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FDA: Safety signal emerged with higher dose of tofacitinib in RA study
the Food and Drug Administration reported.
The trial’s Data Safety and Monitoring Board identified the signal in patients taking a 10-mg dose of tofacitinib twice daily, the FDA said in a safety announcement.
Pfizer, the trial’s sponsor, took “immediate action” to transition patients in the ongoing trial from the 10-mg, twice-daily dose to 5 mg twice daily, which is the approved dose for adult patients with moderate to severe rheumatoid arthritis, the agency said. The 10-mg, twice-daily dose is approved only in the dosing regimen for patients with ulcerative colitis. Xeljanz is also approved to treat psoriatic arthritis. The 11-mg, once-daily dose of Xeljanz XR that is approved to treat rheumatoid arthritis and psoriatic arthritis was not tested in the trial.
The ongoing study was designed to assess risks of cardiovascular events, cancer, and opportunistic infections with tofacitinib 10 mg twice daily or 5 mg twice daily versus the risks in a control group treated with a tumor necrosis factor (TNF) inhibitor, according to the statement.
Patients had to be 50 years of age or older and have at least one cardiovascular risk factor to be eligible for the study, which was required by the agency in 2012 when it approved tofacitinib, the statement says.
The FDA is reviewing trial data and working with Pfizer to better understand the safety signal, its effect on patients, and how tofacitinib should be used, Janet Woodcock, MD, director of the FDA’s Center for Drug Evaluation and Research, said in a news release. The trial will continue and is expected to be completed by the end of 2019.
“The agency will take appropriate action, as warranted, to ensure patients enrolled in this and other trials are protected and that health care professionals and clinical trial researchers understand the risks associated with this use,” she added.
Health care professionals should follow tofacitinib prescribing information, monitor patients for the signs and symptoms of pulmonary embolism, and advise patients to seek medical attention immediately if they experience those signs and symptoms, according to the statement.
“We are communicating now, given the serious nature of the safety issue, to ensure that patients taking tofacitinib are aware that the FDA still believes the benefits of taking tofacitinib for its approved uses continue to outweigh the risks,” Dr. Woodcock said in the release.
While not approved in rheumatoid arthritis, the 10-mg, twice-daily dose of tofacitinib is approved in the dosing regimen for patients with ulcerative colitis, the release says.
the Food and Drug Administration reported.
The trial’s Data Safety and Monitoring Board identified the signal in patients taking a 10-mg dose of tofacitinib twice daily, the FDA said in a safety announcement.
Pfizer, the trial’s sponsor, took “immediate action” to transition patients in the ongoing trial from the 10-mg, twice-daily dose to 5 mg twice daily, which is the approved dose for adult patients with moderate to severe rheumatoid arthritis, the agency said. The 10-mg, twice-daily dose is approved only in the dosing regimen for patients with ulcerative colitis. Xeljanz is also approved to treat psoriatic arthritis. The 11-mg, once-daily dose of Xeljanz XR that is approved to treat rheumatoid arthritis and psoriatic arthritis was not tested in the trial.
The ongoing study was designed to assess risks of cardiovascular events, cancer, and opportunistic infections with tofacitinib 10 mg twice daily or 5 mg twice daily versus the risks in a control group treated with a tumor necrosis factor (TNF) inhibitor, according to the statement.
Patients had to be 50 years of age or older and have at least one cardiovascular risk factor to be eligible for the study, which was required by the agency in 2012 when it approved tofacitinib, the statement says.
The FDA is reviewing trial data and working with Pfizer to better understand the safety signal, its effect on patients, and how tofacitinib should be used, Janet Woodcock, MD, director of the FDA’s Center for Drug Evaluation and Research, said in a news release. The trial will continue and is expected to be completed by the end of 2019.
“The agency will take appropriate action, as warranted, to ensure patients enrolled in this and other trials are protected and that health care professionals and clinical trial researchers understand the risks associated with this use,” she added.
Health care professionals should follow tofacitinib prescribing information, monitor patients for the signs and symptoms of pulmonary embolism, and advise patients to seek medical attention immediately if they experience those signs and symptoms, according to the statement.
“We are communicating now, given the serious nature of the safety issue, to ensure that patients taking tofacitinib are aware that the FDA still believes the benefits of taking tofacitinib for its approved uses continue to outweigh the risks,” Dr. Woodcock said in the release.
While not approved in rheumatoid arthritis, the 10-mg, twice-daily dose of tofacitinib is approved in the dosing regimen for patients with ulcerative colitis, the release says.
the Food and Drug Administration reported.
The trial’s Data Safety and Monitoring Board identified the signal in patients taking a 10-mg dose of tofacitinib twice daily, the FDA said in a safety announcement.
Pfizer, the trial’s sponsor, took “immediate action” to transition patients in the ongoing trial from the 10-mg, twice-daily dose to 5 mg twice daily, which is the approved dose for adult patients with moderate to severe rheumatoid arthritis, the agency said. The 10-mg, twice-daily dose is approved only in the dosing regimen for patients with ulcerative colitis. Xeljanz is also approved to treat psoriatic arthritis. The 11-mg, once-daily dose of Xeljanz XR that is approved to treat rheumatoid arthritis and psoriatic arthritis was not tested in the trial.
The ongoing study was designed to assess risks of cardiovascular events, cancer, and opportunistic infections with tofacitinib 10 mg twice daily or 5 mg twice daily versus the risks in a control group treated with a tumor necrosis factor (TNF) inhibitor, according to the statement.
Patients had to be 50 years of age or older and have at least one cardiovascular risk factor to be eligible for the study, which was required by the agency in 2012 when it approved tofacitinib, the statement says.
The FDA is reviewing trial data and working with Pfizer to better understand the safety signal, its effect on patients, and how tofacitinib should be used, Janet Woodcock, MD, director of the FDA’s Center for Drug Evaluation and Research, said in a news release. The trial will continue and is expected to be completed by the end of 2019.
“The agency will take appropriate action, as warranted, to ensure patients enrolled in this and other trials are protected and that health care professionals and clinical trial researchers understand the risks associated with this use,” she added.
Health care professionals should follow tofacitinib prescribing information, monitor patients for the signs and symptoms of pulmonary embolism, and advise patients to seek medical attention immediately if they experience those signs and symptoms, according to the statement.
“We are communicating now, given the serious nature of the safety issue, to ensure that patients taking tofacitinib are aware that the FDA still believes the benefits of taking tofacitinib for its approved uses continue to outweigh the risks,” Dr. Woodcock said in the release.
While not approved in rheumatoid arthritis, the 10-mg, twice-daily dose of tofacitinib is approved in the dosing regimen for patients with ulcerative colitis, the release says.
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
Anti-GM-CSF antibody reduced CAR T-cell toxicity
HOUSTON – Neutralizing granulocyte-macrophage colony-stimulating factor (GM-CSF) may be an effective strategy not only to manage toxicities associated with chimeric antigen receptor (CAR) T-cell therapy, but also to enhance CAR-T cell function, an investigator reported at the Transplantation & Cellular Therapy Meetings.
The GM-CSF targeted monoclonal antibody lenzilumab reduced neurotoxicity and cytokine release syndrome (CRS) related to CD19-targeted CAR T-cell therapy in a patient-derived xenograft model, said investigator Rosalie M. Sterner, an MD-PhD student in the department of immunology at Mayo Clinic, Rochester, Minn.
Other investigations showed that neutralizing or knocking out GM-CSF enhanced the antitumor functions of the CAR T cells, Ms. Sterner said in a podium presentation at the meeting 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).
“GM-CSF blockade does not impair CAR T-cell effector function, and in fact, enhances CAR T-cell effector functions in certain models, and actually can help to ameliorate CAR T-cell associated toxicities,” Ms. Sterner said.
Based on these early findings, the investigators have designed a phase 2 clinical trial to see if lenzilumab can prevent CAR T cell-related toxicities in patients with diffuse large B-cell lymphoma.
GM-CSF, a cytokine produced by T cells and myeloid cells, is the most statistically significantly elevated serum marker in patients with severe neurotoxicity related to CAR T-cell therapy, Ms. Sterner told attendees.
Investigations have shown that the combination of lenzilumab plus CD19-targeted T-cell therapy did not impair CAR T-cell function in vivo or in vitro, she said.
In other studies, they investigated the impact of GM-CSF neutralization in mice engrafted with primary acute lymphocytic leukemia (ALL) blasts and treated with high doses of CD19 CAR T-cells, lenzilumab, and a murine GM-CSF blocking antibody to neutralize the mouse GM-CSF. That strategy prevented weight loss, decreased myeloid cytokines, reduced cerebral edema, and enhanced disease control, Ms. Sterner said.
Investigators also reported on CD19 CAR T-cells with reduced GM-CSF secretion due to CRISPR/Cas9 gene editing of the GM-CSF gene during the CAR T-cell manufacturing process. Xenograft model results showed a slight enhancement of disease control for those GM-CSF knockout CAR T cells versus standard CAR T cells.
More details of the investigations were recently published in Blood (2019;133:697-709).
Taken together, the investigations highlight GM-CSF inhibition as a novel approach to reducing neurotoxicity and CRS that may also enhance CAR T-cell effector functions, Ms. Sterner said.
Ms. Sterner reported having no financial disclosures related to her presentation.
SOURCE: Sterner R et al. TCT 2019, Abstract 5.
HOUSTON – Neutralizing granulocyte-macrophage colony-stimulating factor (GM-CSF) may be an effective strategy not only to manage toxicities associated with chimeric antigen receptor (CAR) T-cell therapy, but also to enhance CAR-T cell function, an investigator reported at the Transplantation & Cellular Therapy Meetings.
The GM-CSF targeted monoclonal antibody lenzilumab reduced neurotoxicity and cytokine release syndrome (CRS) related to CD19-targeted CAR T-cell therapy in a patient-derived xenograft model, said investigator Rosalie M. Sterner, an MD-PhD student in the department of immunology at Mayo Clinic, Rochester, Minn.
Other investigations showed that neutralizing or knocking out GM-CSF enhanced the antitumor functions of the CAR T cells, Ms. Sterner said in a podium presentation at the meeting 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).
“GM-CSF blockade does not impair CAR T-cell effector function, and in fact, enhances CAR T-cell effector functions in certain models, and actually can help to ameliorate CAR T-cell associated toxicities,” Ms. Sterner said.
Based on these early findings, the investigators have designed a phase 2 clinical trial to see if lenzilumab can prevent CAR T cell-related toxicities in patients with diffuse large B-cell lymphoma.
GM-CSF, a cytokine produced by T cells and myeloid cells, is the most statistically significantly elevated serum marker in patients with severe neurotoxicity related to CAR T-cell therapy, Ms. Sterner told attendees.
Investigations have shown that the combination of lenzilumab plus CD19-targeted T-cell therapy did not impair CAR T-cell function in vivo or in vitro, she said.
In other studies, they investigated the impact of GM-CSF neutralization in mice engrafted with primary acute lymphocytic leukemia (ALL) blasts and treated with high doses of CD19 CAR T-cells, lenzilumab, and a murine GM-CSF blocking antibody to neutralize the mouse GM-CSF. That strategy prevented weight loss, decreased myeloid cytokines, reduced cerebral edema, and enhanced disease control, Ms. Sterner said.
Investigators also reported on CD19 CAR T-cells with reduced GM-CSF secretion due to CRISPR/Cas9 gene editing of the GM-CSF gene during the CAR T-cell manufacturing process. Xenograft model results showed a slight enhancement of disease control for those GM-CSF knockout CAR T cells versus standard CAR T cells.
More details of the investigations were recently published in Blood (2019;133:697-709).
Taken together, the investigations highlight GM-CSF inhibition as a novel approach to reducing neurotoxicity and CRS that may also enhance CAR T-cell effector functions, Ms. Sterner said.
Ms. Sterner reported having no financial disclosures related to her presentation.
SOURCE: Sterner R et al. TCT 2019, Abstract 5.
HOUSTON – Neutralizing granulocyte-macrophage colony-stimulating factor (GM-CSF) may be an effective strategy not only to manage toxicities associated with chimeric antigen receptor (CAR) T-cell therapy, but also to enhance CAR-T cell function, an investigator reported at the Transplantation & Cellular Therapy Meetings.
The GM-CSF targeted monoclonal antibody lenzilumab reduced neurotoxicity and cytokine release syndrome (CRS) related to CD19-targeted CAR T-cell therapy in a patient-derived xenograft model, said investigator Rosalie M. Sterner, an MD-PhD student in the department of immunology at Mayo Clinic, Rochester, Minn.
Other investigations showed that neutralizing or knocking out GM-CSF enhanced the antitumor functions of the CAR T cells, Ms. Sterner said in a podium presentation at the meeting 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).
“GM-CSF blockade does not impair CAR T-cell effector function, and in fact, enhances CAR T-cell effector functions in certain models, and actually can help to ameliorate CAR T-cell associated toxicities,” Ms. Sterner said.
Based on these early findings, the investigators have designed a phase 2 clinical trial to see if lenzilumab can prevent CAR T cell-related toxicities in patients with diffuse large B-cell lymphoma.
GM-CSF, a cytokine produced by T cells and myeloid cells, is the most statistically significantly elevated serum marker in patients with severe neurotoxicity related to CAR T-cell therapy, Ms. Sterner told attendees.
Investigations have shown that the combination of lenzilumab plus CD19-targeted T-cell therapy did not impair CAR T-cell function in vivo or in vitro, she said.
In other studies, they investigated the impact of GM-CSF neutralization in mice engrafted with primary acute lymphocytic leukemia (ALL) blasts and treated with high doses of CD19 CAR T-cells, lenzilumab, and a murine GM-CSF blocking antibody to neutralize the mouse GM-CSF. That strategy prevented weight loss, decreased myeloid cytokines, reduced cerebral edema, and enhanced disease control, Ms. Sterner said.
Investigators also reported on CD19 CAR T-cells with reduced GM-CSF secretion due to CRISPR/Cas9 gene editing of the GM-CSF gene during the CAR T-cell manufacturing process. Xenograft model results showed a slight enhancement of disease control for those GM-CSF knockout CAR T cells versus standard CAR T cells.
More details of the investigations were recently published in Blood (2019;133:697-709).
Taken together, the investigations highlight GM-CSF inhibition as a novel approach to reducing neurotoxicity and CRS that may also enhance CAR T-cell effector functions, Ms. Sterner said.
Ms. Sterner reported having no financial disclosures related to her presentation.
SOURCE: Sterner R et al. TCT 2019, Abstract 5.
REPORTING FROM TCT 2019
Treosulfan may become standard in allo-HCT for AML/MDS
HOUSTON – A treosulfan-based conditioning regimen could become standard prior to allogeneic transplant in elderly or comorbid patients with acute myeloid leukemia or myelodysplastic syndromes, according to the lead investigator in a phase 3 trial.
The treosulfan/fludarabine myeloablative conditioning regimen had noninferior event-free survival, compared with a reduced-intensity busulfan-based regimen in the large, randomized trial that included elderly patients and those with multiple comorbidities, said researcher Dietrich Wilhelm Beelen, MD, PhD.
The experimental regimen was superior to busulfan in overall survival, nonrelapse mortality, and complete donor chimerism in the trial, added Dr. Beelen, who is with the department of bone marrow transplantation at the West German Cancer Center, University Hospital of Essen, Germany.
“The study results point to a potential benefit of the treosulfan/fludarabine regimen, while the early safety profile, engraftment kinetics, acute or chronic graft-versus-host-disease (GvHD), and the relapse risk of both regimens appear comparable,” Dr. Beelen said at the Transplantation & Cellular Therapy Meetings.
Allogeneic hematopoietic cell transplantation (HCT) is challenging in elderly and comorbid patients, who have an increased risk of nonrelapse mortality with standard myeloablative regimens, according to Dr. Beelen, who presented results on behalf of investigators from the international MC-FludT.14/L Study Group.
Their phase 3 randomized trial included patients who were 50-70 years of age, or who had a Hematopoietic Cell Transplantation Comorbidity Index of 2 or greater. The final analysis included 551 patients (352 with AML and 199 with MDS).
The primary endpoint of the study was event-free survival at 2 years. That endpoint comprised relapse/progression of disease, graft failure, or death.
Patient enrollment was terminated early the MC-FludT.14/L study following an interim analysis that investigators said “clearly demonstrated” the noninferiority of the treosulfan/fludarabine regimen versus the reduced intensity busulfan/fludarabine regimen.
In the final analysis, event-free survival at 2 years was about 14.5 percentage points higher in the treosulfan group, at 65.7% versus 51.2% (P = .0000001), Dr. Beelen reported at the meeting.
A number of other secondary endpoints also favored treosulfan/fludarabine over busulfan, including overall survival (P = .0037), nonrelapse mortality (P = .0343), and survival free of chronic GvHD or relapse (P = .0030).
These results help establish the new treosulfan/fludarabine regimen as a “relatively well-tolerable and effective preparative regimen” in elderly or comorbid AML/MDS patients, Dr. Beelen said.
However, treosulfan has not been authorized for use in allogeneic HCT conditioning regimens, and so should be considered experimental in this setting, he said at the meeting 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).
Dr. Beelen reported honoraria, travel support, and trial documentation support provided by medac GmbH, which sponsored the trial.
SOURCE: Beelen DW et al. TCT 2019, Abstract 4.
HOUSTON – A treosulfan-based conditioning regimen could become standard prior to allogeneic transplant in elderly or comorbid patients with acute myeloid leukemia or myelodysplastic syndromes, according to the lead investigator in a phase 3 trial.
The treosulfan/fludarabine myeloablative conditioning regimen had noninferior event-free survival, compared with a reduced-intensity busulfan-based regimen in the large, randomized trial that included elderly patients and those with multiple comorbidities, said researcher Dietrich Wilhelm Beelen, MD, PhD.
The experimental regimen was superior to busulfan in overall survival, nonrelapse mortality, and complete donor chimerism in the trial, added Dr. Beelen, who is with the department of bone marrow transplantation at the West German Cancer Center, University Hospital of Essen, Germany.
“The study results point to a potential benefit of the treosulfan/fludarabine regimen, while the early safety profile, engraftment kinetics, acute or chronic graft-versus-host-disease (GvHD), and the relapse risk of both regimens appear comparable,” Dr. Beelen said at the Transplantation & Cellular Therapy Meetings.
Allogeneic hematopoietic cell transplantation (HCT) is challenging in elderly and comorbid patients, who have an increased risk of nonrelapse mortality with standard myeloablative regimens, according to Dr. Beelen, who presented results on behalf of investigators from the international MC-FludT.14/L Study Group.
Their phase 3 randomized trial included patients who were 50-70 years of age, or who had a Hematopoietic Cell Transplantation Comorbidity Index of 2 or greater. The final analysis included 551 patients (352 with AML and 199 with MDS).
The primary endpoint of the study was event-free survival at 2 years. That endpoint comprised relapse/progression of disease, graft failure, or death.
Patient enrollment was terminated early the MC-FludT.14/L study following an interim analysis that investigators said “clearly demonstrated” the noninferiority of the treosulfan/fludarabine regimen versus the reduced intensity busulfan/fludarabine regimen.
In the final analysis, event-free survival at 2 years was about 14.5 percentage points higher in the treosulfan group, at 65.7% versus 51.2% (P = .0000001), Dr. Beelen reported at the meeting.
A number of other secondary endpoints also favored treosulfan/fludarabine over busulfan, including overall survival (P = .0037), nonrelapse mortality (P = .0343), and survival free of chronic GvHD or relapse (P = .0030).
These results help establish the new treosulfan/fludarabine regimen as a “relatively well-tolerable and effective preparative regimen” in elderly or comorbid AML/MDS patients, Dr. Beelen said.
However, treosulfan has not been authorized for use in allogeneic HCT conditioning regimens, and so should be considered experimental in this setting, he said at the meeting 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).
Dr. Beelen reported honoraria, travel support, and trial documentation support provided by medac GmbH, which sponsored the trial.
SOURCE: Beelen DW et al. TCT 2019, Abstract 4.
HOUSTON – A treosulfan-based conditioning regimen could become standard prior to allogeneic transplant in elderly or comorbid patients with acute myeloid leukemia or myelodysplastic syndromes, according to the lead investigator in a phase 3 trial.
The treosulfan/fludarabine myeloablative conditioning regimen had noninferior event-free survival, compared with a reduced-intensity busulfan-based regimen in the large, randomized trial that included elderly patients and those with multiple comorbidities, said researcher Dietrich Wilhelm Beelen, MD, PhD.
The experimental regimen was superior to busulfan in overall survival, nonrelapse mortality, and complete donor chimerism in the trial, added Dr. Beelen, who is with the department of bone marrow transplantation at the West German Cancer Center, University Hospital of Essen, Germany.
“The study results point to a potential benefit of the treosulfan/fludarabine regimen, while the early safety profile, engraftment kinetics, acute or chronic graft-versus-host-disease (GvHD), and the relapse risk of both regimens appear comparable,” Dr. Beelen said at the Transplantation & Cellular Therapy Meetings.
Allogeneic hematopoietic cell transplantation (HCT) is challenging in elderly and comorbid patients, who have an increased risk of nonrelapse mortality with standard myeloablative regimens, according to Dr. Beelen, who presented results on behalf of investigators from the international MC-FludT.14/L Study Group.
Their phase 3 randomized trial included patients who were 50-70 years of age, or who had a Hematopoietic Cell Transplantation Comorbidity Index of 2 or greater. The final analysis included 551 patients (352 with AML and 199 with MDS).
The primary endpoint of the study was event-free survival at 2 years. That endpoint comprised relapse/progression of disease, graft failure, or death.
Patient enrollment was terminated early the MC-FludT.14/L study following an interim analysis that investigators said “clearly demonstrated” the noninferiority of the treosulfan/fludarabine regimen versus the reduced intensity busulfan/fludarabine regimen.
In the final analysis, event-free survival at 2 years was about 14.5 percentage points higher in the treosulfan group, at 65.7% versus 51.2% (P = .0000001), Dr. Beelen reported at the meeting.
A number of other secondary endpoints also favored treosulfan/fludarabine over busulfan, including overall survival (P = .0037), nonrelapse mortality (P = .0343), and survival free of chronic GvHD or relapse (P = .0030).
These results help establish the new treosulfan/fludarabine regimen as a “relatively well-tolerable and effective preparative regimen” in elderly or comorbid AML/MDS patients, Dr. Beelen said.
However, treosulfan has not been authorized for use in allogeneic HCT conditioning regimens, and so should be considered experimental in this setting, he said at the meeting 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).
Dr. Beelen reported honoraria, travel support, and trial documentation support provided by medac GmbH, which sponsored the trial.
SOURCE: Beelen DW et al. TCT 2019, Abstract 4.
REPORTING FROM TCT 2019
Ultrasound method predicts liver complications in pediatric transplant
HOUSTON – An ultrasound method for assessing liver stiffness might be useful for predicting which pediatric patients will develop a life-threatening complication of hematopoietic stem cell transplantation.
Shear wave elastography values predicted severe hepatic sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) at least 4 days before standard diagnostic criteria in most patients treated in a small, prospective, two-center study, Sherwin S. Chan, MD, PhD, said at the Transplantation & Cellular Therapy Meetings.
Early identification of SOS/VOD using elastography could be beneficial in light of data showing that timing is critical in the administration of defibrotide, a treatment recommended for severe and very severe patients, according to Dr. Chan, vice chair of radiology for the University of Missouri at Kansas City.
“If you’re able to initiate it early, you can really increase day 100 survival,” Dr. Chan said in an oral presentation.
The data presented included 54 pediatric patients undergoing transplantation at one of two institutions.
At one site, the patients underwent shear wave elastography evaluation 10 days before the conditioning regimen began, and again at 5 and 14 days after the transplant. At the other site, patients with suspected SOS/VOD were enrolled and underwent elastography every other day for up to 10 exams.
Those are very different imaging protocols, Dr. Chan acknowledged in his presentation, noting that the studies started independently and data were pooled as investigators at the two institutions became aware of one another’s work.
A total of 16 patients, or 30%, developed SOS/VOD, Dr. Chan reported. Of those 16 cases, 12 (75%) were severe or very severe by the recent European Society for Blood and Marrow Transplantation (EBMT) criteria.
Increased shear wave elastography velocity was the best predictor of severe SOS/VOD, according to Dr. Chan, with a cutoff value of 1.65 m/s being 92% sensitive and 67% specific for severe SOS/VOD.
That threshold was passed at least 4 days before severe grading or death in 9 out of the 12 severe cases, he added.
Accordingly, a prospective, multicenter trial has been initiated at a number of U.S. centers to investigate whether the findings of this study are generalizable to other patient populations, Dr. Chan said at the meeting held by the American Society of Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research. At this meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy.
That prospective, multicenter trial is supported by Jazz Pharmaceuticals, according to Dr. Chan, who reported consulting with Jazz Pharmaceuticals in his disclosure statement.
SOURCE: Chan SS et al. TCT 2019, Abstract 55.
HOUSTON – An ultrasound method for assessing liver stiffness might be useful for predicting which pediatric patients will develop a life-threatening complication of hematopoietic stem cell transplantation.
Shear wave elastography values predicted severe hepatic sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) at least 4 days before standard diagnostic criteria in most patients treated in a small, prospective, two-center study, Sherwin S. Chan, MD, PhD, said at the Transplantation & Cellular Therapy Meetings.
Early identification of SOS/VOD using elastography could be beneficial in light of data showing that timing is critical in the administration of defibrotide, a treatment recommended for severe and very severe patients, according to Dr. Chan, vice chair of radiology for the University of Missouri at Kansas City.
“If you’re able to initiate it early, you can really increase day 100 survival,” Dr. Chan said in an oral presentation.
The data presented included 54 pediatric patients undergoing transplantation at one of two institutions.
At one site, the patients underwent shear wave elastography evaluation 10 days before the conditioning regimen began, and again at 5 and 14 days after the transplant. At the other site, patients with suspected SOS/VOD were enrolled and underwent elastography every other day for up to 10 exams.
Those are very different imaging protocols, Dr. Chan acknowledged in his presentation, noting that the studies started independently and data were pooled as investigators at the two institutions became aware of one another’s work.
A total of 16 patients, or 30%, developed SOS/VOD, Dr. Chan reported. Of those 16 cases, 12 (75%) were severe or very severe by the recent European Society for Blood and Marrow Transplantation (EBMT) criteria.
Increased shear wave elastography velocity was the best predictor of severe SOS/VOD, according to Dr. Chan, with a cutoff value of 1.65 m/s being 92% sensitive and 67% specific for severe SOS/VOD.
That threshold was passed at least 4 days before severe grading or death in 9 out of the 12 severe cases, he added.
Accordingly, a prospective, multicenter trial has been initiated at a number of U.S. centers to investigate whether the findings of this study are generalizable to other patient populations, Dr. Chan said at the meeting held by the American Society of Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research. At this meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy.
That prospective, multicenter trial is supported by Jazz Pharmaceuticals, according to Dr. Chan, who reported consulting with Jazz Pharmaceuticals in his disclosure statement.
SOURCE: Chan SS et al. TCT 2019, Abstract 55.
HOUSTON – An ultrasound method for assessing liver stiffness might be useful for predicting which pediatric patients will develop a life-threatening complication of hematopoietic stem cell transplantation.
Shear wave elastography values predicted severe hepatic sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) at least 4 days before standard diagnostic criteria in most patients treated in a small, prospective, two-center study, Sherwin S. Chan, MD, PhD, said at the Transplantation & Cellular Therapy Meetings.
Early identification of SOS/VOD using elastography could be beneficial in light of data showing that timing is critical in the administration of defibrotide, a treatment recommended for severe and very severe patients, according to Dr. Chan, vice chair of radiology for the University of Missouri at Kansas City.
“If you’re able to initiate it early, you can really increase day 100 survival,” Dr. Chan said in an oral presentation.
The data presented included 54 pediatric patients undergoing transplantation at one of two institutions.
At one site, the patients underwent shear wave elastography evaluation 10 days before the conditioning regimen began, and again at 5 and 14 days after the transplant. At the other site, patients with suspected SOS/VOD were enrolled and underwent elastography every other day for up to 10 exams.
Those are very different imaging protocols, Dr. Chan acknowledged in his presentation, noting that the studies started independently and data were pooled as investigators at the two institutions became aware of one another’s work.
A total of 16 patients, or 30%, developed SOS/VOD, Dr. Chan reported. Of those 16 cases, 12 (75%) were severe or very severe by the recent European Society for Blood and Marrow Transplantation (EBMT) criteria.
Increased shear wave elastography velocity was the best predictor of severe SOS/VOD, according to Dr. Chan, with a cutoff value of 1.65 m/s being 92% sensitive and 67% specific for severe SOS/VOD.
That threshold was passed at least 4 days before severe grading or death in 9 out of the 12 severe cases, he added.
Accordingly, a prospective, multicenter trial has been initiated at a number of U.S. centers to investigate whether the findings of this study are generalizable to other patient populations, Dr. Chan said at the meeting held by the American Society of Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research. At this meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy.
That prospective, multicenter trial is supported by Jazz Pharmaceuticals, according to Dr. Chan, who reported consulting with Jazz Pharmaceuticals in his disclosure statement.
SOURCE: Chan SS et al. TCT 2019, Abstract 55.
REPORTING FROM TCT 2019
AACE/ACE algorithm provides practical clinical guidance on managing diabetes
Leading endocrinology societies have copublished an algorithm offering updated, specific clinical guidance on lifestyle therapy, management of hypertension and dyslipidemia, and glucose control in patients with type 2 diabetes.
This update from the American Association of Clinical Endocrinologists and the American College of Endocrinology, published in Endocrine Practice, also highlights obesity and prediabetes as underlying risk factors for development of diabetes.
The algorithm, based on new and “comprehensive clinical data” on type 2 diabetes management, is designed as a supplement 2015 AACE/ACE clinical practice guidelines, according to Alan J. Garber, MD, PhD, chair of the Diabetes Management Algorithm Task Force.
“It’s intended to provide clinicians with a practical guide that prompts them to look for factors or influences in the patient’s lifestyle or health that may be a factor in identifying the best treatment approach or medication,” he said in a statement.
Lifestyle medication is critical for all patients with diabetes, according to Dr. Garber and the algorithm coauthors, who recommended a “primarily plant-based meal plan” that limits intake of saturated fatty acids and avoids trans fats. They said overweight patients should restrict caloric intake with a goal of reducing body weight by up to 10%.
Physical activity should include at least 150 minutes per week of activities such as brisk walking or weight training, they said, adding that patients should be advised to sleep 7 hours per night, on average.
Weight loss medications might be needed along with lifestyle modification for patients with body mass index (BMI) over 27 kg/m2 with complications, and for all patients with BMI over 30 regardless of whether they have complications, according to the AACE/ACE committee members who drafted the report.
Bariatric surgery might be considered in patients with BMI over 35 and comorbidities, particularly if patients fail to achieve weight loss goals using other means, they added.
The primary goal of prediabetes management is weight loss, wrote the authors. While there are no Food and Drug Administration–approved agents for prediabetes management, they said, antihyperglycemic agents such as metformin and acarbose have been shown to reduce risk of diabetes by 25%-30% in patients with prediabetes.
While pressure control needs to be individualized, but a goal of less than 130/80 mm Hg is warranted for most patients with diabetes, according to the authors, who note that most patients will require medication to reach their goal.
“Because angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers can slow progression of nephropathy and retinopathy, they are preferred for patients with type 2 diabetes,” said Dr. Garber and his coauthors in the executive summary accompanying the algorithm.
Early and intensive management of dyslipidemia is important to reduce the significant risk of atherosclerotic cardiovascular disease in patients with diabetes, according to the authors, who say diabetes patients should be classified as high risk, very high risk, or extreme risk. They recommended LDL cholesterol targets of less than 100 mg/dL for high-risk patients, less than 70 mg/dL for very-high-risk patients, and less than 55 mg/dL for the extreme-risk group.
Statins should be considered first-line treatment for lowering cholesterol, unless contraindicated, with other lipid-modifying agents added as needed to reach lipid targets.
Inhibitors of proprotein convertase subtilisin/kexin type 9 serine protease (PCSK9) address a “large unmet need” for more aggressive lipid lowering in patients with clinical atherosclerotic disease and diabetes, the authors noted.
Added to maximal statin therapy, PCSK9 inhibitors reduce LDL cholesterol by about 50% while also raising HDL cholesterol and having positive effects on other lipids, according to the authors.
Pharmacotherapy for type 2 diabetes requires a “nuanced approach” that takes into account factors such as age, comorbidities, and risk of hypoglycemia, the authors wrote, noting that the AACE supports a hemoglobin A1c target of 6.5% or less for most patients.
The algorithm for glycemic control lists glucose-lowering agents in order of recommended usage. For example, in patients with an entry HbA1c less than 7.5%, the strongest recommendations for were monotherapy with metformin, followed by GLP1 receptor agonists and sodium-glucose cotransporter 2 (SGLT2) inhibitors.
If insulin becomes necessary, the recommended approach is to add a single daily dose of basal insulin, and if a basal insulin regimen fails to control glucose, it may help to add a GLP1 receptor agonist or dipeptidyl peptidase 4 (DPP4) inhibitor, according to the algorithm.
Avoiding hypoglycemia is important, and one possible “safety measure” to prevent that is using a continuous glucose monitoring device that provides real-time glucose data. “Significant advances have been made in accuracy and availability of CGM devices,” the authors wrote.
Current expert consensus is that clinical CGM devices should be considered if patients have not achieved their glycemic target after 3 months or if they need a treatment that puts them at risk for hypoglycemia, according to Dr. Garber and his colleagues.
Dr. Garber reported that he had no financial relationships relevant to the consensus statement and algorithm. Coauthors of the report provided disclosures related to Novo Nordisk, Eli Lilly, Janssen Pharmaceuticals, Abbott, Sanofi-Aventis, and other pharmaceutical companies.
cenews@mdedge.com
SOURCE: Garber AJ et al. Endocr Pract. 2019 Jan;25(1):91-120.
Leading endocrinology societies have copublished an algorithm offering updated, specific clinical guidance on lifestyle therapy, management of hypertension and dyslipidemia, and glucose control in patients with type 2 diabetes.
This update from the American Association of Clinical Endocrinologists and the American College of Endocrinology, published in Endocrine Practice, also highlights obesity and prediabetes as underlying risk factors for development of diabetes.
The algorithm, based on new and “comprehensive clinical data” on type 2 diabetes management, is designed as a supplement 2015 AACE/ACE clinical practice guidelines, according to Alan J. Garber, MD, PhD, chair of the Diabetes Management Algorithm Task Force.
“It’s intended to provide clinicians with a practical guide that prompts them to look for factors or influences in the patient’s lifestyle or health that may be a factor in identifying the best treatment approach or medication,” he said in a statement.
Lifestyle medication is critical for all patients with diabetes, according to Dr. Garber and the algorithm coauthors, who recommended a “primarily plant-based meal plan” that limits intake of saturated fatty acids and avoids trans fats. They said overweight patients should restrict caloric intake with a goal of reducing body weight by up to 10%.
Physical activity should include at least 150 minutes per week of activities such as brisk walking or weight training, they said, adding that patients should be advised to sleep 7 hours per night, on average.
Weight loss medications might be needed along with lifestyle modification for patients with body mass index (BMI) over 27 kg/m2 with complications, and for all patients with BMI over 30 regardless of whether they have complications, according to the AACE/ACE committee members who drafted the report.
Bariatric surgery might be considered in patients with BMI over 35 and comorbidities, particularly if patients fail to achieve weight loss goals using other means, they added.
The primary goal of prediabetes management is weight loss, wrote the authors. While there are no Food and Drug Administration–approved agents for prediabetes management, they said, antihyperglycemic agents such as metformin and acarbose have been shown to reduce risk of diabetes by 25%-30% in patients with prediabetes.
While pressure control needs to be individualized, but a goal of less than 130/80 mm Hg is warranted for most patients with diabetes, according to the authors, who note that most patients will require medication to reach their goal.
“Because angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers can slow progression of nephropathy and retinopathy, they are preferred for patients with type 2 diabetes,” said Dr. Garber and his coauthors in the executive summary accompanying the algorithm.
Early and intensive management of dyslipidemia is important to reduce the significant risk of atherosclerotic cardiovascular disease in patients with diabetes, according to the authors, who say diabetes patients should be classified as high risk, very high risk, or extreme risk. They recommended LDL cholesterol targets of less than 100 mg/dL for high-risk patients, less than 70 mg/dL for very-high-risk patients, and less than 55 mg/dL for the extreme-risk group.
Statins should be considered first-line treatment for lowering cholesterol, unless contraindicated, with other lipid-modifying agents added as needed to reach lipid targets.
Inhibitors of proprotein convertase subtilisin/kexin type 9 serine protease (PCSK9) address a “large unmet need” for more aggressive lipid lowering in patients with clinical atherosclerotic disease and diabetes, the authors noted.
Added to maximal statin therapy, PCSK9 inhibitors reduce LDL cholesterol by about 50% while also raising HDL cholesterol and having positive effects on other lipids, according to the authors.
Pharmacotherapy for type 2 diabetes requires a “nuanced approach” that takes into account factors such as age, comorbidities, and risk of hypoglycemia, the authors wrote, noting that the AACE supports a hemoglobin A1c target of 6.5% or less for most patients.
The algorithm for glycemic control lists glucose-lowering agents in order of recommended usage. For example, in patients with an entry HbA1c less than 7.5%, the strongest recommendations for were monotherapy with metformin, followed by GLP1 receptor agonists and sodium-glucose cotransporter 2 (SGLT2) inhibitors.
If insulin becomes necessary, the recommended approach is to add a single daily dose of basal insulin, and if a basal insulin regimen fails to control glucose, it may help to add a GLP1 receptor agonist or dipeptidyl peptidase 4 (DPP4) inhibitor, according to the algorithm.
Avoiding hypoglycemia is important, and one possible “safety measure” to prevent that is using a continuous glucose monitoring device that provides real-time glucose data. “Significant advances have been made in accuracy and availability of CGM devices,” the authors wrote.
Current expert consensus is that clinical CGM devices should be considered if patients have not achieved their glycemic target after 3 months or if they need a treatment that puts them at risk for hypoglycemia, according to Dr. Garber and his colleagues.
Dr. Garber reported that he had no financial relationships relevant to the consensus statement and algorithm. Coauthors of the report provided disclosures related to Novo Nordisk, Eli Lilly, Janssen Pharmaceuticals, Abbott, Sanofi-Aventis, and other pharmaceutical companies.
cenews@mdedge.com
SOURCE: Garber AJ et al. Endocr Pract. 2019 Jan;25(1):91-120.
Leading endocrinology societies have copublished an algorithm offering updated, specific clinical guidance on lifestyle therapy, management of hypertension and dyslipidemia, and glucose control in patients with type 2 diabetes.
This update from the American Association of Clinical Endocrinologists and the American College of Endocrinology, published in Endocrine Practice, also highlights obesity and prediabetes as underlying risk factors for development of diabetes.
The algorithm, based on new and “comprehensive clinical data” on type 2 diabetes management, is designed as a supplement 2015 AACE/ACE clinical practice guidelines, according to Alan J. Garber, MD, PhD, chair of the Diabetes Management Algorithm Task Force.
“It’s intended to provide clinicians with a practical guide that prompts them to look for factors or influences in the patient’s lifestyle or health that may be a factor in identifying the best treatment approach or medication,” he said in a statement.
Lifestyle medication is critical for all patients with diabetes, according to Dr. Garber and the algorithm coauthors, who recommended a “primarily plant-based meal plan” that limits intake of saturated fatty acids and avoids trans fats. They said overweight patients should restrict caloric intake with a goal of reducing body weight by up to 10%.
Physical activity should include at least 150 minutes per week of activities such as brisk walking or weight training, they said, adding that patients should be advised to sleep 7 hours per night, on average.
Weight loss medications might be needed along with lifestyle modification for patients with body mass index (BMI) over 27 kg/m2 with complications, and for all patients with BMI over 30 regardless of whether they have complications, according to the AACE/ACE committee members who drafted the report.
Bariatric surgery might be considered in patients with BMI over 35 and comorbidities, particularly if patients fail to achieve weight loss goals using other means, they added.
The primary goal of prediabetes management is weight loss, wrote the authors. While there are no Food and Drug Administration–approved agents for prediabetes management, they said, antihyperglycemic agents such as metformin and acarbose have been shown to reduce risk of diabetes by 25%-30% in patients with prediabetes.
While pressure control needs to be individualized, but a goal of less than 130/80 mm Hg is warranted for most patients with diabetes, according to the authors, who note that most patients will require medication to reach their goal.
“Because angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers can slow progression of nephropathy and retinopathy, they are preferred for patients with type 2 diabetes,” said Dr. Garber and his coauthors in the executive summary accompanying the algorithm.
Early and intensive management of dyslipidemia is important to reduce the significant risk of atherosclerotic cardiovascular disease in patients with diabetes, according to the authors, who say diabetes patients should be classified as high risk, very high risk, or extreme risk. They recommended LDL cholesterol targets of less than 100 mg/dL for high-risk patients, less than 70 mg/dL for very-high-risk patients, and less than 55 mg/dL for the extreme-risk group.
Statins should be considered first-line treatment for lowering cholesterol, unless contraindicated, with other lipid-modifying agents added as needed to reach lipid targets.
Inhibitors of proprotein convertase subtilisin/kexin type 9 serine protease (PCSK9) address a “large unmet need” for more aggressive lipid lowering in patients with clinical atherosclerotic disease and diabetes, the authors noted.
Added to maximal statin therapy, PCSK9 inhibitors reduce LDL cholesterol by about 50% while also raising HDL cholesterol and having positive effects on other lipids, according to the authors.
Pharmacotherapy for type 2 diabetes requires a “nuanced approach” that takes into account factors such as age, comorbidities, and risk of hypoglycemia, the authors wrote, noting that the AACE supports a hemoglobin A1c target of 6.5% or less for most patients.
The algorithm for glycemic control lists glucose-lowering agents in order of recommended usage. For example, in patients with an entry HbA1c less than 7.5%, the strongest recommendations for were monotherapy with metformin, followed by GLP1 receptor agonists and sodium-glucose cotransporter 2 (SGLT2) inhibitors.
If insulin becomes necessary, the recommended approach is to add a single daily dose of basal insulin, and if a basal insulin regimen fails to control glucose, it may help to add a GLP1 receptor agonist or dipeptidyl peptidase 4 (DPP4) inhibitor, according to the algorithm.
Avoiding hypoglycemia is important, and one possible “safety measure” to prevent that is using a continuous glucose monitoring device that provides real-time glucose data. “Significant advances have been made in accuracy and availability of CGM devices,” the authors wrote.
Current expert consensus is that clinical CGM devices should be considered if patients have not achieved their glycemic target after 3 months or if they need a treatment that puts them at risk for hypoglycemia, according to Dr. Garber and his colleagues.
Dr. Garber reported that he had no financial relationships relevant to the consensus statement and algorithm. Coauthors of the report provided disclosures related to Novo Nordisk, Eli Lilly, Janssen Pharmaceuticals, Abbott, Sanofi-Aventis, and other pharmaceutical companies.
cenews@mdedge.com
SOURCE: Garber AJ et al. Endocr Pract. 2019 Jan;25(1):91-120.
FROM ENDOCRINE PRACTICE
PTSD, cardiovascular disease link likely caused by higher comorbidity burden
Although PTSD is strongly linked to cardiovascular disease, it is not an independent risk factor, results of a recent analysis suggest.
Instead, the association between PTSD and cardiovascular disease (CVD) is likely explained by factors such as smoking and physical and psychiatric disorders, according to authors of the analysis based on EHR data for more than 4,000 U.S. veterans.
Individuals with PTSD were 41% more likely than those without it to develop cardiovascular disease, according to the researchers, led by Jeffrey F. Scherrer, PhD, of Saint Louis University and the Harry S. Truman Veterans Administration Medical Center in Columbia, Mo.
However, PTSD was not associated with CVD in the study after adjustment for physical, psychiatric, and behavioral conditions, Dr. Scherrer and his colleagues reported in the Journal of the American Heart Association.
“Recognizing that PTSD does not preordain CVD may empower patients to seek care to prevent and/or manage CVD risk factors,” they wrote.
Health behavior change and management of chronic disease can mitigate risk of CVD in patients with or without PTSD, they added.
This result contrasts with earlier work associating PTSD with CVD, the authors wrote. In particular, a few well-designed studies did indicate that the link between PTSD and CVD was weakened, but still significant, when controlling for traditional CVD risk factors such as smoking, diabetes, and hypertension.
In the current study, investigators controlled for a variety of physical and psychiatric conditions, as well as smoking, in data for Veterans Affairs patients, of whom 2,519 had a PTSD diagnosis and 1,659 did not. These patients were 87% male, 60% white, and had an average age of 50 years.
The investigators found that PTSD was significantly associated with incident CVD after adjusting for age, with a hazard ratio of 1.41 (95% confidence interval, 1.21-1.63; P less than .0001).
That association remained significant after adjusting for diabetes, obesity, hypertension, and hyperlipidemia, but the magnitude of the association dropped considerably (HR, 1.23; 95% CI, 1.06-1.44; P less than .007) and dropped out altogether after controlling for smoking, substance abuse, sleep disorders, anxiety, and depression (HR, 0.96; 95% CI, 0.81-1.15; P = .691).
Taken together, these findings suggest the association with incident CVD may be explained by combinations of comorbidities that are more prevalent in patients who have PTSD than in those who do not, Dr. Scherrer and his coauthors wrote.
“Because these conditions are more common in patients with PTSD, closer monitoring for comorbidities may be warranted,” they concluded. “Early detection and effective management may reduce the burden of CVD associated with PTSD.”
One study coinvestigator reported consulting for Noblis Therapeutics and grant-related disclosures with the Department of Veterans Affairs, Department of Defense, and National Institute of Mental Health.
SOURCE: Scherrer JF et al. J Am Heart Assoc. 2019 Feb 13. doi: 10.1161/JAHA.118.011133.
Although PTSD is strongly linked to cardiovascular disease, it is not an independent risk factor, results of a recent analysis suggest.
Instead, the association between PTSD and cardiovascular disease (CVD) is likely explained by factors such as smoking and physical and psychiatric disorders, according to authors of the analysis based on EHR data for more than 4,000 U.S. veterans.
Individuals with PTSD were 41% more likely than those without it to develop cardiovascular disease, according to the researchers, led by Jeffrey F. Scherrer, PhD, of Saint Louis University and the Harry S. Truman Veterans Administration Medical Center in Columbia, Mo.
However, PTSD was not associated with CVD in the study after adjustment for physical, psychiatric, and behavioral conditions, Dr. Scherrer and his colleagues reported in the Journal of the American Heart Association.
“Recognizing that PTSD does not preordain CVD may empower patients to seek care to prevent and/or manage CVD risk factors,” they wrote.
Health behavior change and management of chronic disease can mitigate risk of CVD in patients with or without PTSD, they added.
This result contrasts with earlier work associating PTSD with CVD, the authors wrote. In particular, a few well-designed studies did indicate that the link between PTSD and CVD was weakened, but still significant, when controlling for traditional CVD risk factors such as smoking, diabetes, and hypertension.
In the current study, investigators controlled for a variety of physical and psychiatric conditions, as well as smoking, in data for Veterans Affairs patients, of whom 2,519 had a PTSD diagnosis and 1,659 did not. These patients were 87% male, 60% white, and had an average age of 50 years.
The investigators found that PTSD was significantly associated with incident CVD after adjusting for age, with a hazard ratio of 1.41 (95% confidence interval, 1.21-1.63; P less than .0001).
That association remained significant after adjusting for diabetes, obesity, hypertension, and hyperlipidemia, but the magnitude of the association dropped considerably (HR, 1.23; 95% CI, 1.06-1.44; P less than .007) and dropped out altogether after controlling for smoking, substance abuse, sleep disorders, anxiety, and depression (HR, 0.96; 95% CI, 0.81-1.15; P = .691).
Taken together, these findings suggest the association with incident CVD may be explained by combinations of comorbidities that are more prevalent in patients who have PTSD than in those who do not, Dr. Scherrer and his coauthors wrote.
“Because these conditions are more common in patients with PTSD, closer monitoring for comorbidities may be warranted,” they concluded. “Early detection and effective management may reduce the burden of CVD associated with PTSD.”
One study coinvestigator reported consulting for Noblis Therapeutics and grant-related disclosures with the Department of Veterans Affairs, Department of Defense, and National Institute of Mental Health.
SOURCE: Scherrer JF et al. J Am Heart Assoc. 2019 Feb 13. doi: 10.1161/JAHA.118.011133.
Although PTSD is strongly linked to cardiovascular disease, it is not an independent risk factor, results of a recent analysis suggest.
Instead, the association between PTSD and cardiovascular disease (CVD) is likely explained by factors such as smoking and physical and psychiatric disorders, according to authors of the analysis based on EHR data for more than 4,000 U.S. veterans.
Individuals with PTSD were 41% more likely than those without it to develop cardiovascular disease, according to the researchers, led by Jeffrey F. Scherrer, PhD, of Saint Louis University and the Harry S. Truman Veterans Administration Medical Center in Columbia, Mo.
However, PTSD was not associated with CVD in the study after adjustment for physical, psychiatric, and behavioral conditions, Dr. Scherrer and his colleagues reported in the Journal of the American Heart Association.
“Recognizing that PTSD does not preordain CVD may empower patients to seek care to prevent and/or manage CVD risk factors,” they wrote.
Health behavior change and management of chronic disease can mitigate risk of CVD in patients with or without PTSD, they added.
This result contrasts with earlier work associating PTSD with CVD, the authors wrote. In particular, a few well-designed studies did indicate that the link between PTSD and CVD was weakened, but still significant, when controlling for traditional CVD risk factors such as smoking, diabetes, and hypertension.
In the current study, investigators controlled for a variety of physical and psychiatric conditions, as well as smoking, in data for Veterans Affairs patients, of whom 2,519 had a PTSD diagnosis and 1,659 did not. These patients were 87% male, 60% white, and had an average age of 50 years.
The investigators found that PTSD was significantly associated with incident CVD after adjusting for age, with a hazard ratio of 1.41 (95% confidence interval, 1.21-1.63; P less than .0001).
That association remained significant after adjusting for diabetes, obesity, hypertension, and hyperlipidemia, but the magnitude of the association dropped considerably (HR, 1.23; 95% CI, 1.06-1.44; P less than .007) and dropped out altogether after controlling for smoking, substance abuse, sleep disorders, anxiety, and depression (HR, 0.96; 95% CI, 0.81-1.15; P = .691).
Taken together, these findings suggest the association with incident CVD may be explained by combinations of comorbidities that are more prevalent in patients who have PTSD than in those who do not, Dr. Scherrer and his coauthors wrote.
“Because these conditions are more common in patients with PTSD, closer monitoring for comorbidities may be warranted,” they concluded. “Early detection and effective management may reduce the burden of CVD associated with PTSD.”
One study coinvestigator reported consulting for Noblis Therapeutics and grant-related disclosures with the Department of Veterans Affairs, Department of Defense, and National Institute of Mental Health.
SOURCE: Scherrer JF et al. J Am Heart Assoc. 2019 Feb 13. doi: 10.1161/JAHA.118.011133.
FROM THE JOURNAL OF THE AMERICAN HEART ASSOCIATION
Key clinical point: The link between PTSD and cardiovascular disease may be explained by higher prevalence of comorbidities in individuals with the disorder, rather than the disorder itself.
Major finding: PTSD was significantly associated with incident cardiovascular disease after adjusting for age, but was no longer associated with cardiovascular disease after further adjustment for physical and psychological comorbidities and smoking (hazard ratio, 0.96; 95% confidence interval, 0.81-1.15; P = 0.691).
Study details: A retrospective study of EHR data for Veterans Affairs patients, of whom 2,519 had a PTSD diagnosis and 1,659 did not.
Disclosures: One study author reported financial disclosures related to Noblis Therapeutics, the Department of Veterans Affairs, Department of Defense, the National Institute of Mental Health.
Source: Scherrer JF et al. J Am Heart Assoc. 2019 Feb 13. doi: 10.1161/JAHA.118.011133.
DAAs reduce mortality, cancer risk in HCV study
Direct-acting antivirals significantly decrease risk of hepatocellular carcinoma and mortality in persons with hepatitis C, according to results of the first prospective, longitudinal study to evaluate the effect of the drugs on complications related to the infection.
Compared with no treatment, DAA therapy cut risk of hepatocellular carcinoma by about one-third and all-cause mortality by about half in the study, which included about 10,000 adult patients with chronic hepatitis C virus (HCV) infection treated at 1 of 32 hepatology centers in France (NCT01953458).
There were no signs of increased risk of hepatocellular carcinoma during treatment with DAAs, providing more evidence refuting earlier, single-center reports that had suggested an increased incidence early after treatment. These findings also counterbalance a recent Cochrane review that could not confirm or reject a potential benefit of drugs on long-term morbidity and mortality.
Results of the study, published in the Lancet, are based on analysis of 9,895 patients, including 7,344 who started DAA treatment and 2,551 who remained untreated at a median follow-up of more than 31 months. The median patient age was 56 years, and 53% were men.
Treatment with DAAs reduced risk of hepatocellular carcinoma when compared with no DAA treatment, with a hazard ratio of 0.66 (95% confidence interval, 0.46-0.93), and reduced risk of all-cause mortality, with an HR of 0.48 (95% CI, 0.33-0.70), investigators reported in a multivariable analysis that adjusted for variables including age, sex, fibrosis score, HCV genotype, alcohol use, and more.
“These inverse associations persisted in the subgroup of patients who achieved a sustained virological response, whereas those who did not achieve a sustained virological response were a higher risk for hepatocellular carcinoma,” said the investigators, led by Fabrice Carrat, PhD, of Sorbonne Université, Institut National de la Santé et de la Recherche Médicale (INSERM), Paris.
Sustained virologic response was observed in 94% of patients who had known response status and sufficient follow-up, investigators said.
In patients with cirrhosis at baseline, DAA treatment had a similarly strong association with reduced hepatocellular carcinoma and mortality, with a sustained virologic response rate of 92% in those for whom sufficient data was available, they said.
There was no evidence for an increased risk of hepatocellular carcinoma on treatment, with an adjusted HR of 0.74 (95% CI, 0.49-1.13; P = 0.17), they added.
“Our results support urgent treatment of patients with advanced liver disease and extension of the follow-up of treated patients with less severe disease to assess the long-term clinical effect of direct-acting antiviral treatment,” Dr. Carrat and colleagues said in a commentary on their results.
However, the long-term effect of DAAs on liver decompensation has yet to be clarified, they added, noting that their study excluded patients with decompensated cirrhosis or a history of hepatocellular carcinoma.
Funding for the study came from INSERM, Agence Nationale de la Recherche, DGS (Direction Générale de la Santé), MSD, Janssen, Gilead, AbbVie, Bristol-Myers Squibb, and Roche. Dr. Carrat reported personal fees from Imaxio not related to the present study. Coauthors provided additional disclosures related to Gilead, AbbVie, Bristol-Myers Squibb, MSD, and Janssen, among others.
SOURCE: Carrat F et al. Lancet. 2019 Feb 11. doi: 10.1016/S0140-6736(18)32111-1
This study provides “substantive evidence” that curing hepatitis C virus with all-oral direct-acting antiviral regimens provides clinical benefits, according to Raymond T. Chung, MD, and his coauthors of a related editorial.
Investigators in this study provide the best evidence so far in support of guidelines that advise direct-acting antiviral (DAA) treatment for all patients with chronic hepatitis C virus (HCV) infection, the editorial’s authors stated.
Results of the French study provide a strong counterpoint to the findings of a recent Cochrane review of DAA trials that could not confirm or reject whether DAAs had effects on long-term morbidity and mortality related to HCV, added Dr. Chung and his coauthors. “Finally, they provide credence to the achievability of the goals set out by the World Health Organization (WHO), not only to eliminate HCV but also to substantially reduce its complications.”
The WHO targets were established in light of earlier evidence that sustained virologic responses are linked to reductions in hepatocellular carcinoma, liver transplantation, and mortality, they said.
“In view of the high sustained virological response and excellent tolerability achieved with DAAs, it seemed highly plausible to envision reductions in chronic HCV infection–related complications with these drugs,” they said in reference to the study by Carrat and colleagues.
This editorial appearing in the Lancet was authored by Jacinta A. Holmes, Stephanie M. Rutledge, and Raymond T. Chung of the Liver Center, Gastrointestinal Division, Massachusetts General Hospital, Boston. Dr. Chung provided disclosures related to AbbVie, Gilead, Merck, Bristol-Myers Squibb, Roche, Janssen, and Boehringer Ingelheim.
This study provides “substantive evidence” that curing hepatitis C virus with all-oral direct-acting antiviral regimens provides clinical benefits, according to Raymond T. Chung, MD, and his coauthors of a related editorial.
Investigators in this study provide the best evidence so far in support of guidelines that advise direct-acting antiviral (DAA) treatment for all patients with chronic hepatitis C virus (HCV) infection, the editorial’s authors stated.
Results of the French study provide a strong counterpoint to the findings of a recent Cochrane review of DAA trials that could not confirm or reject whether DAAs had effects on long-term morbidity and mortality related to HCV, added Dr. Chung and his coauthors. “Finally, they provide credence to the achievability of the goals set out by the World Health Organization (WHO), not only to eliminate HCV but also to substantially reduce its complications.”
The WHO targets were established in light of earlier evidence that sustained virologic responses are linked to reductions in hepatocellular carcinoma, liver transplantation, and mortality, they said.
“In view of the high sustained virological response and excellent tolerability achieved with DAAs, it seemed highly plausible to envision reductions in chronic HCV infection–related complications with these drugs,” they said in reference to the study by Carrat and colleagues.
This editorial appearing in the Lancet was authored by Jacinta A. Holmes, Stephanie M. Rutledge, and Raymond T. Chung of the Liver Center, Gastrointestinal Division, Massachusetts General Hospital, Boston. Dr. Chung provided disclosures related to AbbVie, Gilead, Merck, Bristol-Myers Squibb, Roche, Janssen, and Boehringer Ingelheim.
This study provides “substantive evidence” that curing hepatitis C virus with all-oral direct-acting antiviral regimens provides clinical benefits, according to Raymond T. Chung, MD, and his coauthors of a related editorial.
Investigators in this study provide the best evidence so far in support of guidelines that advise direct-acting antiviral (DAA) treatment for all patients with chronic hepatitis C virus (HCV) infection, the editorial’s authors stated.
Results of the French study provide a strong counterpoint to the findings of a recent Cochrane review of DAA trials that could not confirm or reject whether DAAs had effects on long-term morbidity and mortality related to HCV, added Dr. Chung and his coauthors. “Finally, they provide credence to the achievability of the goals set out by the World Health Organization (WHO), not only to eliminate HCV but also to substantially reduce its complications.”
The WHO targets were established in light of earlier evidence that sustained virologic responses are linked to reductions in hepatocellular carcinoma, liver transplantation, and mortality, they said.
“In view of the high sustained virological response and excellent tolerability achieved with DAAs, it seemed highly plausible to envision reductions in chronic HCV infection–related complications with these drugs,” they said in reference to the study by Carrat and colleagues.
This editorial appearing in the Lancet was authored by Jacinta A. Holmes, Stephanie M. Rutledge, and Raymond T. Chung of the Liver Center, Gastrointestinal Division, Massachusetts General Hospital, Boston. Dr. Chung provided disclosures related to AbbVie, Gilead, Merck, Bristol-Myers Squibb, Roche, Janssen, and Boehringer Ingelheim.
Direct-acting antivirals significantly decrease risk of hepatocellular carcinoma and mortality in persons with hepatitis C, according to results of the first prospective, longitudinal study to evaluate the effect of the drugs on complications related to the infection.
Compared with no treatment, DAA therapy cut risk of hepatocellular carcinoma by about one-third and all-cause mortality by about half in the study, which included about 10,000 adult patients with chronic hepatitis C virus (HCV) infection treated at 1 of 32 hepatology centers in France (NCT01953458).
There were no signs of increased risk of hepatocellular carcinoma during treatment with DAAs, providing more evidence refuting earlier, single-center reports that had suggested an increased incidence early after treatment. These findings also counterbalance a recent Cochrane review that could not confirm or reject a potential benefit of drugs on long-term morbidity and mortality.
Results of the study, published in the Lancet, are based on analysis of 9,895 patients, including 7,344 who started DAA treatment and 2,551 who remained untreated at a median follow-up of more than 31 months. The median patient age was 56 years, and 53% were men.
Treatment with DAAs reduced risk of hepatocellular carcinoma when compared with no DAA treatment, with a hazard ratio of 0.66 (95% confidence interval, 0.46-0.93), and reduced risk of all-cause mortality, with an HR of 0.48 (95% CI, 0.33-0.70), investigators reported in a multivariable analysis that adjusted for variables including age, sex, fibrosis score, HCV genotype, alcohol use, and more.
“These inverse associations persisted in the subgroup of patients who achieved a sustained virological response, whereas those who did not achieve a sustained virological response were a higher risk for hepatocellular carcinoma,” said the investigators, led by Fabrice Carrat, PhD, of Sorbonne Université, Institut National de la Santé et de la Recherche Médicale (INSERM), Paris.
Sustained virologic response was observed in 94% of patients who had known response status and sufficient follow-up, investigators said.
In patients with cirrhosis at baseline, DAA treatment had a similarly strong association with reduced hepatocellular carcinoma and mortality, with a sustained virologic response rate of 92% in those for whom sufficient data was available, they said.
There was no evidence for an increased risk of hepatocellular carcinoma on treatment, with an adjusted HR of 0.74 (95% CI, 0.49-1.13; P = 0.17), they added.
“Our results support urgent treatment of patients with advanced liver disease and extension of the follow-up of treated patients with less severe disease to assess the long-term clinical effect of direct-acting antiviral treatment,” Dr. Carrat and colleagues said in a commentary on their results.
However, the long-term effect of DAAs on liver decompensation has yet to be clarified, they added, noting that their study excluded patients with decompensated cirrhosis or a history of hepatocellular carcinoma.
Funding for the study came from INSERM, Agence Nationale de la Recherche, DGS (Direction Générale de la Santé), MSD, Janssen, Gilead, AbbVie, Bristol-Myers Squibb, and Roche. Dr. Carrat reported personal fees from Imaxio not related to the present study. Coauthors provided additional disclosures related to Gilead, AbbVie, Bristol-Myers Squibb, MSD, and Janssen, among others.
SOURCE: Carrat F et al. Lancet. 2019 Feb 11. doi: 10.1016/S0140-6736(18)32111-1
Direct-acting antivirals significantly decrease risk of hepatocellular carcinoma and mortality in persons with hepatitis C, according to results of the first prospective, longitudinal study to evaluate the effect of the drugs on complications related to the infection.
Compared with no treatment, DAA therapy cut risk of hepatocellular carcinoma by about one-third and all-cause mortality by about half in the study, which included about 10,000 adult patients with chronic hepatitis C virus (HCV) infection treated at 1 of 32 hepatology centers in France (NCT01953458).
There were no signs of increased risk of hepatocellular carcinoma during treatment with DAAs, providing more evidence refuting earlier, single-center reports that had suggested an increased incidence early after treatment. These findings also counterbalance a recent Cochrane review that could not confirm or reject a potential benefit of drugs on long-term morbidity and mortality.
Results of the study, published in the Lancet, are based on analysis of 9,895 patients, including 7,344 who started DAA treatment and 2,551 who remained untreated at a median follow-up of more than 31 months. The median patient age was 56 years, and 53% were men.
Treatment with DAAs reduced risk of hepatocellular carcinoma when compared with no DAA treatment, with a hazard ratio of 0.66 (95% confidence interval, 0.46-0.93), and reduced risk of all-cause mortality, with an HR of 0.48 (95% CI, 0.33-0.70), investigators reported in a multivariable analysis that adjusted for variables including age, sex, fibrosis score, HCV genotype, alcohol use, and more.
“These inverse associations persisted in the subgroup of patients who achieved a sustained virological response, whereas those who did not achieve a sustained virological response were a higher risk for hepatocellular carcinoma,” said the investigators, led by Fabrice Carrat, PhD, of Sorbonne Université, Institut National de la Santé et de la Recherche Médicale (INSERM), Paris.
Sustained virologic response was observed in 94% of patients who had known response status and sufficient follow-up, investigators said.
In patients with cirrhosis at baseline, DAA treatment had a similarly strong association with reduced hepatocellular carcinoma and mortality, with a sustained virologic response rate of 92% in those for whom sufficient data was available, they said.
There was no evidence for an increased risk of hepatocellular carcinoma on treatment, with an adjusted HR of 0.74 (95% CI, 0.49-1.13; P = 0.17), they added.
“Our results support urgent treatment of patients with advanced liver disease and extension of the follow-up of treated patients with less severe disease to assess the long-term clinical effect of direct-acting antiviral treatment,” Dr. Carrat and colleagues said in a commentary on their results.
However, the long-term effect of DAAs on liver decompensation has yet to be clarified, they added, noting that their study excluded patients with decompensated cirrhosis or a history of hepatocellular carcinoma.
Funding for the study came from INSERM, Agence Nationale de la Recherche, DGS (Direction Générale de la Santé), MSD, Janssen, Gilead, AbbVie, Bristol-Myers Squibb, and Roche. Dr. Carrat reported personal fees from Imaxio not related to the present study. Coauthors provided additional disclosures related to Gilead, AbbVie, Bristol-Myers Squibb, MSD, and Janssen, among others.
SOURCE: Carrat F et al. Lancet. 2019 Feb 11. doi: 10.1016/S0140-6736(18)32111-1
FROM THE LANCET
Key clinical point:
Major finding: DAAs reduced risk of hepatocellular carcinoma (HR, 0.66; 95% confidence interval, 0.46-0.93) and all-cause mortality (HR, 0.48; 95% CI, 0.33-0.70).
Study details: A prospective study including about 10,000 adults with chronic HCV infection enrolled at 1 of 32 centers in France.
Disclosures: Funding for the study came from INSERM, Agence Nationale de la Recherche, DGS (Direction Générale de la Santé), MSD, Janssen, Gilead, AbbVie, Bristol-Myers Squibb, and Roche. Dr. Carrat reported personal fees from Imaxio not related to the present study. Coauthors provided additional disclosures related to the study pharma sponsors among others.
Source: Carrat F et al. Lancet. 2019 Feb 11. doi: 10.1016/20S0140-6736(18)32111-1.