

Dr. Summers reported no disclosures related to her presentation.

SAN DIEGO – A hematopoietic cell transplant following chimeric antigen receptor (CAR) T-cell therapy for B-cell acute lymphocytic leukemia (B-ALL) may reduce late relapse risk in certain patients, a retrospective analysis suggests.

Corinne Summers, MD, of Seattle Children’s Hospital, and her colleagues evaluated the potential benefits of allogeneic hematopoietic cell transplant (HCT) in 50 pediatric and young adult B-ALL patients who had sustained leukemic remission after receiving SCRI-CAR19v1, a CD19-specific CAR T-cell product.

Leukemia-free survival was significantly improved for patients with no history of HCT who received CD19 CAR T-cell therapy followed by consolidative HCT, Dr. Summers reported at the annual meeting of the American Society of Hematology.

However, the benefits of consolidative HCT are unclear for patients with a history of HCT, Dr. Summers said at the meeting, noting that larger studies are needed.

In her video interview at ASH 2018, Dr. Summers talked more about the challenges of late leukemic relapse and the potential role of HCT after CAR T-cell therapy.

Dr. Summers reported no disclosures related to her presentation.

Photo from Penn Medicine

Several studies set to be presented at the 2018 ASH Annual Meeting provide new insights regarding chimeric antigen receptor (CAR) T-cell therapies.

One study suggests ibrutinib may enhance CAR T-cell therapy in patients with chronic lymphocytic leukemia (CLL), and another suggests checkpoint inhibitors can augment CAR T-cell therapy in certain patients with B-cell acute lymphoblastic leukemia (ALL).

Two additional studies indicate that responses to tisagenlecleucel are durable in both ALL and diffuse large B-cell lymphoma (DLBCL).

A fifth study suggests hematopoietic stem cell transplant (HSCT) may reduce the risk of relapse after CAR T-cell therapy.

ASH Secretary Robert A. Brodsky, MD, of Johns Hopkins University in Baltimore, Maryland, discussed these studies during a media briefing ahead of the ASH Annual Meeting.

Ibrutinib

In the ibrutinib study (abstract 299), patients received the BTK inhibitor starting 2 weeks prior to leukapheresis and continued until 3 months after treatment with JCAR014.

Data suggest this strategy may improve responses and decrease the incidence of severe cytokine release syndrome in patients with relapsed or refractory CLL.

Responses occurred in 88% of patients who received ibrutinib and 56% of those who did not.

Grade 3-5 cytokine release syndrome occurred in 5 of 19 patients (26%) in the no-ibrutinib cohort and 0 of 17 patients in the ibrutinib cohort.

These findings are “early and preliminary but very exciting” Dr. Brodsky said.

Checkpoint inhibitors

Early results of the checkpoint inhibitor study (abstract 556) suggest that pembrolizumab or nivolumab may augment CD19-directed CAR T-cell therapy.

The 14 patients studied had early CAR T-cell loss, partial response, or no response to CAR T-cell therapy. Thirteen patients had B-cell ALL, and one had B lymphoblastic lymphoma.

CD19-directed CAR T-cell therapy consisted of tisagenlecleucel in four patients and CTL119 in 10. Thirteen patients received pembrolizumab, and one received nivolumab.

Three of six patients who had early B-cell recovery re-established B-cell aplasia with the addition of a checkpoint inhibitor. In two patients, B-cell aplasia persists with ongoing pembrolizumab.

Four patients who did not respond to or relapsed after their initial CAR T-cell therapy had a partial (n=2) or complete response (n=2) with the addition of pembrolizumab.

There were additional partial responses in the remaining four patients. However, one of these patients (with CD19-dim/negative disease) progressed.

“The idea was if you can give pembrolizumab, you can take the brakes off, and maybe you can reinitiate the immune attack,” Dr. Brodsky said.

“[This is a] very small [study with] preliminary data but very exciting that it is safe to give checkpoint inhibitors with CAR T cells, and it may be efficacious at getting the immune response back.”

Tisagenlecleucel follow-up

One of the two tisagenlecleucel updates (abstract 895) consists of data from the ELIANA trial, which includes pediatric and young adult patients with relapsed/refractory ALL.

The overall response rate was 82% (65/79). Of the 65 responders, 29 were still in response at follow-up.

The probability of relapse-free survival was 66% at 12 months and 18 months.

“These are some very fast-growing tumors, and these are refractory, resistant patients, so, as we get further and further out, it’s more encouraging to see that there are durable responses,” Dr. Brodsky said.

The other tisagenlecleucel update (abstract 1684) is from the JULIET trial, which includes adults with relapsed or refractory DLBCL (n=99).

The overall response rate was 54%. The probability of relapse-free survival was 66% at 6 months and 64% at both 12 months and 18 months.

HSCT consolidation

Dr. Brodsky also discussed long-term follow-up from a phase 1/2 trial of SCRI-CAR19v1, a CD19-specific CAR T-cell product, in patients with relapsed/refractory ALL (abstract 967).

Of the 50 evaluable patients, 17 had no history of HSCT prior to CAR T-cell therapy.

Three of the 17 patients did not proceed to HSCT after CAR T-cell therapy, and two of these patients relapsed. Of the 14 patients who did undergo HSCT after CAR T-cell therapy, two relapsed.

There were 33 patients with a prior history of HSCT, and 10 of them had another HSCT after CAR T-cell therapy. Five of them are still alive and in remission.

Of the 23 patients who did not undergo another HSCT, eight are still in remission.

“This study is very small, and it’s retrospective, but it suggests that bone marrow transplant is a good way to consolidate the remission after CAR T-cell therapy,” Dr. Brodsky said.

Photo from Penn Medicine

Several studies set to be presented at the 2018 ASH Annual Meeting provide new insights regarding chimeric antigen receptor (CAR) T-cell therapies.

One study suggests ibrutinib may enhance CAR T-cell therapy in patients with chronic lymphocytic leukemia (CLL), and another suggests checkpoint inhibitors can augment CAR T-cell therapy in certain patients with B-cell acute lymphoblastic leukemia (ALL).

Two additional studies indicate that responses to tisagenlecleucel are durable in both ALL and diffuse large B-cell lymphoma (DLBCL).

A fifth study suggests hematopoietic stem cell transplant (HSCT) may reduce the risk of relapse after CAR T-cell therapy.

ASH Secretary Robert A. Brodsky, MD, of Johns Hopkins University in Baltimore, Maryland, discussed these studies during a media briefing ahead of the ASH Annual Meeting.

Ibrutinib

In the ibrutinib study (abstract 299), patients received the BTK inhibitor starting 2 weeks prior to leukapheresis and continued until 3 months after treatment with JCAR014.

Data suggest this strategy may improve responses and decrease the incidence of severe cytokine release syndrome in patients with relapsed or refractory CLL.

Responses occurred in 88% of patients who received ibrutinib and 56% of those who did not.

Grade 3-5 cytokine release syndrome occurred in 5 of 19 patients (26%) in the no-ibrutinib cohort and 0 of 17 patients in the ibrutinib cohort.

These findings are “early and preliminary but very exciting” Dr. Brodsky said.

Checkpoint inhibitors

Early results of the checkpoint inhibitor study (abstract 556) suggest that pembrolizumab or nivolumab may augment CD19-directed CAR T-cell therapy.

The 14 patients studied had early CAR T-cell loss, partial response, or no response to CAR T-cell therapy. Thirteen patients had B-cell ALL, and one had B lymphoblastic lymphoma.

CD19-directed CAR T-cell therapy consisted of tisagenlecleucel in four patients and CTL119 in 10. Thirteen patients received pembrolizumab, and one received nivolumab.

Three of six patients who had early B-cell recovery re-established B-cell aplasia with the addition of a checkpoint inhibitor. In two patients, B-cell aplasia persists with ongoing pembrolizumab.

Four patients who did not respond to or relapsed after their initial CAR T-cell therapy had a partial (n=2) or complete response (n=2) with the addition of pembrolizumab.

There were additional partial responses in the remaining four patients. However, one of these patients (with CD19-dim/negative disease) progressed.

“The idea was if you can give pembrolizumab, you can take the brakes off, and maybe you can reinitiate the immune attack,” Dr. Brodsky said.

“[This is a] very small [study with] preliminary data but very exciting that it is safe to give checkpoint inhibitors with CAR T cells, and it may be efficacious at getting the immune response back.”

Tisagenlecleucel follow-up

One of the two tisagenlecleucel updates (abstract 895) consists of data from the ELIANA trial, which includes pediatric and young adult patients with relapsed/refractory ALL.

The overall response rate was 82% (65/79). Of the 65 responders, 29 were still in response at follow-up.

The probability of relapse-free survival was 66% at 12 months and 18 months.

“These are some very fast-growing tumors, and these are refractory, resistant patients, so, as we get further and further out, it’s more encouraging to see that there are durable responses,” Dr. Brodsky said.

The other tisagenlecleucel update (abstract 1684) is from the JULIET trial, which includes adults with relapsed or refractory DLBCL (n=99).

The overall response rate was 54%. The probability of relapse-free survival was 66% at 6 months and 64% at both 12 months and 18 months.

HSCT consolidation

Dr. Brodsky also discussed long-term follow-up from a phase 1/2 trial of SCRI-CAR19v1, a CD19-specific CAR T-cell product, in patients with relapsed/refractory ALL (abstract 967).

Of the 50 evaluable patients, 17 had no history of HSCT prior to CAR T-cell therapy.

Three of the 17 patients did not proceed to HSCT after CAR T-cell therapy, and two of these patients relapsed. Of the 14 patients who did undergo HSCT after CAR T-cell therapy, two relapsed.

There were 33 patients with a prior history of HSCT, and 10 of them had another HSCT after CAR T-cell therapy. Five of them are still alive and in remission.

Of the 23 patients who did not undergo another HSCT, eight are still in remission.

“This study is very small, and it’s retrospective, but it suggests that bone marrow transplant is a good way to consolidate the remission after CAR T-cell therapy,” Dr. Brodsky said.

Photo from Penn Medicine

Several studies set to be presented at the 2018 ASH Annual Meeting provide new insights regarding chimeric antigen receptor (CAR) T-cell therapies.

One study suggests ibrutinib may enhance CAR T-cell therapy in patients with chronic lymphocytic leukemia (CLL), and another suggests checkpoint inhibitors can augment CAR T-cell therapy in certain patients with B-cell acute lymphoblastic leukemia (ALL).

Two additional studies indicate that responses to tisagenlecleucel are durable in both ALL and diffuse large B-cell lymphoma (DLBCL).

A fifth study suggests hematopoietic stem cell transplant (HSCT) may reduce the risk of relapse after CAR T-cell therapy.

ASH Secretary Robert A. Brodsky, MD, of Johns Hopkins University in Baltimore, Maryland, discussed these studies during a media briefing ahead of the ASH Annual Meeting.

Ibrutinib

In the ibrutinib study (abstract 299), patients received the BTK inhibitor starting 2 weeks prior to leukapheresis and continued until 3 months after treatment with JCAR014.

Data suggest this strategy may improve responses and decrease the incidence of severe cytokine release syndrome in patients with relapsed or refractory CLL.

Responses occurred in 88% of patients who received ibrutinib and 56% of those who did not.

Grade 3-5 cytokine release syndrome occurred in 5 of 19 patients (26%) in the no-ibrutinib cohort and 0 of 17 patients in the ibrutinib cohort.

These findings are “early and preliminary but very exciting” Dr. Brodsky said.

Checkpoint inhibitors

Early results of the checkpoint inhibitor study (abstract 556) suggest that pembrolizumab or nivolumab may augment CD19-directed CAR T-cell therapy.

The 14 patients studied had early CAR T-cell loss, partial response, or no response to CAR T-cell therapy. Thirteen patients had B-cell ALL, and one had B lymphoblastic lymphoma.

CD19-directed CAR T-cell therapy consisted of tisagenlecleucel in four patients and CTL119 in 10. Thirteen patients received pembrolizumab, and one received nivolumab.

Three of six patients who had early B-cell recovery re-established B-cell aplasia with the addition of a checkpoint inhibitor. In two patients, B-cell aplasia persists with ongoing pembrolizumab.

Four patients who did not respond to or relapsed after their initial CAR T-cell therapy had a partial (n=2) or complete response (n=2) with the addition of pembrolizumab.

There were additional partial responses in the remaining four patients. However, one of these patients (with CD19-dim/negative disease) progressed.

“The idea was if you can give pembrolizumab, you can take the brakes off, and maybe you can reinitiate the immune attack,” Dr. Brodsky said.

“[This is a] very small [study with] preliminary data but very exciting that it is safe to give checkpoint inhibitors with CAR T cells, and it may be efficacious at getting the immune response back.”

Tisagenlecleucel follow-up

One of the two tisagenlecleucel updates (abstract 895) consists of data from the ELIANA trial, which includes pediatric and young adult patients with relapsed/refractory ALL.

The overall response rate was 82% (65/79). Of the 65 responders, 29 were still in response at follow-up.

The probability of relapse-free survival was 66% at 12 months and 18 months.

“These are some very fast-growing tumors, and these are refractory, resistant patients, so, as we get further and further out, it’s more encouraging to see that there are durable responses,” Dr. Brodsky said.

The other tisagenlecleucel update (abstract 1684) is from the JULIET trial, which includes adults with relapsed or refractory DLBCL (n=99).

The overall response rate was 54%. The probability of relapse-free survival was 66% at 6 months and 64% at both 12 months and 18 months.

HSCT consolidation

Dr. Brodsky also discussed long-term follow-up from a phase 1/2 trial of SCRI-CAR19v1, a CD19-specific CAR T-cell product, in patients with relapsed/refractory ALL (abstract 967).

Of the 50 evaluable patients, 17 had no history of HSCT prior to CAR T-cell therapy.

Three of the 17 patients did not proceed to HSCT after CAR T-cell therapy, and two of these patients relapsed. Of the 14 patients who did undergo HSCT after CAR T-cell therapy, two relapsed.

There were 33 patients with a prior history of HSCT, and 10 of them had another HSCT after CAR T-cell therapy. Five of them are still alive and in remission.

Of the 23 patients who did not undergo another HSCT, eight are still in remission.

“This study is very small, and it’s retrospective, but it suggests that bone marrow transplant is a good way to consolidate the remission after CAR T-cell therapy,” Dr. Brodsky said.

Photo courtesy of Amgen

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended expanding marketing authorization for blinatumomab (Blincyto) to include treatment of minimal residual disease (MRD).

The CHMP has recommended approval for blinatumomab as monotherapy for adults with Philadelphia chromosome-negative, CD19-positive, B-cell precursor acute lymphoblastic leukemia (BCP-ALL) in first or second complete remission with MRD greater than or equal to 0.1%.

The CHMP had originally adopted a negative opinion on extending the use of blinatumomab to these patients. However, the committee re-examined its opinion and reversed that decision.

The CHMP has requested that Amgen, the company developing blinatumomab, provide results from ongoing studies to support the new approval.

The CHMP’s recommendations are reviewed by the European Commission (EC), which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.

The EC usually makes a decision within 67 days of CHMP recommendations.

Blinatumomab is already EC-approved as monotherapy for:

• Adults with Philadelphia chromosome-negative, CD19-positive, relapsed or refractory BCP-ALL.
• Pediatric patients age 1 year or older who have relapsed/refractory, Philadelphia chromosome-negative, CD19-positive BCP-ALL and have received at least two prior therapies or relapsed after allogeneic hematopoietic stem cell transplant.

CHMP’s reversal of opinion

In July, the CHMP recommended against approving blinatumomab to treat patients with MRD based on data from the BLAST trial. Results from this phase 2 trial were published in Blood in April.

The CHMP noted that, although blinatumomab produced MRD negativity in many patients in the BLAST trial, there is no strong evidence that this leads to improved survival.

Given the uncertainty, the CHMP was of the opinion that the benefits of blinatumomab do not outweigh its risks in MRD-positive BCP-ALL patients.

However, Amgen request a re-examination of the CHMP’s opinion, and the CHMP complied.

During the re-examination, the CHMP reviewed all the data and consulted a group of experts.

The experts concluded, and the CHMP agreed, that, although there is no strong evidence of improved survival, the available data indicate a good response to blinatumomab, with around 78% of patients becoming MRD-negative after treatment.

The CHMP also noted that MRD-positive patients have a high risk of relapse and few treatment options.

Therefore, the committee concluded that the benefits of blinatumomab outweigh its risks in this patient population.

The CHMP recommended granting the change to the marketing authorization but also requested that Amgen provide data from ongoing studies of blinatumomab in MRD-positive patients, once those data are available.

Photo courtesy of Amgen

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended expanding marketing authorization for blinatumomab (Blincyto) to include treatment of minimal residual disease (MRD).

The CHMP has recommended approval for blinatumomab as monotherapy for adults with Philadelphia chromosome-negative, CD19-positive, B-cell precursor acute lymphoblastic leukemia (BCP-ALL) in first or second complete remission with MRD greater than or equal to 0.1%.

The CHMP had originally adopted a negative opinion on extending the use of blinatumomab to these patients. However, the committee re-examined its opinion and reversed that decision.

The CHMP has requested that Amgen, the company developing blinatumomab, provide results from ongoing studies to support the new approval.

The CHMP’s recommendations are reviewed by the European Commission (EC), which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.

The EC usually makes a decision within 67 days of CHMP recommendations.

Blinatumomab is already EC-approved as monotherapy for:

• Adults with Philadelphia chromosome-negative, CD19-positive, relapsed or refractory BCP-ALL.
• Pediatric patients age 1 year or older who have relapsed/refractory, Philadelphia chromosome-negative, CD19-positive BCP-ALL and have received at least two prior therapies or relapsed after allogeneic hematopoietic stem cell transplant.

CHMP’s reversal of opinion

In July, the CHMP recommended against approving blinatumomab to treat patients with MRD based on data from the BLAST trial. Results from this phase 2 trial were published in Blood in April.

The CHMP noted that, although blinatumomab produced MRD negativity in many patients in the BLAST trial, there is no strong evidence that this leads to improved survival.

Given the uncertainty, the CHMP was of the opinion that the benefits of blinatumomab do not outweigh its risks in MRD-positive BCP-ALL patients.

However, Amgen request a re-examination of the CHMP’s opinion, and the CHMP complied.

During the re-examination, the CHMP reviewed all the data and consulted a group of experts.

The experts concluded, and the CHMP agreed, that, although there is no strong evidence of improved survival, the available data indicate a good response to blinatumomab, with around 78% of patients becoming MRD-negative after treatment.

The CHMP also noted that MRD-positive patients have a high risk of relapse and few treatment options.

Therefore, the committee concluded that the benefits of blinatumomab outweigh its risks in this patient population.

The CHMP recommended granting the change to the marketing authorization but also requested that Amgen provide data from ongoing studies of blinatumomab in MRD-positive patients, once those data are available.

Photo courtesy of Amgen

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended expanding marketing authorization for blinatumomab (Blincyto) to include treatment of minimal residual disease (MRD).

The CHMP has recommended approval for blinatumomab as monotherapy for adults with Philadelphia chromosome-negative, CD19-positive, B-cell precursor acute lymphoblastic leukemia (BCP-ALL) in first or second complete remission with MRD greater than or equal to 0.1%.

The CHMP had originally adopted a negative opinion on extending the use of blinatumomab to these patients. However, the committee re-examined its opinion and reversed that decision.

The CHMP has requested that Amgen, the company developing blinatumomab, provide results from ongoing studies to support the new approval.

The CHMP’s recommendations are reviewed by the European Commission (EC), which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.

The EC usually makes a decision within 67 days of CHMP recommendations.

Blinatumomab is already EC-approved as monotherapy for:

• Adults with Philadelphia chromosome-negative, CD19-positive, relapsed or refractory BCP-ALL.
• Pediatric patients age 1 year or older who have relapsed/refractory, Philadelphia chromosome-negative, CD19-positive BCP-ALL and have received at least two prior therapies or relapsed after allogeneic hematopoietic stem cell transplant.

CHMP’s reversal of opinion

In July, the CHMP recommended against approving blinatumomab to treat patients with MRD based on data from the BLAST trial. Results from this phase 2 trial were published in Blood in April.

The CHMP noted that, although blinatumomab produced MRD negativity in many patients in the BLAST trial, there is no strong evidence that this leads to improved survival.

Given the uncertainty, the CHMP was of the opinion that the benefits of blinatumomab do not outweigh its risks in MRD-positive BCP-ALL patients.

However, Amgen request a re-examination of the CHMP’s opinion, and the CHMP complied.

During the re-examination, the CHMP reviewed all the data and consulted a group of experts.

The experts concluded, and the CHMP agreed, that, although there is no strong evidence of improved survival, the available data indicate a good response to blinatumomab, with around 78% of patients becoming MRD-negative after treatment.

The CHMP also noted that MRD-positive patients have a high risk of relapse and few treatment options.

Therefore, the committee concluded that the benefits of blinatumomab outweigh its risks in this patient population.

The CHMP recommended granting the change to the marketing authorization but also requested that Amgen provide data from ongoing studies of blinatumomab in MRD-positive patients, once those data are available.

Obese lab mouse

Switching to a low-fat diet can improve survival in obese mice with acute lymphoblastic leukemia (ALL), according to new research.

Diet-induced obese (DIO) mice with ALL had a survival rate of 17% if they remained on a high-fat diet while treated with vincristine, but survival rose to 92% for mice that were switched to a low-fat diet before treatment.

However, the dietary switch did not impact the survival of DIO mice treated with dexamethasone or L-asparaginase monotherapy.

Researchers reported these findings in Cancer & Metabolism.

“The most exciting thing, to me, about this study is the fact that this shows that a dietary intervention could potentially help us kill leukemia cells in children with acute lymphoblastic leukemia,” said study author Steven Mittelman, MD, PhD, of the University of Southern California, Los Angeles.

“The current treatments for leukemia are very toxic, so finding a way to use a healthy diet, without increasing the toxicity of therapy to treat people with cancer, would be incredible.”

Building on previous research that showed obesity reduced the effectiveness of chemotherapeutic drugs in children with leukemia, the researchers tested whether a dietary intervention could improve ALL outcomes in obese mice.

Methods

The team used NOD/SCID IL2-receptor gamma chain knockout mice raised on either a 60% or 10% fat-calorie diet. Only male mice were studied because female mice do not become as significantly obese on the high-fat diet.

The researchers implanted GFP+ pre-B-cell ALL transgenic mouse cells into DIO and control mice at about 20 weeks old.

Six to seven days after ALL implantation, the researchers randomized the DIO mice to continue their high-fat diet or switch to the control diet (10% calories from fat).

In some experiments, mice received monotherapy with vincristine, and other experiments used L-asparaginase or dexamethasone.

In additional experiments, the researchers implanted DIO and control mice with patient-derived ALL cells with normal karyotype.

After 17 days of engraftment, the researchers switched half the DIO mice to the control diet. The next day, they treated these mice with vincristine, L-asparaginase, or dexamethasone for 4 weeks.

The team monitored the mice daily for food intake, body weight, and onset of progressive leukemia.

Results

Diet had no impact on DIO or control mice that did not receive chemotherapy. Time to progression was the same in these mice.

When vincristine was started on day 7 after ALL implantation, DIO mice switched to the low-fat diet had the best survival, even better than the control mice.

Overall survival was 92% for the DIO mice that switched diets, 42% for the control group, and 17% for the DIO group maintained on the high-fat diet.

Survival experiments performed using L-asparaginase or dexamethasone monotherapy showed no impact of switching diets. The researchers reported there was “no detectable effect on survival in these experiments.”

The team believes this is the first study to test a diet intervention on treatment outcome in hematologic malignancy.

The researchers plan to study dietary intervention further in both obese and non-obese patients.

This study was supported by the National Cancer Institute and funds from the Saban Research Institute, Children’s Hospital of Los Angeles. The researchers had no competing interests to declare.

Obese lab mouse

Switching to a low-fat diet can improve survival in obese mice with acute lymphoblastic leukemia (ALL), according to new research.

Diet-induced obese (DIO) mice with ALL had a survival rate of 17% if they remained on a high-fat diet while treated with vincristine, but survival rose to 92% for mice that were switched to a low-fat diet before treatment.

However, the dietary switch did not impact the survival of DIO mice treated with dexamethasone or L-asparaginase monotherapy.

Researchers reported these findings in Cancer & Metabolism.

“The most exciting thing, to me, about this study is the fact that this shows that a dietary intervention could potentially help us kill leukemia cells in children with acute lymphoblastic leukemia,” said study author Steven Mittelman, MD, PhD, of the University of Southern California, Los Angeles.

“The current treatments for leukemia are very toxic, so finding a way to use a healthy diet, without increasing the toxicity of therapy to treat people with cancer, would be incredible.”

Building on previous research that showed obesity reduced the effectiveness of chemotherapeutic drugs in children with leukemia, the researchers tested whether a dietary intervention could improve ALL outcomes in obese mice.

Methods

The team used NOD/SCID IL2-receptor gamma chain knockout mice raised on either a 60% or 10% fat-calorie diet. Only male mice were studied because female mice do not become as significantly obese on the high-fat diet.

The researchers implanted GFP+ pre-B-cell ALL transgenic mouse cells into DIO and control mice at about 20 weeks old.

Six to seven days after ALL implantation, the researchers randomized the DIO mice to continue their high-fat diet or switch to the control diet (10% calories from fat).

In some experiments, mice received monotherapy with vincristine, and other experiments used L-asparaginase or dexamethasone.

In additional experiments, the researchers implanted DIO and control mice with patient-derived ALL cells with normal karyotype.

After 17 days of engraftment, the researchers switched half the DIO mice to the control diet. The next day, they treated these mice with vincristine, L-asparaginase, or dexamethasone for 4 weeks.

The team monitored the mice daily for food intake, body weight, and onset of progressive leukemia.

Results

Diet had no impact on DIO or control mice that did not receive chemotherapy. Time to progression was the same in these mice.

When vincristine was started on day 7 after ALL implantation, DIO mice switched to the low-fat diet had the best survival, even better than the control mice.

Overall survival was 92% for the DIO mice that switched diets, 42% for the control group, and 17% for the DIO group maintained on the high-fat diet.

Survival experiments performed using L-asparaginase or dexamethasone monotherapy showed no impact of switching diets. The researchers reported there was “no detectable effect on survival in these experiments.”

The team believes this is the first study to test a diet intervention on treatment outcome in hematologic malignancy.

The researchers plan to study dietary intervention further in both obese and non-obese patients.

This study was supported by the National Cancer Institute and funds from the Saban Research Institute, Children’s Hospital of Los Angeles. The researchers had no competing interests to declare.

Obese lab mouse

Switching to a low-fat diet can improve survival in obese mice with acute lymphoblastic leukemia (ALL), according to new research.

Diet-induced obese (DIO) mice with ALL had a survival rate of 17% if they remained on a high-fat diet while treated with vincristine, but survival rose to 92% for mice that were switched to a low-fat diet before treatment.

However, the dietary switch did not impact the survival of DIO mice treated with dexamethasone or L-asparaginase monotherapy.

Researchers reported these findings in Cancer & Metabolism.

“The most exciting thing, to me, about this study is the fact that this shows that a dietary intervention could potentially help us kill leukemia cells in children with acute lymphoblastic leukemia,” said study author Steven Mittelman, MD, PhD, of the University of Southern California, Los Angeles.

“The current treatments for leukemia are very toxic, so finding a way to use a healthy diet, without increasing the toxicity of therapy to treat people with cancer, would be incredible.”

Building on previous research that showed obesity reduced the effectiveness of chemotherapeutic drugs in children with leukemia, the researchers tested whether a dietary intervention could improve ALL outcomes in obese mice.

Methods

The team used NOD/SCID IL2-receptor gamma chain knockout mice raised on either a 60% or 10% fat-calorie diet. Only male mice were studied because female mice do not become as significantly obese on the high-fat diet.

The researchers implanted GFP+ pre-B-cell ALL transgenic mouse cells into DIO and control mice at about 20 weeks old.

Six to seven days after ALL implantation, the researchers randomized the DIO mice to continue their high-fat diet or switch to the control diet (10% calories from fat).

In some experiments, mice received monotherapy with vincristine, and other experiments used L-asparaginase or dexamethasone.

In additional experiments, the researchers implanted DIO and control mice with patient-derived ALL cells with normal karyotype.

After 17 days of engraftment, the researchers switched half the DIO mice to the control diet. The next day, they treated these mice with vincristine, L-asparaginase, or dexamethasone for 4 weeks.

The team monitored the mice daily for food intake, body weight, and onset of progressive leukemia.

Results

Diet had no impact on DIO or control mice that did not receive chemotherapy. Time to progression was the same in these mice.

When vincristine was started on day 7 after ALL implantation, DIO mice switched to the low-fat diet had the best survival, even better than the control mice.

Overall survival was 92% for the DIO mice that switched diets, 42% for the control group, and 17% for the DIO group maintained on the high-fat diet.

Survival experiments performed using L-asparaginase or dexamethasone monotherapy showed no impact of switching diets. The researchers reported there was “no detectable effect on survival in these experiments.”

The team believes this is the first study to test a diet intervention on treatment outcome in hematologic malignancy.

The researchers plan to study dietary intervention further in both obese and non-obese patients.

This study was supported by the National Cancer Institute and funds from the Saban Research Institute, Children’s Hospital of Los Angeles. The researchers had no competing interests to declare.

CHICAGO – New recognition of the prognostic value of cytogenetic factors, minimal residual disease activity, and Philadelphia chromosome–like signature could improve the treatment and outcomes of acute lymphoblastic leukemia (ALL), according to Anjali Advani, MD.

CD20

About 80% of ALL is B-cell ALL and the majority of patients have pre–B-cell ALL, Dr. Advani, a hematologist and director of the inpatient leukemia program at the Cleveland Clinic, said at the American Society of Hematology Meeting on Hematologic Malignancies.

“And on the B lymphoblast, many antigens are expressed, including CD19, CD20, and CD52,” she said.

Rituximab, a drug often used for the treatment of lymphoma, is a chimeric monoclonal antibody against the protein CD20, which is expressed in 41% of ALL patients.

“Interestingly, CD20 expression in ALL has been associated with an adverse prognostic impact, which suggests that targeting this may potentially improve outcomes in these patients,” Dr. Advani said.

In fact, a recent randomized study by Sébastien Maury, MD, of the University of Paris-Est, and his colleagues, demonstrated that adding 16-18 doses of rituximab to a Berlin-Frankfurt-Münster (BFM)–based chemotherapy in Philadelphia chromosome (Ph)–negative patients aged 18-59 years with CD20-positive pre–B-cell ALL improved 2-year event-free survival from 52% to 65%. The data are consistent with those from prior studies, including a German study that showed a higher degree of minimal residual disease (MRD) negativity in patients treated with rituximab, she noted (N Engl J Med 2016;375:1044-53).

While the study by Dr. Maury and his colleagues didn’t look at MRD, that may offer an explanation for the improved event-free survival in their study, Dr. Advani suggested.
 

MRD

Minimal residual disease has become a standard part of practice in ALL, but pediatric ALL led the way in using early MRD measurement for risk-stratifying therapy, and it has taken a bit longer for it to be incorporated in the adult disease realm, Dr. Advani said.

Either flow cytometry or polymerase chain reaction (PCR) amplification can be used to measure MRD, she noted.


In one of the larger studies done in adults, researchers used PCR to look at MRD at two time points and stratified patients into three risk groups, including low, intermediate, and high risk (Blood. 2006 Feb 1;107:1116-23).

Measuring MRD at those two time points “clearly separated the prognosis of patients not only in terms of disease-free survival but [in] overall survival,” she said. “So that’s why, for ALL, this has really become very important.”

In the United States, where flow-based cytometry is used more, it is necessary to find a properly equipped laboratory that can provide reliable results, she added. “For example, at our center we actually send our MRD to Fred Hutchinson [Cancer Center in Seattle].”

Johns Hopkins [Baltimore] also has such a lab, and both can arrange to accept send-outs, she said.

The other “really exciting thing” in regard to MRD in ALL is the recent approval of blinatumomab for MRD-positive ALL, she said.

In a study of 113 evaluable patients who were treated with the monoclonal antibody, 78% achieved complete molecular response (Blood. 2018 Apr 5;131:1522-31).

“And probably most importantly, when they looked at those patients who responded to blinatumomab in terms of MRD, these patients had, again, not only improved relapse-free survival but also increased overall survival,” she said. “I think this really explains why in ALL, we are measuring MRD and how it can really impact these patients.”

One of the remaining questions that will be important to address going forward is whether patients with MRD-positive ALL should continue to be considered for transplant; some of these studies have shown “very, very good outcomes” in patients who have not been transplanted, she noted.

Ph-like signature

Another important new prognostic feature in ALL is the presence of the Ph-like signature, a gene expression signature that was initially described in children with poor-risk ALL, and which looks a lot like Ph-positive disease.

“When they delved in further, they identified that this signature actually correlated with multiple different [kinase] fusions ... and it turns out that 20%-25% of young adults have this signature,” she said.

Since event-free survival in young adults with ALL is usually in the 65%-70% range, most of the remaining 30%-35% likely have this signature, she explained.

The kinase fusions associated with the Ph-like signature retain intact tyrosine kinase domains, and the spectrum of the fusions changes across age groups.


Treatments targeting some of these – for example, dasatinib for patients with a Ph-like dasatinib-sensitive kinase mutation – are being investigated.

Additionally, the Children’s Oncology Group has developed a clinically adaptable screening assay to identify the signature, she noted.

“So I would say that, and there is probably some difference in opinion, it is now becoming fairly standard that at diagnosis in an adult with ALL we’re sending the Ph-like signature,” she said. “And again, usually you’re going to have to send this out, and at our center we send it out to [Nationwide Children’s Hospital] in Columbus [Ohio].”

As important as it is to identify the Ph-like signature, given its association with poor prognosis, a number of questions remain, including whether transplant improves outcomes.

“The hope is it probably does, and that’s something that’s being evaluated in studies,” she said, noting that clinical studies are also specifically targeting these patients.

“So these patients should probably be enrolled on a clinical trial, because their outcome is clearly inferior,” she said.

Dr. Advani reported consultancy for Pfizer; research funding from Genzyme, Novartis, Pfizer, and Sigma Tau; and honoraria from Genzyme, Pfizer, and Sigma Tau. She is also on the speakers bureau for Sigma Tau.

sworcester@mdedge.com

CHICAGO – New recognition of the prognostic value of cytogenetic factors, minimal residual disease activity, and Philadelphia chromosome–like signature could improve the treatment and outcomes of acute lymphoblastic leukemia (ALL), according to Anjali Advani, MD.

CD20

About 80% of ALL is B-cell ALL and the majority of patients have pre–B-cell ALL, Dr. Advani, a hematologist and director of the inpatient leukemia program at the Cleveland Clinic, said at the American Society of Hematology Meeting on Hematologic Malignancies.

“And on the B lymphoblast, many antigens are expressed, including CD19, CD20, and CD52,” she said.

Rituximab, a drug often used for the treatment of lymphoma, is a chimeric monoclonal antibody against the protein CD20, which is expressed in 41% of ALL patients.

“Interestingly, CD20 expression in ALL has been associated with an adverse prognostic impact, which suggests that targeting this may potentially improve outcomes in these patients,” Dr. Advani said.

In fact, a recent randomized study by Sébastien Maury, MD, of the University of Paris-Est, and his colleagues, demonstrated that adding 16-18 doses of rituximab to a Berlin-Frankfurt-Münster (BFM)–based chemotherapy in Philadelphia chromosome (Ph)–negative patients aged 18-59 years with CD20-positive pre–B-cell ALL improved 2-year event-free survival from 52% to 65%. The data are consistent with those from prior studies, including a German study that showed a higher degree of minimal residual disease (MRD) negativity in patients treated with rituximab, she noted (N Engl J Med 2016;375:1044-53).

While the study by Dr. Maury and his colleagues didn’t look at MRD, that may offer an explanation for the improved event-free survival in their study, Dr. Advani suggested.
 

MRD

Minimal residual disease has become a standard part of practice in ALL, but pediatric ALL led the way in using early MRD measurement for risk-stratifying therapy, and it has taken a bit longer for it to be incorporated in the adult disease realm, Dr. Advani said.

Either flow cytometry or polymerase chain reaction (PCR) amplification can be used to measure MRD, she noted.


In one of the larger studies done in adults, researchers used PCR to look at MRD at two time points and stratified patients into three risk groups, including low, intermediate, and high risk (Blood. 2006 Feb 1;107:1116-23).

Measuring MRD at those two time points “clearly separated the prognosis of patients not only in terms of disease-free survival but [in] overall survival,” she said. “So that’s why, for ALL, this has really become very important.”

In the United States, where flow-based cytometry is used more, it is necessary to find a properly equipped laboratory that can provide reliable results, she added. “For example, at our center we actually send our MRD to Fred Hutchinson [Cancer Center in Seattle].”

Johns Hopkins [Baltimore] also has such a lab, and both can arrange to accept send-outs, she said.

The other “really exciting thing” in regard to MRD in ALL is the recent approval of blinatumomab for MRD-positive ALL, she said.

In a study of 113 evaluable patients who were treated with the monoclonal antibody, 78% achieved complete molecular response (Blood. 2018 Apr 5;131:1522-31).

“And probably most importantly, when they looked at those patients who responded to blinatumomab in terms of MRD, these patients had, again, not only improved relapse-free survival but also increased overall survival,” she said. “I think this really explains why in ALL, we are measuring MRD and how it can really impact these patients.”

One of the remaining questions that will be important to address going forward is whether patients with MRD-positive ALL should continue to be considered for transplant; some of these studies have shown “very, very good outcomes” in patients who have not been transplanted, she noted.

Ph-like signature

Another important new prognostic feature in ALL is the presence of the Ph-like signature, a gene expression signature that was initially described in children with poor-risk ALL, and which looks a lot like Ph-positive disease.

“When they delved in further, they identified that this signature actually correlated with multiple different [kinase] fusions ... and it turns out that 20%-25% of young adults have this signature,” she said.

Since event-free survival in young adults with ALL is usually in the 65%-70% range, most of the remaining 30%-35% likely have this signature, she explained.

The kinase fusions associated with the Ph-like signature retain intact tyrosine kinase domains, and the spectrum of the fusions changes across age groups.


Treatments targeting some of these – for example, dasatinib for patients with a Ph-like dasatinib-sensitive kinase mutation – are being investigated.

Additionally, the Children’s Oncology Group has developed a clinically adaptable screening assay to identify the signature, she noted.

“So I would say that, and there is probably some difference in opinion, it is now becoming fairly standard that at diagnosis in an adult with ALL we’re sending the Ph-like signature,” she said. “And again, usually you’re going to have to send this out, and at our center we send it out to [Nationwide Children’s Hospital] in Columbus [Ohio].”

As important as it is to identify the Ph-like signature, given its association with poor prognosis, a number of questions remain, including whether transplant improves outcomes.

“The hope is it probably does, and that’s something that’s being evaluated in studies,” she said, noting that clinical studies are also specifically targeting these patients.

“So these patients should probably be enrolled on a clinical trial, because their outcome is clearly inferior,” she said.

Dr. Advani reported consultancy for Pfizer; research funding from Genzyme, Novartis, Pfizer, and Sigma Tau; and honoraria from Genzyme, Pfizer, and Sigma Tau. She is also on the speakers bureau for Sigma Tau.

sworcester@mdedge.com

CHICAGO – New recognition of the prognostic value of cytogenetic factors, minimal residual disease activity, and Philadelphia chromosome–like signature could improve the treatment and outcomes of acute lymphoblastic leukemia (ALL), according to Anjali Advani, MD.

CD20

About 80% of ALL is B-cell ALL and the majority of patients have pre–B-cell ALL, Dr. Advani, a hematologist and director of the inpatient leukemia program at the Cleveland Clinic, said at the American Society of Hematology Meeting on Hematologic Malignancies.

“And on the B lymphoblast, many antigens are expressed, including CD19, CD20, and CD52,” she said.

Rituximab, a drug often used for the treatment of lymphoma, is a chimeric monoclonal antibody against the protein CD20, which is expressed in 41% of ALL patients.

“Interestingly, CD20 expression in ALL has been associated with an adverse prognostic impact, which suggests that targeting this may potentially improve outcomes in these patients,” Dr. Advani said.

In fact, a recent randomized study by Sébastien Maury, MD, of the University of Paris-Est, and his colleagues, demonstrated that adding 16-18 doses of rituximab to a Berlin-Frankfurt-Münster (BFM)–based chemotherapy in Philadelphia chromosome (Ph)–negative patients aged 18-59 years with CD20-positive pre–B-cell ALL improved 2-year event-free survival from 52% to 65%. The data are consistent with those from prior studies, including a German study that showed a higher degree of minimal residual disease (MRD) negativity in patients treated with rituximab, she noted (N Engl J Med 2016;375:1044-53).

While the study by Dr. Maury and his colleagues didn’t look at MRD, that may offer an explanation for the improved event-free survival in their study, Dr. Advani suggested.
 

MRD

Minimal residual disease has become a standard part of practice in ALL, but pediatric ALL led the way in using early MRD measurement for risk-stratifying therapy, and it has taken a bit longer for it to be incorporated in the adult disease realm, Dr. Advani said.

Either flow cytometry or polymerase chain reaction (PCR) amplification can be used to measure MRD, she noted.


In one of the larger studies done in adults, researchers used PCR to look at MRD at two time points and stratified patients into three risk groups, including low, intermediate, and high risk (Blood. 2006 Feb 1;107:1116-23).

Measuring MRD at those two time points “clearly separated the prognosis of patients not only in terms of disease-free survival but [in] overall survival,” she said. “So that’s why, for ALL, this has really become very important.”

In the United States, where flow-based cytometry is used more, it is necessary to find a properly equipped laboratory that can provide reliable results, she added. “For example, at our center we actually send our MRD to Fred Hutchinson [Cancer Center in Seattle].”

Johns Hopkins [Baltimore] also has such a lab, and both can arrange to accept send-outs, she said.

The other “really exciting thing” in regard to MRD in ALL is the recent approval of blinatumomab for MRD-positive ALL, she said.

In a study of 113 evaluable patients who were treated with the monoclonal antibody, 78% achieved complete molecular response (Blood. 2018 Apr 5;131:1522-31).

“And probably most importantly, when they looked at those patients who responded to blinatumomab in terms of MRD, these patients had, again, not only improved relapse-free survival but also increased overall survival,” she said. “I think this really explains why in ALL, we are measuring MRD and how it can really impact these patients.”

One of the remaining questions that will be important to address going forward is whether patients with MRD-positive ALL should continue to be considered for transplant; some of these studies have shown “very, very good outcomes” in patients who have not been transplanted, she noted.

Ph-like signature

Another important new prognostic feature in ALL is the presence of the Ph-like signature, a gene expression signature that was initially described in children with poor-risk ALL, and which looks a lot like Ph-positive disease.

“When they delved in further, they identified that this signature actually correlated with multiple different [kinase] fusions ... and it turns out that 20%-25% of young adults have this signature,” she said.

Since event-free survival in young adults with ALL is usually in the 65%-70% range, most of the remaining 30%-35% likely have this signature, she explained.

The kinase fusions associated with the Ph-like signature retain intact tyrosine kinase domains, and the spectrum of the fusions changes across age groups.


Treatments targeting some of these – for example, dasatinib for patients with a Ph-like dasatinib-sensitive kinase mutation – are being investigated.

Additionally, the Children’s Oncology Group has developed a clinically adaptable screening assay to identify the signature, she noted.

“So I would say that, and there is probably some difference in opinion, it is now becoming fairly standard that at diagnosis in an adult with ALL we’re sending the Ph-like signature,” she said. “And again, usually you’re going to have to send this out, and at our center we send it out to [Nationwide Children’s Hospital] in Columbus [Ohio].”

As important as it is to identify the Ph-like signature, given its association with poor prognosis, a number of questions remain, including whether transplant improves outcomes.

“The hope is it probably does, and that’s something that’s being evaluated in studies,” she said, noting that clinical studies are also specifically targeting these patients.

“So these patients should probably be enrolled on a clinical trial, because their outcome is clearly inferior,” she said.

Dr. Advani reported consultancy for Pfizer; research funding from Genzyme, Novartis, Pfizer, and Sigma Tau; and honoraria from Genzyme, Pfizer, and Sigma Tau. She is also on the speakers bureau for Sigma Tau.

sworcester@mdedge.com