User login
MD Anderson–led alliance seeks to advance leukemia drug development
The primarily for leukemia.
The collaboration, led by Hagop Kantarjian, MD, chair of leukemia at MD Anderson, will use Ascentage’s proprietary Protein-Protein Interaction drug discovery technology platform to develop the company’s apoptosis-targeted and tyrosine kinase inhibitor drug candidates.
The drug candidates will be studied as single-agent therapies and in combinations with other approved or investigational therapeutics. The candidates, chosen for their potential to treat acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), myeloproliferative neoplasms, and myelofibrosis, include:
- HQP1351, a third-generation BCR-ABL inhibitor that has been shown to be safe and “highly active” in treating patients with chronic- or accelerated-phase CML, with or without the T3151 mutation. Preliminary results of the phase 1 study were presented at the 2018 annual meeting of the American Society of Hematology (Abstract 791).
- APG-1252, a highly potent Bcl-2 family inhibitor, has high binding affinities to Bcl-2, Bcl-xL and Bcl-w. It has achieved tumor regression in small cell lung cancer, colon, breast, and ALL xenografts. A phase 1, dose-escalating study is currently being conducted (NCT03387332).
- APG-2575, a selective Bcl-2 inhibitor, is being studied in a phase 1, multicenter, single-agent trial in patients with B-cell hematologic malignancies, including multiple myeloma, chronic lymphocytic leukemia, lymphoplasmacytic lymphoma, non-Hodgkin lymphomas, and AML (NCT03537482).
- APG-1387, an inhibitor of apoptosis protein, is being studied in solid tumors and hematologic malignancies (NCT03386526). Investigators asserted that combining it with an anti–programmed death 1 antibody would be “a very attractive approach” for cancer therapy. In advanced solid tumors it has been well tolerated with manageable adverse events, according to a study presented at the 2018 annual meeting of the American Society of Clinical Oncology (Abstract 2593).
- APG-115 is an MDM2-p53 inhibitor that, when combined with radiotherapy, has been shown to enhance the antitumor effect in gastric adenocarcinoma, according to a paper published in the Journal of Experimental & Clinical Cancer Research.
“We will be investigating this pipeline of candidate therapies, and we are interested in the novel mechanism of their actions,” Dr. Kantarjian said in a statement.
The primarily for leukemia.
The collaboration, led by Hagop Kantarjian, MD, chair of leukemia at MD Anderson, will use Ascentage’s proprietary Protein-Protein Interaction drug discovery technology platform to develop the company’s apoptosis-targeted and tyrosine kinase inhibitor drug candidates.
The drug candidates will be studied as single-agent therapies and in combinations with other approved or investigational therapeutics. The candidates, chosen for their potential to treat acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), myeloproliferative neoplasms, and myelofibrosis, include:
- HQP1351, a third-generation BCR-ABL inhibitor that has been shown to be safe and “highly active” in treating patients with chronic- or accelerated-phase CML, with or without the T3151 mutation. Preliminary results of the phase 1 study were presented at the 2018 annual meeting of the American Society of Hematology (Abstract 791).
- APG-1252, a highly potent Bcl-2 family inhibitor, has high binding affinities to Bcl-2, Bcl-xL and Bcl-w. It has achieved tumor regression in small cell lung cancer, colon, breast, and ALL xenografts. A phase 1, dose-escalating study is currently being conducted (NCT03387332).
- APG-2575, a selective Bcl-2 inhibitor, is being studied in a phase 1, multicenter, single-agent trial in patients with B-cell hematologic malignancies, including multiple myeloma, chronic lymphocytic leukemia, lymphoplasmacytic lymphoma, non-Hodgkin lymphomas, and AML (NCT03537482).
- APG-1387, an inhibitor of apoptosis protein, is being studied in solid tumors and hematologic malignancies (NCT03386526). Investigators asserted that combining it with an anti–programmed death 1 antibody would be “a very attractive approach” for cancer therapy. In advanced solid tumors it has been well tolerated with manageable adverse events, according to a study presented at the 2018 annual meeting of the American Society of Clinical Oncology (Abstract 2593).
- APG-115 is an MDM2-p53 inhibitor that, when combined with radiotherapy, has been shown to enhance the antitumor effect in gastric adenocarcinoma, according to a paper published in the Journal of Experimental & Clinical Cancer Research.
“We will be investigating this pipeline of candidate therapies, and we are interested in the novel mechanism of their actions,” Dr. Kantarjian said in a statement.
The primarily for leukemia.
The collaboration, led by Hagop Kantarjian, MD, chair of leukemia at MD Anderson, will use Ascentage’s proprietary Protein-Protein Interaction drug discovery technology platform to develop the company’s apoptosis-targeted and tyrosine kinase inhibitor drug candidates.
The drug candidates will be studied as single-agent therapies and in combinations with other approved or investigational therapeutics. The candidates, chosen for their potential to treat acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), myeloproliferative neoplasms, and myelofibrosis, include:
- HQP1351, a third-generation BCR-ABL inhibitor that has been shown to be safe and “highly active” in treating patients with chronic- or accelerated-phase CML, with or without the T3151 mutation. Preliminary results of the phase 1 study were presented at the 2018 annual meeting of the American Society of Hematology (Abstract 791).
- APG-1252, a highly potent Bcl-2 family inhibitor, has high binding affinities to Bcl-2, Bcl-xL and Bcl-w. It has achieved tumor regression in small cell lung cancer, colon, breast, and ALL xenografts. A phase 1, dose-escalating study is currently being conducted (NCT03387332).
- APG-2575, a selective Bcl-2 inhibitor, is being studied in a phase 1, multicenter, single-agent trial in patients with B-cell hematologic malignancies, including multiple myeloma, chronic lymphocytic leukemia, lymphoplasmacytic lymphoma, non-Hodgkin lymphomas, and AML (NCT03537482).
- APG-1387, an inhibitor of apoptosis protein, is being studied in solid tumors and hematologic malignancies (NCT03386526). Investigators asserted that combining it with an anti–programmed death 1 antibody would be “a very attractive approach” for cancer therapy. In advanced solid tumors it has been well tolerated with manageable adverse events, according to a study presented at the 2018 annual meeting of the American Society of Clinical Oncology (Abstract 2593).
- APG-115 is an MDM2-p53 inhibitor that, when combined with radiotherapy, has been shown to enhance the antitumor effect in gastric adenocarcinoma, according to a paper published in the Journal of Experimental & Clinical Cancer Research.
“We will be investigating this pipeline of candidate therapies, and we are interested in the novel mechanism of their actions,” Dr. Kantarjian said in a statement.
KTE-X19 induces durable CRs, MRD negativity in ALL
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.
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.
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.
Preliminary data suggest UCART19 is safe, effective
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—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—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.
Early switch to dasatinib offers clinical benefit to CML patients
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.
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.
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.
Dasatinib re-challenge feasible as 2nd attempt at TKI discontinuation
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—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—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.
P-BCMA-101 gains FDA regenerative medicine designation
(MM), has received the regenerative medicine advanced therapy (RMAT) designation from the Food and Drug Administration.
P-BCMA-101 modifies patients’ T cells using a nonviral DNA modification system known as piggyBac. The modified T cells target cells expressing B-cell maturation antigen (BCMA), which is expressed on essentially all MM cells.
Early results from the phase 1 clinical trial of P-BCMA-101 were recently reported at the 2018 CAR-TCR Summit by Eric Ostertag, MD, PhD, chief executive officer of Poseida Therapeutics, the company developing P-BCMA-101.
Initial results of the trial (NCT03288493) included data on 11 patients with heavily pretreated MM. Patients were a median age of 60, and 73% were high risk. They had a median of six prior therapies.
Patients received conditioning treatment with fludarabine and cyclophosphamide for 3 days prior to receiving P-BCMA-101. They then received one of three doses of CAR T cells – 51×106 (n=3), 152×106 (n=7), or 430×106 (n=1).
The investigators observed no dose-limiting toxicities. Adverse events included neutropenia in eight patients and thrombocytopenia in five.
One patient may have had cytokine release syndrome, but the condition resolved without drug intervention. And investigators observed no neurotoxicity.
Seven of ten patients evaluable for response by International Myeloma Working Group criteria achieved at least a partial response, including very good partial responses and stringent complete response.
The eleventh patient has oligosecretory disease and was only evaluable by PET, which indicated a near-complete response.
Poseida expects to have additional data to report by the end of the year, according to Dr. Ostertag. The study is funded by the California Institute for Regenerative Medicine and Poseida Therapeutics.RMAT designation is intended to expedite development and review of regenerative medicines that are intended to treat, modify, reverse, or cure a serious or life-threatening disease or condition.
Preliminary evidence must indicate that the therapy has the potential to address unmet medical needs for the disease or condition. RMAT designation includes all the benefits of fast track and breakthrough therapy designations, including early interactions with the FDA.
(MM), has received the regenerative medicine advanced therapy (RMAT) designation from the Food and Drug Administration.
P-BCMA-101 modifies patients’ T cells using a nonviral DNA modification system known as piggyBac. The modified T cells target cells expressing B-cell maturation antigen (BCMA), which is expressed on essentially all MM cells.
Early results from the phase 1 clinical trial of P-BCMA-101 were recently reported at the 2018 CAR-TCR Summit by Eric Ostertag, MD, PhD, chief executive officer of Poseida Therapeutics, the company developing P-BCMA-101.
Initial results of the trial (NCT03288493) included data on 11 patients with heavily pretreated MM. Patients were a median age of 60, and 73% were high risk. They had a median of six prior therapies.
Patients received conditioning treatment with fludarabine and cyclophosphamide for 3 days prior to receiving P-BCMA-101. They then received one of three doses of CAR T cells – 51×106 (n=3), 152×106 (n=7), or 430×106 (n=1).
The investigators observed no dose-limiting toxicities. Adverse events included neutropenia in eight patients and thrombocytopenia in five.
One patient may have had cytokine release syndrome, but the condition resolved without drug intervention. And investigators observed no neurotoxicity.
Seven of ten patients evaluable for response by International Myeloma Working Group criteria achieved at least a partial response, including very good partial responses and stringent complete response.
The eleventh patient has oligosecretory disease and was only evaluable by PET, which indicated a near-complete response.
Poseida expects to have additional data to report by the end of the year, according to Dr. Ostertag. The study is funded by the California Institute for Regenerative Medicine and Poseida Therapeutics.RMAT designation is intended to expedite development and review of regenerative medicines that are intended to treat, modify, reverse, or cure a serious or life-threatening disease or condition.
Preliminary evidence must indicate that the therapy has the potential to address unmet medical needs for the disease or condition. RMAT designation includes all the benefits of fast track and breakthrough therapy designations, including early interactions with the FDA.
(MM), has received the regenerative medicine advanced therapy (RMAT) designation from the Food and Drug Administration.
P-BCMA-101 modifies patients’ T cells using a nonviral DNA modification system known as piggyBac. The modified T cells target cells expressing B-cell maturation antigen (BCMA), which is expressed on essentially all MM cells.
Early results from the phase 1 clinical trial of P-BCMA-101 were recently reported at the 2018 CAR-TCR Summit by Eric Ostertag, MD, PhD, chief executive officer of Poseida Therapeutics, the company developing P-BCMA-101.
Initial results of the trial (NCT03288493) included data on 11 patients with heavily pretreated MM. Patients were a median age of 60, and 73% were high risk. They had a median of six prior therapies.
Patients received conditioning treatment with fludarabine and cyclophosphamide for 3 days prior to receiving P-BCMA-101. They then received one of three doses of CAR T cells – 51×106 (n=3), 152×106 (n=7), or 430×106 (n=1).
The investigators observed no dose-limiting toxicities. Adverse events included neutropenia in eight patients and thrombocytopenia in five.
One patient may have had cytokine release syndrome, but the condition resolved without drug intervention. And investigators observed no neurotoxicity.
Seven of ten patients evaluable for response by International Myeloma Working Group criteria achieved at least a partial response, including very good partial responses and stringent complete response.
The eleventh patient has oligosecretory disease and was only evaluable by PET, which indicated a near-complete response.
Poseida expects to have additional data to report by the end of the year, according to Dr. Ostertag. The study is funded by the California Institute for Regenerative Medicine and Poseida Therapeutics.RMAT designation is intended to expedite development and review of regenerative medicines that are intended to treat, modify, reverse, or cure a serious or life-threatening disease or condition.
Preliminary evidence must indicate that the therapy has the potential to address unmet medical needs for the disease or condition. RMAT designation includes all the benefits of fast track and breakthrough therapy designations, including early interactions with the FDA.
Genomic abnormalities shed light on racial disparity in myeloma
Researchers say they may have determined why African Americans have a two- to threefold increased risk of multiple myeloma (MM), compared with European Americans.
The team genotyped 881 MM samples from various racial groups and identified three gene subtypes – t(11;14), t(14;16), and t(14;20) – that explain the racial disparity.
They found that patients with African ancestry of 80% or more had a significantly higher occurrence of these subtypes, compared with individuals with African ancestry of less than 0.1%.
And these subtypes are driving the disparity in MM diagnoses between the populations.
Previous attempts to explain the disparity relied on self-reported race rather than quantitatively measured genetic ancestry, which could result in bias, Vincent Rajkumar, MD, of the Mayo Clinic in Rochester, Minn., and his colleagues reported in Blood Cancer Journal.
“A major new aspect of this study is that we identified the ancestry of each patient through DNA sequencing, which allowed us to determine ancestry more accurately,” Dr. Rajkumar said in a statement.
All 881 samples had abnormal plasma cell FISH, 851 had a normal chromosome study, and 30 had an abnormal study.
Median age for the entire group was 64 years. More samples were from men (54.3%) than women (45.7%). Researchers observed no significant difference between men and women in the proportion of primary cytogenetic abnormalities.
Of the 881 samples, the median African ancestry was 2.3%, the median European ancestry was 64.7%, and Northern European ancestry was 26.6%.
Thirty percent of the entire cohort had less than 0.1% African ancestry, and 13.6% had 80% or greater African ancestry.
Using a logistic regression model, the researchers determined that a 10% increase in the percentage of African ancestry was associated with a 6% increase in the odds of detecting t(11;14), t(14;16), or t(14;20) odds ratio, 1.06; 95% confidence interval, 1.02-1.11; P = .05).
The researchers plotted the probability of observing these cytogenetic abnormalities with the percentage of African ancestry and found the differences were most striking in the extreme populations – individuals with 80% or greater African ancestry and individuals with less than 0.1% African ancestry.
Upon further analysis, the team found a significantly higher prevalence of t(11;14), t(14;16), and t(14;20) in the group of patients with the greatest proportion of African ancestry (P = .008), compared with the European cohort.
The differences emerged in only the highest and lowest cohorts, they noted. Most patients (60%) were not included in these extreme populations because they had mixed ancestry.
The team observed no significant differences when the cutoff for African ancestry was greater than 50%.
The research was supported by the National Cancer Institute and the Mayo Clinic. One study author reported relationships with Celgene, Takeda, Prothena, Janssen, Pfizer, Alnylam, and GSK. Two authors reported relationships with the DNA Diagnostics Center.
SOURCE: Baughn LB et al. Blood Cancer J. 2018 Oct 10;8(10):96.
Researchers say they may have determined why African Americans have a two- to threefold increased risk of multiple myeloma (MM), compared with European Americans.
The team genotyped 881 MM samples from various racial groups and identified three gene subtypes – t(11;14), t(14;16), and t(14;20) – that explain the racial disparity.
They found that patients with African ancestry of 80% or more had a significantly higher occurrence of these subtypes, compared with individuals with African ancestry of less than 0.1%.
And these subtypes are driving the disparity in MM diagnoses between the populations.
Previous attempts to explain the disparity relied on self-reported race rather than quantitatively measured genetic ancestry, which could result in bias, Vincent Rajkumar, MD, of the Mayo Clinic in Rochester, Minn., and his colleagues reported in Blood Cancer Journal.
“A major new aspect of this study is that we identified the ancestry of each patient through DNA sequencing, which allowed us to determine ancestry more accurately,” Dr. Rajkumar said in a statement.
All 881 samples had abnormal plasma cell FISH, 851 had a normal chromosome study, and 30 had an abnormal study.
Median age for the entire group was 64 years. More samples were from men (54.3%) than women (45.7%). Researchers observed no significant difference between men and women in the proportion of primary cytogenetic abnormalities.
Of the 881 samples, the median African ancestry was 2.3%, the median European ancestry was 64.7%, and Northern European ancestry was 26.6%.
Thirty percent of the entire cohort had less than 0.1% African ancestry, and 13.6% had 80% or greater African ancestry.
Using a logistic regression model, the researchers determined that a 10% increase in the percentage of African ancestry was associated with a 6% increase in the odds of detecting t(11;14), t(14;16), or t(14;20) odds ratio, 1.06; 95% confidence interval, 1.02-1.11; P = .05).
The researchers plotted the probability of observing these cytogenetic abnormalities with the percentage of African ancestry and found the differences were most striking in the extreme populations – individuals with 80% or greater African ancestry and individuals with less than 0.1% African ancestry.
Upon further analysis, the team found a significantly higher prevalence of t(11;14), t(14;16), and t(14;20) in the group of patients with the greatest proportion of African ancestry (P = .008), compared with the European cohort.
The differences emerged in only the highest and lowest cohorts, they noted. Most patients (60%) were not included in these extreme populations because they had mixed ancestry.
The team observed no significant differences when the cutoff for African ancestry was greater than 50%.
The research was supported by the National Cancer Institute and the Mayo Clinic. One study author reported relationships with Celgene, Takeda, Prothena, Janssen, Pfizer, Alnylam, and GSK. Two authors reported relationships with the DNA Diagnostics Center.
SOURCE: Baughn LB et al. Blood Cancer J. 2018 Oct 10;8(10):96.
Researchers say they may have determined why African Americans have a two- to threefold increased risk of multiple myeloma (MM), compared with European Americans.
The team genotyped 881 MM samples from various racial groups and identified three gene subtypes – t(11;14), t(14;16), and t(14;20) – that explain the racial disparity.
They found that patients with African ancestry of 80% or more had a significantly higher occurrence of these subtypes, compared with individuals with African ancestry of less than 0.1%.
And these subtypes are driving the disparity in MM diagnoses between the populations.
Previous attempts to explain the disparity relied on self-reported race rather than quantitatively measured genetic ancestry, which could result in bias, Vincent Rajkumar, MD, of the Mayo Clinic in Rochester, Minn., and his colleagues reported in Blood Cancer Journal.
“A major new aspect of this study is that we identified the ancestry of each patient through DNA sequencing, which allowed us to determine ancestry more accurately,” Dr. Rajkumar said in a statement.
All 881 samples had abnormal plasma cell FISH, 851 had a normal chromosome study, and 30 had an abnormal study.
Median age for the entire group was 64 years. More samples were from men (54.3%) than women (45.7%). Researchers observed no significant difference between men and women in the proportion of primary cytogenetic abnormalities.
Of the 881 samples, the median African ancestry was 2.3%, the median European ancestry was 64.7%, and Northern European ancestry was 26.6%.
Thirty percent of the entire cohort had less than 0.1% African ancestry, and 13.6% had 80% or greater African ancestry.
Using a logistic regression model, the researchers determined that a 10% increase in the percentage of African ancestry was associated with a 6% increase in the odds of detecting t(11;14), t(14;16), or t(14;20) odds ratio, 1.06; 95% confidence interval, 1.02-1.11; P = .05).
The researchers plotted the probability of observing these cytogenetic abnormalities with the percentage of African ancestry and found the differences were most striking in the extreme populations – individuals with 80% or greater African ancestry and individuals with less than 0.1% African ancestry.
Upon further analysis, the team found a significantly higher prevalence of t(11;14), t(14;16), and t(14;20) in the group of patients with the greatest proportion of African ancestry (P = .008), compared with the European cohort.
The differences emerged in only the highest and lowest cohorts, they noted. Most patients (60%) were not included in these extreme populations because they had mixed ancestry.
The team observed no significant differences when the cutoff for African ancestry was greater than 50%.
The research was supported by the National Cancer Institute and the Mayo Clinic. One study author reported relationships with Celgene, Takeda, Prothena, Janssen, Pfizer, Alnylam, and GSK. Two authors reported relationships with the DNA Diagnostics Center.
SOURCE: Baughn LB et al. Blood Cancer J. 2018 Oct 10;8(10):96.
FROM BLOOD CANCER JOURNAL
Key clinical point:
Major finding: There was a significantly higher prevalence of t(11;14), t(14;16), and t(14:20) in patients with 80% or greater African ancestry, compared with the European cohort (P = .008).
Study details: The study included 881 samples from patients with an abnormal plasma cell proliferative disorder FISH result and concurrent conventional G-banded chromosome evaluation.
Disclosures: The research was supported by the National Cancer Institute and the Mayo Clinic. One study author reported relationships with Celgene, Takeda, Prothena, Janssen, Pfizer, Alnylam, and GSK. Two authors reported relationships with the DNA Diagnostics Center.
Source: Baughn LB et al. Blood Cancer J. 2018 Oct 10;8(10):96.
Ground-breaking therapy comes with distinct challenges
NEW YORK—Two chimeric antigen receptor (CAR) T-cell therapies—axicabtagene ciloleucel (Yescarta ®) and tisagenlecleucel (Kymriah™)—are already approved in B-cell lymphoma by the U.S. Food and Drug Administration.
A third, lisocabtagene maraleucel, will most likely be approved before too long.
Despite differences in their costimulatory molecules, persistence, efficacy, and toxicity profiles, they all have high overall response rates and a fall-out of response during the first 3 to 6 months.
Longer-term follow-up is necessary to determine whether CAR T-cell therapy is actually curative.
“But based on the way things are looking,” said Reem Karmali, MD, of Robert H. Lurie Comprehensive Cancer Center of Northwestern University, “it seems this might be a realistic expectation.”
“CAR T-cell therapy is clearly effective and has been a ground-breaking form of therapy,” she said, “but there seems to be two sides to the coin. There are a number of challenges that we face with CAR T-cell therapy.”
Dr. Karmali outlined those challenges in a presentation at the NCCN 13th Annual Congress: Hematologic Malignancies.
Patient selection
One of the biggest challenges, according to Dr. Karmali, is patient selection.
First, patients must have an adequate hematopoietic reserve to ensure successful CAR T-cell manufacture.
Dr. Karmali referred to the JULIET study, in which 7% of patients failed the manufacturing process due to insufficient apheresis.
Second, the patient’s disease must be stable enough to make it through the time it takes to manufacturing the CAR product, which is typically 2 to 4 weeks.
Third, the patient’s overall health must be good enough to tolerate CAR T toxicities. "The patient needs good major organ function as well as preserved neurologic function,” she explained, “to withstand the unique toxicities that come with CAR T-cell therapy, specifically CRS [cytokine release syndrome] and neurotoxicity.”
Toxicities
The major toxicities are CRS and CAR‑T‑cell‑related encephalopathy syndrome (CRES).
Dr. Karmali pointed out there is also a theoretical risk of insertional oncogenesis from viral transduction used in manufacturing the T cells, and an off-tumor on target-effect that can result in B-cell aplasia and hypogammaglobulinemia.
The profiles of inflammatory cytokines and inflammation markers differ for each CAR construct and are driven in different ways. However, IL-6 is an important mediator for CRS and IL-6 receptor blockade is effective in managing the toxicity.
The drug of choice is tocilizumab, Dr. Karmali said, and for patients who are refractory to tocilizumab, siltuximab can be used.
“Steroids are extremely useful for CRS,” she added, “because they hold down inflammation and prevent immune activation.”
Steroids are also the mainstay for managing the neurotoxicity of CAR T-cell therapy because they help stabilize the blood-brain barrier.
“It’s important to make a note,” she said, “that there actually have been a number of analyses that have looked at the impact of using IL-6 receptor blockade and steroids on CAR T-cell expansion and persistence and there really doesn’t seem to be an impact.”
“So we really ought to use these quite liberally for grade 2 or higher toxicity without worrying about dampening the effect of CAR T-cell therapy,” she emphasized.
The Lee grading criteria for the management of CRS and the CTCAE 4.03 and CARTOX-10 for CRES provide guidance in assessing and managing the toxicities.
Future directions
Dr. Karmali outlined a few new directions to address the challenges with CAR T-cell therapy, such as switchable CARs that can be turned on or off and potentially improve safety; development of new constructs that may improve homing; improvement in persistence; use of combination and sequencing strategies; and improved antigen selection that may be effective with other lymphoproliferative diseases.
“A provocative question is whether CAR T-cell therapy can actually replace autologous stem cell transplant as second-line therapy,” she said. “This is actually being actively evaluated in a number of clinical trials including ZUMA-7 (NCT03391466).”
“I think another provocative question is whether CAR T-cell therapy can be used as consolidation in CR1 [first complete remission],” she added.
The rationale for using CAR Ts as either a replacement for autologous stem cell transplant or in CR1 is that there may be minimal residual disease present that would be enough to elicit a CAR T-cell effect, she explained.
“Ultimately, one envisions the following paradigm for the treatment of lymphomas across the board,” Dr. Karmali concluded.
“Specifically, chemotherapy with a targeted agent for rapid cytoreduction, followed by CAR T-cell consolidation in combination with either other cellular therapies or immunotherapy as a means of eradicating the minimal residual disease and ensuring a pathway to cure.”
NEW YORK—Two chimeric antigen receptor (CAR) T-cell therapies—axicabtagene ciloleucel (Yescarta ®) and tisagenlecleucel (Kymriah™)—are already approved in B-cell lymphoma by the U.S. Food and Drug Administration.
A third, lisocabtagene maraleucel, will most likely be approved before too long.
Despite differences in their costimulatory molecules, persistence, efficacy, and toxicity profiles, they all have high overall response rates and a fall-out of response during the first 3 to 6 months.
Longer-term follow-up is necessary to determine whether CAR T-cell therapy is actually curative.
“But based on the way things are looking,” said Reem Karmali, MD, of Robert H. Lurie Comprehensive Cancer Center of Northwestern University, “it seems this might be a realistic expectation.”
“CAR T-cell therapy is clearly effective and has been a ground-breaking form of therapy,” she said, “but there seems to be two sides to the coin. There are a number of challenges that we face with CAR T-cell therapy.”
Dr. Karmali outlined those challenges in a presentation at the NCCN 13th Annual Congress: Hematologic Malignancies.
Patient selection
One of the biggest challenges, according to Dr. Karmali, is patient selection.
First, patients must have an adequate hematopoietic reserve to ensure successful CAR T-cell manufacture.
Dr. Karmali referred to the JULIET study, in which 7% of patients failed the manufacturing process due to insufficient apheresis.
Second, the patient’s disease must be stable enough to make it through the time it takes to manufacturing the CAR product, which is typically 2 to 4 weeks.
Third, the patient’s overall health must be good enough to tolerate CAR T toxicities. "The patient needs good major organ function as well as preserved neurologic function,” she explained, “to withstand the unique toxicities that come with CAR T-cell therapy, specifically CRS [cytokine release syndrome] and neurotoxicity.”
Toxicities
The major toxicities are CRS and CAR‑T‑cell‑related encephalopathy syndrome (CRES).
Dr. Karmali pointed out there is also a theoretical risk of insertional oncogenesis from viral transduction used in manufacturing the T cells, and an off-tumor on target-effect that can result in B-cell aplasia and hypogammaglobulinemia.
The profiles of inflammatory cytokines and inflammation markers differ for each CAR construct and are driven in different ways. However, IL-6 is an important mediator for CRS and IL-6 receptor blockade is effective in managing the toxicity.
The drug of choice is tocilizumab, Dr. Karmali said, and for patients who are refractory to tocilizumab, siltuximab can be used.
“Steroids are extremely useful for CRS,” she added, “because they hold down inflammation and prevent immune activation.”
Steroids are also the mainstay for managing the neurotoxicity of CAR T-cell therapy because they help stabilize the blood-brain barrier.
“It’s important to make a note,” she said, “that there actually have been a number of analyses that have looked at the impact of using IL-6 receptor blockade and steroids on CAR T-cell expansion and persistence and there really doesn’t seem to be an impact.”
“So we really ought to use these quite liberally for grade 2 or higher toxicity without worrying about dampening the effect of CAR T-cell therapy,” she emphasized.
The Lee grading criteria for the management of CRS and the CTCAE 4.03 and CARTOX-10 for CRES provide guidance in assessing and managing the toxicities.
Future directions
Dr. Karmali outlined a few new directions to address the challenges with CAR T-cell therapy, such as switchable CARs that can be turned on or off and potentially improve safety; development of new constructs that may improve homing; improvement in persistence; use of combination and sequencing strategies; and improved antigen selection that may be effective with other lymphoproliferative diseases.
“A provocative question is whether CAR T-cell therapy can actually replace autologous stem cell transplant as second-line therapy,” she said. “This is actually being actively evaluated in a number of clinical trials including ZUMA-7 (NCT03391466).”
“I think another provocative question is whether CAR T-cell therapy can be used as consolidation in CR1 [first complete remission],” she added.
The rationale for using CAR Ts as either a replacement for autologous stem cell transplant or in CR1 is that there may be minimal residual disease present that would be enough to elicit a CAR T-cell effect, she explained.
“Ultimately, one envisions the following paradigm for the treatment of lymphomas across the board,” Dr. Karmali concluded.
“Specifically, chemotherapy with a targeted agent for rapid cytoreduction, followed by CAR T-cell consolidation in combination with either other cellular therapies or immunotherapy as a means of eradicating the minimal residual disease and ensuring a pathway to cure.”
NEW YORK—Two chimeric antigen receptor (CAR) T-cell therapies—axicabtagene ciloleucel (Yescarta ®) and tisagenlecleucel (Kymriah™)—are already approved in B-cell lymphoma by the U.S. Food and Drug Administration.
A third, lisocabtagene maraleucel, will most likely be approved before too long.
Despite differences in their costimulatory molecules, persistence, efficacy, and toxicity profiles, they all have high overall response rates and a fall-out of response during the first 3 to 6 months.
Longer-term follow-up is necessary to determine whether CAR T-cell therapy is actually curative.
“But based on the way things are looking,” said Reem Karmali, MD, of Robert H. Lurie Comprehensive Cancer Center of Northwestern University, “it seems this might be a realistic expectation.”
“CAR T-cell therapy is clearly effective and has been a ground-breaking form of therapy,” she said, “but there seems to be two sides to the coin. There are a number of challenges that we face with CAR T-cell therapy.”
Dr. Karmali outlined those challenges in a presentation at the NCCN 13th Annual Congress: Hematologic Malignancies.
Patient selection
One of the biggest challenges, according to Dr. Karmali, is patient selection.
First, patients must have an adequate hematopoietic reserve to ensure successful CAR T-cell manufacture.
Dr. Karmali referred to the JULIET study, in which 7% of patients failed the manufacturing process due to insufficient apheresis.
Second, the patient’s disease must be stable enough to make it through the time it takes to manufacturing the CAR product, which is typically 2 to 4 weeks.
Third, the patient’s overall health must be good enough to tolerate CAR T toxicities. "The patient needs good major organ function as well as preserved neurologic function,” she explained, “to withstand the unique toxicities that come with CAR T-cell therapy, specifically CRS [cytokine release syndrome] and neurotoxicity.”
Toxicities
The major toxicities are CRS and CAR‑T‑cell‑related encephalopathy syndrome (CRES).
Dr. Karmali pointed out there is also a theoretical risk of insertional oncogenesis from viral transduction used in manufacturing the T cells, and an off-tumor on target-effect that can result in B-cell aplasia and hypogammaglobulinemia.
The profiles of inflammatory cytokines and inflammation markers differ for each CAR construct and are driven in different ways. However, IL-6 is an important mediator for CRS and IL-6 receptor blockade is effective in managing the toxicity.
The drug of choice is tocilizumab, Dr. Karmali said, and for patients who are refractory to tocilizumab, siltuximab can be used.
“Steroids are extremely useful for CRS,” she added, “because they hold down inflammation and prevent immune activation.”
Steroids are also the mainstay for managing the neurotoxicity of CAR T-cell therapy because they help stabilize the blood-brain barrier.
“It’s important to make a note,” she said, “that there actually have been a number of analyses that have looked at the impact of using IL-6 receptor blockade and steroids on CAR T-cell expansion and persistence and there really doesn’t seem to be an impact.”
“So we really ought to use these quite liberally for grade 2 or higher toxicity without worrying about dampening the effect of CAR T-cell therapy,” she emphasized.
The Lee grading criteria for the management of CRS and the CTCAE 4.03 and CARTOX-10 for CRES provide guidance in assessing and managing the toxicities.
Future directions
Dr. Karmali outlined a few new directions to address the challenges with CAR T-cell therapy, such as switchable CARs that can be turned on or off and potentially improve safety; development of new constructs that may improve homing; improvement in persistence; use of combination and sequencing strategies; and improved antigen selection that may be effective with other lymphoproliferative diseases.
“A provocative question is whether CAR T-cell therapy can actually replace autologous stem cell transplant as second-line therapy,” she said. “This is actually being actively evaluated in a number of clinical trials including ZUMA-7 (NCT03391466).”
“I think another provocative question is whether CAR T-cell therapy can be used as consolidation in CR1 [first complete remission],” she added.
The rationale for using CAR Ts as either a replacement for autologous stem cell transplant or in CR1 is that there may be minimal residual disease present that would be enough to elicit a CAR T-cell effect, she explained.
“Ultimately, one envisions the following paradigm for the treatment of lymphomas across the board,” Dr. Karmali concluded.
“Specifically, chemotherapy with a targeted agent for rapid cytoreduction, followed by CAR T-cell consolidation in combination with either other cellular therapies or immunotherapy as a means of eradicating the minimal residual disease and ensuring a pathway to cure.”
Novel agents changing treatment algorithm in AML
NEW YORK—Recent drug approvals for acute myeloid leukemia (AML) have greatly expanded options for treating patients, according to a presentation at the NCCN 13th Annual Congress: Hematologic Malignancies.
Richard M. Stone, MD, of the Dana-Farber Cancer Institute in Boston, M.A., gave this presentation, providing some guidance for how to incorporate newly approved AML drugs into practice.
Dr. Stone also discussed therapies and treatment strategies that are under investigation.
Midostaurin
Midostaurin was approved by the U.S. Food and Drug Administration (FDA) in 2017. It is approved for use in combination with standard cytarabine and daunorubicin induction, followed by cytarabine consolidation, in adults with newly diagnosed AML who are FLT3-mutation-positive, as detected by an FDA-approved test.
Even though FLT3-ITD mutation confers a bad prognosis in AML, midostaurin capitalizes on the activated enzyme by inhibiting it.
The RATIFY trial (CALGB 10603) enrolled only FLT3-mutated AML patients younger than 60 and randomized them to induction and consolidation with or without midostaurin.
“Bottom line, being on midostaurin was a good thing,” Dr. Stone said.
Midostaurin led to a 23% reduction in the risk of death, and the 4-year survival rate was improved by about 7%.
“What is meaningful, if you happen to get a transplant in CR1 [first complete remission], you may be going to transplant with lower disease burden,” Dr. Stone explained. “Adding midostaurin is probably a good thing for mutated FLT3.”
The addition of midostaurin to induction may also be appropriate for fit older adults with FLT3 mutations, Dr. Stone said.
Gemtuzumab ozogamicin
The antibody-drug conjugate gemtuzumab ozogamicin has been around for almost 20 years and has an “interesting” history, according to Dr. Stone.
Gemtuzumab ozogamicin was first approved by the FDA in 2000, based on a 30% remission rate in relapsed AML.
However, the agent was voluntarily withdrawn from the market in 2010 because it was used in the upfront setting with chemotherapy and didn’t show a benefit.
Recent studies of the agent suggested use of the agent should be revisited but with lower doses.
Data from the ALFA 0701 study was key for the FDA’s re-approval of gemtuzumab in 2017.
According to Dr. Stone, the most important finding of this trial was the major event-free survival benefit for those on gemtuzumab, which was 41% at 2 years, compared to 17% for the control group.
Overall survival, however, was not significantly superior with gemtuzumab.
A meta-analysis of 5 trials showed that adding gemtuzumab to treatment of patients with favorable and intermediate risk conferred a survival advantage, but this was not the case in patients with adverse-risk cytogenetics.
Fit older adults with CBF mutation may benefit from the addition of gemtuzumab, Dr. Stone said.
He also pointed out that gemtuzumab has a big “booby prize,” which is veno-occlusive disease, shown to be a problem with high doses of gemtuzumab and transplant.
CPX-351
CPX-351 is a liposomal co-formulation of cytarabine and daunorubicin, the two drugs delivered separately in the standard induction chemotherapy referred to as 7+3.
Last year, the FDA approved CPX-351 to treat adults who have AML with myelodysplasia-related changes or newly diagnosed, therapy-related AML.
In a phase 3 trial, CPX-351 conferred a survival advantage over standard 7+3. There was a 31% reduction in the risk of death with CPX-351.
Patients who went on to transplant after CPX-351 did much better than patients who received 7+3 and transplant, with a hazard ratio of 0.51.
Dr. Stone noted that minimal residual disease was not measured, “but it’s quite possible that patients who had CPX went into transplant with a lower level of disease burden.”
Dr. Stone also said CPX-351 may be added to induction for fit older patients with secondary AML.
Enasidenib and ivosidenib
In relapsed AML, the treatment approach is to induce a second complete remission and then proceed to allogeneic stem cell transplant.
Traditionally, FLAG-IDA (fludarabine, cytarabine, idarubicin, and G-CSF) and MEC (mitoxantrone, etoposide, and cytarabine) have been used as salvage, and another course of 7+3 is an option if the patient has been disease-free for over a year.
Now, however, enasidenib and ivosidenib may be an option for IDH2- and IDH1-mutated patients, respectively.
The FDA approved enasidenib in 2017 to treat adults with relapsed or refractory AML and an IDH2 mutation, as detected by an FDA-approved test.
Ivosidenib was approved by the FDA this year to treat adults with relapsed or refractory AML who have an IDH1 mutation, as detected by an FDA-approved test.
New approaches on the horizon
Dr. Stone noted that gilteritinib and quizartinib are currently in development for FLT3-mutated patients, and he anticipates these therapies will be approved by the FDA in 2019.
Dr. Stone also touched on other new approaches under investigation, such as hedgehog pathway inhibition, dysregulation of the spliceosome complex, inhibiting MDM2, and strengthening the immune system.
However, he believes the most important is BCL-2 inhibition with venetoclax.
Venetoclax combined with a hypomethylator (azacitidine or decitabine) produced a response rate of 75% with azacitidine, double what one would expect with azacitidine or decitabine alone, Dr. Stone noted.
And venetoclax with low-dose cytarabine may enable elderly good-risk patients to avoid 7+3.
Dr. Stone’s presentation also covered genes commonly mutated in AML, the increasing scrutiny of complete remission, and minimal residual disease assessment. An account of this part of the presentation can be found here: “Current management of AML patients.”
NEW YORK—Recent drug approvals for acute myeloid leukemia (AML) have greatly expanded options for treating patients, according to a presentation at the NCCN 13th Annual Congress: Hematologic Malignancies.
Richard M. Stone, MD, of the Dana-Farber Cancer Institute in Boston, M.A., gave this presentation, providing some guidance for how to incorporate newly approved AML drugs into practice.
Dr. Stone also discussed therapies and treatment strategies that are under investigation.
Midostaurin
Midostaurin was approved by the U.S. Food and Drug Administration (FDA) in 2017. It is approved for use in combination with standard cytarabine and daunorubicin induction, followed by cytarabine consolidation, in adults with newly diagnosed AML who are FLT3-mutation-positive, as detected by an FDA-approved test.
Even though FLT3-ITD mutation confers a bad prognosis in AML, midostaurin capitalizes on the activated enzyme by inhibiting it.
The RATIFY trial (CALGB 10603) enrolled only FLT3-mutated AML patients younger than 60 and randomized them to induction and consolidation with or without midostaurin.
“Bottom line, being on midostaurin was a good thing,” Dr. Stone said.
Midostaurin led to a 23% reduction in the risk of death, and the 4-year survival rate was improved by about 7%.
“What is meaningful, if you happen to get a transplant in CR1 [first complete remission], you may be going to transplant with lower disease burden,” Dr. Stone explained. “Adding midostaurin is probably a good thing for mutated FLT3.”
The addition of midostaurin to induction may also be appropriate for fit older adults with FLT3 mutations, Dr. Stone said.
Gemtuzumab ozogamicin
The antibody-drug conjugate gemtuzumab ozogamicin has been around for almost 20 years and has an “interesting” history, according to Dr. Stone.
Gemtuzumab ozogamicin was first approved by the FDA in 2000, based on a 30% remission rate in relapsed AML.
However, the agent was voluntarily withdrawn from the market in 2010 because it was used in the upfront setting with chemotherapy and didn’t show a benefit.
Recent studies of the agent suggested use of the agent should be revisited but with lower doses.
Data from the ALFA 0701 study was key for the FDA’s re-approval of gemtuzumab in 2017.
According to Dr. Stone, the most important finding of this trial was the major event-free survival benefit for those on gemtuzumab, which was 41% at 2 years, compared to 17% for the control group.
Overall survival, however, was not significantly superior with gemtuzumab.
A meta-analysis of 5 trials showed that adding gemtuzumab to treatment of patients with favorable and intermediate risk conferred a survival advantage, but this was not the case in patients with adverse-risk cytogenetics.
Fit older adults with CBF mutation may benefit from the addition of gemtuzumab, Dr. Stone said.
He also pointed out that gemtuzumab has a big “booby prize,” which is veno-occlusive disease, shown to be a problem with high doses of gemtuzumab and transplant.
CPX-351
CPX-351 is a liposomal co-formulation of cytarabine and daunorubicin, the two drugs delivered separately in the standard induction chemotherapy referred to as 7+3.
Last year, the FDA approved CPX-351 to treat adults who have AML with myelodysplasia-related changes or newly diagnosed, therapy-related AML.
In a phase 3 trial, CPX-351 conferred a survival advantage over standard 7+3. There was a 31% reduction in the risk of death with CPX-351.
Patients who went on to transplant after CPX-351 did much better than patients who received 7+3 and transplant, with a hazard ratio of 0.51.
Dr. Stone noted that minimal residual disease was not measured, “but it’s quite possible that patients who had CPX went into transplant with a lower level of disease burden.”
Dr. Stone also said CPX-351 may be added to induction for fit older patients with secondary AML.
Enasidenib and ivosidenib
In relapsed AML, the treatment approach is to induce a second complete remission and then proceed to allogeneic stem cell transplant.
Traditionally, FLAG-IDA (fludarabine, cytarabine, idarubicin, and G-CSF) and MEC (mitoxantrone, etoposide, and cytarabine) have been used as salvage, and another course of 7+3 is an option if the patient has been disease-free for over a year.
Now, however, enasidenib and ivosidenib may be an option for IDH2- and IDH1-mutated patients, respectively.
The FDA approved enasidenib in 2017 to treat adults with relapsed or refractory AML and an IDH2 mutation, as detected by an FDA-approved test.
Ivosidenib was approved by the FDA this year to treat adults with relapsed or refractory AML who have an IDH1 mutation, as detected by an FDA-approved test.
New approaches on the horizon
Dr. Stone noted that gilteritinib and quizartinib are currently in development for FLT3-mutated patients, and he anticipates these therapies will be approved by the FDA in 2019.
Dr. Stone also touched on other new approaches under investigation, such as hedgehog pathway inhibition, dysregulation of the spliceosome complex, inhibiting MDM2, and strengthening the immune system.
However, he believes the most important is BCL-2 inhibition with venetoclax.
Venetoclax combined with a hypomethylator (azacitidine or decitabine) produced a response rate of 75% with azacitidine, double what one would expect with azacitidine or decitabine alone, Dr. Stone noted.
And venetoclax with low-dose cytarabine may enable elderly good-risk patients to avoid 7+3.
Dr. Stone’s presentation also covered genes commonly mutated in AML, the increasing scrutiny of complete remission, and minimal residual disease assessment. An account of this part of the presentation can be found here: “Current management of AML patients.”
NEW YORK—Recent drug approvals for acute myeloid leukemia (AML) have greatly expanded options for treating patients, according to a presentation at the NCCN 13th Annual Congress: Hematologic Malignancies.
Richard M. Stone, MD, of the Dana-Farber Cancer Institute in Boston, M.A., gave this presentation, providing some guidance for how to incorporate newly approved AML drugs into practice.
Dr. Stone also discussed therapies and treatment strategies that are under investigation.
Midostaurin
Midostaurin was approved by the U.S. Food and Drug Administration (FDA) in 2017. It is approved for use in combination with standard cytarabine and daunorubicin induction, followed by cytarabine consolidation, in adults with newly diagnosed AML who are FLT3-mutation-positive, as detected by an FDA-approved test.
Even though FLT3-ITD mutation confers a bad prognosis in AML, midostaurin capitalizes on the activated enzyme by inhibiting it.
The RATIFY trial (CALGB 10603) enrolled only FLT3-mutated AML patients younger than 60 and randomized them to induction and consolidation with or without midostaurin.
“Bottom line, being on midostaurin was a good thing,” Dr. Stone said.
Midostaurin led to a 23% reduction in the risk of death, and the 4-year survival rate was improved by about 7%.
“What is meaningful, if you happen to get a transplant in CR1 [first complete remission], you may be going to transplant with lower disease burden,” Dr. Stone explained. “Adding midostaurin is probably a good thing for mutated FLT3.”
The addition of midostaurin to induction may also be appropriate for fit older adults with FLT3 mutations, Dr. Stone said.
Gemtuzumab ozogamicin
The antibody-drug conjugate gemtuzumab ozogamicin has been around for almost 20 years and has an “interesting” history, according to Dr. Stone.
Gemtuzumab ozogamicin was first approved by the FDA in 2000, based on a 30% remission rate in relapsed AML.
However, the agent was voluntarily withdrawn from the market in 2010 because it was used in the upfront setting with chemotherapy and didn’t show a benefit.
Recent studies of the agent suggested use of the agent should be revisited but with lower doses.
Data from the ALFA 0701 study was key for the FDA’s re-approval of gemtuzumab in 2017.
According to Dr. Stone, the most important finding of this trial was the major event-free survival benefit for those on gemtuzumab, which was 41% at 2 years, compared to 17% for the control group.
Overall survival, however, was not significantly superior with gemtuzumab.
A meta-analysis of 5 trials showed that adding gemtuzumab to treatment of patients with favorable and intermediate risk conferred a survival advantage, but this was not the case in patients with adverse-risk cytogenetics.
Fit older adults with CBF mutation may benefit from the addition of gemtuzumab, Dr. Stone said.
He also pointed out that gemtuzumab has a big “booby prize,” which is veno-occlusive disease, shown to be a problem with high doses of gemtuzumab and transplant.
CPX-351
CPX-351 is a liposomal co-formulation of cytarabine and daunorubicin, the two drugs delivered separately in the standard induction chemotherapy referred to as 7+3.
Last year, the FDA approved CPX-351 to treat adults who have AML with myelodysplasia-related changes or newly diagnosed, therapy-related AML.
In a phase 3 trial, CPX-351 conferred a survival advantage over standard 7+3. There was a 31% reduction in the risk of death with CPX-351.
Patients who went on to transplant after CPX-351 did much better than patients who received 7+3 and transplant, with a hazard ratio of 0.51.
Dr. Stone noted that minimal residual disease was not measured, “but it’s quite possible that patients who had CPX went into transplant with a lower level of disease burden.”
Dr. Stone also said CPX-351 may be added to induction for fit older patients with secondary AML.
Enasidenib and ivosidenib
In relapsed AML, the treatment approach is to induce a second complete remission and then proceed to allogeneic stem cell transplant.
Traditionally, FLAG-IDA (fludarabine, cytarabine, idarubicin, and G-CSF) and MEC (mitoxantrone, etoposide, and cytarabine) have been used as salvage, and another course of 7+3 is an option if the patient has been disease-free for over a year.
Now, however, enasidenib and ivosidenib may be an option for IDH2- and IDH1-mutated patients, respectively.
The FDA approved enasidenib in 2017 to treat adults with relapsed or refractory AML and an IDH2 mutation, as detected by an FDA-approved test.
Ivosidenib was approved by the FDA this year to treat adults with relapsed or refractory AML who have an IDH1 mutation, as detected by an FDA-approved test.
New approaches on the horizon
Dr. Stone noted that gilteritinib and quizartinib are currently in development for FLT3-mutated patients, and he anticipates these therapies will be approved by the FDA in 2019.
Dr. Stone also touched on other new approaches under investigation, such as hedgehog pathway inhibition, dysregulation of the spliceosome complex, inhibiting MDM2, and strengthening the immune system.
However, he believes the most important is BCL-2 inhibition with venetoclax.
Venetoclax combined with a hypomethylator (azacitidine or decitabine) produced a response rate of 75% with azacitidine, double what one would expect with azacitidine or decitabine alone, Dr. Stone noted.
And venetoclax with low-dose cytarabine may enable elderly good-risk patients to avoid 7+3.
Dr. Stone’s presentation also covered genes commonly mutated in AML, the increasing scrutiny of complete remission, and minimal residual disease assessment. An account of this part of the presentation can be found here: “Current management of AML patients.”
Current management of AML patients
NEW YORK—A presentation at the NCCN 13th Annual Congress: Hematologic Malignancies outlined current practices for managing patients with acute myeloid leukemia (AML).
Richard M. Stone, MD, of the Dana-Farber Cancer Institute in Boston, M.A., noted that management of AML now includes increased screening of commonly mutated genes, greater scrutiny of complete remission (CR), and a focus on minimal residual disease (MRD).
Genetics and cytogenetics
Genome sequencing projects in AML have revealed about 30 genes commonly mutated in AML patients, which can be further divided into 9 subcategories, Dr. Stone said.
He noted that the list of genes to screen for is getting longer every year, from FLT3-ITD, NPM1, and CEBPA last year, to RUNX1, TP53, ASXL1, KIT, and CBF mutations this year.
“Just looking at genetics, you can tell if you have CEBPA mutation, you are most likely going to be free of AML, and if you have TP53, you are in big trouble,” Dr. Stone said.
He added that the mutation status of IDH1/2, DNMT3A, and TET2 will be important in the future.
“So, basically, I like to have an NGS [next-generation sequencing] panel on all of our patients with AML today,” Dr. Stone said. “It’s probably going to be cheaper than trying to do the shotgun approach we were recently used to.”
Achieving CR
Dr. Stone noted that the first goal of AML treatment is to reduce the gross leukemia to undetectable levels with induction therapy and to achieve a CR.
“But there are real good remissions and not so good remissions,” he said. “But once we get into remission, that’s just the beginning of the curative approach.”
The second goal is to reduce patients’ leukemic cells still present at CR to a level low enough to achieve prolonged disease-free survival.
“CR is coming under more scrutiny,” according to Dr. Stone, because some patients with CR have low blasts, but the blood counts aren’t returning to normal.
“[T]here’s CRc, CRi, CRp, you name it, all the little subscripts, which mean the remission really isn’t as strong as it should be,” Dr. Stone said.
“But if you do have a complete remission with low blast counts in the marrow and blood and normal blood counts, you might have an MRD-negative remission, which is the goal.”
Quantitation techniques and MRD
The European LeukemiaNet recommends all AML patients have an MRD assessment at the time of remission by either multiparameter flow cytometry (MFC) or molecular means.
The most sensitive techniques to determine disease burden are MFC and polymerase chain reaction (PCR)-based methods, both of which are sensitive enough to find one leukemic cell in 10,000 cells (10-4).
NGS techniques are becoming more sensitive, Dr. Stone added, but probably not down to the level of 10-4.
In a study by Ivey et al, MRD levels based on PCR of NPM1-mutated patients after two rounds of chemotherapy could independently predict clinical outcome. Overall survival was 73% for MRD-negative patients and 24% for MRD-positive patients.
MFC and NGS data have been shown in a study by Jongen-Lavrencic et al to be mutually helpful. If a patient is positive by neither method, the relapse rate is low. If the patient is positive by both, the relapse rate is high. And if the patient is positive by one and negative by the other, the relapse rate is intermediate.
“So what do we do with this?” Dr. Stone asked. “The problem is, I don’t know what to do with that data except get worried.”
The dilemma is that if patients are MRD-positive in remission, they are probably not going to respond well to a transplant. And if they are MRD-negative, they don’t need a transplant.
A retrospective study by Milano et al indicated that MRD-positive patients seem to fare better than expected with a double umbilical cord blood transplant. However, Dr. Stone noted that this finding has not been confirmed prospectively.
The most exciting aspect of MRD in AML, Dr. Stone said, is it may allow us to get to new drugs quicker by revealing whether a drug is actually lowering MRD burden.
Dr. Stone also discussed newly approved drugs for AML and new treatment approaches under investigation. Details on that portion of his presentation are available here: “Novel agents changing treatment algorithm in AML.”
NEW YORK—A presentation at the NCCN 13th Annual Congress: Hematologic Malignancies outlined current practices for managing patients with acute myeloid leukemia (AML).
Richard M. Stone, MD, of the Dana-Farber Cancer Institute in Boston, M.A., noted that management of AML now includes increased screening of commonly mutated genes, greater scrutiny of complete remission (CR), and a focus on minimal residual disease (MRD).
Genetics and cytogenetics
Genome sequencing projects in AML have revealed about 30 genes commonly mutated in AML patients, which can be further divided into 9 subcategories, Dr. Stone said.
He noted that the list of genes to screen for is getting longer every year, from FLT3-ITD, NPM1, and CEBPA last year, to RUNX1, TP53, ASXL1, KIT, and CBF mutations this year.
“Just looking at genetics, you can tell if you have CEBPA mutation, you are most likely going to be free of AML, and if you have TP53, you are in big trouble,” Dr. Stone said.
He added that the mutation status of IDH1/2, DNMT3A, and TET2 will be important in the future.
“So, basically, I like to have an NGS [next-generation sequencing] panel on all of our patients with AML today,” Dr. Stone said. “It’s probably going to be cheaper than trying to do the shotgun approach we were recently used to.”
Achieving CR
Dr. Stone noted that the first goal of AML treatment is to reduce the gross leukemia to undetectable levels with induction therapy and to achieve a CR.
“But there are real good remissions and not so good remissions,” he said. “But once we get into remission, that’s just the beginning of the curative approach.”
The second goal is to reduce patients’ leukemic cells still present at CR to a level low enough to achieve prolonged disease-free survival.
“CR is coming under more scrutiny,” according to Dr. Stone, because some patients with CR have low blasts, but the blood counts aren’t returning to normal.
“[T]here’s CRc, CRi, CRp, you name it, all the little subscripts, which mean the remission really isn’t as strong as it should be,” Dr. Stone said.
“But if you do have a complete remission with low blast counts in the marrow and blood and normal blood counts, you might have an MRD-negative remission, which is the goal.”
Quantitation techniques and MRD
The European LeukemiaNet recommends all AML patients have an MRD assessment at the time of remission by either multiparameter flow cytometry (MFC) or molecular means.
The most sensitive techniques to determine disease burden are MFC and polymerase chain reaction (PCR)-based methods, both of which are sensitive enough to find one leukemic cell in 10,000 cells (10-4).
NGS techniques are becoming more sensitive, Dr. Stone added, but probably not down to the level of 10-4.
In a study by Ivey et al, MRD levels based on PCR of NPM1-mutated patients after two rounds of chemotherapy could independently predict clinical outcome. Overall survival was 73% for MRD-negative patients and 24% for MRD-positive patients.
MFC and NGS data have been shown in a study by Jongen-Lavrencic et al to be mutually helpful. If a patient is positive by neither method, the relapse rate is low. If the patient is positive by both, the relapse rate is high. And if the patient is positive by one and negative by the other, the relapse rate is intermediate.
“So what do we do with this?” Dr. Stone asked. “The problem is, I don’t know what to do with that data except get worried.”
The dilemma is that if patients are MRD-positive in remission, they are probably not going to respond well to a transplant. And if they are MRD-negative, they don’t need a transplant.
A retrospective study by Milano et al indicated that MRD-positive patients seem to fare better than expected with a double umbilical cord blood transplant. However, Dr. Stone noted that this finding has not been confirmed prospectively.
The most exciting aspect of MRD in AML, Dr. Stone said, is it may allow us to get to new drugs quicker by revealing whether a drug is actually lowering MRD burden.
Dr. Stone also discussed newly approved drugs for AML and new treatment approaches under investigation. Details on that portion of his presentation are available here: “Novel agents changing treatment algorithm in AML.”
NEW YORK—A presentation at the NCCN 13th Annual Congress: Hematologic Malignancies outlined current practices for managing patients with acute myeloid leukemia (AML).
Richard M. Stone, MD, of the Dana-Farber Cancer Institute in Boston, M.A., noted that management of AML now includes increased screening of commonly mutated genes, greater scrutiny of complete remission (CR), and a focus on minimal residual disease (MRD).
Genetics and cytogenetics
Genome sequencing projects in AML have revealed about 30 genes commonly mutated in AML patients, which can be further divided into 9 subcategories, Dr. Stone said.
He noted that the list of genes to screen for is getting longer every year, from FLT3-ITD, NPM1, and CEBPA last year, to RUNX1, TP53, ASXL1, KIT, and CBF mutations this year.
“Just looking at genetics, you can tell if you have CEBPA mutation, you are most likely going to be free of AML, and if you have TP53, you are in big trouble,” Dr. Stone said.
He added that the mutation status of IDH1/2, DNMT3A, and TET2 will be important in the future.
“So, basically, I like to have an NGS [next-generation sequencing] panel on all of our patients with AML today,” Dr. Stone said. “It’s probably going to be cheaper than trying to do the shotgun approach we were recently used to.”
Achieving CR
Dr. Stone noted that the first goal of AML treatment is to reduce the gross leukemia to undetectable levels with induction therapy and to achieve a CR.
“But there are real good remissions and not so good remissions,” he said. “But once we get into remission, that’s just the beginning of the curative approach.”
The second goal is to reduce patients’ leukemic cells still present at CR to a level low enough to achieve prolonged disease-free survival.
“CR is coming under more scrutiny,” according to Dr. Stone, because some patients with CR have low blasts, but the blood counts aren’t returning to normal.
“[T]here’s CRc, CRi, CRp, you name it, all the little subscripts, which mean the remission really isn’t as strong as it should be,” Dr. Stone said.
“But if you do have a complete remission with low blast counts in the marrow and blood and normal blood counts, you might have an MRD-negative remission, which is the goal.”
Quantitation techniques and MRD
The European LeukemiaNet recommends all AML patients have an MRD assessment at the time of remission by either multiparameter flow cytometry (MFC) or molecular means.
The most sensitive techniques to determine disease burden are MFC and polymerase chain reaction (PCR)-based methods, both of which are sensitive enough to find one leukemic cell in 10,000 cells (10-4).
NGS techniques are becoming more sensitive, Dr. Stone added, but probably not down to the level of 10-4.
In a study by Ivey et al, MRD levels based on PCR of NPM1-mutated patients after two rounds of chemotherapy could independently predict clinical outcome. Overall survival was 73% for MRD-negative patients and 24% for MRD-positive patients.
MFC and NGS data have been shown in a study by Jongen-Lavrencic et al to be mutually helpful. If a patient is positive by neither method, the relapse rate is low. If the patient is positive by both, the relapse rate is high. And if the patient is positive by one and negative by the other, the relapse rate is intermediate.
“So what do we do with this?” Dr. Stone asked. “The problem is, I don’t know what to do with that data except get worried.”
The dilemma is that if patients are MRD-positive in remission, they are probably not going to respond well to a transplant. And if they are MRD-negative, they don’t need a transplant.
A retrospective study by Milano et al indicated that MRD-positive patients seem to fare better than expected with a double umbilical cord blood transplant. However, Dr. Stone noted that this finding has not been confirmed prospectively.
The most exciting aspect of MRD in AML, Dr. Stone said, is it may allow us to get to new drugs quicker by revealing whether a drug is actually lowering MRD burden.
Dr. Stone also discussed newly approved drugs for AML and new treatment approaches under investigation. Details on that portion of his presentation are available here: “Novel agents changing treatment algorithm in AML.”