Leukemia, Myelodysplasia, Transplantation

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.

©ASH/Scott Morgan 2018

SAN DIEGO—In a phase 3 trial, ibrutinib plus rituximab (IR) improved survival when compared with standard chemoimmunotherapy in patients younger than 70 with untreated chronic lymphocytic leukemia (CLL).

Patients who received IR had superior progression-free survival (PFS) and overall survival compared to patients who received fludarabine, cyclophosphamide, and rituximab (FCR).

“This establishes ibrutinib-based therapy as the most effective treatment tested to date in this disease for untreated patients,” said Tait D. Shanafelt, MD, of Stanford University in California.

In fact, the study results are likely to dethrone FCR as the most active chemoimmunotherapy regimen against CLL, Dr. Shanafelt said.

He presented the results during the late-breaking abstract session at the 2018 ASH Annual Meeting (abstract LBA-4*).

The trial (NCT02048813) included 529 patients age 70 or younger with previously untreated CLL. They were randomized on a 2:1 basis to either six cycles of FCR according to standard protocols (n=175) or IR (n=354).

IR consisted of ibrutinib given at 420 mg daily for each 28-day cycle and rituximab given at 50 mg/m² on day 1 of cycle 2, at 325 mg/m² on day 2 of cycle 2, and at 500 mg/m² on day 1 for cycles 3 to 7.

From cycle 8 on, patients in the IR arm received daily ibrutinib at 420 mg until disease progression.

Dr. Shanafelt said patient characteristics were well-balanced between the treatment arms.

He presented results from both an intent-to-treat (ITT) analysis and a per-protocol analysis excluding 22 patients in the IR arm and nine patients in the FCR arm who were randomized but later found not to meet eligibility criteria.

PFS

In the ITT analysis, there were 37 cases of progression or death in the IR arm and 40 cases in the FCR arm. This difference translated into a hazard ratio (HR) for progression or death of 0.35 with IR (P<0.00001).

In the per-protocol analysis, there were 33 cases of progression or death in the IR arm and 39 cases in the FCR arm. The HR was 0.32 favoring IR (P<0.00001).

In a subgroup analysis of PFS, IR was superior to FCR regardless of patient age, sex, performance status, disease stage, or the presence or absence of the 11q23.3 deletion.

PFS was significantly better with IR in patients with unmutated IGHV (HR= 0.26, P<0.00001) but not in patients with mutated IGHV (HR=0.44, P=0.07).

Overall survival

In the ITT analysis, there were four deaths in the IR arm and 10 in the FCR arm (HR=0.17, P<0.0003).

In the per-protocol analysis, there were three deaths in the IR arm and 10 deaths in the FCR arm (HR=0.13, P<0.0001).

Dr. Shanafelt noted that, although the overall number of deaths was relatively small, there were twice as many patients enrolled in the IR arm as in the FCR arm, meaning the rate of death in the FCR arm was five-fold higher than in the IR arm.

Safety and cost

Grade 3 or greater treatment-related adverse events (AEs) occurred in 58.5% of patients in the IR arm and 72.1% of patients in the FCR arm (P=0.004).

Specific AEs that occurred significantly less often with IR included neutropenia (22.7% vs. 43.7%), anemia (2.6% vs. 12.0%), thrombocytopenia (2.9% vs. 13.9%), any infection (7.1% vs. 19.0%), and neutropenic fever (2.3% vs. 15.8%; P<0.001 for all comparisons).

AEs that occurred more frequently with IR than FCR included atrial fibrillation (2.9% vs. 0%, P=0.04) and hypertension (7.4% vs. 1.9%, P=0.01).

Dr. Shanafelt acknowledged that one possible barrier to the IR regimen is cost. The monthly cost of ibrutinib maintenance is about $10,000, he said, although he noted that cost considerations were not studied in the trial.

“Future trials testing novel agent combinations to see if we can eliminate the need for chronic therapy should be pursued,” he said.

The trial was sponsored by the National Cancer Institute with additional support from Pharmacyclics. Dr. Shanafelt reported patents and royalties from the Mayo Clinic, and research funding from Celgene, GlaxoSmithKline, Genentech, AbbVie, Pharmacyclics, and Janssen.

*Data in the abstract differ from the presentation.

©ASH/Scott Morgan 2018

SAN DIEGO—In a phase 3 trial, ibrutinib plus rituximab (IR) improved survival when compared with standard chemoimmunotherapy in patients younger than 70 with untreated chronic lymphocytic leukemia (CLL).

Patients who received IR had superior progression-free survival (PFS) and overall survival compared to patients who received fludarabine, cyclophosphamide, and rituximab (FCR).

“This establishes ibrutinib-based therapy as the most effective treatment tested to date in this disease for untreated patients,” said Tait D. Shanafelt, MD, of Stanford University in California.

In fact, the study results are likely to dethrone FCR as the most active chemoimmunotherapy regimen against CLL, Dr. Shanafelt said.

He presented the results during the late-breaking abstract session at the 2018 ASH Annual Meeting (abstract LBA-4*).

The trial (NCT02048813) included 529 patients age 70 or younger with previously untreated CLL. They were randomized on a 2:1 basis to either six cycles of FCR according to standard protocols (n=175) or IR (n=354).

IR consisted of ibrutinib given at 420 mg daily for each 28-day cycle and rituximab given at 50 mg/m² on day 1 of cycle 2, at 325 mg/m² on day 2 of cycle 2, and at 500 mg/m² on day 1 for cycles 3 to 7.

From cycle 8 on, patients in the IR arm received daily ibrutinib at 420 mg until disease progression.

Dr. Shanafelt said patient characteristics were well-balanced between the treatment arms.

He presented results from both an intent-to-treat (ITT) analysis and a per-protocol analysis excluding 22 patients in the IR arm and nine patients in the FCR arm who were randomized but later found not to meet eligibility criteria.

PFS

In the ITT analysis, there were 37 cases of progression or death in the IR arm and 40 cases in the FCR arm. This difference translated into a hazard ratio (HR) for progression or death of 0.35 with IR (P<0.00001).

In the per-protocol analysis, there were 33 cases of progression or death in the IR arm and 39 cases in the FCR arm. The HR was 0.32 favoring IR (P<0.00001).

In a subgroup analysis of PFS, IR was superior to FCR regardless of patient age, sex, performance status, disease stage, or the presence or absence of the 11q23.3 deletion.

PFS was significantly better with IR in patients with unmutated IGHV (HR= 0.26, P<0.00001) but not in patients with mutated IGHV (HR=0.44, P=0.07).

Overall survival

In the ITT analysis, there were four deaths in the IR arm and 10 in the FCR arm (HR=0.17, P<0.0003).

In the per-protocol analysis, there were three deaths in the IR arm and 10 deaths in the FCR arm (HR=0.13, P<0.0001).

Dr. Shanafelt noted that, although the overall number of deaths was relatively small, there were twice as many patients enrolled in the IR arm as in the FCR arm, meaning the rate of death in the FCR arm was five-fold higher than in the IR arm.

Safety and cost

Grade 3 or greater treatment-related adverse events (AEs) occurred in 58.5% of patients in the IR arm and 72.1% of patients in the FCR arm (P=0.004).

Specific AEs that occurred significantly less often with IR included neutropenia (22.7% vs. 43.7%), anemia (2.6% vs. 12.0%), thrombocytopenia (2.9% vs. 13.9%), any infection (7.1% vs. 19.0%), and neutropenic fever (2.3% vs. 15.8%; P<0.001 for all comparisons).

AEs that occurred more frequently with IR than FCR included atrial fibrillation (2.9% vs. 0%, P=0.04) and hypertension (7.4% vs. 1.9%, P=0.01).

Dr. Shanafelt acknowledged that one possible barrier to the IR regimen is cost. The monthly cost of ibrutinib maintenance is about $10,000, he said, although he noted that cost considerations were not studied in the trial.

“Future trials testing novel agent combinations to see if we can eliminate the need for chronic therapy should be pursued,” he said.

The trial was sponsored by the National Cancer Institute with additional support from Pharmacyclics. Dr. Shanafelt reported patents and royalties from the Mayo Clinic, and research funding from Celgene, GlaxoSmithKline, Genentech, AbbVie, Pharmacyclics, and Janssen.

*Data in the abstract differ from the presentation.

©ASH/Scott Morgan 2018

SAN DIEGO—In a phase 3 trial, ibrutinib plus rituximab (IR) improved survival when compared with standard chemoimmunotherapy in patients younger than 70 with untreated chronic lymphocytic leukemia (CLL).

Patients who received IR had superior progression-free survival (PFS) and overall survival compared to patients who received fludarabine, cyclophosphamide, and rituximab (FCR).

“This establishes ibrutinib-based therapy as the most effective treatment tested to date in this disease for untreated patients,” said Tait D. Shanafelt, MD, of Stanford University in California.

In fact, the study results are likely to dethrone FCR as the most active chemoimmunotherapy regimen against CLL, Dr. Shanafelt said.

He presented the results during the late-breaking abstract session at the 2018 ASH Annual Meeting (abstract LBA-4*).

The trial (NCT02048813) included 529 patients age 70 or younger with previously untreated CLL. They were randomized on a 2:1 basis to either six cycles of FCR according to standard protocols (n=175) or IR (n=354).

IR consisted of ibrutinib given at 420 mg daily for each 28-day cycle and rituximab given at 50 mg/m² on day 1 of cycle 2, at 325 mg/m² on day 2 of cycle 2, and at 500 mg/m² on day 1 for cycles 3 to 7.

From cycle 8 on, patients in the IR arm received daily ibrutinib at 420 mg until disease progression.

Dr. Shanafelt said patient characteristics were well-balanced between the treatment arms.

He presented results from both an intent-to-treat (ITT) analysis and a per-protocol analysis excluding 22 patients in the IR arm and nine patients in the FCR arm who were randomized but later found not to meet eligibility criteria.

PFS

In the ITT analysis, there were 37 cases of progression or death in the IR arm and 40 cases in the FCR arm. This difference translated into a hazard ratio (HR) for progression or death of 0.35 with IR (P<0.00001).

In the per-protocol analysis, there were 33 cases of progression or death in the IR arm and 39 cases in the FCR arm. The HR was 0.32 favoring IR (P<0.00001).

In a subgroup analysis of PFS, IR was superior to FCR regardless of patient age, sex, performance status, disease stage, or the presence or absence of the 11q23.3 deletion.

PFS was significantly better with IR in patients with unmutated IGHV (HR= 0.26, P<0.00001) but not in patients with mutated IGHV (HR=0.44, P=0.07).

Overall survival

In the ITT analysis, there were four deaths in the IR arm and 10 in the FCR arm (HR=0.17, P<0.0003).

In the per-protocol analysis, there were three deaths in the IR arm and 10 deaths in the FCR arm (HR=0.13, P<0.0001).

Dr. Shanafelt noted that, although the overall number of deaths was relatively small, there were twice as many patients enrolled in the IR arm as in the FCR arm, meaning the rate of death in the FCR arm was five-fold higher than in the IR arm.

Safety and cost

Grade 3 or greater treatment-related adverse events (AEs) occurred in 58.5% of patients in the IR arm and 72.1% of patients in the FCR arm (P=0.004).

Specific AEs that occurred significantly less often with IR included neutropenia (22.7% vs. 43.7%), anemia (2.6% vs. 12.0%), thrombocytopenia (2.9% vs. 13.9%), any infection (7.1% vs. 19.0%), and neutropenic fever (2.3% vs. 15.8%; P<0.001 for all comparisons).

AEs that occurred more frequently with IR than FCR included atrial fibrillation (2.9% vs. 0%, P=0.04) and hypertension (7.4% vs. 1.9%, P=0.01).

Dr. Shanafelt acknowledged that one possible barrier to the IR regimen is cost. The monthly cost of ibrutinib maintenance is about $10,000, he said, although he noted that cost considerations were not studied in the trial.

“Future trials testing novel agent combinations to see if we can eliminate the need for chronic therapy should be pursued,” he said.

The trial was sponsored by the National Cancer Institute with additional support from Pharmacyclics. Dr. Shanafelt reported patents and royalties from the Mayo Clinic, and research funding from Celgene, GlaxoSmithKline, Genentech, AbbVie, Pharmacyclics, and Janssen.

*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.

SAN DIEGO – The combination of ibrutinib and rituximab was associated with a two-thirds reduction in chronic lymphocytic leukemia (CLL) progression, compared with standard chemoimmunotherapy in patients younger than 70 years old, interim results of a phase 3 randomized trial showed.

Among 529 patients with previously untreated, symptomatic CLL randomly assigned to ibrutinib-rituximab (IR) or to chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab (FCR), the IR regimen was associated with a 65% reduction in risk for disease progression, which was the trial’s primary endpoint.

The IR regimen was also associated with better overall survival out to 4 years of follow-up, reported Tait D. Shanafelt, MD, of Stanford (Calif.) University.

“This establishes ibrutinib-based therapy as the most effective treatment tested to date in this disease for untreated patients,” he said at a media briefing prior at the annual meeting of the American Society of Hematology.

The study results are likely to dethrone FCR as the most active chemoimmunotherapy regimen against CLL, Dr. Shanafelt said.

In the ECOG-ACRIN Cancer Research Group E1912 trial, 529 patients aged 70 or younger with previously untreated CLL were enrolled and randomly assigned on a 2:1 basis to either standard therapy with six cycles of FCR according to standard protocols (175 patients), or IR, with ibrutinib 420 mg daily for each cycle, and rituximab delivered 50 mg/m² intravenously on day 1 of cycle 2, and 325 mg/m² on day 2 of the same cycle, and 500 mg/m² on day 1 for all remaining cycles (354 patients).

From cycle 8 until progression, patients in the IR arm received daily ibrutinib 420 mg.

Dr. Shanafelt presented results from both an intention-to-treat analysis and a per-protocol analysis excluding 22 patients in the IR arm and 9 patients in the FCR arm who were randomized but later found not to meet eligibility criteria.

After a mean follow-up of 34 months, there were 37 PFS events in the IR arm, compared with 40 events in the FCR arm in an intention-to-treat analysis. The difference translated into a hazard ratio for progression of 0.35 with IR (P less than .00001).

The results were similar in the per-protocol analysis, with an HR of 0.32 favoring IR (P less than .00001).*

There were four deaths in the IR arm, compared with 10 in the FCR arm at the time of the data lock, translating into a hazard ratio (HR) for overall survival of 0.17 (P less than .0003) in the intention-to-treat analysis, and 0.13 in the per-protocol analysis (P less than .0001).

Dr. Shanafelt noted that although the overall number of deaths was relatively small, there were twice as many patients enrolled in the IR arm as in the FCR arm, meaning that the rate of deaths in the FCR arm was fivefold higher than in the IR arm.

In a subgroup analysis of PFS, IR was superior to FCR regardless of patient age, sex, performance status, disease stage, or the presence or absence of the 11q23.3 deletion.

PFS was also significantly better with IR in patients with unmutated immunoglobulin heavy chain variable (IGHV) regions (HR 0.26, P less than .00001), but not in patients with mutated IGHV.*

Grade 3 or greater treatment-related adverse events occurred in 58.5% of patients in the IR arm, compared with 72.1% of patients in the FCR arm. Specific events that occurred significantly less often with IR included neutropenia (22.7% vs. 43.7%), anemia (2.6% vs. 12.0%), thrombocytopenia (2.9% vs. 13.9%), any infection (7.1% vs. 19.0%), and neutropenic fever (2.3% vs. 15.8%; P less than .001 for all comparisons).

Events that occurred more frequently with IR than FCR included atrial fibrillation (2.9% vs. 0%, P = .04), and hypertension (7.4% vs. 1.9%, P = .01).

Dr. Shanafelt acknowledged that one possible barrier to the IR regimen is cost; the monthly cost of ibrutinib maintenance is about $10,000, he said, although he noted that cost considerations were not studied in the trial.

“Future trials testing novel agent combinations to see if we can eliminate the need for chronic therapy should be pursued,” he said.

The trial was sponsored by the National Cancer Institute with additional support from Pharmacyclics. Dr. Shanafelt reported patents and royalties from the Mayo Clinic, and research funding from Celgene, GlaxoSmithKline, Genentech, Abbvie, Pharmacyclics, and Janssen.

SOURCE: Shanafelt TD et al. ASH 2018, Abstract LBA-4.

*Correction, 12/12/2018: An earlier version of this story misstated the P value in two comparisons.

SAN DIEGO – The combination of ibrutinib and rituximab was associated with a two-thirds reduction in chronic lymphocytic leukemia (CLL) progression, compared with standard chemoimmunotherapy in patients younger than 70 years old, interim results of a phase 3 randomized trial showed.

Among 529 patients with previously untreated, symptomatic CLL randomly assigned to ibrutinib-rituximab (IR) or to chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab (FCR), the IR regimen was associated with a 65% reduction in risk for disease progression, which was the trial’s primary endpoint.

The IR regimen was also associated with better overall survival out to 4 years of follow-up, reported Tait D. Shanafelt, MD, of Stanford (Calif.) University.

“This establishes ibrutinib-based therapy as the most effective treatment tested to date in this disease for untreated patients,” he said at a media briefing prior at the annual meeting of the American Society of Hematology.

The study results are likely to dethrone FCR as the most active chemoimmunotherapy regimen against CLL, Dr. Shanafelt said.

In the ECOG-ACRIN Cancer Research Group E1912 trial, 529 patients aged 70 or younger with previously untreated CLL were enrolled and randomly assigned on a 2:1 basis to either standard therapy with six cycles of FCR according to standard protocols (175 patients), or IR, with ibrutinib 420 mg daily for each cycle, and rituximab delivered 50 mg/m² intravenously on day 1 of cycle 2, and 325 mg/m² on day 2 of the same cycle, and 500 mg/m² on day 1 for all remaining cycles (354 patients).

From cycle 8 until progression, patients in the IR arm received daily ibrutinib 420 mg.

Dr. Shanafelt presented results from both an intention-to-treat analysis and a per-protocol analysis excluding 22 patients in the IR arm and 9 patients in the FCR arm who were randomized but later found not to meet eligibility criteria.

After a mean follow-up of 34 months, there were 37 PFS events in the IR arm, compared with 40 events in the FCR arm in an intention-to-treat analysis. The difference translated into a hazard ratio for progression of 0.35 with IR (P less than .00001).

The results were similar in the per-protocol analysis, with an HR of 0.32 favoring IR (P less than .00001).*

There were four deaths in the IR arm, compared with 10 in the FCR arm at the time of the data lock, translating into a hazard ratio (HR) for overall survival of 0.17 (P less than .0003) in the intention-to-treat analysis, and 0.13 in the per-protocol analysis (P less than .0001).

Dr. Shanafelt noted that although the overall number of deaths was relatively small, there were twice as many patients enrolled in the IR arm as in the FCR arm, meaning that the rate of deaths in the FCR arm was fivefold higher than in the IR arm.

In a subgroup analysis of PFS, IR was superior to FCR regardless of patient age, sex, performance status, disease stage, or the presence or absence of the 11q23.3 deletion.

PFS was also significantly better with IR in patients with unmutated immunoglobulin heavy chain variable (IGHV) regions (HR 0.26, P less than .00001), but not in patients with mutated IGHV.*

Grade 3 or greater treatment-related adverse events occurred in 58.5% of patients in the IR arm, compared with 72.1% of patients in the FCR arm. Specific events that occurred significantly less often with IR included neutropenia (22.7% vs. 43.7%), anemia (2.6% vs. 12.0%), thrombocytopenia (2.9% vs. 13.9%), any infection (7.1% vs. 19.0%), and neutropenic fever (2.3% vs. 15.8%; P less than .001 for all comparisons).

Events that occurred more frequently with IR than FCR included atrial fibrillation (2.9% vs. 0%, P = .04), and hypertension (7.4% vs. 1.9%, P = .01).

Dr. Shanafelt acknowledged that one possible barrier to the IR regimen is cost; the monthly cost of ibrutinib maintenance is about $10,000, he said, although he noted that cost considerations were not studied in the trial.

“Future trials testing novel agent combinations to see if we can eliminate the need for chronic therapy should be pursued,” he said.

The trial was sponsored by the National Cancer Institute with additional support from Pharmacyclics. Dr. Shanafelt reported patents and royalties from the Mayo Clinic, and research funding from Celgene, GlaxoSmithKline, Genentech, Abbvie, Pharmacyclics, and Janssen.

SOURCE: Shanafelt TD et al. ASH 2018, Abstract LBA-4.

*Correction, 12/12/2018: An earlier version of this story misstated the P value in two comparisons.

SAN DIEGO – The combination of ibrutinib and rituximab was associated with a two-thirds reduction in chronic lymphocytic leukemia (CLL) progression, compared with standard chemoimmunotherapy in patients younger than 70 years old, interim results of a phase 3 randomized trial showed.

Among 529 patients with previously untreated, symptomatic CLL randomly assigned to ibrutinib-rituximab (IR) or to chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab (FCR), the IR regimen was associated with a 65% reduction in risk for disease progression, which was the trial’s primary endpoint.

The IR regimen was also associated with better overall survival out to 4 years of follow-up, reported Tait D. Shanafelt, MD, of Stanford (Calif.) University.

“This establishes ibrutinib-based therapy as the most effective treatment tested to date in this disease for untreated patients,” he said at a media briefing prior at the annual meeting of the American Society of Hematology.

The study results are likely to dethrone FCR as the most active chemoimmunotherapy regimen against CLL, Dr. Shanafelt said.

In the ECOG-ACRIN Cancer Research Group E1912 trial, 529 patients aged 70 or younger with previously untreated CLL were enrolled and randomly assigned on a 2:1 basis to either standard therapy with six cycles of FCR according to standard protocols (175 patients), or IR, with ibrutinib 420 mg daily for each cycle, and rituximab delivered 50 mg/m² intravenously on day 1 of cycle 2, and 325 mg/m² on day 2 of the same cycle, and 500 mg/m² on day 1 for all remaining cycles (354 patients).

From cycle 8 until progression, patients in the IR arm received daily ibrutinib 420 mg.

Dr. Shanafelt presented results from both an intention-to-treat analysis and a per-protocol analysis excluding 22 patients in the IR arm and 9 patients in the FCR arm who were randomized but later found not to meet eligibility criteria.

After a mean follow-up of 34 months, there were 37 PFS events in the IR arm, compared with 40 events in the FCR arm in an intention-to-treat analysis. The difference translated into a hazard ratio for progression of 0.35 with IR (P less than .00001).

The results were similar in the per-protocol analysis, with an HR of 0.32 favoring IR (P less than .00001).*

There were four deaths in the IR arm, compared with 10 in the FCR arm at the time of the data lock, translating into a hazard ratio (HR) for overall survival of 0.17 (P less than .0003) in the intention-to-treat analysis, and 0.13 in the per-protocol analysis (P less than .0001).

Dr. Shanafelt noted that although the overall number of deaths was relatively small, there were twice as many patients enrolled in the IR arm as in the FCR arm, meaning that the rate of deaths in the FCR arm was fivefold higher than in the IR arm.

In a subgroup analysis of PFS, IR was superior to FCR regardless of patient age, sex, performance status, disease stage, or the presence or absence of the 11q23.3 deletion.

PFS was also significantly better with IR in patients with unmutated immunoglobulin heavy chain variable (IGHV) regions (HR 0.26, P less than .00001), but not in patients with mutated IGHV.*

Grade 3 or greater treatment-related adverse events occurred in 58.5% of patients in the IR arm, compared with 72.1% of patients in the FCR arm. Specific events that occurred significantly less often with IR included neutropenia (22.7% vs. 43.7%), anemia (2.6% vs. 12.0%), thrombocytopenia (2.9% vs. 13.9%), any infection (7.1% vs. 19.0%), and neutropenic fever (2.3% vs. 15.8%; P less than .001 for all comparisons).

Events that occurred more frequently with IR than FCR included atrial fibrillation (2.9% vs. 0%, P = .04), and hypertension (7.4% vs. 1.9%, P = .01).

Dr. Shanafelt acknowledged that one possible barrier to the IR regimen is cost; the monthly cost of ibrutinib maintenance is about $10,000, he said, although he noted that cost considerations were not studied in the trial.

“Future trials testing novel agent combinations to see if we can eliminate the need for chronic therapy should be pursued,” he said.

The trial was sponsored by the National Cancer Institute with additional support from Pharmacyclics. Dr. Shanafelt reported patents and royalties from the Mayo Clinic, and research funding from Celgene, GlaxoSmithKline, Genentech, Abbvie, Pharmacyclics, and Janssen.

SOURCE: Shanafelt TD et al. ASH 2018, Abstract LBA-4.

*Correction, 12/12/2018: An earlier version of this story misstated the P value in two comparisons.

Photo by Jen Smith

SAN DIEGO—Early results of the DASCERN trial indicate that patients with chronic myeloid leukemia (CML) in chronic phase who have a suboptimal response to imatinib as a first-line treatment benefit from switching to dasatinib at 3 months.

Twenty-nine percent of dasatinib-treated patients achieved a major molecular response (MMR) at 12 months, compared to 13% of patients who remained on imatinib (P=0.005).

Dasatinib-treated patients also attained MMR much faster than those on imatinib, at a median of 14 months, compared to 20 months for those treated with imatinib.

DASCERN is the first study, according to investigators, to explore the significance of an early switch for patients who have not achieved an early molecular response (EMR) with imatinib.

“[EMRs] are important because they correlate with the outcome of patients, certainly with progression-free survival and overall survival,” explained Jorge E. Cortes, MD, of The University of Texas MD Anderson Cancer Center in Houston.

“[T]he possibility of changing to dasatinib appears, with these early results, to suggest that there may be a benefit to switching these patients to achieve better long-term outcomes. But also, those patients that have these early molecular responses have a better probability of achieving deep molecular responses that we desire for treatment-free remission.”

Dr. Cortes elaborated on the DASCERN data at the 2018 ASH Annual Meeting (abstract 788*).

Study design

DASCERN (NCT01593254) is a randomized, open-label, international, phase 2b trial in adult patients with chronic-phase CML who had achieved a complete hematologic response but still had more than 10% BCR-ABL1 transcripts at 3 months.

Patients were initially treated with imatinib at 400 mg daily, and 1,126 patients had a molecular assessment at 3 months.

Those who did not achieve an MMR (n=260) were randomized in a 2:1 fashion to 100 mg daily of dasatinib (n=174) or 400 mg daily or twice daily of imatinib (n=86).

If patients subsequently failed imatinib treatment by European LeukemiaNet standards, they could cross over to dasatinib.

“Importantly, there was a window of enrollment up to 8 weeks after the 3-month assessment, allowing for time to get response results and screen and enroll patients onto the study,” Dr. Cortes clarified.

Patients were also stratified according to Sokal risk score and time from molecular assessment to randomization.

Dr. Cortes noted that about 40% of patients were started on treatment within 4 weeks of the 3-month assessment. And another 58% were enrolled between 4 and 8 weeks from the 3-month assessment.

The primary endpoint is the achievement of MMR at 12 months from the first day of imatinib treatment; that is, at about 9 months from the start of the protocol treatment, in both trial arms.

Patient characteristics

Seventy-eight percent of patients were male, and 95% were younger than 65.

“This is a relatively younger patient population,” Dr. Cortes noted. “This has to do with the fact that this was an international study with a significant representation of patients that were from Asia (73%).”

The Asian patients were primarily from China, Dr. Cortes said, “and we know that, in some parts of the world, including Asia, patients seem to be younger.”

“This is also associated with a higher percentage of patients with high-risk Sokal scores, more than 20%,” he added. “That is different than what’s seen, for example, in the U.S. or in Europe.”

The prevalence of male patients, he said, broadly represents the distribution of patients in other parts of the world.

Patient disposition

Patients were followed for a median of 30 months.

Of the randomized patients—the intent-to-treat (ITT) population—143 (84%) in the dasatinib arm and 72 (84%) in the imatinib arm continued on treatment.

Study drug toxicity was the most common reason for discontinuing treatment and occurred in 9 patients (5%) in the dasatinib arm and 3 (4%) in the imatinib arm.

Nearly half the imatinib patients (n=42, 49%) crossed over to dasatinib at a median of 9 months.

The median duration of treatment was 22 months (range, 1 – 44) for patients on imatinib who did not cross over and 15 months (range, <1 – 38) for patients on dasatinib after crossing over from imatinib.

Response

In the ITT population, the rate of MMR at 12 months was 29% in the dasatinib arm and 13% in the imatinib arm (P=0.005).

The median time to MMR was significantly shorter for patients who received dasatinib compared with imatinib—14 months and 20 months, respectively (P=0.053).

“Over 60% of patients on the dasatinib arm achieved a major molecular response,” Dr. Cortes said. “This compares to about 55% of patients on the imatinib arm, even when you consider the crossover of a significant number of these patients.”

A few patients achieved a molecular response of a 4.5-log reduction in BCR-ABL1 transcripts (MR4.5).

“Of course, the follow-up is short, but we had twice as many patients [on dasatinib] at 12 months with MR4.5— 5% with dasatinib versus 2% with imatinib,” Dr. Cortes said.

Survival outcomes

Both overall and progression-free survival “look very good with both treatment approaches,” Dr. Cortes pointed out.

At a median follow-up of 30 months, the overall survival in the ITT population was 98.8% in each treatment arm.

Progression-free survival was 96.9% in the dasatinib arm and 97.6% in the imatinib arm.

“It is important to note that no patient in either treatment arm has transformed to accelerated or blast phase,” Dr. Cortes said.

Safety

Treatment was well tolerated with both agents, Dr. Cortes observed, with very few grade 3 adverse events (AEs) noted to date.

“The one that stands out here, and it’s only 2% of patients, is headache with dasatinib,” he said.

The headache did not lead to treatment discontinuation, and the patients were managed with dose adjustments.

The investigators observed no new safety signals with either drug.

Treatment-emergent AEs of any grade occurring in 15% or fewer dasatinib- or imatinib-treated patients, respectively, in the ITT population included headache (15%, 9%), diarrhea (9%, 8%), nausea (9%, 8%), eyelid edema (1%, 9%), hypocalcemia (1%, 7%), and muscle spasms (1%, 8%).

Patients who crossed over to dasatinib had similar rates of AEs to those documented for imatinib.

“They are typical for what we know of both of these tyrosine kinase inhibitors,” Dr. Cortes stated.

Investigators observed pleural effusion in 9 (5%) patients on dasatinib, and only one grade 3. That patient discontinued therapy due to the AE.

Of the patients who were on imatinib and crossed over to dasatinib, 3 (7%) experienced pleural effusion, most of them grade 1 or 2. One patient with grade 4 discontinued therapy with dasatinib due to the AE.

“Hematologic toxicity has been mild,” Dr. Cortes said, and in keeping with the known toxicities of dasatinib and imatinib.

Grade 3/4 treatment-emergent AEs in the dasatinib and imatinib arms, respectively, in the ITT population included anemia (5%, 4%), neutropenia (11%, 16%), thrombocytopenia (11%, 11%), and leukopenia (1%, 1%).

Patients who crossed over to dasatinib experienced more of these AEs than patients who did not cross over, Dr. Cortes clarified, but they are still within the expected range with these agents.

“We acknowledge the results are early and we need to continue following for both safety and efficacy, as it will be important to see if those rates of MR4.5 continue to increase with the same difference in favor of dasatinib that we are starting to see very early on,” Dr. Cortes said.

He disclosed serving as a consultant for Pfizer, Daiichi Sankyo, Astellas Pharma, Novartis, and Bristol-Myers Squibb, and he received research funding from Pfizer, Daiichi Sankyo, Arog Pharmaceuticals, Astellas Pharma, Novartis, and Bristol-Myers Squibb.

The study was supported by Bristol-Myers Squibb. 

*Data in the abstract differ from the presentation.

Photo by Jen Smith

SAN DIEGO—Early results of the DASCERN trial indicate that patients with chronic myeloid leukemia (CML) in chronic phase who have a suboptimal response to imatinib as a first-line treatment benefit from switching to dasatinib at 3 months.

Twenty-nine percent of dasatinib-treated patients achieved a major molecular response (MMR) at 12 months, compared to 13% of patients who remained on imatinib (P=0.005).

Dasatinib-treated patients also attained MMR much faster than those on imatinib, at a median of 14 months, compared to 20 months for those treated with imatinib.

DASCERN is the first study, according to investigators, to explore the significance of an early switch for patients who have not achieved an early molecular response (EMR) with imatinib.

“[EMRs] are important because they correlate with the outcome of patients, certainly with progression-free survival and overall survival,” explained Jorge E. Cortes, MD, of The University of Texas MD Anderson Cancer Center in Houston.

“[T]he possibility of changing to dasatinib appears, with these early results, to suggest that there may be a benefit to switching these patients to achieve better long-term outcomes. But also, those patients that have these early molecular responses have a better probability of achieving deep molecular responses that we desire for treatment-free remission.”

Dr. Cortes elaborated on the DASCERN data at the 2018 ASH Annual Meeting (abstract 788*).

Study design

DASCERN (NCT01593254) is a randomized, open-label, international, phase 2b trial in adult patients with chronic-phase CML who had achieved a complete hematologic response but still had more than 10% BCR-ABL1 transcripts at 3 months.

Patients were initially treated with imatinib at 400 mg daily, and 1,126 patients had a molecular assessment at 3 months.

Those who did not achieve an MMR (n=260) were randomized in a 2:1 fashion to 100 mg daily of dasatinib (n=174) or 400 mg daily or twice daily of imatinib (n=86).

If patients subsequently failed imatinib treatment by European LeukemiaNet standards, they could cross over to dasatinib.

“Importantly, there was a window of enrollment up to 8 weeks after the 3-month assessment, allowing for time to get response results and screen and enroll patients onto the study,” Dr. Cortes clarified.

Patients were also stratified according to Sokal risk score and time from molecular assessment to randomization.

Dr. Cortes noted that about 40% of patients were started on treatment within 4 weeks of the 3-month assessment. And another 58% were enrolled between 4 and 8 weeks from the 3-month assessment.

The primary endpoint is the achievement of MMR at 12 months from the first day of imatinib treatment; that is, at about 9 months from the start of the protocol treatment, in both trial arms.

Patient characteristics

Seventy-eight percent of patients were male, and 95% were younger than 65.

“This is a relatively younger patient population,” Dr. Cortes noted. “This has to do with the fact that this was an international study with a significant representation of patients that were from Asia (73%).”

The Asian patients were primarily from China, Dr. Cortes said, “and we know that, in some parts of the world, including Asia, patients seem to be younger.”

“This is also associated with a higher percentage of patients with high-risk Sokal scores, more than 20%,” he added. “That is different than what’s seen, for example, in the U.S. or in Europe.”

The prevalence of male patients, he said, broadly represents the distribution of patients in other parts of the world.

Patient disposition

Patients were followed for a median of 30 months.

Of the randomized patients—the intent-to-treat (ITT) population—143 (84%) in the dasatinib arm and 72 (84%) in the imatinib arm continued on treatment.

Study drug toxicity was the most common reason for discontinuing treatment and occurred in 9 patients (5%) in the dasatinib arm and 3 (4%) in the imatinib arm.

Nearly half the imatinib patients (n=42, 49%) crossed over to dasatinib at a median of 9 months.

The median duration of treatment was 22 months (range, 1 – 44) for patients on imatinib who did not cross over and 15 months (range, <1 – 38) for patients on dasatinib after crossing over from imatinib.

Response

In the ITT population, the rate of MMR at 12 months was 29% in the dasatinib arm and 13% in the imatinib arm (P=0.005).

The median time to MMR was significantly shorter for patients who received dasatinib compared with imatinib—14 months and 20 months, respectively (P=0.053).

“Over 60% of patients on the dasatinib arm achieved a major molecular response,” Dr. Cortes said. “This compares to about 55% of patients on the imatinib arm, even when you consider the crossover of a significant number of these patients.”

A few patients achieved a molecular response of a 4.5-log reduction in BCR-ABL1 transcripts (MR4.5).

“Of course, the follow-up is short, but we had twice as many patients [on dasatinib] at 12 months with MR4.5— 5% with dasatinib versus 2% with imatinib,” Dr. Cortes said.

Survival outcomes

Both overall and progression-free survival “look very good with both treatment approaches,” Dr. Cortes pointed out.

At a median follow-up of 30 months, the overall survival in the ITT population was 98.8% in each treatment arm.

Progression-free survival was 96.9% in the dasatinib arm and 97.6% in the imatinib arm.

“It is important to note that no patient in either treatment arm has transformed to accelerated or blast phase,” Dr. Cortes said.

Safety

Treatment was well tolerated with both agents, Dr. Cortes observed, with very few grade 3 adverse events (AEs) noted to date.

“The one that stands out here, and it’s only 2% of patients, is headache with dasatinib,” he said.

The headache did not lead to treatment discontinuation, and the patients were managed with dose adjustments.

The investigators observed no new safety signals with either drug.

Treatment-emergent AEs of any grade occurring in 15% or fewer dasatinib- or imatinib-treated patients, respectively, in the ITT population included headache (15%, 9%), diarrhea (9%, 8%), nausea (9%, 8%), eyelid edema (1%, 9%), hypocalcemia (1%, 7%), and muscle spasms (1%, 8%).

Patients who crossed over to dasatinib had similar rates of AEs to those documented for imatinib.

“They are typical for what we know of both of these tyrosine kinase inhibitors,” Dr. Cortes stated.

Investigators observed pleural effusion in 9 (5%) patients on dasatinib, and only one grade 3. That patient discontinued therapy due to the AE.

Of the patients who were on imatinib and crossed over to dasatinib, 3 (7%) experienced pleural effusion, most of them grade 1 or 2. One patient with grade 4 discontinued therapy with dasatinib due to the AE.

“Hematologic toxicity has been mild,” Dr. Cortes said, and in keeping with the known toxicities of dasatinib and imatinib.

Grade 3/4 treatment-emergent AEs in the dasatinib and imatinib arms, respectively, in the ITT population included anemia (5%, 4%), neutropenia (11%, 16%), thrombocytopenia (11%, 11%), and leukopenia (1%, 1%).

Patients who crossed over to dasatinib experienced more of these AEs than patients who did not cross over, Dr. Cortes clarified, but they are still within the expected range with these agents.

“We acknowledge the results are early and we need to continue following for both safety and efficacy, as it will be important to see if those rates of MR4.5 continue to increase with the same difference in favor of dasatinib that we are starting to see very early on,” Dr. Cortes said.

He disclosed serving as a consultant for Pfizer, Daiichi Sankyo, Astellas Pharma, Novartis, and Bristol-Myers Squibb, and he received research funding from Pfizer, Daiichi Sankyo, Arog Pharmaceuticals, Astellas Pharma, Novartis, and Bristol-Myers Squibb.

The study was supported by Bristol-Myers Squibb. 

*Data in the abstract differ from the presentation.

Photo by Jen Smith

SAN DIEGO—Early results of the DASCERN trial indicate that patients with chronic myeloid leukemia (CML) in chronic phase who have a suboptimal response to imatinib as a first-line treatment benefit from switching to dasatinib at 3 months.

Twenty-nine percent of dasatinib-treated patients achieved a major molecular response (MMR) at 12 months, compared to 13% of patients who remained on imatinib (P=0.005).

Dasatinib-treated patients also attained MMR much faster than those on imatinib, at a median of 14 months, compared to 20 months for those treated with imatinib.

DASCERN is the first study, according to investigators, to explore the significance of an early switch for patients who have not achieved an early molecular response (EMR) with imatinib.

“[EMRs] are important because they correlate with the outcome of patients, certainly with progression-free survival and overall survival,” explained Jorge E. Cortes, MD, of The University of Texas MD Anderson Cancer Center in Houston.

“[T]he possibility of changing to dasatinib appears, with these early results, to suggest that there may be a benefit to switching these patients to achieve better long-term outcomes. But also, those patients that have these early molecular responses have a better probability of achieving deep molecular responses that we desire for treatment-free remission.”

Dr. Cortes elaborated on the DASCERN data at the 2018 ASH Annual Meeting (abstract 788*).

Study design

DASCERN (NCT01593254) is a randomized, open-label, international, phase 2b trial in adult patients with chronic-phase CML who had achieved a complete hematologic response but still had more than 10% BCR-ABL1 transcripts at 3 months.

Patients were initially treated with imatinib at 400 mg daily, and 1,126 patients had a molecular assessment at 3 months.

Those who did not achieve an MMR (n=260) were randomized in a 2:1 fashion to 100 mg daily of dasatinib (n=174) or 400 mg daily or twice daily of imatinib (n=86).

If patients subsequently failed imatinib treatment by European LeukemiaNet standards, they could cross over to dasatinib.

“Importantly, there was a window of enrollment up to 8 weeks after the 3-month assessment, allowing for time to get response results and screen and enroll patients onto the study,” Dr. Cortes clarified.

Patients were also stratified according to Sokal risk score and time from molecular assessment to randomization.

Dr. Cortes noted that about 40% of patients were started on treatment within 4 weeks of the 3-month assessment. And another 58% were enrolled between 4 and 8 weeks from the 3-month assessment.

The primary endpoint is the achievement of MMR at 12 months from the first day of imatinib treatment; that is, at about 9 months from the start of the protocol treatment, in both trial arms.

Patient characteristics

Seventy-eight percent of patients were male, and 95% were younger than 65.

“This is a relatively younger patient population,” Dr. Cortes noted. “This has to do with the fact that this was an international study with a significant representation of patients that were from Asia (73%).”

The Asian patients were primarily from China, Dr. Cortes said, “and we know that, in some parts of the world, including Asia, patients seem to be younger.”

“This is also associated with a higher percentage of patients with high-risk Sokal scores, more than 20%,” he added. “That is different than what’s seen, for example, in the U.S. or in Europe.”

The prevalence of male patients, he said, broadly represents the distribution of patients in other parts of the world.

Patient disposition

Patients were followed for a median of 30 months.

Of the randomized patients—the intent-to-treat (ITT) population—143 (84%) in the dasatinib arm and 72 (84%) in the imatinib arm continued on treatment.

Study drug toxicity was the most common reason for discontinuing treatment and occurred in 9 patients (5%) in the dasatinib arm and 3 (4%) in the imatinib arm.

Nearly half the imatinib patients (n=42, 49%) crossed over to dasatinib at a median of 9 months.

The median duration of treatment was 22 months (range, 1 – 44) for patients on imatinib who did not cross over and 15 months (range, <1 – 38) for patients on dasatinib after crossing over from imatinib.

Response

In the ITT population, the rate of MMR at 12 months was 29% in the dasatinib arm and 13% in the imatinib arm (P=0.005).

The median time to MMR was significantly shorter for patients who received dasatinib compared with imatinib—14 months and 20 months, respectively (P=0.053).

“Over 60% of patients on the dasatinib arm achieved a major molecular response,” Dr. Cortes said. “This compares to about 55% of patients on the imatinib arm, even when you consider the crossover of a significant number of these patients.”

A few patients achieved a molecular response of a 4.5-log reduction in BCR-ABL1 transcripts (MR4.5).

“Of course, the follow-up is short, but we had twice as many patients [on dasatinib] at 12 months with MR4.5— 5% with dasatinib versus 2% with imatinib,” Dr. Cortes said.

Survival outcomes

Both overall and progression-free survival “look very good with both treatment approaches,” Dr. Cortes pointed out.

At a median follow-up of 30 months, the overall survival in the ITT population was 98.8% in each treatment arm.

Progression-free survival was 96.9% in the dasatinib arm and 97.6% in the imatinib arm.

“It is important to note that no patient in either treatment arm has transformed to accelerated or blast phase,” Dr. Cortes said.

Safety

Treatment was well tolerated with both agents, Dr. Cortes observed, with very few grade 3 adverse events (AEs) noted to date.

“The one that stands out here, and it’s only 2% of patients, is headache with dasatinib,” he said.

The headache did not lead to treatment discontinuation, and the patients were managed with dose adjustments.

The investigators observed no new safety signals with either drug.

Treatment-emergent AEs of any grade occurring in 15% or fewer dasatinib- or imatinib-treated patients, respectively, in the ITT population included headache (15%, 9%), diarrhea (9%, 8%), nausea (9%, 8%), eyelid edema (1%, 9%), hypocalcemia (1%, 7%), and muscle spasms (1%, 8%).

Patients who crossed over to dasatinib had similar rates of AEs to those documented for imatinib.

“They are typical for what we know of both of these tyrosine kinase inhibitors,” Dr. Cortes stated.

Investigators observed pleural effusion in 9 (5%) patients on dasatinib, and only one grade 3. That patient discontinued therapy due to the AE.

Of the patients who were on imatinib and crossed over to dasatinib, 3 (7%) experienced pleural effusion, most of them grade 1 or 2. One patient with grade 4 discontinued therapy with dasatinib due to the AE.

“Hematologic toxicity has been mild,” Dr. Cortes said, and in keeping with the known toxicities of dasatinib and imatinib.

Grade 3/4 treatment-emergent AEs in the dasatinib and imatinib arms, respectively, in the ITT population included anemia (5%, 4%), neutropenia (11%, 16%), thrombocytopenia (11%, 11%), and leukopenia (1%, 1%).

Patients who crossed over to dasatinib experienced more of these AEs than patients who did not cross over, Dr. Cortes clarified, but they are still within the expected range with these agents.

“We acknowledge the results are early and we need to continue following for both safety and efficacy, as it will be important to see if those rates of MR4.5 continue to increase with the same difference in favor of dasatinib that we are starting to see very early on,” Dr. Cortes said.

He disclosed serving as a consultant for Pfizer, Daiichi Sankyo, Astellas Pharma, Novartis, and Bristol-Myers Squibb, and he received research funding from Pfizer, Daiichi Sankyo, Arog Pharmaceuticals, Astellas Pharma, Novartis, and Bristol-Myers Squibb.

The study was supported by Bristol-Myers Squibb. 

*Data in the abstract differ from the presentation.

Photo by Jen Smith

SAN DIEGO—An algorithm has proven effective for identifying differentiation syndrome (DS) in patients taking ivosidenib or enasidenib, according to a speaker at the 2018 ASH Annual Meeting.

The U.S. Food and Drug Administration (FDA) recently announced that DS is going unnoticed in some patients with acute myeloid leukemia (AML) who are taking the IDH2 inhibitor enasidenib (Idhifa) or the IDH1 inhibitor ivosidenib (Tibsovo).

Though both drug labels include boxed warnings detailing the risk of DS, the FDA found evidence to suggest that DS is underdiagnosed, which can result in fatalities.

The FDA performed a systematic analysis of DS in AML patients taking either drug to determine if an algorithm could uncover a higher incidence of DS than was previously reported.

Kelly J. Norsworthy, MD, of the FDA, described the results of this analysis at ASH as abstract 288.

The analysis included patients with relapsed/refractory AML treated on a phase 1 study of ivosidenib (NCT02074839, AG120-C-001) and a phase 1/2 study of enasidenib (NCT01915498, AG221-C-001).

There were 179 patients treated with the approved dose of ivosidenib and 214 treated with the approved dose of enasidenib.

The researchers searched for DS events in the first 90 days of therapy. Patients were categorized as having DS if they had at least one investigator-reported DS event (IDH DS or retinoic acid syndrome) or if they had at least two signs or symptoms of DS, according to revised Montesinos criteria, within 7 days.

The signs/symptoms included:

• Dyspnea
• Unexplained fever
• Weight gain
• Unexplained hypotension
• Acute renal failure
• Pulmonary infiltrates or pleuropericardial effusion
• Multiple organ dysfunction.

“We added an event for multiple organ dysfunction since this adverse event could satisfy multiple Montesinos criteria,” Dr. Norsworthy said.

“Although leukocytosis is not a diagnostic criterion for DS, it is frequently seen in association with DS, so we performed an additional query for concomitant leukocytosis,” she added.

The researchers looked for adverse events of leukocytosis, hyperleukocytosis, white blood cell count increase, and leukocyte count greater than 10 Gi/L within 7 days of clinical signs/symptoms.

DS incidence

The algorithm suggested 40% of patients in each treatment group had potential DS—72 of 179 patients treated with ivosidenib and 86 of 214 patients treated with enasidenib.

“We reviewed case narratives and laboratory data from the algorithmically defined cases of DS to adjudicate whether cases were DS or unlikely DS due to an alternative explanation, most commonly due to a clinical course inconsistent with DS or confirmed infection,” Dr. Norsworthy said.

The reviewer-adjudicated incidence of DS was 19% in both groups—34 patients on ivosidenib and 41 patients on enasidenib.

“This contrasts with the DS incidence of 11% to 14% reported by investigators,” Dr. Norsworthy said. “Thus, there was a subset of patients where the syndrome was not recognized by investigators.”

Characteristics of DS

The median time to DS onset in this analysis was 20 days (range, 1 to 78) in the ivosidenib group and 19 days in the enasidenib group (range, 1 to 86).

In both treatment groups, most patients had moderate DS—71% (n=24) in the ivosidenib group and 80% (n=33) in the enasidenib group. Moderate DS was defined as meeting two to three of the aforementioned criteria for DS.

Fewer patients had severe DS (four or more criteria)—24% (n=8) in the ivosidenib group and 12% (n=5) in the enasidenib group.

For the remaining patients, DS severity could not be determined—6% (n=2) in the ivosidenib group and 10% (n=4) in the enasidenib group. These were investigator-reported cases of DS.

Most DS cases in the ivosidenib and enasidenib groups—68% (n=23) and 66% (n=27), respectively— included grade 3 or higher adverse reactions.

Two patients in each group died of DS—6% and 5%, respectively. Only one of these cases was recognized as DS and treated with steroids, Dr. Norsworthy noted.

She also pointed out that most patients with DS had leukocytosis—79% (n=27) in the ivosidenib group and 61% (n=25) in the enasidenib group.

In addition, rates of complete response (CR) and CR with incomplete hematologic recovery (CRh) were numerically lower among patients with DS, although the confidence intervals (CI) overlap.

Among patients on ivosidenib, the CR/CRh rate was 18% (95% CI, 7-35) in those with DS and 36% (95% CI, 28-45) in those without DS.

Among patients on enasidenib, the CR/CRh rate was 18% (95% CI, 7-33) in those with DS and 25% (95% CI, 18-32) in those without DS.

“[F]irm conclusions regarding the impact on response cannot be inferred based on this post-hoc subgroup analysis,” Dr. Norsworthy stressed.

Predicting DS

Dr. Norsworthy noted that baseline patient and disease characteristics were similar between patients with and without DS.

The researchers did see a trend toward higher blasts in the marrow and peripheral blood as well as higher white blood cell counts at baseline among patients with DS.

“However, there did not appear to be a distinct baseline white blood cell count or absolute blast cell count cutoff above which DS was more common,” Dr. Norsworthy said.

She added that the patient numbers are small, so it’s not possible to make firm conclusions about prognostic factors for DS.

In closing, Dr. Norsworthy said the algorithmic approach used here “led to the recognition of additional cases of DS not identified by investigators or review committee determination for patients treated with the IDH inhibitors ivo and ena.”

“Increased recognition of the signs and symptoms of DS through the framework of the Montesinos criteria may lead to early diagnosis and treatment, which may decrease severe complications and mortality. Furthermore, integration of the algorithm into clinical trials of differentiating therapies, in a prospective fashion, may help to systematically monitor the incidence and severity of DS.”

Dr. Norsworthy declared no conflicts of interest.

Photo by Jen Smith

SAN DIEGO—An algorithm has proven effective for identifying differentiation syndrome (DS) in patients taking ivosidenib or enasidenib, according to a speaker at the 2018 ASH Annual Meeting.

The U.S. Food and Drug Administration (FDA) recently announced that DS is going unnoticed in some patients with acute myeloid leukemia (AML) who are taking the IDH2 inhibitor enasidenib (Idhifa) or the IDH1 inhibitor ivosidenib (Tibsovo).

Though both drug labels include boxed warnings detailing the risk of DS, the FDA found evidence to suggest that DS is underdiagnosed, which can result in fatalities.

The FDA performed a systematic analysis of DS in AML patients taking either drug to determine if an algorithm could uncover a higher incidence of DS than was previously reported.

Kelly J. Norsworthy, MD, of the FDA, described the results of this analysis at ASH as abstract 288.

The analysis included patients with relapsed/refractory AML treated on a phase 1 study of ivosidenib (NCT02074839, AG120-C-001) and a phase 1/2 study of enasidenib (NCT01915498, AG221-C-001).

There were 179 patients treated with the approved dose of ivosidenib and 214 treated with the approved dose of enasidenib.

The researchers searched for DS events in the first 90 days of therapy. Patients were categorized as having DS if they had at least one investigator-reported DS event (IDH DS or retinoic acid syndrome) or if they had at least two signs or symptoms of DS, according to revised Montesinos criteria, within 7 days.

The signs/symptoms included:

• Dyspnea
• Unexplained fever
• Weight gain
• Unexplained hypotension
• Acute renal failure
• Pulmonary infiltrates or pleuropericardial effusion
• Multiple organ dysfunction.

“We added an event for multiple organ dysfunction since this adverse event could satisfy multiple Montesinos criteria,” Dr. Norsworthy said.

“Although leukocytosis is not a diagnostic criterion for DS, it is frequently seen in association with DS, so we performed an additional query for concomitant leukocytosis,” she added.

The researchers looked for adverse events of leukocytosis, hyperleukocytosis, white blood cell count increase, and leukocyte count greater than 10 Gi/L within 7 days of clinical signs/symptoms.

DS incidence

The algorithm suggested 40% of patients in each treatment group had potential DS—72 of 179 patients treated with ivosidenib and 86 of 214 patients treated with enasidenib.

“We reviewed case narratives and laboratory data from the algorithmically defined cases of DS to adjudicate whether cases were DS or unlikely DS due to an alternative explanation, most commonly due to a clinical course inconsistent with DS or confirmed infection,” Dr. Norsworthy said.

The reviewer-adjudicated incidence of DS was 19% in both groups—34 patients on ivosidenib and 41 patients on enasidenib.

“This contrasts with the DS incidence of 11% to 14% reported by investigators,” Dr. Norsworthy said. “Thus, there was a subset of patients where the syndrome was not recognized by investigators.”

Characteristics of DS

The median time to DS onset in this analysis was 20 days (range, 1 to 78) in the ivosidenib group and 19 days in the enasidenib group (range, 1 to 86).

In both treatment groups, most patients had moderate DS—71% (n=24) in the ivosidenib group and 80% (n=33) in the enasidenib group. Moderate DS was defined as meeting two to three of the aforementioned criteria for DS.

Fewer patients had severe DS (four or more criteria)—24% (n=8) in the ivosidenib group and 12% (n=5) in the enasidenib group.

For the remaining patients, DS severity could not be determined—6% (n=2) in the ivosidenib group and 10% (n=4) in the enasidenib group. These were investigator-reported cases of DS.

Most DS cases in the ivosidenib and enasidenib groups—68% (n=23) and 66% (n=27), respectively— included grade 3 or higher adverse reactions.

Two patients in each group died of DS—6% and 5%, respectively. Only one of these cases was recognized as DS and treated with steroids, Dr. Norsworthy noted.

She also pointed out that most patients with DS had leukocytosis—79% (n=27) in the ivosidenib group and 61% (n=25) in the enasidenib group.

In addition, rates of complete response (CR) and CR with incomplete hematologic recovery (CRh) were numerically lower among patients with DS, although the confidence intervals (CI) overlap.

Among patients on ivosidenib, the CR/CRh rate was 18% (95% CI, 7-35) in those with DS and 36% (95% CI, 28-45) in those without DS.

Among patients on enasidenib, the CR/CRh rate was 18% (95% CI, 7-33) in those with DS and 25% (95% CI, 18-32) in those without DS.

“[F]irm conclusions regarding the impact on response cannot be inferred based on this post-hoc subgroup analysis,” Dr. Norsworthy stressed.

Predicting DS

Dr. Norsworthy noted that baseline patient and disease characteristics were similar between patients with and without DS.

The researchers did see a trend toward higher blasts in the marrow and peripheral blood as well as higher white blood cell counts at baseline among patients with DS.

“However, there did not appear to be a distinct baseline white blood cell count or absolute blast cell count cutoff above which DS was more common,” Dr. Norsworthy said.

She added that the patient numbers are small, so it’s not possible to make firm conclusions about prognostic factors for DS.

In closing, Dr. Norsworthy said the algorithmic approach used here “led to the recognition of additional cases of DS not identified by investigators or review committee determination for patients treated with the IDH inhibitors ivo and ena.”

“Increased recognition of the signs and symptoms of DS through the framework of the Montesinos criteria may lead to early diagnosis and treatment, which may decrease severe complications and mortality. Furthermore, integration of the algorithm into clinical trials of differentiating therapies, in a prospective fashion, may help to systematically monitor the incidence and severity of DS.”

Dr. Norsworthy declared no conflicts of interest.

Photo by Jen Smith

SAN DIEGO—An algorithm has proven effective for identifying differentiation syndrome (DS) in patients taking ivosidenib or enasidenib, according to a speaker at the 2018 ASH Annual Meeting.

The U.S. Food and Drug Administration (FDA) recently announced that DS is going unnoticed in some patients with acute myeloid leukemia (AML) who are taking the IDH2 inhibitor enasidenib (Idhifa) or the IDH1 inhibitor ivosidenib (Tibsovo).

Though both drug labels include boxed warnings detailing the risk of DS, the FDA found evidence to suggest that DS is underdiagnosed, which can result in fatalities.

The FDA performed a systematic analysis of DS in AML patients taking either drug to determine if an algorithm could uncover a higher incidence of DS than was previously reported.

Kelly J. Norsworthy, MD, of the FDA, described the results of this analysis at ASH as abstract 288.

The analysis included patients with relapsed/refractory AML treated on a phase 1 study of ivosidenib (NCT02074839, AG120-C-001) and a phase 1/2 study of enasidenib (NCT01915498, AG221-C-001).

There were 179 patients treated with the approved dose of ivosidenib and 214 treated with the approved dose of enasidenib.

The researchers searched for DS events in the first 90 days of therapy. Patients were categorized as having DS if they had at least one investigator-reported DS event (IDH DS or retinoic acid syndrome) or if they had at least two signs or symptoms of DS, according to revised Montesinos criteria, within 7 days.

The signs/symptoms included:

• Dyspnea
• Unexplained fever
• Weight gain
• Unexplained hypotension
• Acute renal failure
• Pulmonary infiltrates or pleuropericardial effusion
• Multiple organ dysfunction.

“We added an event for multiple organ dysfunction since this adverse event could satisfy multiple Montesinos criteria,” Dr. Norsworthy said.

“Although leukocytosis is not a diagnostic criterion for DS, it is frequently seen in association with DS, so we performed an additional query for concomitant leukocytosis,” she added.

The researchers looked for adverse events of leukocytosis, hyperleukocytosis, white blood cell count increase, and leukocyte count greater than 10 Gi/L within 7 days of clinical signs/symptoms.

DS incidence

The algorithm suggested 40% of patients in each treatment group had potential DS—72 of 179 patients treated with ivosidenib and 86 of 214 patients treated with enasidenib.

“We reviewed case narratives and laboratory data from the algorithmically defined cases of DS to adjudicate whether cases were DS or unlikely DS due to an alternative explanation, most commonly due to a clinical course inconsistent with DS or confirmed infection,” Dr. Norsworthy said.

The reviewer-adjudicated incidence of DS was 19% in both groups—34 patients on ivosidenib and 41 patients on enasidenib.

“This contrasts with the DS incidence of 11% to 14% reported by investigators,” Dr. Norsworthy said. “Thus, there was a subset of patients where the syndrome was not recognized by investigators.”

Characteristics of DS

The median time to DS onset in this analysis was 20 days (range, 1 to 78) in the ivosidenib group and 19 days in the enasidenib group (range, 1 to 86).

In both treatment groups, most patients had moderate DS—71% (n=24) in the ivosidenib group and 80% (n=33) in the enasidenib group. Moderate DS was defined as meeting two to three of the aforementioned criteria for DS.

Fewer patients had severe DS (four or more criteria)—24% (n=8) in the ivosidenib group and 12% (n=5) in the enasidenib group.

For the remaining patients, DS severity could not be determined—6% (n=2) in the ivosidenib group and 10% (n=4) in the enasidenib group. These were investigator-reported cases of DS.

Most DS cases in the ivosidenib and enasidenib groups—68% (n=23) and 66% (n=27), respectively— included grade 3 or higher adverse reactions.

Two patients in each group died of DS—6% and 5%, respectively. Only one of these cases was recognized as DS and treated with steroids, Dr. Norsworthy noted.

She also pointed out that most patients with DS had leukocytosis—79% (n=27) in the ivosidenib group and 61% (n=25) in the enasidenib group.

In addition, rates of complete response (CR) and CR with incomplete hematologic recovery (CRh) were numerically lower among patients with DS, although the confidence intervals (CI) overlap.

Among patients on ivosidenib, the CR/CRh rate was 18% (95% CI, 7-35) in those with DS and 36% (95% CI, 28-45) in those without DS.

Among patients on enasidenib, the CR/CRh rate was 18% (95% CI, 7-33) in those with DS and 25% (95% CI, 18-32) in those without DS.

“[F]irm conclusions regarding the impact on response cannot be inferred based on this post-hoc subgroup analysis,” Dr. Norsworthy stressed.

Predicting DS

Dr. Norsworthy noted that baseline patient and disease characteristics were similar between patients with and without DS.

The researchers did see a trend toward higher blasts in the marrow and peripheral blood as well as higher white blood cell counts at baseline among patients with DS.

“However, there did not appear to be a distinct baseline white blood cell count or absolute blast cell count cutoff above which DS was more common,” Dr. Norsworthy said.

She added that the patient numbers are small, so it’s not possible to make firm conclusions about prognostic factors for DS.

In closing, Dr. Norsworthy said the algorithmic approach used here “led to the recognition of additional cases of DS not identified by investigators or review committee determination for patients treated with the IDH inhibitors ivo and ena.”

“Increased recognition of the signs and symptoms of DS through the framework of the Montesinos criteria may lead to early diagnosis and treatment, which may decrease severe complications and mortality. Furthermore, integration of the algorithm into clinical trials of differentiating therapies, in a prospective fashion, may help to systematically monitor the incidence and severity of DS.”

Dr. Norsworthy declared no conflicts of interest.

Photo by Jen Smith

SAN DIEGO—Preliminary trial results suggest re-treatment with dasatinib is feasible and safe for a second attempt at tyrosine kinase inhibitor (TKI) discontinuation in chronic myeloid leukemia (CML) patients who fail to achieve treatment-free remission (TFR) after discontinuing imatinib.

However, investigators reported the rate of second TFR (TFR2) was 21% at 6 months, which was not enough to confirm, at this time, that dasatinib could improve the TFR2 rate after imatinib discontinuation failure.

Dennis Kim, MD, of the University of Toronto in Ontario, Canada, presented these results at the 2018 ASH Annual Meeting (abstract 787).

The design of this trial (NCT02268370) includes three phases: the imatinib discontinuation phase, the dasatinib re-challenge phase to achieve a molecular response of ≥ 4.5-log reduction in BCR-ABL1 transcripts (MR4.5), and the dasatinib discontinuation phase.

The primary objective of the trial is to determine the proportion of patients who remain in deep molecular remission (> MR4.5) after discontinuing dasatinib following a failed attempt at discontinuation of imatinib.

If patients had a confirmed molecular relapse after discontinuing imatinib, they were started on 100 mg of dasatinib daily, and, after achieving MR4.5 or greater for 12 months, they discontinued dasatinib for a try at the second TFR.

Investigators defined loss of molecular response, or relapse, as a loss of a major molecular response (MMR) once or loss of MR4.0 on two consecutive occasions.

Patient characteristics

The 131 enrolled CML patients were a median age of 61 (range, 21 to 84), and 62% were male.

Patients had a median 9.36 years of disease duration, 9.18 years of imatinib treatment, 6.82 years of MR4 duration, and 5.08 years of MR4.5 duration.

“The cohort has a very long history of imatinib treatment as well as MR4 duration,” Dr. Kim pointed out, “which also can affect our TFR1 rate, and I think, also, it can affect our TFR2 rate.”

TFR1 and TFR2 rates

As of October 25, the TFR1 rate using loss of MMR as the measure was 69.9% at 12 months from imatinib discontinuation. Relapse-free survival was 57.2% at that time.

Of the 53 patients who lost response, 51 patients received dasatinib. At 3 months of treatment, 97.7% achieved an MMR, 89.9% achieved MR4, and 84.6% achieved MR4.5.

Twenty-five of 51 patients treated with dasatinib attained MR4.5 for 12 months or longer and discontinued treatment for a second attempt at TFR.

Twenty-one patients are still receiving dasatinib and have attained MR4.5, but not for the 12-month duration yet.

Dr. Kim noted that the median time to achievement of molecular response after dasatinib re-challenge ranged from 2.76 months for MR4.5 to 1.71 months for MMR.

Twenty-one of 25 patients (84.0%) who discontinued dasatinib lost their molecular response at a median of 3.7 months.

The estimated TFR2 rate after dasatinib discontinuation is 21.0% to 24.4% at 6 months, which means the investigators cannot reject the null hypothesis of 28% or more patients remaining in remission.

Patients who lost response rapidly after dasatinib discontinuation also tended to lose response rapidly after imatinib discontinuation, Dr. Kim pointed out.

“However, you see some patients who do not lose their response after dasatinib discontinuation or who lose the response but later after the dasatinib discontinuation, they tend to lose their imatinib response also in a later time point,” he said. “So we started to look at the risk factors.”

Risk factor analysis

Out of seven potential risk factors, the investigators were able to demonstrate that time to molecular relapse after imatinib discontinuation, molecular relapse pattern after imatinib discontinuation, and BCR-ABL1 quantitative polymerase chain reaction (qPCR) value prior to dasatinib discontinuation “seemed to be very significant,” Dr. Kim said.

Time to molecular relapse after discontinuation of imatinib correlates with TFR2. The group of patients who relapsed in 3 to 6 months of stopping imatinib had a significantly longer TFR2 than patients who relapsed within 3 months of stopping imatinib (P=0.018).

The molecular relapse pattern also correlates with TFR2. The group with a single loss of MMR after imatinib discontinuation had a significantly shorter TFR2 than those who lost MR4 twice after imatinib discontinuation (P=0.043).

And 0% of the patients who had qPCR transcript levels between a 4.5 and 5.4 log reduction maintained TFR2 at 6 months. However, 28.7% who had qPCR deeper than 5.5 logs prior to dasatinib discontinuation had TFR2 at 6 months (P=0.017).

The risk factor analysis shed light, in part, on the reason the trial thus far failed to satisfy the null hypothesis.

“In other words, because we have selected a really good-risk group for TFR1, the remaining patients are actually a high-risk group for TFR2,” Dr. Kim said. “Because of that, the TFR2 rate might be somewhat lower than we had expected.”

“Or is it related to our conservative treatment with dasatinib, which is 12 months after achieving MR4.5 or deeper response? That may affect our TFR2 rate. We still have to think about that.”

Dr. Kim suggested stricter criteria be considered for attempting TFR2, such as achieving a 5.5 log reduction or deeper in BCR-ABL1 qPCR levels prior to the second TKI discontinuation attempt, and/or an MR4 duration of more than 12 months.

Dr. Kim disclosed receiving honoraria and research funding from Novartis and Bristol-Myers Squibb and serving as a consultant for Pfizer, Paladin, Novartis, and Bristol-Myers Squibb. 

Photo by Jen Smith

SAN DIEGO—Preliminary trial results suggest re-treatment with dasatinib is feasible and safe for a second attempt at tyrosine kinase inhibitor (TKI) discontinuation in chronic myeloid leukemia (CML) patients who fail to achieve treatment-free remission (TFR) after discontinuing imatinib.

However, investigators reported the rate of second TFR (TFR2) was 21% at 6 months, which was not enough to confirm, at this time, that dasatinib could improve the TFR2 rate after imatinib discontinuation failure.

Dennis Kim, MD, of the University of Toronto in Ontario, Canada, presented these results at the 2018 ASH Annual Meeting (abstract 787).

The design of this trial (NCT02268370) includes three phases: the imatinib discontinuation phase, the dasatinib re-challenge phase to achieve a molecular response of ≥ 4.5-log reduction in BCR-ABL1 transcripts (MR4.5), and the dasatinib discontinuation phase.

The primary objective of the trial is to determine the proportion of patients who remain in deep molecular remission (> MR4.5) after discontinuing dasatinib following a failed attempt at discontinuation of imatinib.

If patients had a confirmed molecular relapse after discontinuing imatinib, they were started on 100 mg of dasatinib daily, and, after achieving MR4.5 or greater for 12 months, they discontinued dasatinib for a try at the second TFR.

Investigators defined loss of molecular response, or relapse, as a loss of a major molecular response (MMR) once or loss of MR4.0 on two consecutive occasions.

Patient characteristics

The 131 enrolled CML patients were a median age of 61 (range, 21 to 84), and 62% were male.

Patients had a median 9.36 years of disease duration, 9.18 years of imatinib treatment, 6.82 years of MR4 duration, and 5.08 years of MR4.5 duration.

“The cohort has a very long history of imatinib treatment as well as MR4 duration,” Dr. Kim pointed out, “which also can affect our TFR1 rate, and I think, also, it can affect our TFR2 rate.”

TFR1 and TFR2 rates

As of October 25, the TFR1 rate using loss of MMR as the measure was 69.9% at 12 months from imatinib discontinuation. Relapse-free survival was 57.2% at that time.

Of the 53 patients who lost response, 51 patients received dasatinib. At 3 months of treatment, 97.7% achieved an MMR, 89.9% achieved MR4, and 84.6% achieved MR4.5.

Twenty-five of 51 patients treated with dasatinib attained MR4.5 for 12 months or longer and discontinued treatment for a second attempt at TFR.

Twenty-one patients are still receiving dasatinib and have attained MR4.5, but not for the 12-month duration yet.

Dr. Kim noted that the median time to achievement of molecular response after dasatinib re-challenge ranged from 2.76 months for MR4.5 to 1.71 months for MMR.

Twenty-one of 25 patients (84.0%) who discontinued dasatinib lost their molecular response at a median of 3.7 months.

The estimated TFR2 rate after dasatinib discontinuation is 21.0% to 24.4% at 6 months, which means the investigators cannot reject the null hypothesis of 28% or more patients remaining in remission.

Patients who lost response rapidly after dasatinib discontinuation also tended to lose response rapidly after imatinib discontinuation, Dr. Kim pointed out.

“However, you see some patients who do not lose their response after dasatinib discontinuation or who lose the response but later after the dasatinib discontinuation, they tend to lose their imatinib response also in a later time point,” he said. “So we started to look at the risk factors.”

Risk factor analysis

Out of seven potential risk factors, the investigators were able to demonstrate that time to molecular relapse after imatinib discontinuation, molecular relapse pattern after imatinib discontinuation, and BCR-ABL1 quantitative polymerase chain reaction (qPCR) value prior to dasatinib discontinuation “seemed to be very significant,” Dr. Kim said.

Time to molecular relapse after discontinuation of imatinib correlates with TFR2. The group of patients who relapsed in 3 to 6 months of stopping imatinib had a significantly longer TFR2 than patients who relapsed within 3 months of stopping imatinib (P=0.018).

The molecular relapse pattern also correlates with TFR2. The group with a single loss of MMR after imatinib discontinuation had a significantly shorter TFR2 than those who lost MR4 twice after imatinib discontinuation (P=0.043).

And 0% of the patients who had qPCR transcript levels between a 4.5 and 5.4 log reduction maintained TFR2 at 6 months. However, 28.7% who had qPCR deeper than 5.5 logs prior to dasatinib discontinuation had TFR2 at 6 months (P=0.017).

The risk factor analysis shed light, in part, on the reason the trial thus far failed to satisfy the null hypothesis.

“In other words, because we have selected a really good-risk group for TFR1, the remaining patients are actually a high-risk group for TFR2,” Dr. Kim said. “Because of that, the TFR2 rate might be somewhat lower than we had expected.”

“Or is it related to our conservative treatment with dasatinib, which is 12 months after achieving MR4.5 or deeper response? That may affect our TFR2 rate. We still have to think about that.”

Dr. Kim suggested stricter criteria be considered for attempting TFR2, such as achieving a 5.5 log reduction or deeper in BCR-ABL1 qPCR levels prior to the second TKI discontinuation attempt, and/or an MR4 duration of more than 12 months.

Dr. Kim disclosed receiving honoraria and research funding from Novartis and Bristol-Myers Squibb and serving as a consultant for Pfizer, Paladin, Novartis, and Bristol-Myers Squibb. 

Photo by Jen Smith

SAN DIEGO—Preliminary trial results suggest re-treatment with dasatinib is feasible and safe for a second attempt at tyrosine kinase inhibitor (TKI) discontinuation in chronic myeloid leukemia (CML) patients who fail to achieve treatment-free remission (TFR) after discontinuing imatinib.

However, investigators reported the rate of second TFR (TFR2) was 21% at 6 months, which was not enough to confirm, at this time, that dasatinib could improve the TFR2 rate after imatinib discontinuation failure.

Dennis Kim, MD, of the University of Toronto in Ontario, Canada, presented these results at the 2018 ASH Annual Meeting (abstract 787).

The design of this trial (NCT02268370) includes three phases: the imatinib discontinuation phase, the dasatinib re-challenge phase to achieve a molecular response of ≥ 4.5-log reduction in BCR-ABL1 transcripts (MR4.5), and the dasatinib discontinuation phase.

The primary objective of the trial is to determine the proportion of patients who remain in deep molecular remission (> MR4.5) after discontinuing dasatinib following a failed attempt at discontinuation of imatinib.

If patients had a confirmed molecular relapse after discontinuing imatinib, they were started on 100 mg of dasatinib daily, and, after achieving MR4.5 or greater for 12 months, they discontinued dasatinib for a try at the second TFR.

Investigators defined loss of molecular response, or relapse, as a loss of a major molecular response (MMR) once or loss of MR4.0 on two consecutive occasions.

Patient characteristics

The 131 enrolled CML patients were a median age of 61 (range, 21 to 84), and 62% were male.

Patients had a median 9.36 years of disease duration, 9.18 years of imatinib treatment, 6.82 years of MR4 duration, and 5.08 years of MR4.5 duration.

“The cohort has a very long history of imatinib treatment as well as MR4 duration,” Dr. Kim pointed out, “which also can affect our TFR1 rate, and I think, also, it can affect our TFR2 rate.”

TFR1 and TFR2 rates

As of October 25, the TFR1 rate using loss of MMR as the measure was 69.9% at 12 months from imatinib discontinuation. Relapse-free survival was 57.2% at that time.

Of the 53 patients who lost response, 51 patients received dasatinib. At 3 months of treatment, 97.7% achieved an MMR, 89.9% achieved MR4, and 84.6% achieved MR4.5.

Twenty-five of 51 patients treated with dasatinib attained MR4.5 for 12 months or longer and discontinued treatment for a second attempt at TFR.

Twenty-one patients are still receiving dasatinib and have attained MR4.5, but not for the 12-month duration yet.

Dr. Kim noted that the median time to achievement of molecular response after dasatinib re-challenge ranged from 2.76 months for MR4.5 to 1.71 months for MMR.

Twenty-one of 25 patients (84.0%) who discontinued dasatinib lost their molecular response at a median of 3.7 months.

The estimated TFR2 rate after dasatinib discontinuation is 21.0% to 24.4% at 6 months, which means the investigators cannot reject the null hypothesis of 28% or more patients remaining in remission.

Patients who lost response rapidly after dasatinib discontinuation also tended to lose response rapidly after imatinib discontinuation, Dr. Kim pointed out.

“However, you see some patients who do not lose their response after dasatinib discontinuation or who lose the response but later after the dasatinib discontinuation, they tend to lose their imatinib response also in a later time point,” he said. “So we started to look at the risk factors.”

Risk factor analysis

Out of seven potential risk factors, the investigators were able to demonstrate that time to molecular relapse after imatinib discontinuation, molecular relapse pattern after imatinib discontinuation, and BCR-ABL1 quantitative polymerase chain reaction (qPCR) value prior to dasatinib discontinuation “seemed to be very significant,” Dr. Kim said.

Time to molecular relapse after discontinuation of imatinib correlates with TFR2. The group of patients who relapsed in 3 to 6 months of stopping imatinib had a significantly longer TFR2 than patients who relapsed within 3 months of stopping imatinib (P=0.018).

The molecular relapse pattern also correlates with TFR2. The group with a single loss of MMR after imatinib discontinuation had a significantly shorter TFR2 than those who lost MR4 twice after imatinib discontinuation (P=0.043).

And 0% of the patients who had qPCR transcript levels between a 4.5 and 5.4 log reduction maintained TFR2 at 6 months. However, 28.7% who had qPCR deeper than 5.5 logs prior to dasatinib discontinuation had TFR2 at 6 months (P=0.017).

The risk factor analysis shed light, in part, on the reason the trial thus far failed to satisfy the null hypothesis.

“In other words, because we have selected a really good-risk group for TFR1, the remaining patients are actually a high-risk group for TFR2,” Dr. Kim said. “Because of that, the TFR2 rate might be somewhat lower than we had expected.”

“Or is it related to our conservative treatment with dasatinib, which is 12 months after achieving MR4.5 or deeper response? That may affect our TFR2 rate. We still have to think about that.”

Dr. Kim suggested stricter criteria be considered for attempting TFR2, such as achieving a 5.5 log reduction or deeper in BCR-ABL1 qPCR levels prior to the second TKI discontinuation attempt, and/or an MR4 duration of more than 12 months.

Dr. Kim disclosed receiving honoraria and research funding from Novartis and Bristol-Myers Squibb and serving as a consultant for Pfizer, Paladin, Novartis, and Bristol-Myers Squibb. 

SAN DIEGO – In the phase 3 Alliance A041202 trial of older patients with previously untreated chronic lymphocytic leukemia (CLL), ibrutinib showed superior progression-free survival (PFS). Results of the trial were reported by Jennifer A. Woyach, MD, of the Ohio State University in Columbus during a press briefing at the recently concluded American Society of Hematology 2018 meeting. The briefing was based on an abstract from the meeting.

“There was no difference in progression-free survival between ibrutinib and ibrutinib plus rituximab,” said Dr. Woyach. “We undertook this study to determine the most effective therapy for older patients with CLL.” She noted that the findings justify the use of ibrutinib as a standard-of-care treatment for CLL patients aged 65 years and older.

Median age of patients in the study was 71 years and 67% of the patient were men, a profile that is similar, to those of patients with CLL seen at the US Department of Veterans Affairs. 

The 2-year PFS was 74% in 183 patients randomized to receive standard chemoimmunotherapy with bendamustine and rituximab (BR), compared with 87% in 182 patients randomized to receive ibrutinib alone (hazard ratio, 0.39 vs. BR), and 88% in 182 patients who received ibrutinib and rituximab (IR; HR, 0.38 vs. BR). Median PFS in this study was 43 months in the BR arm, and was not reached in either of the ibrutinib-containing arms, she said. No significant differences in overall survival (OS) were seen among the treatment arms, which may have been because of short follow-up and the fact that patients in the BR arm were allowed to cross over to ibrutinib if they progressed on treatment.

The results suggest that the additional of rituximab provided little benefit to the patients though it does add to both the costs and the chair time in an infusion center, according to former Association of VA Hematology/Oncology Mary Thomas, MS, CNS, AOCN.  

“I think this really does indicate that ibrutinib as front-line therapy, which many clinicians have been doing, is a very reasonable practice,” said David P. Steensma, MD, of Dana-Farber Cancer Institute in Boston, who moderated the press briefing.

Dr. Woyach added, however, that while ibrutinib represents a major therapeutic advance, its cost and its toxicities in older patients are a concern that warrant close monitoring and development of strategies to reduce the need for long-term continuous treatment.

Thomas agreed noting that health care providers needs to be aware of the risk of  atrial fib and bleeding when using ibrutinib and to ensure that patient will be able to adhere to daily dosing.

Additional phase 3 studies set to open soon will compare ibrutinib in combination with venetoclax and obinutuzumab with standard ibrutinib.

Dr. Woyach and Ms. Thomas reported having no disclosures. Dr. Steensma reported receiving research funding from, and/or serving as a consultant, board member, or adviser for Takeda Pharmaceutical, Syros Pharmaceuticals, Otsuka Pharmaceutical, Onconova Therapeutics, Novartis, Kura Oncology, Janssen, H3 Biosciences, Celgene, Amphivena Therapeutics, and Acceleron Pharma.

SAN DIEGO – In the phase 3 Alliance A041202 trial of older patients with previously untreated chronic lymphocytic leukemia (CLL), ibrutinib showed superior progression-free survival (PFS). Results of the trial were reported by Jennifer A. Woyach, MD, of the Ohio State University in Columbus during a press briefing at the recently concluded American Society of Hematology 2018 meeting. The briefing was based on an abstract from the meeting.

“There was no difference in progression-free survival between ibrutinib and ibrutinib plus rituximab,” said Dr. Woyach. “We undertook this study to determine the most effective therapy for older patients with CLL.” She noted that the findings justify the use of ibrutinib as a standard-of-care treatment for CLL patients aged 65 years and older.

Median age of patients in the study was 71 years and 67% of the patient were men, a profile that is similar, to those of patients with CLL seen at the US Department of Veterans Affairs. 

The 2-year PFS was 74% in 183 patients randomized to receive standard chemoimmunotherapy with bendamustine and rituximab (BR), compared with 87% in 182 patients randomized to receive ibrutinib alone (hazard ratio, 0.39 vs. BR), and 88% in 182 patients who received ibrutinib and rituximab (IR; HR, 0.38 vs. BR). Median PFS in this study was 43 months in the BR arm, and was not reached in either of the ibrutinib-containing arms, she said. No significant differences in overall survival (OS) were seen among the treatment arms, which may have been because of short follow-up and the fact that patients in the BR arm were allowed to cross over to ibrutinib if they progressed on treatment.

The results suggest that the additional of rituximab provided little benefit to the patients though it does add to both the costs and the chair time in an infusion center, according to former Association of VA Hematology/Oncology Mary Thomas, MS, CNS, AOCN.  

“I think this really does indicate that ibrutinib as front-line therapy, which many clinicians have been doing, is a very reasonable practice,” said David P. Steensma, MD, of Dana-Farber Cancer Institute in Boston, who moderated the press briefing.

Dr. Woyach added, however, that while ibrutinib represents a major therapeutic advance, its cost and its toxicities in older patients are a concern that warrant close monitoring and development of strategies to reduce the need for long-term continuous treatment.

Thomas agreed noting that health care providers needs to be aware of the risk of  atrial fib and bleeding when using ibrutinib and to ensure that patient will be able to adhere to daily dosing.

Additional phase 3 studies set to open soon will compare ibrutinib in combination with venetoclax and obinutuzumab with standard ibrutinib.

Dr. Woyach and Ms. Thomas reported having no disclosures. Dr. Steensma reported receiving research funding from, and/or serving as a consultant, board member, or adviser for Takeda Pharmaceutical, Syros Pharmaceuticals, Otsuka Pharmaceutical, Onconova Therapeutics, Novartis, Kura Oncology, Janssen, H3 Biosciences, Celgene, Amphivena Therapeutics, and Acceleron Pharma.

SAN DIEGO – In the phase 3 Alliance A041202 trial of older patients with previously untreated chronic lymphocytic leukemia (CLL), ibrutinib showed superior progression-free survival (PFS). Results of the trial were reported by Jennifer A. Woyach, MD, of the Ohio State University in Columbus during a press briefing at the recently concluded American Society of Hematology 2018 meeting. The briefing was based on an abstract from the meeting.

“There was no difference in progression-free survival between ibrutinib and ibrutinib plus rituximab,” said Dr. Woyach. “We undertook this study to determine the most effective therapy for older patients with CLL.” She noted that the findings justify the use of ibrutinib as a standard-of-care treatment for CLL patients aged 65 years and older.

Median age of patients in the study was 71 years and 67% of the patient were men, a profile that is similar, to those of patients with CLL seen at the US Department of Veterans Affairs. 

The 2-year PFS was 74% in 183 patients randomized to receive standard chemoimmunotherapy with bendamustine and rituximab (BR), compared with 87% in 182 patients randomized to receive ibrutinib alone (hazard ratio, 0.39 vs. BR), and 88% in 182 patients who received ibrutinib and rituximab (IR; HR, 0.38 vs. BR). Median PFS in this study was 43 months in the BR arm, and was not reached in either of the ibrutinib-containing arms, she said. No significant differences in overall survival (OS) were seen among the treatment arms, which may have been because of short follow-up and the fact that patients in the BR arm were allowed to cross over to ibrutinib if they progressed on treatment.

The results suggest that the additional of rituximab provided little benefit to the patients though it does add to both the costs and the chair time in an infusion center, according to former Association of VA Hematology/Oncology Mary Thomas, MS, CNS, AOCN.  

“I think this really does indicate that ibrutinib as front-line therapy, which many clinicians have been doing, is a very reasonable practice,” said David P. Steensma, MD, of Dana-Farber Cancer Institute in Boston, who moderated the press briefing.

Dr. Woyach added, however, that while ibrutinib represents a major therapeutic advance, its cost and its toxicities in older patients are a concern that warrant close monitoring and development of strategies to reduce the need for long-term continuous treatment.

Thomas agreed noting that health care providers needs to be aware of the risk of  atrial fib and bleeding when using ibrutinib and to ensure that patient will be able to adhere to daily dosing.

Additional phase 3 studies set to open soon will compare ibrutinib in combination with venetoclax and obinutuzumab with standard ibrutinib.

Dr. Woyach and Ms. Thomas reported having no disclosures. Dr. Steensma reported receiving research funding from, and/or serving as a consultant, board member, or adviser for Takeda Pharmaceutical, Syros Pharmaceuticals, Otsuka Pharmaceutical, Onconova Therapeutics, Novartis, Kura Oncology, Janssen, H3 Biosciences, Celgene, Amphivena Therapeutics, and Acceleron Pharma.

SAN DIEGO – A recurrent mutation in BCL2, the therapeutic target of venetoclax (Venclexta), appears to be a major contributor to drug resistance in patients with chronic lymphocytic leukemia (CLL), investigators reported.

The mutation has been detected in some patients with CLL up to 2 years before resistance to venetoclax actually develops, said lead author Piers Blombery, MBBS, from the Peter MacCallum Cancer Center in Melbourne.

“We have identified the first acquired BCL2 mutation developed in patients clinically treated with venetoclax,” he said in a late-breaking oral abstract session at the annual meeting of the American Society of Hematology.

The mutation, which the investigators have labeled BCL2 Gly101Val, “is a recurrent and frequent mediator of resistance and may be detected years before clinical relapse occurs,” he added.

The paper was published online in Cancer Discovery (2018 Dec 4. doi: 10.1158/2159-8290.CD-18-1119) to coincide with the presentation at ASH.

Despite the demonstrated efficacy of venetoclax as continuous therapy in patients with relapsed or refractory CLL, the majority of patients experience disease progression, prompting the investigators to explore molecular mechanisms of secondary resistance.

To do this, they analyzed paired samples from 15 patients with CLL, enrolled in clinical trials of venetoclax, collected both before the start of venetoclax therapy and at the time of disease progression.

In seven of the patients, they identified a novel mutation that showed up at the time of progression, but was absent from the pre-venetoclax samples. The mutation first became detectable from about 19 to 42 months after the start of therapy and preceded clinical progression by as much as 25 months, the investigators found.

They pinned the mutation down to the BH3-binding groove on BCL2, the same molecular site targeted by venetoclax. They found that the mutation was not present in samples from 96 patients with venetoclax-naive CLL nor in any other B-cell malignancies. Searches for references to the mutation in both a cancer database (COSMIC) and a population database (gnomAD) came up empty.

In other experiments, they determined that cell lines overexpressing BCL2 Gly101Val are resistant to venetoclax, and that in the presence of venetoclax in vitro, BCL2 Gly101Val-expressing cells have a growth advantage, compared with wild type cells.

Additionally, they showed that the mutation results in impaired venetoclax binding in vitro.

“BCL2 Gly101Val is observed subclonally, implicating multiple mechanisms of venetoclax resistance in the same patient,” Dr. Blombery said.

In an interview, Dr. Blombery said that the identification of the resistance mutation is a strong rationale for using combination therapy to treat patients with relapsed or refractory CLL to help prevent or attenuate selection pressures that lead to resistance.

The investigators were supported by the Wilson Center for Lymphoma Genomics, Snowdome Foundation, National Health Medical Research Council, Leukemia and Lymphoma Society, Leukemia Foundation, Cancer Council of Victoria, and Australian Cancer Research Foundation. Dr. Blombery reported having no relevant disclosures.

SOURCE: Blombery P et al. ASH 2018, Abstract LBA-7.

SAN DIEGO – A recurrent mutation in BCL2, the therapeutic target of venetoclax (Venclexta), appears to be a major contributor to drug resistance in patients with chronic lymphocytic leukemia (CLL), investigators reported.

The mutation has been detected in some patients with CLL up to 2 years before resistance to venetoclax actually develops, said lead author Piers Blombery, MBBS, from the Peter MacCallum Cancer Center in Melbourne.

“We have identified the first acquired BCL2 mutation developed in patients clinically treated with venetoclax,” he said in a late-breaking oral abstract session at the annual meeting of the American Society of Hematology.

The mutation, which the investigators have labeled BCL2 Gly101Val, “is a recurrent and frequent mediator of resistance and may be detected years before clinical relapse occurs,” he added.

The paper was published online in Cancer Discovery (2018 Dec 4. doi: 10.1158/2159-8290.CD-18-1119) to coincide with the presentation at ASH.

Despite the demonstrated efficacy of venetoclax as continuous therapy in patients with relapsed or refractory CLL, the majority of patients experience disease progression, prompting the investigators to explore molecular mechanisms of secondary resistance.

To do this, they analyzed paired samples from 15 patients with CLL, enrolled in clinical trials of venetoclax, collected both before the start of venetoclax therapy and at the time of disease progression.

In seven of the patients, they identified a novel mutation that showed up at the time of progression, but was absent from the pre-venetoclax samples. The mutation first became detectable from about 19 to 42 months after the start of therapy and preceded clinical progression by as much as 25 months, the investigators found.

They pinned the mutation down to the BH3-binding groove on BCL2, the same molecular site targeted by venetoclax. They found that the mutation was not present in samples from 96 patients with venetoclax-naive CLL nor in any other B-cell malignancies. Searches for references to the mutation in both a cancer database (COSMIC) and a population database (gnomAD) came up empty.

In other experiments, they determined that cell lines overexpressing BCL2 Gly101Val are resistant to venetoclax, and that in the presence of venetoclax in vitro, BCL2 Gly101Val-expressing cells have a growth advantage, compared with wild type cells.

Additionally, they showed that the mutation results in impaired venetoclax binding in vitro.

“BCL2 Gly101Val is observed subclonally, implicating multiple mechanisms of venetoclax resistance in the same patient,” Dr. Blombery said.

In an interview, Dr. Blombery said that the identification of the resistance mutation is a strong rationale for using combination therapy to treat patients with relapsed or refractory CLL to help prevent or attenuate selection pressures that lead to resistance.

The investigators were supported by the Wilson Center for Lymphoma Genomics, Snowdome Foundation, National Health Medical Research Council, Leukemia and Lymphoma Society, Leukemia Foundation, Cancer Council of Victoria, and Australian Cancer Research Foundation. Dr. Blombery reported having no relevant disclosures.

SOURCE: Blombery P et al. ASH 2018, Abstract LBA-7.

SAN DIEGO – A recurrent mutation in BCL2, the therapeutic target of venetoclax (Venclexta), appears to be a major contributor to drug resistance in patients with chronic lymphocytic leukemia (CLL), investigators reported.

The mutation has been detected in some patients with CLL up to 2 years before resistance to venetoclax actually develops, said lead author Piers Blombery, MBBS, from the Peter MacCallum Cancer Center in Melbourne.

“We have identified the first acquired BCL2 mutation developed in patients clinically treated with venetoclax,” he said in a late-breaking oral abstract session at the annual meeting of the American Society of Hematology.

The mutation, which the investigators have labeled BCL2 Gly101Val, “is a recurrent and frequent mediator of resistance and may be detected years before clinical relapse occurs,” he added.

The paper was published online in Cancer Discovery (2018 Dec 4. doi: 10.1158/2159-8290.CD-18-1119) to coincide with the presentation at ASH.

Despite the demonstrated efficacy of venetoclax as continuous therapy in patients with relapsed or refractory CLL, the majority of patients experience disease progression, prompting the investigators to explore molecular mechanisms of secondary resistance.

To do this, they analyzed paired samples from 15 patients with CLL, enrolled in clinical trials of venetoclax, collected both before the start of venetoclax therapy and at the time of disease progression.

In seven of the patients, they identified a novel mutation that showed up at the time of progression, but was absent from the pre-venetoclax samples. The mutation first became detectable from about 19 to 42 months after the start of therapy and preceded clinical progression by as much as 25 months, the investigators found.

They pinned the mutation down to the BH3-binding groove on BCL2, the same molecular site targeted by venetoclax. They found that the mutation was not present in samples from 96 patients with venetoclax-naive CLL nor in any other B-cell malignancies. Searches for references to the mutation in both a cancer database (COSMIC) and a population database (gnomAD) came up empty.

In other experiments, they determined that cell lines overexpressing BCL2 Gly101Val are resistant to venetoclax, and that in the presence of venetoclax in vitro, BCL2 Gly101Val-expressing cells have a growth advantage, compared with wild type cells.

Additionally, they showed that the mutation results in impaired venetoclax binding in vitro.

“BCL2 Gly101Val is observed subclonally, implicating multiple mechanisms of venetoclax resistance in the same patient,” Dr. Blombery said.

In an interview, Dr. Blombery said that the identification of the resistance mutation is a strong rationale for using combination therapy to treat patients with relapsed or refractory CLL to help prevent or attenuate selection pressures that lead to resistance.

The investigators were supported by the Wilson Center for Lymphoma Genomics, Snowdome Foundation, National Health Medical Research Council, Leukemia and Lymphoma Society, Leukemia Foundation, Cancer Council of Victoria, and Australian Cancer Research Foundation. Dr. Blombery reported having no relevant disclosures.

SOURCE: Blombery P et al. ASH 2018, Abstract LBA-7.