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ZUMA-1 update: Axi-cel responses persist at 2 years
HOUSTON – With a median follow-up now exceeding 2 years, 39% of refractory large B-cell lymphoma patients enrolled in the pivotal ZUMA-1 trial have maintained ongoing response to axicabtagene ciloleucel, according to an investigator involved in the study.
Median duration of response to axi-cel and median overall survival have not yet been reached, while a recent subset analysis showed that nearly half of patients with certain high-risk characteristics had a durable response, said investigator Sattva S. Neelapu, MD, of the University of Texas MD Anderson Cancer Center, Houston.
Evidence of B-cell recovery and a decrease in detectable, gene-marked CAR T cells have been noted in further follow-up, suggesting that functional CAR T-cell persistence may not be required for long-term remissions, Dr. Neelapu added.
“These data support [the conclusion] that axi-cel induces durable remissions in patients with large B-cell lymphoma who otherwise lack curative options,” Dr. Neelapu said at the Transplantation & Cellular Therapy Meetings.
The update on the phase 1/2 ZUMA-1 study included 108 patients with refractory large B-cell lymphoma who received axi-cel, the CD19-directed autologous chimeric antigen receptor (CAR) T-cell therapy.
In a previously reported 1-year update on the trial, 42% of patients had ongoing responses, Dr. Neelapu said. In the present update, with a median follow-up of 27.1 months, ongoing responses were seen in 39%, most of whom (37%) were in complete response, according to the data presented.
Thirty-three patients in the phase 2 portion of ZUMA-1 were known to have double-expressor or high-grade B-cell lymphoma, according to the investigator. In this high-risk subset, 48% were in ongoing complete response at the 2-year follow-up.
Progression-free survival in ZUMA-1 plateaued at the 6 month-follow-up, according to Dr. Neelapu, who said that plateau has been largely maintained, with just 10 patients progressing since then. Median progression-free survival is 5.9 months and median overall survival has not been reached, with a 24-month overall survival of 51%.
Late-onset serious adverse events mainly consisted of manageable infections, none of which were considered related to axi-cel treatment, according to Dr. Neelapu.
The proportion of ongoing responders with detectable CAR T-cells has decreased over time, from 95% at 3 months to 66% at 24 months, Dr. Neelapu reported. Meanwhile, the proportion of ongoing responders with detectable B cells after axi-cel treatment has gone from 17% to 75%.
More details on the 2-year follow-up data from ZUMA-1 were reported recently in the Lancet Oncology (2019 Jan;20[1]:31-42).
Funding for ZUMA-1 came from Kite and the Leukemia & Lymphoma Society. Dr. Neelapu reported disclosures related to Kite, Celgene, Cellectis, Merck, Poseida, Acerta, Karus, Bristol-Myers Squibb, Novartis, and Unum Therapeutics.
The meeting was held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research. At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).
SOURCE: Neelapu SS et al. TCT 2019, Abstract 82.
HOUSTON – With a median follow-up now exceeding 2 years, 39% of refractory large B-cell lymphoma patients enrolled in the pivotal ZUMA-1 trial have maintained ongoing response to axicabtagene ciloleucel, according to an investigator involved in the study.
Median duration of response to axi-cel and median overall survival have not yet been reached, while a recent subset analysis showed that nearly half of patients with certain high-risk characteristics had a durable response, said investigator Sattva S. Neelapu, MD, of the University of Texas MD Anderson Cancer Center, Houston.
Evidence of B-cell recovery and a decrease in detectable, gene-marked CAR T cells have been noted in further follow-up, suggesting that functional CAR T-cell persistence may not be required for long-term remissions, Dr. Neelapu added.
“These data support [the conclusion] that axi-cel induces durable remissions in patients with large B-cell lymphoma who otherwise lack curative options,” Dr. Neelapu said at the Transplantation & Cellular Therapy Meetings.
The update on the phase 1/2 ZUMA-1 study included 108 patients with refractory large B-cell lymphoma who received axi-cel, the CD19-directed autologous chimeric antigen receptor (CAR) T-cell therapy.
In a previously reported 1-year update on the trial, 42% of patients had ongoing responses, Dr. Neelapu said. In the present update, with a median follow-up of 27.1 months, ongoing responses were seen in 39%, most of whom (37%) were in complete response, according to the data presented.
Thirty-three patients in the phase 2 portion of ZUMA-1 were known to have double-expressor or high-grade B-cell lymphoma, according to the investigator. In this high-risk subset, 48% were in ongoing complete response at the 2-year follow-up.
Progression-free survival in ZUMA-1 plateaued at the 6 month-follow-up, according to Dr. Neelapu, who said that plateau has been largely maintained, with just 10 patients progressing since then. Median progression-free survival is 5.9 months and median overall survival has not been reached, with a 24-month overall survival of 51%.
Late-onset serious adverse events mainly consisted of manageable infections, none of which were considered related to axi-cel treatment, according to Dr. Neelapu.
The proportion of ongoing responders with detectable CAR T-cells has decreased over time, from 95% at 3 months to 66% at 24 months, Dr. Neelapu reported. Meanwhile, the proportion of ongoing responders with detectable B cells after axi-cel treatment has gone from 17% to 75%.
More details on the 2-year follow-up data from ZUMA-1 were reported recently in the Lancet Oncology (2019 Jan;20[1]:31-42).
Funding for ZUMA-1 came from Kite and the Leukemia & Lymphoma Society. Dr. Neelapu reported disclosures related to Kite, Celgene, Cellectis, Merck, Poseida, Acerta, Karus, Bristol-Myers Squibb, Novartis, and Unum Therapeutics.
The meeting was held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research. At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).
SOURCE: Neelapu SS et al. TCT 2019, Abstract 82.
HOUSTON – With a median follow-up now exceeding 2 years, 39% of refractory large B-cell lymphoma patients enrolled in the pivotal ZUMA-1 trial have maintained ongoing response to axicabtagene ciloleucel, according to an investigator involved in the study.
Median duration of response to axi-cel and median overall survival have not yet been reached, while a recent subset analysis showed that nearly half of patients with certain high-risk characteristics had a durable response, said investigator Sattva S. Neelapu, MD, of the University of Texas MD Anderson Cancer Center, Houston.
Evidence of B-cell recovery and a decrease in detectable, gene-marked CAR T cells have been noted in further follow-up, suggesting that functional CAR T-cell persistence may not be required for long-term remissions, Dr. Neelapu added.
“These data support [the conclusion] that axi-cel induces durable remissions in patients with large B-cell lymphoma who otherwise lack curative options,” Dr. Neelapu said at the Transplantation & Cellular Therapy Meetings.
The update on the phase 1/2 ZUMA-1 study included 108 patients with refractory large B-cell lymphoma who received axi-cel, the CD19-directed autologous chimeric antigen receptor (CAR) T-cell therapy.
In a previously reported 1-year update on the trial, 42% of patients had ongoing responses, Dr. Neelapu said. In the present update, with a median follow-up of 27.1 months, ongoing responses were seen in 39%, most of whom (37%) were in complete response, according to the data presented.
Thirty-three patients in the phase 2 portion of ZUMA-1 were known to have double-expressor or high-grade B-cell lymphoma, according to the investigator. In this high-risk subset, 48% were in ongoing complete response at the 2-year follow-up.
Progression-free survival in ZUMA-1 plateaued at the 6 month-follow-up, according to Dr. Neelapu, who said that plateau has been largely maintained, with just 10 patients progressing since then. Median progression-free survival is 5.9 months and median overall survival has not been reached, with a 24-month overall survival of 51%.
Late-onset serious adverse events mainly consisted of manageable infections, none of which were considered related to axi-cel treatment, according to Dr. Neelapu.
The proportion of ongoing responders with detectable CAR T-cells has decreased over time, from 95% at 3 months to 66% at 24 months, Dr. Neelapu reported. Meanwhile, the proportion of ongoing responders with detectable B cells after axi-cel treatment has gone from 17% to 75%.
More details on the 2-year follow-up data from ZUMA-1 were reported recently in the Lancet Oncology (2019 Jan;20[1]:31-42).
Funding for ZUMA-1 came from Kite and the Leukemia & Lymphoma Society. Dr. Neelapu reported disclosures related to Kite, Celgene, Cellectis, Merck, Poseida, Acerta, Karus, Bristol-Myers Squibb, Novartis, and Unum Therapeutics.
The meeting was held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research. At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).
SOURCE: Neelapu SS et al. TCT 2019, Abstract 82.
REPORTING FROM TCT 2019
Dual-targeted CAR T shows ‘clinical signal’ in NHL
HOUSTON – A dual-targeted, locally manufactured, anti-CD19/CD20 chimeric antigen receptor (CAR) T-cell therapy was safe and produced ongoing complete responses in a phase 1 study of heavily pretreated non-Hodgkin lymphoma patients, an investigator reported.
The bispecific CAR T-cell product, designed to limit relapses due to loss of target antigen, was produced at the point of care with a 100% success rate for these heavily pretreated patients, the first of whom has now maintained a complete response for 19 months, said Parameswaran Hari, MD, of the Medical College of Wisconsin, Milwaukee.
“So far, this trial has demonstrated safety for this bispecific vector and suggests a clinical signal, with 7 out of 12 patients with ongoing CR, and with minimal toxicity,” Dr. Hari said at the Transplantation & Cellular Therapy Meetings.
“Point of care delivery, we think, allowed patients to have fresh infusion of CAR T cells, with the avoidance of cryopreservation,” added Dr. Hari, who presented the results on behalf of coinvestigators at the Medical College of Wisconsin and Lentigen Technology.
There was no grade 3 or 4 neurotoxicity or cytokine release syndrome among the 12 patients reported to date in the phase 1, dose-escalation trial, and no patient required intensive care, according to Dr. Hari. Grade 1 and 2 neurotoxicity occurred in two and one patients, respectively, while grade 1 and 2 cytokine release syndrome was observed in three patients each.
Among the 12 patients treated to date, the overall response rate was 81% at day 28, Dr. Hari said, noting that of 6 patients treated at the goal dose of 2.5 x 106 cells/kg, 5 remain in ongoing complete remission.
The median age of patients enrolled in the study was 55 years. Six patients had diffuse large B-cell lymphoma, five had mantle cell lymphoma, and two had chronic lymphocytic leukemia. All but one patient underwent fludarabine/cyclophosphamide lymphodepletion prior to receiving the inpatient CAR T-cell infusions, given over the course of 2 days.
Dr. Hari specifically highlighted the mantle cell lymphoma patient subset, noting that four out of five patients were in complete remission at day 28, and remained in ongoing complete remission at times ranging from 1 to 16 months.
With a set manufacturing time of 14 days, production was successful in all 12 patients, and 10 were able to receive fresh product, while 3 received cryopreserved product due to illness-related delays and a holiday, according to the investigators.
“The time to actual delivery of CAR T cell in the patient is actually shortened dramatically,” Dr. Hari said. “We hope to get it down to day 10.”
Local manufacturing can also reduce some costs associated with CAR T-cell production, such as shipping and courier costs, he added.
Taken together, these findings suggest that locally manufactured anti-CD19/CD20 CAR T cells could improve clinical outcomes for patients with relapsed and refractory B-cell NHL, with efficiency through point-of-care delivery, Dr. Hari concluded.
Further studies are planned to evaluate the efficacy of the product and to investigate the mechanism of relapse or progression in patients who experience treatment failure, he said.
Dr. Hari reported disclosures related to Juno, Kite, Spectrum, Janssen, Takeda, Celgene, and BMS. Several study coauthors reported that they were employed by Lentigen Technology, a Miltenyi Biotec Company.
The meeting was held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research. At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).
SOURCE: Shah NN et al. TCT 2019, Abstract 80.
HOUSTON – A dual-targeted, locally manufactured, anti-CD19/CD20 chimeric antigen receptor (CAR) T-cell therapy was safe and produced ongoing complete responses in a phase 1 study of heavily pretreated non-Hodgkin lymphoma patients, an investigator reported.
The bispecific CAR T-cell product, designed to limit relapses due to loss of target antigen, was produced at the point of care with a 100% success rate for these heavily pretreated patients, the first of whom has now maintained a complete response for 19 months, said Parameswaran Hari, MD, of the Medical College of Wisconsin, Milwaukee.
“So far, this trial has demonstrated safety for this bispecific vector and suggests a clinical signal, with 7 out of 12 patients with ongoing CR, and with minimal toxicity,” Dr. Hari said at the Transplantation & Cellular Therapy Meetings.
“Point of care delivery, we think, allowed patients to have fresh infusion of CAR T cells, with the avoidance of cryopreservation,” added Dr. Hari, who presented the results on behalf of coinvestigators at the Medical College of Wisconsin and Lentigen Technology.
There was no grade 3 or 4 neurotoxicity or cytokine release syndrome among the 12 patients reported to date in the phase 1, dose-escalation trial, and no patient required intensive care, according to Dr. Hari. Grade 1 and 2 neurotoxicity occurred in two and one patients, respectively, while grade 1 and 2 cytokine release syndrome was observed in three patients each.
Among the 12 patients treated to date, the overall response rate was 81% at day 28, Dr. Hari said, noting that of 6 patients treated at the goal dose of 2.5 x 106 cells/kg, 5 remain in ongoing complete remission.
The median age of patients enrolled in the study was 55 years. Six patients had diffuse large B-cell lymphoma, five had mantle cell lymphoma, and two had chronic lymphocytic leukemia. All but one patient underwent fludarabine/cyclophosphamide lymphodepletion prior to receiving the inpatient CAR T-cell infusions, given over the course of 2 days.
Dr. Hari specifically highlighted the mantle cell lymphoma patient subset, noting that four out of five patients were in complete remission at day 28, and remained in ongoing complete remission at times ranging from 1 to 16 months.
With a set manufacturing time of 14 days, production was successful in all 12 patients, and 10 were able to receive fresh product, while 3 received cryopreserved product due to illness-related delays and a holiday, according to the investigators.
“The time to actual delivery of CAR T cell in the patient is actually shortened dramatically,” Dr. Hari said. “We hope to get it down to day 10.”
Local manufacturing can also reduce some costs associated with CAR T-cell production, such as shipping and courier costs, he added.
Taken together, these findings suggest that locally manufactured anti-CD19/CD20 CAR T cells could improve clinical outcomes for patients with relapsed and refractory B-cell NHL, with efficiency through point-of-care delivery, Dr. Hari concluded.
Further studies are planned to evaluate the efficacy of the product and to investigate the mechanism of relapse or progression in patients who experience treatment failure, he said.
Dr. Hari reported disclosures related to Juno, Kite, Spectrum, Janssen, Takeda, Celgene, and BMS. Several study coauthors reported that they were employed by Lentigen Technology, a Miltenyi Biotec Company.
The meeting was held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research. At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).
SOURCE: Shah NN et al. TCT 2019, Abstract 80.
HOUSTON – A dual-targeted, locally manufactured, anti-CD19/CD20 chimeric antigen receptor (CAR) T-cell therapy was safe and produced ongoing complete responses in a phase 1 study of heavily pretreated non-Hodgkin lymphoma patients, an investigator reported.
The bispecific CAR T-cell product, designed to limit relapses due to loss of target antigen, was produced at the point of care with a 100% success rate for these heavily pretreated patients, the first of whom has now maintained a complete response for 19 months, said Parameswaran Hari, MD, of the Medical College of Wisconsin, Milwaukee.
“So far, this trial has demonstrated safety for this bispecific vector and suggests a clinical signal, with 7 out of 12 patients with ongoing CR, and with minimal toxicity,” Dr. Hari said at the Transplantation & Cellular Therapy Meetings.
“Point of care delivery, we think, allowed patients to have fresh infusion of CAR T cells, with the avoidance of cryopreservation,” added Dr. Hari, who presented the results on behalf of coinvestigators at the Medical College of Wisconsin and Lentigen Technology.
There was no grade 3 or 4 neurotoxicity or cytokine release syndrome among the 12 patients reported to date in the phase 1, dose-escalation trial, and no patient required intensive care, according to Dr. Hari. Grade 1 and 2 neurotoxicity occurred in two and one patients, respectively, while grade 1 and 2 cytokine release syndrome was observed in three patients each.
Among the 12 patients treated to date, the overall response rate was 81% at day 28, Dr. Hari said, noting that of 6 patients treated at the goal dose of 2.5 x 106 cells/kg, 5 remain in ongoing complete remission.
The median age of patients enrolled in the study was 55 years. Six patients had diffuse large B-cell lymphoma, five had mantle cell lymphoma, and two had chronic lymphocytic leukemia. All but one patient underwent fludarabine/cyclophosphamide lymphodepletion prior to receiving the inpatient CAR T-cell infusions, given over the course of 2 days.
Dr. Hari specifically highlighted the mantle cell lymphoma patient subset, noting that four out of five patients were in complete remission at day 28, and remained in ongoing complete remission at times ranging from 1 to 16 months.
With a set manufacturing time of 14 days, production was successful in all 12 patients, and 10 were able to receive fresh product, while 3 received cryopreserved product due to illness-related delays and a holiday, according to the investigators.
“The time to actual delivery of CAR T cell in the patient is actually shortened dramatically,” Dr. Hari said. “We hope to get it down to day 10.”
Local manufacturing can also reduce some costs associated with CAR T-cell production, such as shipping and courier costs, he added.
Taken together, these findings suggest that locally manufactured anti-CD19/CD20 CAR T cells could improve clinical outcomes for patients with relapsed and refractory B-cell NHL, with efficiency through point-of-care delivery, Dr. Hari concluded.
Further studies are planned to evaluate the efficacy of the product and to investigate the mechanism of relapse or progression in patients who experience treatment failure, he said.
Dr. Hari reported disclosures related to Juno, Kite, Spectrum, Janssen, Takeda, Celgene, and BMS. Several study coauthors reported that they were employed by Lentigen Technology, a Miltenyi Biotec Company.
The meeting was held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research. At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).
SOURCE: Shah NN et al. TCT 2019, Abstract 80.
REPORTING FROM TCT 2019
MRD negativity linked to survival in MM after auto-HCT
HOUSTON – Minimal residual disease (MRD) negativity by multiparameter flow cytometry was linked to survival benefit in multiple myeloma patients undergoing autologous transplantation, according to results of the first U.S.-based study evaluating this endpoint as part of a national randomized clinical trial.
MRD-negative status was prognostic for improved progression-free survival at all time points measured over the course of 1 year post transplant, in this ancillary study of patients in the randomized, 3-arm STAMiNA trial.
Moreover, there was an overall survival benefit for MRD-negative status at 1 year post transplant, investigator Theresa A. Hahn, PhD, of Roswell Park Comprehensive Cancer Center, Buffalo, N.Y., reported at the Transplantation & Cellular Therapy Meetings.
There was no significant difference in rate of conversion to MRD negativity in the arms of the trial, which evaluated several different upfront approaches to autologous hematopoietic stem cell transplantation (HCT).
Assessments of MRD beyond 1 year post transplant may be valuable in future trials, Dr. Hahn said.
“Trials are needed incorporating MRD as an endpoint for treatment decisions to augment, change, or discontinue therapy,” she added.
Results of the ancillary study known as PRIMeR (Prognostic Immunophenotyping for Myeloma Response) included 445 patients from STAMiNA who underwent MRD assessment at baseline, prior to maintenance, and at 1 year post transplantation.
As part of the overall STAMiNA trial, they were randomized to single autologous hematopoietic cell transplantation (HCT); autologous HCT followed by a second autologous HCT (tandem autologous HCT); or single autologous HCT followed by four cycles of consolidation with lenalidomide, bortezomib, and dexamethasone (RVD). All three arms continued on lenalidomide maintenance after those interventions.
Overall results of the STAMiNA trial, previously reported, showed no significant differences in progression-free survival or overall survival among the three transplant strategies (J Clin Oncol. 2019 Jan 17. doi: 10.1200/JCO.18.00685).
In this PRIMeR substudy, by contrast, progression-free survival was significantly increased for patients who were MRD negative at all three time points measured, Dr. Hahn reported, while overall survival was significantly improved based on MRD status measured at the 1-year time point.
The rate of MRD negativity did not differ significantly between arms at baseline or premaintenance time points, Dr. Hahn said. Those rates were 42%, 47%, and 40%, respectively, for the single transplant, tandem transplant, and single transplant plus consolidation arms, while the premaintenance MRD negativity rates were 77%, 83%, and 76%.
At 1 year, MRD negativity rates were significantly different between arms, but only in the intent-to-treat analysis.
Most of the difference was due to an increased rate of MRD negativity in the tandem-transplant arm, compared to a single auto-transplant. However, about 30% of patients in the tandem transplant arm did not receive the therapy, so in the analysis by actual treatment received, the rates of MRD negativity were 81% for single transplant, 90% for tandem transplant, and 85% for single transplant plus consolidation (P = 0.2).
Dr. Hahn said she and her colleagues will be updating their analysis of the PRIMeR study to assess the predictive value of MRD status in patients who were negative at all time points evaluated, versus those who converted to MRD negativity at the 1-year analysis.
The MRD assessments used in this trial have been incorporated into the recently completed BMT CTN 1401 trial and the ongoing BMT CTN 1302 study of allogeneic HCT plus ixazomib in high-risk myeloma, she added.
Dr. Hahn reported research funding from Celgene and the National Institutes of Health.
The meeting was held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research. At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).
SOURCE: Hahn TE et al. TCT 2019, Abstract 6.
HOUSTON – Minimal residual disease (MRD) negativity by multiparameter flow cytometry was linked to survival benefit in multiple myeloma patients undergoing autologous transplantation, according to results of the first U.S.-based study evaluating this endpoint as part of a national randomized clinical trial.
MRD-negative status was prognostic for improved progression-free survival at all time points measured over the course of 1 year post transplant, in this ancillary study of patients in the randomized, 3-arm STAMiNA trial.
Moreover, there was an overall survival benefit for MRD-negative status at 1 year post transplant, investigator Theresa A. Hahn, PhD, of Roswell Park Comprehensive Cancer Center, Buffalo, N.Y., reported at the Transplantation & Cellular Therapy Meetings.
There was no significant difference in rate of conversion to MRD negativity in the arms of the trial, which evaluated several different upfront approaches to autologous hematopoietic stem cell transplantation (HCT).
Assessments of MRD beyond 1 year post transplant may be valuable in future trials, Dr. Hahn said.
“Trials are needed incorporating MRD as an endpoint for treatment decisions to augment, change, or discontinue therapy,” she added.
Results of the ancillary study known as PRIMeR (Prognostic Immunophenotyping for Myeloma Response) included 445 patients from STAMiNA who underwent MRD assessment at baseline, prior to maintenance, and at 1 year post transplantation.
As part of the overall STAMiNA trial, they were randomized to single autologous hematopoietic cell transplantation (HCT); autologous HCT followed by a second autologous HCT (tandem autologous HCT); or single autologous HCT followed by four cycles of consolidation with lenalidomide, bortezomib, and dexamethasone (RVD). All three arms continued on lenalidomide maintenance after those interventions.
Overall results of the STAMiNA trial, previously reported, showed no significant differences in progression-free survival or overall survival among the three transplant strategies (J Clin Oncol. 2019 Jan 17. doi: 10.1200/JCO.18.00685).
In this PRIMeR substudy, by contrast, progression-free survival was significantly increased for patients who were MRD negative at all three time points measured, Dr. Hahn reported, while overall survival was significantly improved based on MRD status measured at the 1-year time point.
The rate of MRD negativity did not differ significantly between arms at baseline or premaintenance time points, Dr. Hahn said. Those rates were 42%, 47%, and 40%, respectively, for the single transplant, tandem transplant, and single transplant plus consolidation arms, while the premaintenance MRD negativity rates were 77%, 83%, and 76%.
At 1 year, MRD negativity rates were significantly different between arms, but only in the intent-to-treat analysis.
Most of the difference was due to an increased rate of MRD negativity in the tandem-transplant arm, compared to a single auto-transplant. However, about 30% of patients in the tandem transplant arm did not receive the therapy, so in the analysis by actual treatment received, the rates of MRD negativity were 81% for single transplant, 90% for tandem transplant, and 85% for single transplant plus consolidation (P = 0.2).
Dr. Hahn said she and her colleagues will be updating their analysis of the PRIMeR study to assess the predictive value of MRD status in patients who were negative at all time points evaluated, versus those who converted to MRD negativity at the 1-year analysis.
The MRD assessments used in this trial have been incorporated into the recently completed BMT CTN 1401 trial and the ongoing BMT CTN 1302 study of allogeneic HCT plus ixazomib in high-risk myeloma, she added.
Dr. Hahn reported research funding from Celgene and the National Institutes of Health.
The meeting was held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research. At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).
SOURCE: Hahn TE et al. TCT 2019, Abstract 6.
HOUSTON – Minimal residual disease (MRD) negativity by multiparameter flow cytometry was linked to survival benefit in multiple myeloma patients undergoing autologous transplantation, according to results of the first U.S.-based study evaluating this endpoint as part of a national randomized clinical trial.
MRD-negative status was prognostic for improved progression-free survival at all time points measured over the course of 1 year post transplant, in this ancillary study of patients in the randomized, 3-arm STAMiNA trial.
Moreover, there was an overall survival benefit for MRD-negative status at 1 year post transplant, investigator Theresa A. Hahn, PhD, of Roswell Park Comprehensive Cancer Center, Buffalo, N.Y., reported at the Transplantation & Cellular Therapy Meetings.
There was no significant difference in rate of conversion to MRD negativity in the arms of the trial, which evaluated several different upfront approaches to autologous hematopoietic stem cell transplantation (HCT).
Assessments of MRD beyond 1 year post transplant may be valuable in future trials, Dr. Hahn said.
“Trials are needed incorporating MRD as an endpoint for treatment decisions to augment, change, or discontinue therapy,” she added.
Results of the ancillary study known as PRIMeR (Prognostic Immunophenotyping for Myeloma Response) included 445 patients from STAMiNA who underwent MRD assessment at baseline, prior to maintenance, and at 1 year post transplantation.
As part of the overall STAMiNA trial, they were randomized to single autologous hematopoietic cell transplantation (HCT); autologous HCT followed by a second autologous HCT (tandem autologous HCT); or single autologous HCT followed by four cycles of consolidation with lenalidomide, bortezomib, and dexamethasone (RVD). All three arms continued on lenalidomide maintenance after those interventions.
Overall results of the STAMiNA trial, previously reported, showed no significant differences in progression-free survival or overall survival among the three transplant strategies (J Clin Oncol. 2019 Jan 17. doi: 10.1200/JCO.18.00685).
In this PRIMeR substudy, by contrast, progression-free survival was significantly increased for patients who were MRD negative at all three time points measured, Dr. Hahn reported, while overall survival was significantly improved based on MRD status measured at the 1-year time point.
The rate of MRD negativity did not differ significantly between arms at baseline or premaintenance time points, Dr. Hahn said. Those rates were 42%, 47%, and 40%, respectively, for the single transplant, tandem transplant, and single transplant plus consolidation arms, while the premaintenance MRD negativity rates were 77%, 83%, and 76%.
At 1 year, MRD negativity rates were significantly different between arms, but only in the intent-to-treat analysis.
Most of the difference was due to an increased rate of MRD negativity in the tandem-transplant arm, compared to a single auto-transplant. However, about 30% of patients in the tandem transplant arm did not receive the therapy, so in the analysis by actual treatment received, the rates of MRD negativity were 81% for single transplant, 90% for tandem transplant, and 85% for single transplant plus consolidation (P = 0.2).
Dr. Hahn said she and her colleagues will be updating their analysis of the PRIMeR study to assess the predictive value of MRD status in patients who were negative at all time points evaluated, versus those who converted to MRD negativity at the 1-year analysis.
The MRD assessments used in this trial have been incorporated into the recently completed BMT CTN 1401 trial and the ongoing BMT CTN 1302 study of allogeneic HCT plus ixazomib in high-risk myeloma, she added.
Dr. Hahn reported research funding from Celgene and the National Institutes of Health.
The meeting was held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research. At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).
SOURCE: Hahn TE et al. TCT 2019, Abstract 6.
REPORTING FROM TCT 2019
Similar results for once- or twice-weekly carfilzomib in MM
Patients with newly diagnosed multiple myeloma have similar outcomes whether they receive carfilzomib once or twice a week, according to a pooled analysis of trial data.
Researchers found no significant difference in safety, progression-free survival (PFS), or overall survival (OS) whether patients received carfilzomib at 70 mg/m2 once a week or 36 mg/m2 twice a week.
Sara Bringhen, MD, PhD, of University of Turin, Italy, and her colleagues conducted this analysis and detailed the results in Haematologica.
The researchers pooled data from a phase 1/2 trial (NCT01857115) and a phase 2 trial (NCT01346787), both enrolling transplant-ineligible patients with newly diagnosed multiple myeloma.
In both studies, induction consisted of nine 4-week cycles of carfilzomib (given once or twice weekly), cyclophosphamide (300 mg on days 1, 8, and 15), and dexamethasone (40 mg on days 1, 8, 15, and 22). After induction, patients received carfilzomib maintenance (at either dose) until progression or intolerable toxicity.
The pooled analysis included 121 patients: 63 who received carfilzomib at 70 mg/m2 once weekly and 58 who received carfilzomib at 36 mg/m2 twice weekly.
There were no significant differences in baseline characteristics between the dosing groups. For the entire cohort, the median age at diagnosis was 72 years (range, 55-86), and the median follow-up was 39 months.
A total of 119 patients started induction (63 in the once-weekly group and 56 in the twice-weekly group), and 90 patients received maintenance (47 and 43, respectively). Patients received maintenance for a median of 17 months in the once-weekly group and 20 months in the twice-weekly group (P = .17).
There was no significant difference between the groups with regard to PFS or OS, either from enrollment or the start of maintenance.
From enrollment, the median PFS was 35.7 months in the once-weekly group and 35.5 months in the twice-weekly group (hazard ratio [HR] = 1.39; P = .26). The 3-year OS was 70% and 72%, respectively (HR = 1.27; P = .5).
From the start of maintenance, the 3-year PFS was 47% in the once-weekly group and 51% in the twice-weekly group (HR = 1.04; P = .92). The 3-year OS was 72% and 73%, respectively (HR = 0.82; P = .71).
There were no significant between-group differences in the rates of grade 3-5 adverse events (AEs) or the need for carfilzomib dose reduction or discontinuation.
Grade 3-5 hematologic AEs occurred in 24% of patients in the once-weekly group and 30% of those in the twice-weekly group. Grade 3-5 nonhematologic AEs occurred in 38% and 41%, respectively.
Twenty-nine percent of patients in the once-weekly group required a reduction in carfilzomib dose, as did 30% of patients in the twice-weekly group. Common AEs leading to dose reduction were acute kidney injury, infections, and hypertension.
AEs leading to carfilzomib discontinuation occurred in 27% of patients in the once-weekly group and 30% of those in the twice-weekly group. Common AEs leading to discontinuation were cardiac injury, infections, and thromboembolism.
Both trials were sponsored by Stichting Hemato-Oncologie voor Volwassenen Nederland in collaboration with Fondazione Neoplasie Sangue ONLUS and supported by funding from Amgen (Onyx Pharmaceuticals). Dr. Bringhen reported relationships with Amgen and other companies. Coauthor Antonio Palumbo, MD, is an employee of Takeda, and other authors reported relationships with a range of companies.
SOURCE: Bringhen S et al. Haematologica. 2019 Feb 7. doi: 10.3324/haematol.2018.208272.
Patients with newly diagnosed multiple myeloma have similar outcomes whether they receive carfilzomib once or twice a week, according to a pooled analysis of trial data.
Researchers found no significant difference in safety, progression-free survival (PFS), or overall survival (OS) whether patients received carfilzomib at 70 mg/m2 once a week or 36 mg/m2 twice a week.
Sara Bringhen, MD, PhD, of University of Turin, Italy, and her colleagues conducted this analysis and detailed the results in Haematologica.
The researchers pooled data from a phase 1/2 trial (NCT01857115) and a phase 2 trial (NCT01346787), both enrolling transplant-ineligible patients with newly diagnosed multiple myeloma.
In both studies, induction consisted of nine 4-week cycles of carfilzomib (given once or twice weekly), cyclophosphamide (300 mg on days 1, 8, and 15), and dexamethasone (40 mg on days 1, 8, 15, and 22). After induction, patients received carfilzomib maintenance (at either dose) until progression or intolerable toxicity.
The pooled analysis included 121 patients: 63 who received carfilzomib at 70 mg/m2 once weekly and 58 who received carfilzomib at 36 mg/m2 twice weekly.
There were no significant differences in baseline characteristics between the dosing groups. For the entire cohort, the median age at diagnosis was 72 years (range, 55-86), and the median follow-up was 39 months.
A total of 119 patients started induction (63 in the once-weekly group and 56 in the twice-weekly group), and 90 patients received maintenance (47 and 43, respectively). Patients received maintenance for a median of 17 months in the once-weekly group and 20 months in the twice-weekly group (P = .17).
There was no significant difference between the groups with regard to PFS or OS, either from enrollment or the start of maintenance.
From enrollment, the median PFS was 35.7 months in the once-weekly group and 35.5 months in the twice-weekly group (hazard ratio [HR] = 1.39; P = .26). The 3-year OS was 70% and 72%, respectively (HR = 1.27; P = .5).
From the start of maintenance, the 3-year PFS was 47% in the once-weekly group and 51% in the twice-weekly group (HR = 1.04; P = .92). The 3-year OS was 72% and 73%, respectively (HR = 0.82; P = .71).
There were no significant between-group differences in the rates of grade 3-5 adverse events (AEs) or the need for carfilzomib dose reduction or discontinuation.
Grade 3-5 hematologic AEs occurred in 24% of patients in the once-weekly group and 30% of those in the twice-weekly group. Grade 3-5 nonhematologic AEs occurred in 38% and 41%, respectively.
Twenty-nine percent of patients in the once-weekly group required a reduction in carfilzomib dose, as did 30% of patients in the twice-weekly group. Common AEs leading to dose reduction were acute kidney injury, infections, and hypertension.
AEs leading to carfilzomib discontinuation occurred in 27% of patients in the once-weekly group and 30% of those in the twice-weekly group. Common AEs leading to discontinuation were cardiac injury, infections, and thromboembolism.
Both trials were sponsored by Stichting Hemato-Oncologie voor Volwassenen Nederland in collaboration with Fondazione Neoplasie Sangue ONLUS and supported by funding from Amgen (Onyx Pharmaceuticals). Dr. Bringhen reported relationships with Amgen and other companies. Coauthor Antonio Palumbo, MD, is an employee of Takeda, and other authors reported relationships with a range of companies.
SOURCE: Bringhen S et al. Haematologica. 2019 Feb 7. doi: 10.3324/haematol.2018.208272.
Patients with newly diagnosed multiple myeloma have similar outcomes whether they receive carfilzomib once or twice a week, according to a pooled analysis of trial data.
Researchers found no significant difference in safety, progression-free survival (PFS), or overall survival (OS) whether patients received carfilzomib at 70 mg/m2 once a week or 36 mg/m2 twice a week.
Sara Bringhen, MD, PhD, of University of Turin, Italy, and her colleagues conducted this analysis and detailed the results in Haematologica.
The researchers pooled data from a phase 1/2 trial (NCT01857115) and a phase 2 trial (NCT01346787), both enrolling transplant-ineligible patients with newly diagnosed multiple myeloma.
In both studies, induction consisted of nine 4-week cycles of carfilzomib (given once or twice weekly), cyclophosphamide (300 mg on days 1, 8, and 15), and dexamethasone (40 mg on days 1, 8, 15, and 22). After induction, patients received carfilzomib maintenance (at either dose) until progression or intolerable toxicity.
The pooled analysis included 121 patients: 63 who received carfilzomib at 70 mg/m2 once weekly and 58 who received carfilzomib at 36 mg/m2 twice weekly.
There were no significant differences in baseline characteristics between the dosing groups. For the entire cohort, the median age at diagnosis was 72 years (range, 55-86), and the median follow-up was 39 months.
A total of 119 patients started induction (63 in the once-weekly group and 56 in the twice-weekly group), and 90 patients received maintenance (47 and 43, respectively). Patients received maintenance for a median of 17 months in the once-weekly group and 20 months in the twice-weekly group (P = .17).
There was no significant difference between the groups with regard to PFS or OS, either from enrollment or the start of maintenance.
From enrollment, the median PFS was 35.7 months in the once-weekly group and 35.5 months in the twice-weekly group (hazard ratio [HR] = 1.39; P = .26). The 3-year OS was 70% and 72%, respectively (HR = 1.27; P = .5).
From the start of maintenance, the 3-year PFS was 47% in the once-weekly group and 51% in the twice-weekly group (HR = 1.04; P = .92). The 3-year OS was 72% and 73%, respectively (HR = 0.82; P = .71).
There were no significant between-group differences in the rates of grade 3-5 adverse events (AEs) or the need for carfilzomib dose reduction or discontinuation.
Grade 3-5 hematologic AEs occurred in 24% of patients in the once-weekly group and 30% of those in the twice-weekly group. Grade 3-5 nonhematologic AEs occurred in 38% and 41%, respectively.
Twenty-nine percent of patients in the once-weekly group required a reduction in carfilzomib dose, as did 30% of patients in the twice-weekly group. Common AEs leading to dose reduction were acute kidney injury, infections, and hypertension.
AEs leading to carfilzomib discontinuation occurred in 27% of patients in the once-weekly group and 30% of those in the twice-weekly group. Common AEs leading to discontinuation were cardiac injury, infections, and thromboembolism.
Both trials were sponsored by Stichting Hemato-Oncologie voor Volwassenen Nederland in collaboration with Fondazione Neoplasie Sangue ONLUS and supported by funding from Amgen (Onyx Pharmaceuticals). Dr. Bringhen reported relationships with Amgen and other companies. Coauthor Antonio Palumbo, MD, is an employee of Takeda, and other authors reported relationships with a range of companies.
SOURCE: Bringhen S et al. Haematologica. 2019 Feb 7. doi: 10.3324/haematol.2018.208272.
FROM HAEMATOLOGICA
Alisertib response rate in PTCL patients was 33%
An open-label randomized phase 3 trial of oral alisertib for relapsed/refractory peripheral T-cell lymphoma (rrPTCL) was terminated in 2015 after it became clear that it was not going to prove significantly superior to options already on the market.
A new report explains what happened. Oral Alisertib was compared to two agents approved for rrPTCL: intravenous pralatrexate (Folotyn) and romidepsin (Istodax), as well as a common off-label option, intravenous gemcitabine (Gemzar). In all, 138 adults were randomized to alisertib 50 mg two times per day on days 1-7, with a median of four 21-day cycles; 133 were randomized to a comparator, the majority to gemcitabine, and again with repeated cycles as tolerated (J Clin Oncol. 2019 Feb 1. doi: 10.1200/JCO.18.00899).
Overall response rate (ORR) was 33% for alisertib versus 45% for the comparator arm (odds ratio, 0.60; 95% confidence interval, 0.33-1.08). Median progression-free survival was 115 days for alisertib versus 104 days for the comparators, a non–statistically significant difference (hazard ratio, 0.87; 95% CI, 0.637-1.178). Median overall survival was 415 days in the alisertib arm versus 367 days in the comparator arm, also not statistically significant (HR, 0.98; 95% CI, 0.707-1.369).
In patients with rrPTCL, alisertib “did not demonstrate superior efficacy over comparators,” concluded investigators led by oncologist Owen A. O’Connor, MD, PhD, of the Columbia University Medical Center, New York.
Another downside to this drug is that it was associated with adverse events in more than half of patients who took it. While 53% of alisertib patients developed anemia and 47% became neutropenic, in the comparator arm, only 34% and 31% developed anemia and neutropenia, respectively. Further, three deaths in the trial were judged to have be related to alisertib. An additional two deaths occurred in this trial; those were judged to have been related to the rival treatments.
Despite alisertib’s less than great results, the story of this drug’s use for rrPTCL may not be over.
There were hints of benefits for rrPCLT, which might play out in a more focused trial, maybe “in a subgroup of patients with PTCL who responded poorly to comparator agents,” perhaps as a last ditch option. There’s also “potential for treatment combinations of alisertib with novel agents,” the investigators said.
The ORR differences were driven mostly by better performance with the approved agents: ORR was 61% with romidepsin and 43% with pralatrexate; however, alisertib’s ORR (33%) was similar to that for gemcitabine (35%) with “the potential benefits of ... oral administration,” the researchers said.
Also, the number of patients who discontinued treatment because of adverse events was higher in the comparator arm (14%) than in the alisertib group (9%), and more comparator patients required dose reductions (33% versus 28%) because of drug side effects.
Alisertib binds to and inhibits Aurora A kinase (AAK), which is essential for mitosis; studies have demonstrated overexpression in PTCL, which supports AAK inhibition as a novel therapeutic strategy. Research on alisertib for other cancer indications continues, including breast and lung cancer and leukemia.
Most of the subjects in both study arms were white, and about two-thirds were men; the median age was 63 years in both arms.
The work was funded by alisertib maker Millennium Pharmaceuticals, a subsidiary of Takeda. Dr. O’Connor and other investigators reported various ties to Millennium and Takeda, including research funding, honoraria, and consulting work. The study included employees of the companies.
SOURCE: O’Connor OA et al. J Clin Oncol. 2019 Feb 1. doi: 10.1200/JCO.18.00899.
An open-label randomized phase 3 trial of oral alisertib for relapsed/refractory peripheral T-cell lymphoma (rrPTCL) was terminated in 2015 after it became clear that it was not going to prove significantly superior to options already on the market.
A new report explains what happened. Oral Alisertib was compared to two agents approved for rrPTCL: intravenous pralatrexate (Folotyn) and romidepsin (Istodax), as well as a common off-label option, intravenous gemcitabine (Gemzar). In all, 138 adults were randomized to alisertib 50 mg two times per day on days 1-7, with a median of four 21-day cycles; 133 were randomized to a comparator, the majority to gemcitabine, and again with repeated cycles as tolerated (J Clin Oncol. 2019 Feb 1. doi: 10.1200/JCO.18.00899).
Overall response rate (ORR) was 33% for alisertib versus 45% for the comparator arm (odds ratio, 0.60; 95% confidence interval, 0.33-1.08). Median progression-free survival was 115 days for alisertib versus 104 days for the comparators, a non–statistically significant difference (hazard ratio, 0.87; 95% CI, 0.637-1.178). Median overall survival was 415 days in the alisertib arm versus 367 days in the comparator arm, also not statistically significant (HR, 0.98; 95% CI, 0.707-1.369).
In patients with rrPTCL, alisertib “did not demonstrate superior efficacy over comparators,” concluded investigators led by oncologist Owen A. O’Connor, MD, PhD, of the Columbia University Medical Center, New York.
Another downside to this drug is that it was associated with adverse events in more than half of patients who took it. While 53% of alisertib patients developed anemia and 47% became neutropenic, in the comparator arm, only 34% and 31% developed anemia and neutropenia, respectively. Further, three deaths in the trial were judged to have be related to alisertib. An additional two deaths occurred in this trial; those were judged to have been related to the rival treatments.
Despite alisertib’s less than great results, the story of this drug’s use for rrPTCL may not be over.
There were hints of benefits for rrPCLT, which might play out in a more focused trial, maybe “in a subgroup of patients with PTCL who responded poorly to comparator agents,” perhaps as a last ditch option. There’s also “potential for treatment combinations of alisertib with novel agents,” the investigators said.
The ORR differences were driven mostly by better performance with the approved agents: ORR was 61% with romidepsin and 43% with pralatrexate; however, alisertib’s ORR (33%) was similar to that for gemcitabine (35%) with “the potential benefits of ... oral administration,” the researchers said.
Also, the number of patients who discontinued treatment because of adverse events was higher in the comparator arm (14%) than in the alisertib group (9%), and more comparator patients required dose reductions (33% versus 28%) because of drug side effects.
Alisertib binds to and inhibits Aurora A kinase (AAK), which is essential for mitosis; studies have demonstrated overexpression in PTCL, which supports AAK inhibition as a novel therapeutic strategy. Research on alisertib for other cancer indications continues, including breast and lung cancer and leukemia.
Most of the subjects in both study arms were white, and about two-thirds were men; the median age was 63 years in both arms.
The work was funded by alisertib maker Millennium Pharmaceuticals, a subsidiary of Takeda. Dr. O’Connor and other investigators reported various ties to Millennium and Takeda, including research funding, honoraria, and consulting work. The study included employees of the companies.
SOURCE: O’Connor OA et al. J Clin Oncol. 2019 Feb 1. doi: 10.1200/JCO.18.00899.
An open-label randomized phase 3 trial of oral alisertib for relapsed/refractory peripheral T-cell lymphoma (rrPTCL) was terminated in 2015 after it became clear that it was not going to prove significantly superior to options already on the market.
A new report explains what happened. Oral Alisertib was compared to two agents approved for rrPTCL: intravenous pralatrexate (Folotyn) and romidepsin (Istodax), as well as a common off-label option, intravenous gemcitabine (Gemzar). In all, 138 adults were randomized to alisertib 50 mg two times per day on days 1-7, with a median of four 21-day cycles; 133 were randomized to a comparator, the majority to gemcitabine, and again with repeated cycles as tolerated (J Clin Oncol. 2019 Feb 1. doi: 10.1200/JCO.18.00899).
Overall response rate (ORR) was 33% for alisertib versus 45% for the comparator arm (odds ratio, 0.60; 95% confidence interval, 0.33-1.08). Median progression-free survival was 115 days for alisertib versus 104 days for the comparators, a non–statistically significant difference (hazard ratio, 0.87; 95% CI, 0.637-1.178). Median overall survival was 415 days in the alisertib arm versus 367 days in the comparator arm, also not statistically significant (HR, 0.98; 95% CI, 0.707-1.369).
In patients with rrPTCL, alisertib “did not demonstrate superior efficacy over comparators,” concluded investigators led by oncologist Owen A. O’Connor, MD, PhD, of the Columbia University Medical Center, New York.
Another downside to this drug is that it was associated with adverse events in more than half of patients who took it. While 53% of alisertib patients developed anemia and 47% became neutropenic, in the comparator arm, only 34% and 31% developed anemia and neutropenia, respectively. Further, three deaths in the trial were judged to have be related to alisertib. An additional two deaths occurred in this trial; those were judged to have been related to the rival treatments.
Despite alisertib’s less than great results, the story of this drug’s use for rrPTCL may not be over.
There were hints of benefits for rrPCLT, which might play out in a more focused trial, maybe “in a subgroup of patients with PTCL who responded poorly to comparator agents,” perhaps as a last ditch option. There’s also “potential for treatment combinations of alisertib with novel agents,” the investigators said.
The ORR differences were driven mostly by better performance with the approved agents: ORR was 61% with romidepsin and 43% with pralatrexate; however, alisertib’s ORR (33%) was similar to that for gemcitabine (35%) with “the potential benefits of ... oral administration,” the researchers said.
Also, the number of patients who discontinued treatment because of adverse events was higher in the comparator arm (14%) than in the alisertib group (9%), and more comparator patients required dose reductions (33% versus 28%) because of drug side effects.
Alisertib binds to and inhibits Aurora A kinase (AAK), which is essential for mitosis; studies have demonstrated overexpression in PTCL, which supports AAK inhibition as a novel therapeutic strategy. Research on alisertib for other cancer indications continues, including breast and lung cancer and leukemia.
Most of the subjects in both study arms were white, and about two-thirds were men; the median age was 63 years in both arms.
The work was funded by alisertib maker Millennium Pharmaceuticals, a subsidiary of Takeda. Dr. O’Connor and other investigators reported various ties to Millennium and Takeda, including research funding, honoraria, and consulting work. The study included employees of the companies.
SOURCE: O’Connor OA et al. J Clin Oncol. 2019 Feb 1. doi: 10.1200/JCO.18.00899.
FROM THE JOURNAL OF CLINICAL ONCOLOGY
Regimen shows promise as salvage for classical HL
A retrospective study suggests a four-drug regimen can be effective salvage therapy for patients with relapsed or refractory classical Hodgkin lymphoma.
The regimen – brentuximab vedotin plus ifosfamide, gemcitabine, and vinorelbine (BV-IGEV) – produced responses in 27 of 28 patients studied, allowing them to undergo autologous hematopoietic stem cell transplant (HSCT).
After HSCT, the estimated 2-year progression-free survival (PFS) was 87.1% and the overall survival (OS) was 73.5%.
Though this study was limited by its small population and retrospective nature, the results “warrant further investigation,” according to Khadega A. Abuelgasim, MD, of King Abdullah International Medical Research Center in Riyadh, Saudi Arabia, and colleagues.
The researchers reported the results in a letter to Bone Marrow Transplantation.
The study included 28 patients with classical Hodgkin lymphoma, 15 of them male. The patients’ median age at HSCT was 25 years (range, 15-49 years). Twenty patients (71%) had constitutional symptoms at diagnosis, and eight (29%) had bulky disease.
Twenty-three patients (82%) received doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) as frontline therapy, and four (14%) received ABVD followed by escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone. One patient received a different frontline regimen.
The median time to relapse was 7.9 months (range, 1.9-133 months), and 12 patients (43%) were refractory to frontline treatment.
Half of patients (n = 14) received BV-IGEV as first salvage. The regimen was given as follows: ifosfamide at 2,000 mg/m2 on days 1-4, gemcitabine at 800 mg/m2 on days 1 and 4, vinorelbine at 20 mg/m2 on day 1, prednisolone at 100 mg on days 1-4, and BV at a dose of 1.8 mg/kg on day 1 of each 3-week IGEV course.
All patients received at least two cycles of BV-IGEV and were assessed for response after one or two cycles. The median follow-up was 17 months (range, 0-65 months).
Twenty patients (71%) had a complete metabolic response to BV-IGEV, seven (25%) had a partial metabolic response, and one patient (4%) had stable disease. The patient with stable disease went on to receive another salvage regimen and achieved a partial response to that regimen.
The most common adverse events during BV-IGEV treatment were grade 3-4 neutropenia (n = 27; 96%) and thrombocytopenia (n = 25; 89%). Febrile neutropenia was also common (n = 16; 57%), as were mucositis (n = 6; 21%) and diarrhea (n = 6; 21%). Six patients had a reduction in BV dose because of an adverse event.
All patients underwent autologous HSCT. They received carmustine, etoposide, cytarabine, and melphalan as conditioning beforehand, and 18 patients (64%) received consolidative BV after transplant.
PFS and OS were calculated from the date of stem cell infusion. The estimated 2-year PFS was 87.1%, and the estimated 2-year OS was 73.5%.
Patients who received BV-IGEV as first salvage fared better than those who received the regimen as second salvage. The PFS rates were 100% and 75%, respectively (P = .0078), and OS rates were 100% and 50%, respectively (P = .08).
Six patients relapsed after HSCT, and three died. Two patients died of progressive disease and one died of pulmonary infection.
These results suggest BV-IGEV can produce high response rates without compromising stem cell mobilization, but the combination should be investigated further, according to the researchers.
The researchers reported having no conflicts of interest.
SOURCE: Abuelgasim KA et al. Bone Marrow Transplant. 2019 Jan 30. doi: 10.1038/s41409-019-0454-z.
A retrospective study suggests a four-drug regimen can be effective salvage therapy for patients with relapsed or refractory classical Hodgkin lymphoma.
The regimen – brentuximab vedotin plus ifosfamide, gemcitabine, and vinorelbine (BV-IGEV) – produced responses in 27 of 28 patients studied, allowing them to undergo autologous hematopoietic stem cell transplant (HSCT).
After HSCT, the estimated 2-year progression-free survival (PFS) was 87.1% and the overall survival (OS) was 73.5%.
Though this study was limited by its small population and retrospective nature, the results “warrant further investigation,” according to Khadega A. Abuelgasim, MD, of King Abdullah International Medical Research Center in Riyadh, Saudi Arabia, and colleagues.
The researchers reported the results in a letter to Bone Marrow Transplantation.
The study included 28 patients with classical Hodgkin lymphoma, 15 of them male. The patients’ median age at HSCT was 25 years (range, 15-49 years). Twenty patients (71%) had constitutional symptoms at diagnosis, and eight (29%) had bulky disease.
Twenty-three patients (82%) received doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) as frontline therapy, and four (14%) received ABVD followed by escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone. One patient received a different frontline regimen.
The median time to relapse was 7.9 months (range, 1.9-133 months), and 12 patients (43%) were refractory to frontline treatment.
Half of patients (n = 14) received BV-IGEV as first salvage. The regimen was given as follows: ifosfamide at 2,000 mg/m2 on days 1-4, gemcitabine at 800 mg/m2 on days 1 and 4, vinorelbine at 20 mg/m2 on day 1, prednisolone at 100 mg on days 1-4, and BV at a dose of 1.8 mg/kg on day 1 of each 3-week IGEV course.
All patients received at least two cycles of BV-IGEV and were assessed for response after one or two cycles. The median follow-up was 17 months (range, 0-65 months).
Twenty patients (71%) had a complete metabolic response to BV-IGEV, seven (25%) had a partial metabolic response, and one patient (4%) had stable disease. The patient with stable disease went on to receive another salvage regimen and achieved a partial response to that regimen.
The most common adverse events during BV-IGEV treatment were grade 3-4 neutropenia (n = 27; 96%) and thrombocytopenia (n = 25; 89%). Febrile neutropenia was also common (n = 16; 57%), as were mucositis (n = 6; 21%) and diarrhea (n = 6; 21%). Six patients had a reduction in BV dose because of an adverse event.
All patients underwent autologous HSCT. They received carmustine, etoposide, cytarabine, and melphalan as conditioning beforehand, and 18 patients (64%) received consolidative BV after transplant.
PFS and OS were calculated from the date of stem cell infusion. The estimated 2-year PFS was 87.1%, and the estimated 2-year OS was 73.5%.
Patients who received BV-IGEV as first salvage fared better than those who received the regimen as second salvage. The PFS rates were 100% and 75%, respectively (P = .0078), and OS rates were 100% and 50%, respectively (P = .08).
Six patients relapsed after HSCT, and three died. Two patients died of progressive disease and one died of pulmonary infection.
These results suggest BV-IGEV can produce high response rates without compromising stem cell mobilization, but the combination should be investigated further, according to the researchers.
The researchers reported having no conflicts of interest.
SOURCE: Abuelgasim KA et al. Bone Marrow Transplant. 2019 Jan 30. doi: 10.1038/s41409-019-0454-z.
A retrospective study suggests a four-drug regimen can be effective salvage therapy for patients with relapsed or refractory classical Hodgkin lymphoma.
The regimen – brentuximab vedotin plus ifosfamide, gemcitabine, and vinorelbine (BV-IGEV) – produced responses in 27 of 28 patients studied, allowing them to undergo autologous hematopoietic stem cell transplant (HSCT).
After HSCT, the estimated 2-year progression-free survival (PFS) was 87.1% and the overall survival (OS) was 73.5%.
Though this study was limited by its small population and retrospective nature, the results “warrant further investigation,” according to Khadega A. Abuelgasim, MD, of King Abdullah International Medical Research Center in Riyadh, Saudi Arabia, and colleagues.
The researchers reported the results in a letter to Bone Marrow Transplantation.
The study included 28 patients with classical Hodgkin lymphoma, 15 of them male. The patients’ median age at HSCT was 25 years (range, 15-49 years). Twenty patients (71%) had constitutional symptoms at diagnosis, and eight (29%) had bulky disease.
Twenty-three patients (82%) received doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) as frontline therapy, and four (14%) received ABVD followed by escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone. One patient received a different frontline regimen.
The median time to relapse was 7.9 months (range, 1.9-133 months), and 12 patients (43%) were refractory to frontline treatment.
Half of patients (n = 14) received BV-IGEV as first salvage. The regimen was given as follows: ifosfamide at 2,000 mg/m2 on days 1-4, gemcitabine at 800 mg/m2 on days 1 and 4, vinorelbine at 20 mg/m2 on day 1, prednisolone at 100 mg on days 1-4, and BV at a dose of 1.8 mg/kg on day 1 of each 3-week IGEV course.
All patients received at least two cycles of BV-IGEV and were assessed for response after one or two cycles. The median follow-up was 17 months (range, 0-65 months).
Twenty patients (71%) had a complete metabolic response to BV-IGEV, seven (25%) had a partial metabolic response, and one patient (4%) had stable disease. The patient with stable disease went on to receive another salvage regimen and achieved a partial response to that regimen.
The most common adverse events during BV-IGEV treatment were grade 3-4 neutropenia (n = 27; 96%) and thrombocytopenia (n = 25; 89%). Febrile neutropenia was also common (n = 16; 57%), as were mucositis (n = 6; 21%) and diarrhea (n = 6; 21%). Six patients had a reduction in BV dose because of an adverse event.
All patients underwent autologous HSCT. They received carmustine, etoposide, cytarabine, and melphalan as conditioning beforehand, and 18 patients (64%) received consolidative BV after transplant.
PFS and OS were calculated from the date of stem cell infusion. The estimated 2-year PFS was 87.1%, and the estimated 2-year OS was 73.5%.
Patients who received BV-IGEV as first salvage fared better than those who received the regimen as second salvage. The PFS rates were 100% and 75%, respectively (P = .0078), and OS rates were 100% and 50%, respectively (P = .08).
Six patients relapsed after HSCT, and three died. Two patients died of progressive disease and one died of pulmonary infection.
These results suggest BV-IGEV can produce high response rates without compromising stem cell mobilization, but the combination should be investigated further, according to the researchers.
The researchers reported having no conflicts of interest.
SOURCE: Abuelgasim KA et al. Bone Marrow Transplant. 2019 Jan 30. doi: 10.1038/s41409-019-0454-z.
FROM BONE MARROW TRANSPLANTATION
Haplo-HCT shows viability in DLBCL
For patients with diffuse large B-cell lymphoma (DLBCL) who need allogeneic hematopoietic cell transplantation (allo-HCT), a haploidentical family member could be a viable donor, according to a retrospective study of 1,438 patients.
When combined with nonmyeloablative/reduced intensity conditioning (NMC/RIC) and posttransplant cyclophosphamide (PTCy), patients treated with haploidentical HCT (haplo-HCT) had outcomes similar to those seen in patients with matched donors, reported Peter Dreger, MD, of the University of Heidelberg (Germany) and his colleagues.
“Using well-matched sibling donors (MSDs) or unrelated donors (MUDs), allo-HCT can result in sustained disease control in 30% to 45% of patients with DLBCL who have early disease recurrence after standard chemoimmunotherapy or have failed auto-HCT [autologous HCT],” the investigators wrote in Blood Advances. “However, the search for a well-matched unrelated donor could be time-consuming and unsuccessful in up to 50% of the patients in need.”
But the present findings suggest that haplo-HCT may one day improve these odds by providing a larger pool of potential donors.
The patients in the study were divided into four treatment groups: haplo-HCT (n = 132), MSD (n = 525), MUD with T-cell depletion (n = 403), and MUD without T-cell depletion (n = 378). For graft-versus-host disease (GVHD) prophylaxis, patients in the haplo-HCT group received PTCy, with or without a calcineurin inhibitor and mycophenolate mofetil, whereas all patients with matched donors received a calcineurin inhibitor. T-cell depletion was accomplished by in vivo antithymocyte globulin and alemtuzumab.
The primary end point was overall survival (OS). Secondary end points were progression-free survival (PFS), progression/relapse, and nonrelapse mortality (NRM).
After a median follow-up of 4.1 years, all groups had similar outcomes, without statistical differences in multivariable analysis.
In the haplo-HCT group, the 3-year OS rate was 46%, the NRM rate was 22%, the PFS rate was 38%, and the relapse/progression rate was 41%.
Of note, patients receiving haplo-HCT did have a lower cumulative incidence of chronic GVHD, at 15% after 1 year and 18% after 2 years. These rates were significantly lower than the other groups’ 1- and 2-year GVHD rates, which were as follows: MSD, 41% and 48%; MUD with T-cell depletion, 23% and 27%; and MUD without T-cell depletion, 48% and 57%.
The investigators noted that these disparities may actually be caused by the use of bone marrow grafts in the haplo-HCT group instead of peripheral blood grafts, which were used in most of the patients in the other groups.
Overall, the findings were encouraging, but the investigators cautioned that “additional studies are needed before haploidentical donors can be considered as equivalent to well-matched related or unrelated donors in patients with DLBCL.”
The study was funded by the Center for International Blood & Marrow Transplant Research (CIBMTR) and the European Society for Blood and Marrow Transplantation. CIBMTR is supported by grants from the U.S. government and the pharmaceutical industry. The authors reported having no competing financial interests.
SOURCE: Dreger P et al. Blood Adv. 2019 Feb 12;3(3):360-9.
For patients with diffuse large B-cell lymphoma (DLBCL) who need allogeneic hematopoietic cell transplantation (allo-HCT), a haploidentical family member could be a viable donor, according to a retrospective study of 1,438 patients.
When combined with nonmyeloablative/reduced intensity conditioning (NMC/RIC) and posttransplant cyclophosphamide (PTCy), patients treated with haploidentical HCT (haplo-HCT) had outcomes similar to those seen in patients with matched donors, reported Peter Dreger, MD, of the University of Heidelberg (Germany) and his colleagues.
“Using well-matched sibling donors (MSDs) or unrelated donors (MUDs), allo-HCT can result in sustained disease control in 30% to 45% of patients with DLBCL who have early disease recurrence after standard chemoimmunotherapy or have failed auto-HCT [autologous HCT],” the investigators wrote in Blood Advances. “However, the search for a well-matched unrelated donor could be time-consuming and unsuccessful in up to 50% of the patients in need.”
But the present findings suggest that haplo-HCT may one day improve these odds by providing a larger pool of potential donors.
The patients in the study were divided into four treatment groups: haplo-HCT (n = 132), MSD (n = 525), MUD with T-cell depletion (n = 403), and MUD without T-cell depletion (n = 378). For graft-versus-host disease (GVHD) prophylaxis, patients in the haplo-HCT group received PTCy, with or without a calcineurin inhibitor and mycophenolate mofetil, whereas all patients with matched donors received a calcineurin inhibitor. T-cell depletion was accomplished by in vivo antithymocyte globulin and alemtuzumab.
The primary end point was overall survival (OS). Secondary end points were progression-free survival (PFS), progression/relapse, and nonrelapse mortality (NRM).
After a median follow-up of 4.1 years, all groups had similar outcomes, without statistical differences in multivariable analysis.
In the haplo-HCT group, the 3-year OS rate was 46%, the NRM rate was 22%, the PFS rate was 38%, and the relapse/progression rate was 41%.
Of note, patients receiving haplo-HCT did have a lower cumulative incidence of chronic GVHD, at 15% after 1 year and 18% after 2 years. These rates were significantly lower than the other groups’ 1- and 2-year GVHD rates, which were as follows: MSD, 41% and 48%; MUD with T-cell depletion, 23% and 27%; and MUD without T-cell depletion, 48% and 57%.
The investigators noted that these disparities may actually be caused by the use of bone marrow grafts in the haplo-HCT group instead of peripheral blood grafts, which were used in most of the patients in the other groups.
Overall, the findings were encouraging, but the investigators cautioned that “additional studies are needed before haploidentical donors can be considered as equivalent to well-matched related or unrelated donors in patients with DLBCL.”
The study was funded by the Center for International Blood & Marrow Transplant Research (CIBMTR) and the European Society for Blood and Marrow Transplantation. CIBMTR is supported by grants from the U.S. government and the pharmaceutical industry. The authors reported having no competing financial interests.
SOURCE: Dreger P et al. Blood Adv. 2019 Feb 12;3(3):360-9.
For patients with diffuse large B-cell lymphoma (DLBCL) who need allogeneic hematopoietic cell transplantation (allo-HCT), a haploidentical family member could be a viable donor, according to a retrospective study of 1,438 patients.
When combined with nonmyeloablative/reduced intensity conditioning (NMC/RIC) and posttransplant cyclophosphamide (PTCy), patients treated with haploidentical HCT (haplo-HCT) had outcomes similar to those seen in patients with matched donors, reported Peter Dreger, MD, of the University of Heidelberg (Germany) and his colleagues.
“Using well-matched sibling donors (MSDs) or unrelated donors (MUDs), allo-HCT can result in sustained disease control in 30% to 45% of patients with DLBCL who have early disease recurrence after standard chemoimmunotherapy or have failed auto-HCT [autologous HCT],” the investigators wrote in Blood Advances. “However, the search for a well-matched unrelated donor could be time-consuming and unsuccessful in up to 50% of the patients in need.”
But the present findings suggest that haplo-HCT may one day improve these odds by providing a larger pool of potential donors.
The patients in the study were divided into four treatment groups: haplo-HCT (n = 132), MSD (n = 525), MUD with T-cell depletion (n = 403), and MUD without T-cell depletion (n = 378). For graft-versus-host disease (GVHD) prophylaxis, patients in the haplo-HCT group received PTCy, with or without a calcineurin inhibitor and mycophenolate mofetil, whereas all patients with matched donors received a calcineurin inhibitor. T-cell depletion was accomplished by in vivo antithymocyte globulin and alemtuzumab.
The primary end point was overall survival (OS). Secondary end points were progression-free survival (PFS), progression/relapse, and nonrelapse mortality (NRM).
After a median follow-up of 4.1 years, all groups had similar outcomes, without statistical differences in multivariable analysis.
In the haplo-HCT group, the 3-year OS rate was 46%, the NRM rate was 22%, the PFS rate was 38%, and the relapse/progression rate was 41%.
Of note, patients receiving haplo-HCT did have a lower cumulative incidence of chronic GVHD, at 15% after 1 year and 18% after 2 years. These rates were significantly lower than the other groups’ 1- and 2-year GVHD rates, which were as follows: MSD, 41% and 48%; MUD with T-cell depletion, 23% and 27%; and MUD without T-cell depletion, 48% and 57%.
The investigators noted that these disparities may actually be caused by the use of bone marrow grafts in the haplo-HCT group instead of peripheral blood grafts, which were used in most of the patients in the other groups.
Overall, the findings were encouraging, but the investigators cautioned that “additional studies are needed before haploidentical donors can be considered as equivalent to well-matched related or unrelated donors in patients with DLBCL.”
The study was funded by the Center for International Blood & Marrow Transplant Research (CIBMTR) and the European Society for Blood and Marrow Transplantation. CIBMTR is supported by grants from the U.S. government and the pharmaceutical industry. The authors reported having no competing financial interests.
SOURCE: Dreger P et al. Blood Adv. 2019 Feb 12;3(3):360-9.
FROM BLOOD ADVANCES
FDA grants priority review to polatuzumab vedotin for DLBCL
With this BLA, Genentech is seeking approval for polatuzumab vedotin in combination with bendamustine and rituximab (BR) to treat patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL).
The FDA grants priority review to applications for products that are expected to provide significant improvements in the treatment, diagnosis, or prevention of serious conditions. The agency aims to take action on a priority review application within 6 months, rather than the standard 10 months.
The FDA is expected to make a decision on this BLA by Aug. 19, 2019.
The BLA is supported by a phase 1b/2 trial (NCT02257567) of patients with relapsed or refractory follicular lymphoma or DLBCL who received polatuzumab vedotin in combination with BR or obinutuzumab.
The trial’s phase 2 stage included 80 DLBCL patients who were randomized to receive BR or BR plus polatuzumab vedotin, according to Genentech.
The complete response rate was 40% in the polatuzumab vedotin arm and 18% in the BR arm. The median duration of response was 10.3 months and 4.1 months, respectively (hazard ratio [HR] = 0.44).
The median progression-free survival was 7.6 months in the polatuzumab vedotin arm and 2.0 months in the BR arm (HR = 0.34).
Among patients who were ineligible for a transplant, the median overall survival (an exploratory endpoint) was 12.4 months in the polatuzumab vedotin arm and 4.7 months in the BR arm (HR = 0.42).
Patients who received polatuzumab vedotin had higher rates of grade 3-4 cytopenias, compared with patients who received BR alone. Rates of infection and transfusion were similar between the arms.
With this BLA, Genentech is seeking approval for polatuzumab vedotin in combination with bendamustine and rituximab (BR) to treat patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL).
The FDA grants priority review to applications for products that are expected to provide significant improvements in the treatment, diagnosis, or prevention of serious conditions. The agency aims to take action on a priority review application within 6 months, rather than the standard 10 months.
The FDA is expected to make a decision on this BLA by Aug. 19, 2019.
The BLA is supported by a phase 1b/2 trial (NCT02257567) of patients with relapsed or refractory follicular lymphoma or DLBCL who received polatuzumab vedotin in combination with BR or obinutuzumab.
The trial’s phase 2 stage included 80 DLBCL patients who were randomized to receive BR or BR plus polatuzumab vedotin, according to Genentech.
The complete response rate was 40% in the polatuzumab vedotin arm and 18% in the BR arm. The median duration of response was 10.3 months and 4.1 months, respectively (hazard ratio [HR] = 0.44).
The median progression-free survival was 7.6 months in the polatuzumab vedotin arm and 2.0 months in the BR arm (HR = 0.34).
Among patients who were ineligible for a transplant, the median overall survival (an exploratory endpoint) was 12.4 months in the polatuzumab vedotin arm and 4.7 months in the BR arm (HR = 0.42).
Patients who received polatuzumab vedotin had higher rates of grade 3-4 cytopenias, compared with patients who received BR alone. Rates of infection and transfusion were similar between the arms.
With this BLA, Genentech is seeking approval for polatuzumab vedotin in combination with bendamustine and rituximab (BR) to treat patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL).
The FDA grants priority review to applications for products that are expected to provide significant improvements in the treatment, diagnosis, or prevention of serious conditions. The agency aims to take action on a priority review application within 6 months, rather than the standard 10 months.
The FDA is expected to make a decision on this BLA by Aug. 19, 2019.
The BLA is supported by a phase 1b/2 trial (NCT02257567) of patients with relapsed or refractory follicular lymphoma or DLBCL who received polatuzumab vedotin in combination with BR or obinutuzumab.
The trial’s phase 2 stage included 80 DLBCL patients who were randomized to receive BR or BR plus polatuzumab vedotin, according to Genentech.
The complete response rate was 40% in the polatuzumab vedotin arm and 18% in the BR arm. The median duration of response was 10.3 months and 4.1 months, respectively (hazard ratio [HR] = 0.44).
The median progression-free survival was 7.6 months in the polatuzumab vedotin arm and 2.0 months in the BR arm (HR = 0.34).
Among patients who were ineligible for a transplant, the median overall survival (an exploratory endpoint) was 12.4 months in the polatuzumab vedotin arm and 4.7 months in the BR arm (HR = 0.42).
Patients who received polatuzumab vedotin had higher rates of grade 3-4 cytopenias, compared with patients who received BR alone. Rates of infection and transfusion were similar between the arms.
Researchers characterize new subtype of high-grade DLBCL
(DLBCL)
Patients with this subtype, dubbed “molecular high-grade” (MHG) DLBCL, were more likely to have germinal center B-cell-like (GCB) DLBCL, MYC rearrangements, and double-hit lymphoma.
When compared to other DLBCL patients, those with MHG DLBCL had inferior progression-free and overall survival.
Chulin Sha, PhD, of the University of Leeds (England), and colleagues reported these findings in the Journal of Clinical Oncology. The findings were published alongside a related editorial and a similar study from another group.
Dr. Sha and colleagues began their study by applying a previously developed gene expression classifier (Genome Med. 2015 Jul 1;7[1]:64) to 928 DLBCL patients enrolled in the REMoDL-B trial. REMoDL-B was designed to compare rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) to R-CHOP plus bortezomib (Hematol Oncol. 2017;35:130-1).
Dr. Sha and colleagues looked for somatic mutations in 400 REMoDL-B patient samples that were sequenced for a 70-gene panel.
The team also tested 360 samples for MYC, BCL2, and BCL6 chromosomal rearrangements using fluorescent in situ hybridization, and they tested 355 samples for MYC and BCL2 protein expression with immunohistochemistry.
Characteristics of MHG DLBCL
The researchers identified 83 REMoDL-B patients as having MHG DLBCL (9%). Most of the MHG patients had GCB DLBCL (90%), 48.6% had MYC rearrangements, and 36.1% had double-hit lymphoma.
Patients with MHG DLBCL had higher International Prognostic Index scores (P = .004), greater tumor bulk (P = .007), higher disease stage (P = .06), and higher lactate dehydrogenase levels (P less than .001) than patients with non-MHG DLBCL.
Although most MHG patients had GCB DLBCL, the researchers found key differences between patients with MHG DLBCL and non-MHG GCB DLBCL. MHG patients were significantly more likely than patients with non-MHG GCB DLBCL to have mutations in KMT2D, BCL2, MYC, and DDX3X. Additionally, some genes frequently mutated in GCB DLBCL — such as B2M, SGK1, and NFKBIA — were rare in MHG DLBCL.
Dr. Sha and colleagues also compared the MHG patients to 70 patients with Burkitt lymphoma (BL) who had been analyzed in a previous study (Genome Med. 2015 Jul 1;7[1]:64).
The researchers found that BL has more upregulated genes than GCB (2,483 genes) and MHG DLBCL (1,784 genes), and MHG DLBCL has more upregulated genes than GCB DLBCL (382 genes). The team observed a similar pattern with downregulated genes and said this suggests “MHG is an intermediate group but closer to GCB than to BL.”
The researchers also found, however, that “MHG and BL share high expression of signatures that contain cell-cycle genes, ribosome biogenesis, MYC overexpression, and TCF3 targets, which suggests a shared proliferative phenotype.”
The team determined that MHG has “a highly proliferative phenotype and shares features with centroblasts of the germinal center dark zone.”
Another discovery was that MHG patients in the REMoDL-B trial had worse progression-free survival (PFS) than their peers.
Among patients who received R-CHOP, the estimated 3-year PFS was:
- 37% for MHG patients
- 78% for patients with GCB DLBCL
- 64% for patients with activated B-cell like (ABC) DLBCL
- 65% for patients with unclassified DLBCL.
Among patients who received bortezomib plus R-CHOP, there was a trend toward improved PFS for patients with MHG DLBCL (58%; P = .08).
Validation cohort
Dr. Sha and colleagues validated their initial findings using RNA sequencing data from another group of DLBCL patients (Cell. 2017 Oct 5;171[2]:481-94.e15). This data set included 624 patients who received rituximab-based therapy.
Seventy-two patients in this group had MHG DLBCL (11.5%), and most MHG patients had GCB DLBCL (82%).
The researchers said the MHG group in this cohort “showed similar associations with clinical variables” and a “similar mutation spectrum” as the MHG group in the REMoDL-B cohort. Additionally, MHG patients in the validation cohort had inferior overall survival (P less than .001) compared to patients with non-MHG GCB DLBCL.
Dr. Sha and colleagues said the poor prognosis in MHG patients in both cohorts suggests a need for different treatment approaches in this group.
In the related editorial, Wing C. Chan, MD, of City of Hope Medical Center in Duarte, Calif., echoed that sentiment and said it will be important to include patients with high-risk DLBCL in clinical trials.
“Their tumors should be comprehensively characterize[d] for correlative analysis to determine the molecular lesions that underlie their biology and response to treatment,” Dr. Chan wrote.
Dr. Chan disclosed a patent for a diagnostic algorithm on GCB/ABC-type DLBCL and a patent on a diagnostic algorithm for peripheral T-cell lymphoma.
Dr. Sha and colleagues disclosed relationships with a range of pharmaceutical companies. The team’s research was supported by a grant from Bloodwise.
The REMoDL-B trial was endorsed by Cancer Research UK and was funded by Janssen-Cillag.
SOURCES: Sha C et al. J Clin Oncol. 2019 Jan 20;37(3):202-12. doi: 10.1200/JCO.18.01314; Chan WC. J Clin Oncol. 2019 Jan 20;37(3):175-7. doi: 10.1200/JCO.18.01910; Ennishi D et al. J Clin Oncol. 2019 Jan 20;37(3):190-201. doi: 10.1200/JCO.18.01583
(DLBCL)
Patients with this subtype, dubbed “molecular high-grade” (MHG) DLBCL, were more likely to have germinal center B-cell-like (GCB) DLBCL, MYC rearrangements, and double-hit lymphoma.
When compared to other DLBCL patients, those with MHG DLBCL had inferior progression-free and overall survival.
Chulin Sha, PhD, of the University of Leeds (England), and colleagues reported these findings in the Journal of Clinical Oncology. The findings were published alongside a related editorial and a similar study from another group.
Dr. Sha and colleagues began their study by applying a previously developed gene expression classifier (Genome Med. 2015 Jul 1;7[1]:64) to 928 DLBCL patients enrolled in the REMoDL-B trial. REMoDL-B was designed to compare rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) to R-CHOP plus bortezomib (Hematol Oncol. 2017;35:130-1).
Dr. Sha and colleagues looked for somatic mutations in 400 REMoDL-B patient samples that were sequenced for a 70-gene panel.
The team also tested 360 samples for MYC, BCL2, and BCL6 chromosomal rearrangements using fluorescent in situ hybridization, and they tested 355 samples for MYC and BCL2 protein expression with immunohistochemistry.
Characteristics of MHG DLBCL
The researchers identified 83 REMoDL-B patients as having MHG DLBCL (9%). Most of the MHG patients had GCB DLBCL (90%), 48.6% had MYC rearrangements, and 36.1% had double-hit lymphoma.
Patients with MHG DLBCL had higher International Prognostic Index scores (P = .004), greater tumor bulk (P = .007), higher disease stage (P = .06), and higher lactate dehydrogenase levels (P less than .001) than patients with non-MHG DLBCL.
Although most MHG patients had GCB DLBCL, the researchers found key differences between patients with MHG DLBCL and non-MHG GCB DLBCL. MHG patients were significantly more likely than patients with non-MHG GCB DLBCL to have mutations in KMT2D, BCL2, MYC, and DDX3X. Additionally, some genes frequently mutated in GCB DLBCL — such as B2M, SGK1, and NFKBIA — were rare in MHG DLBCL.
Dr. Sha and colleagues also compared the MHG patients to 70 patients with Burkitt lymphoma (BL) who had been analyzed in a previous study (Genome Med. 2015 Jul 1;7[1]:64).
The researchers found that BL has more upregulated genes than GCB (2,483 genes) and MHG DLBCL (1,784 genes), and MHG DLBCL has more upregulated genes than GCB DLBCL (382 genes). The team observed a similar pattern with downregulated genes and said this suggests “MHG is an intermediate group but closer to GCB than to BL.”
The researchers also found, however, that “MHG and BL share high expression of signatures that contain cell-cycle genes, ribosome biogenesis, MYC overexpression, and TCF3 targets, which suggests a shared proliferative phenotype.”
The team determined that MHG has “a highly proliferative phenotype and shares features with centroblasts of the germinal center dark zone.”
Another discovery was that MHG patients in the REMoDL-B trial had worse progression-free survival (PFS) than their peers.
Among patients who received R-CHOP, the estimated 3-year PFS was:
- 37% for MHG patients
- 78% for patients with GCB DLBCL
- 64% for patients with activated B-cell like (ABC) DLBCL
- 65% for patients with unclassified DLBCL.
Among patients who received bortezomib plus R-CHOP, there was a trend toward improved PFS for patients with MHG DLBCL (58%; P = .08).
Validation cohort
Dr. Sha and colleagues validated their initial findings using RNA sequencing data from another group of DLBCL patients (Cell. 2017 Oct 5;171[2]:481-94.e15). This data set included 624 patients who received rituximab-based therapy.
Seventy-two patients in this group had MHG DLBCL (11.5%), and most MHG patients had GCB DLBCL (82%).
The researchers said the MHG group in this cohort “showed similar associations with clinical variables” and a “similar mutation spectrum” as the MHG group in the REMoDL-B cohort. Additionally, MHG patients in the validation cohort had inferior overall survival (P less than .001) compared to patients with non-MHG GCB DLBCL.
Dr. Sha and colleagues said the poor prognosis in MHG patients in both cohorts suggests a need for different treatment approaches in this group.
In the related editorial, Wing C. Chan, MD, of City of Hope Medical Center in Duarte, Calif., echoed that sentiment and said it will be important to include patients with high-risk DLBCL in clinical trials.
“Their tumors should be comprehensively characterize[d] for correlative analysis to determine the molecular lesions that underlie their biology and response to treatment,” Dr. Chan wrote.
Dr. Chan disclosed a patent for a diagnostic algorithm on GCB/ABC-type DLBCL and a patent on a diagnostic algorithm for peripheral T-cell lymphoma.
Dr. Sha and colleagues disclosed relationships with a range of pharmaceutical companies. The team’s research was supported by a grant from Bloodwise.
The REMoDL-B trial was endorsed by Cancer Research UK and was funded by Janssen-Cillag.
SOURCES: Sha C et al. J Clin Oncol. 2019 Jan 20;37(3):202-12. doi: 10.1200/JCO.18.01314; Chan WC. J Clin Oncol. 2019 Jan 20;37(3):175-7. doi: 10.1200/JCO.18.01910; Ennishi D et al. J Clin Oncol. 2019 Jan 20;37(3):190-201. doi: 10.1200/JCO.18.01583
(DLBCL)
Patients with this subtype, dubbed “molecular high-grade” (MHG) DLBCL, were more likely to have germinal center B-cell-like (GCB) DLBCL, MYC rearrangements, and double-hit lymphoma.
When compared to other DLBCL patients, those with MHG DLBCL had inferior progression-free and overall survival.
Chulin Sha, PhD, of the University of Leeds (England), and colleagues reported these findings in the Journal of Clinical Oncology. The findings were published alongside a related editorial and a similar study from another group.
Dr. Sha and colleagues began their study by applying a previously developed gene expression classifier (Genome Med. 2015 Jul 1;7[1]:64) to 928 DLBCL patients enrolled in the REMoDL-B trial. REMoDL-B was designed to compare rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) to R-CHOP plus bortezomib (Hematol Oncol. 2017;35:130-1).
Dr. Sha and colleagues looked for somatic mutations in 400 REMoDL-B patient samples that were sequenced for a 70-gene panel.
The team also tested 360 samples for MYC, BCL2, and BCL6 chromosomal rearrangements using fluorescent in situ hybridization, and they tested 355 samples for MYC and BCL2 protein expression with immunohistochemistry.
Characteristics of MHG DLBCL
The researchers identified 83 REMoDL-B patients as having MHG DLBCL (9%). Most of the MHG patients had GCB DLBCL (90%), 48.6% had MYC rearrangements, and 36.1% had double-hit lymphoma.
Patients with MHG DLBCL had higher International Prognostic Index scores (P = .004), greater tumor bulk (P = .007), higher disease stage (P = .06), and higher lactate dehydrogenase levels (P less than .001) than patients with non-MHG DLBCL.
Although most MHG patients had GCB DLBCL, the researchers found key differences between patients with MHG DLBCL and non-MHG GCB DLBCL. MHG patients were significantly more likely than patients with non-MHG GCB DLBCL to have mutations in KMT2D, BCL2, MYC, and DDX3X. Additionally, some genes frequently mutated in GCB DLBCL — such as B2M, SGK1, and NFKBIA — were rare in MHG DLBCL.
Dr. Sha and colleagues also compared the MHG patients to 70 patients with Burkitt lymphoma (BL) who had been analyzed in a previous study (Genome Med. 2015 Jul 1;7[1]:64).
The researchers found that BL has more upregulated genes than GCB (2,483 genes) and MHG DLBCL (1,784 genes), and MHG DLBCL has more upregulated genes than GCB DLBCL (382 genes). The team observed a similar pattern with downregulated genes and said this suggests “MHG is an intermediate group but closer to GCB than to BL.”
The researchers also found, however, that “MHG and BL share high expression of signatures that contain cell-cycle genes, ribosome biogenesis, MYC overexpression, and TCF3 targets, which suggests a shared proliferative phenotype.”
The team determined that MHG has “a highly proliferative phenotype and shares features with centroblasts of the germinal center dark zone.”
Another discovery was that MHG patients in the REMoDL-B trial had worse progression-free survival (PFS) than their peers.
Among patients who received R-CHOP, the estimated 3-year PFS was:
- 37% for MHG patients
- 78% for patients with GCB DLBCL
- 64% for patients with activated B-cell like (ABC) DLBCL
- 65% for patients with unclassified DLBCL.
Among patients who received bortezomib plus R-CHOP, there was a trend toward improved PFS for patients with MHG DLBCL (58%; P = .08).
Validation cohort
Dr. Sha and colleagues validated their initial findings using RNA sequencing data from another group of DLBCL patients (Cell. 2017 Oct 5;171[2]:481-94.e15). This data set included 624 patients who received rituximab-based therapy.
Seventy-two patients in this group had MHG DLBCL (11.5%), and most MHG patients had GCB DLBCL (82%).
The researchers said the MHG group in this cohort “showed similar associations with clinical variables” and a “similar mutation spectrum” as the MHG group in the REMoDL-B cohort. Additionally, MHG patients in the validation cohort had inferior overall survival (P less than .001) compared to patients with non-MHG GCB DLBCL.
Dr. Sha and colleagues said the poor prognosis in MHG patients in both cohorts suggests a need for different treatment approaches in this group.
In the related editorial, Wing C. Chan, MD, of City of Hope Medical Center in Duarte, Calif., echoed that sentiment and said it will be important to include patients with high-risk DLBCL in clinical trials.
“Their tumors should be comprehensively characterize[d] for correlative analysis to determine the molecular lesions that underlie their biology and response to treatment,” Dr. Chan wrote.
Dr. Chan disclosed a patent for a diagnostic algorithm on GCB/ABC-type DLBCL and a patent on a diagnostic algorithm for peripheral T-cell lymphoma.
Dr. Sha and colleagues disclosed relationships with a range of pharmaceutical companies. The team’s research was supported by a grant from Bloodwise.
The REMoDL-B trial was endorsed by Cancer Research UK and was funded by Janssen-Cillag.
SOURCES: Sha C et al. J Clin Oncol. 2019 Jan 20;37(3):202-12. doi: 10.1200/JCO.18.01314; Chan WC. J Clin Oncol. 2019 Jan 20;37(3):175-7. doi: 10.1200/JCO.18.01910; Ennishi D et al. J Clin Oncol. 2019 Jan 20;37(3):190-201. doi: 10.1200/JCO.18.01583
FROM THE JOURNAL OF CLINICAL ONCOLOGY
CAR T-cell therapies difficult to compare
One chimeric antigen receptor (CAR) T-cell therapy may appear better than another, but confounding factors make it difficult to compare these therapies effectively, according to a review published in the Journal of Clinical Oncology.
Caron A. Jacobson, MD, of the Dana-Farber Cancer Institute in Boston, reviewed results from three trials of CAR T-cell therapies in patients with B-cell non-Hodgkin lymphoma (B-NHL).
She noted that cross-trial comparisons are always limited, but such comparisons of CAR T-cell therapies are hindered by several confounding factors.
Dr. Jacobson said differences in manufacturing procedures and turnaround time, differences in patient eligibility and management, and the complexity of CAR T-cell therapies make it difficult to compare results from three CAR-T trials in B-NHL:
• The ZUMA-1 trial (NCT02348216) of axicabtagene ciloleucel (axi-cel, Yescarta)
• The JULIET trial (NCT02445248) of tisagenlecleucel (t-cel, Kymriah)
• The TRANSCEND-NHL-001 trial (NCT02631044) of lisocabtagene maraleucel (liso-cel, JCAR017).
Looking at response rates alone, axi-cel appears the most promising. The overall response rate (ORR) was 82% with axi-cel, 75% with liso-cel, and 52% with t-cel.
When considering cytokine release syndrome (CRS), liso-cel appears the safest. The rate of CRS was 93% with axi-cel (13% grade 3 or higher), 58% with t-cel (22% grade 3 or higher), and 39% with liso-cel (1% grade 3 or higher).
However, as Dr. Jacobson pointed out, it’s impossible to know if these differences in efficacy and toxicity are “statistically meaningful.”
Dr. Jacobson also noted that bridging therapy may have affected these results, as it might reduce tumor burden and increase toxicity, but bridging therapy was not used uniformly across these trials.
Most patients received bridging therapy before t-cel, none received it before axi-cel, and the use of bridging therapy was not reported in the trial of liso-cel.
“It is not possible to know whether patients treated on the ZUMA-1 trial, who were more likely to receive their CAR T cells, were healthier and more fit than patients on other studies or, because they were not allowed to receive bridging therapy, were actually sicker with a higher tumor burden and were therefore at risk for greater toxicity,” Dr. Jacobson wrote.
The fact that ZUMA-1 patients were more likely to receive CAR T cells brings up another issue—the difference between the reported results and the intent-to-treat (ITT) results in these trials. Since most patients on ZUMA-1 received the study treatment, there isn't much difference between the reported results and ITT results. However, about a third of patients who underwent apheresis on the JULIET trial did not ultimately receive CAR T cells, which means a bigger difference between the reported results and ITT results.
In ZUMA-1, 111 patients underwent leukapheresis, and 101 received treatment with axi-cel and were evaluable for efficacy. So the ORR was 75% (83/111) in the ITT population, compared to 82% in the population evaluable for efficacy.
In JULIET, 165 patients underwent leukapheresis, 111 received t-cel, and 93 were evaluable. The ORR was 30% (48/161) in the ITT population, compared to 52% in the evaluable population.
In TRANSCEND-NHL-001, 134 patients underwent leukapheresis, 114 patients received liso-cel, and 102 were evaluable. The ORR was 63% (77/122) in the ITT population, compared to 75% in the evaluable population.
Dr. Jacobson said these differences can be explained, in part, by differences in manufacturing. The time to manufacture cells was longer on the JULIET trial than on ZUMA-1, which may have been due to differences in transfection and manufacturing procedures as well as manufacturing ability.
In addition, differences in patient eligibility may have played a role, as healthier patients might be able to tolerate a longer manufacturing period than sicker patients.
Unfortunately, these differences cannot be accounted for without a randomized trial, but Dr. Jacobson said a randomized trial of these therapies is unlikely to occur.
“[S]o perhaps the best answers will come from institutions that have experience with all three products,” she wrote. “And in these cases, physicians and institutions will have to decide to what extent they would sacrifice efficacy for improved safety or sacrifice safety for improved reliability and consistency of treatment delivery.”
Dr. Jacobson disclosed relationships with Kite Pharma/Gilead Sciences, Bayer AG, Pfizer, Precision BioSciences, Novartis, Celgene, and Cowen.
SOURCE: Jacobson CA. J Clin Oncol. 2019 Feb 1;37(4):328-35. doi: 10.1200/JCO.18.01457
One chimeric antigen receptor (CAR) T-cell therapy may appear better than another, but confounding factors make it difficult to compare these therapies effectively, according to a review published in the Journal of Clinical Oncology.
Caron A. Jacobson, MD, of the Dana-Farber Cancer Institute in Boston, reviewed results from three trials of CAR T-cell therapies in patients with B-cell non-Hodgkin lymphoma (B-NHL).
She noted that cross-trial comparisons are always limited, but such comparisons of CAR T-cell therapies are hindered by several confounding factors.
Dr. Jacobson said differences in manufacturing procedures and turnaround time, differences in patient eligibility and management, and the complexity of CAR T-cell therapies make it difficult to compare results from three CAR-T trials in B-NHL:
• The ZUMA-1 trial (NCT02348216) of axicabtagene ciloleucel (axi-cel, Yescarta)
• The JULIET trial (NCT02445248) of tisagenlecleucel (t-cel, Kymriah)
• The TRANSCEND-NHL-001 trial (NCT02631044) of lisocabtagene maraleucel (liso-cel, JCAR017).
Looking at response rates alone, axi-cel appears the most promising. The overall response rate (ORR) was 82% with axi-cel, 75% with liso-cel, and 52% with t-cel.
When considering cytokine release syndrome (CRS), liso-cel appears the safest. The rate of CRS was 93% with axi-cel (13% grade 3 or higher), 58% with t-cel (22% grade 3 or higher), and 39% with liso-cel (1% grade 3 or higher).
However, as Dr. Jacobson pointed out, it’s impossible to know if these differences in efficacy and toxicity are “statistically meaningful.”
Dr. Jacobson also noted that bridging therapy may have affected these results, as it might reduce tumor burden and increase toxicity, but bridging therapy was not used uniformly across these trials.
Most patients received bridging therapy before t-cel, none received it before axi-cel, and the use of bridging therapy was not reported in the trial of liso-cel.
“It is not possible to know whether patients treated on the ZUMA-1 trial, who were more likely to receive their CAR T cells, were healthier and more fit than patients on other studies or, because they were not allowed to receive bridging therapy, were actually sicker with a higher tumor burden and were therefore at risk for greater toxicity,” Dr. Jacobson wrote.
The fact that ZUMA-1 patients were more likely to receive CAR T cells brings up another issue—the difference between the reported results and the intent-to-treat (ITT) results in these trials. Since most patients on ZUMA-1 received the study treatment, there isn't much difference between the reported results and ITT results. However, about a third of patients who underwent apheresis on the JULIET trial did not ultimately receive CAR T cells, which means a bigger difference between the reported results and ITT results.
In ZUMA-1, 111 patients underwent leukapheresis, and 101 received treatment with axi-cel and were evaluable for efficacy. So the ORR was 75% (83/111) in the ITT population, compared to 82% in the population evaluable for efficacy.
In JULIET, 165 patients underwent leukapheresis, 111 received t-cel, and 93 were evaluable. The ORR was 30% (48/161) in the ITT population, compared to 52% in the evaluable population.
In TRANSCEND-NHL-001, 134 patients underwent leukapheresis, 114 patients received liso-cel, and 102 were evaluable. The ORR was 63% (77/122) in the ITT population, compared to 75% in the evaluable population.
Dr. Jacobson said these differences can be explained, in part, by differences in manufacturing. The time to manufacture cells was longer on the JULIET trial than on ZUMA-1, which may have been due to differences in transfection and manufacturing procedures as well as manufacturing ability.
In addition, differences in patient eligibility may have played a role, as healthier patients might be able to tolerate a longer manufacturing period than sicker patients.
Unfortunately, these differences cannot be accounted for without a randomized trial, but Dr. Jacobson said a randomized trial of these therapies is unlikely to occur.
“[S]o perhaps the best answers will come from institutions that have experience with all three products,” she wrote. “And in these cases, physicians and institutions will have to decide to what extent they would sacrifice efficacy for improved safety or sacrifice safety for improved reliability and consistency of treatment delivery.”
Dr. Jacobson disclosed relationships with Kite Pharma/Gilead Sciences, Bayer AG, Pfizer, Precision BioSciences, Novartis, Celgene, and Cowen.
SOURCE: Jacobson CA. J Clin Oncol. 2019 Feb 1;37(4):328-35. doi: 10.1200/JCO.18.01457
One chimeric antigen receptor (CAR) T-cell therapy may appear better than another, but confounding factors make it difficult to compare these therapies effectively, according to a review published in the Journal of Clinical Oncology.
Caron A. Jacobson, MD, of the Dana-Farber Cancer Institute in Boston, reviewed results from three trials of CAR T-cell therapies in patients with B-cell non-Hodgkin lymphoma (B-NHL).
She noted that cross-trial comparisons are always limited, but such comparisons of CAR T-cell therapies are hindered by several confounding factors.
Dr. Jacobson said differences in manufacturing procedures and turnaround time, differences in patient eligibility and management, and the complexity of CAR T-cell therapies make it difficult to compare results from three CAR-T trials in B-NHL:
• The ZUMA-1 trial (NCT02348216) of axicabtagene ciloleucel (axi-cel, Yescarta)
• The JULIET trial (NCT02445248) of tisagenlecleucel (t-cel, Kymriah)
• The TRANSCEND-NHL-001 trial (NCT02631044) of lisocabtagene maraleucel (liso-cel, JCAR017).
Looking at response rates alone, axi-cel appears the most promising. The overall response rate (ORR) was 82% with axi-cel, 75% with liso-cel, and 52% with t-cel.
When considering cytokine release syndrome (CRS), liso-cel appears the safest. The rate of CRS was 93% with axi-cel (13% grade 3 or higher), 58% with t-cel (22% grade 3 or higher), and 39% with liso-cel (1% grade 3 or higher).
However, as Dr. Jacobson pointed out, it’s impossible to know if these differences in efficacy and toxicity are “statistically meaningful.”
Dr. Jacobson also noted that bridging therapy may have affected these results, as it might reduce tumor burden and increase toxicity, but bridging therapy was not used uniformly across these trials.
Most patients received bridging therapy before t-cel, none received it before axi-cel, and the use of bridging therapy was not reported in the trial of liso-cel.
“It is not possible to know whether patients treated on the ZUMA-1 trial, who were more likely to receive their CAR T cells, were healthier and more fit than patients on other studies or, because they were not allowed to receive bridging therapy, were actually sicker with a higher tumor burden and were therefore at risk for greater toxicity,” Dr. Jacobson wrote.
The fact that ZUMA-1 patients were more likely to receive CAR T cells brings up another issue—the difference between the reported results and the intent-to-treat (ITT) results in these trials. Since most patients on ZUMA-1 received the study treatment, there isn't much difference between the reported results and ITT results. However, about a third of patients who underwent apheresis on the JULIET trial did not ultimately receive CAR T cells, which means a bigger difference between the reported results and ITT results.
In ZUMA-1, 111 patients underwent leukapheresis, and 101 received treatment with axi-cel and were evaluable for efficacy. So the ORR was 75% (83/111) in the ITT population, compared to 82% in the population evaluable for efficacy.
In JULIET, 165 patients underwent leukapheresis, 111 received t-cel, and 93 were evaluable. The ORR was 30% (48/161) in the ITT population, compared to 52% in the evaluable population.
In TRANSCEND-NHL-001, 134 patients underwent leukapheresis, 114 patients received liso-cel, and 102 were evaluable. The ORR was 63% (77/122) in the ITT population, compared to 75% in the evaluable population.
Dr. Jacobson said these differences can be explained, in part, by differences in manufacturing. The time to manufacture cells was longer on the JULIET trial than on ZUMA-1, which may have been due to differences in transfection and manufacturing procedures as well as manufacturing ability.
In addition, differences in patient eligibility may have played a role, as healthier patients might be able to tolerate a longer manufacturing period than sicker patients.
Unfortunately, these differences cannot be accounted for without a randomized trial, but Dr. Jacobson said a randomized trial of these therapies is unlikely to occur.
“[S]o perhaps the best answers will come from institutions that have experience with all three products,” she wrote. “And in these cases, physicians and institutions will have to decide to what extent they would sacrifice efficacy for improved safety or sacrifice safety for improved reliability and consistency of treatment delivery.”
Dr. Jacobson disclosed relationships with Kite Pharma/Gilead Sciences, Bayer AG, Pfizer, Precision BioSciences, Novartis, Celgene, and Cowen.
SOURCE: Jacobson CA. J Clin Oncol. 2019 Feb 1;37(4):328-35. doi: 10.1200/JCO.18.01457
FROM JOURNAL OF CLINICAL ONCOLOGY