Hematology

Tisagenlecleucel failed to outperform standard of care treatment when given as a second-line treatment for certain patients with relapsed/refractory aggressive non-Hodgkin lymphomas, according to results of a randomized, phase 3 trial.

The chimeric antigen receptor (CAR) T-cell therapy did not improve event-free survival (EFS) in this phase 3 BELINDA study, potentially because of study design decisions or imbalances in relevant patient characteristics, according to the study investigators.

Despite the negative result, insights from this study will inform the development of future clinical trials of CAR T-cell therapy, said BELINDA investigator Michael R. Bishop, MD, of the David and Etta Jonas Center for Cellular Therapy, University of Chicago.

Findings of BELINDA, presented at the annual meeting of the American Society of Hematology, stand in contrast to two other high-profile CAR T-cell therapy studies also presented at the meeting. Those other studies demonstrated significant improvements in EFS in the second-line treatment of large B-cell lymphomas.

“All of us are excited to see that the other two trials were positive, and we were hoping that ours would be as well, but there are significant differences in the trial design,” Dr. Bishop said in a press conference held at the ASH meeting.

Tisagenlecleucel (tisa-cel), an anti-CD19 CAR T-cell therapy, is already approved by the Food and Drug Administration for the treatment of patients with relapsed or refractory large B-cell lymphomas after at least two other lines of systemic therapy.

The aim of the pivotal phase 3, randomized, multicenter BELINDA study was to evaluate tisa-cel earlier in the course of treatment for patients with more aggressive disease, according to Dr. Bishop.

About two-thirds of non-Hodgkin lymphoma patients will be cured with first-line treatment. However, very poor outcomes are seen among patients with disease that does not respond to the initial treatment or that reoccurs shortly afterward, Dr. Bishop said.

The standard of care approach for those patients is second-line therapy, he noted, usually with combination chemoimmunotherapy, followed by autologous stem cell transplant if the disease responds to chemotherapy.

“Unfortunately, only a minority of those patients will be found to have chemotherapy-sensitive disease and be able to go on to autologous stem cell transplantation,” Dr. Bishop said. “And even in that subgroup of patients, the outcomes are relatively poor.”

Accordingly, the phase 3 BELINDA study enrolled patients with aggressive non-Hodgkin lymphomas that either did not respond to first-line treatment or that reoccurred within 12 months.

The primary endpoint of the study was EFS, defined as the time from randomization to either stable or progressive disease at or after a week 12 assessment or to any-cause death at any time.

While that primary endpoint was not met for tisa-cel versus standard of care therapy, two other randomized, phase 3 studies presented at the ASH meeting did demonstrate that CAR T-cell therapy extended EFS when given as a second-line lymphoma treatment.

In the randomized, phase 3 ZUMA-7 trial, axicabtagene ciloleucel (axi-cel) significantly improved EFS versus standard of care in the treatment of patients with large B-cell lymphoma refractory to or relapsed within 12 months of adequate first-line therapy, according to investigators.

Similarly, the investigators said that treatment with lisocabtagene maraleucel (liso-cel) led to a significant improvement in EFS in TRANSFORM, a randomized, phase 3 clinical trial that enrolled patients with large B-cell lymphoma that was refractory to first-line therapy or else relapsed within 12 months of that treatment.

“It’s very possible that either or both the patient characteristics and the study design is what led to the difference in the top-line study results,” lymphoma specialist Andrew M. Evens, DO, said in an interview.

There were substantial differences between the studies in terms of what was allowed as optional bridging therapy and salvage therapy, according to Dr. Evens, associate director for clinical services and director of the lymphoma program at Rutgers Cancer Institute in New Brunswick, N.J.

“In ZUMA-7, they only allowed steroids as bridging therapy,” said Dr. Evens, who was not an investigator on any of the three second-line CAR T-cell studies.

In the BELINDA study, optional platinum-based chemotherapy bridging treatment allowed in one arm of the study could have potentially delayed tisa-cel infusion until after the week 6 assessment, study investigators reported in their ASH meeting abstract.

Differences in lymphodepleting therapy prior to CAR T-cell therapy could have also played a role. According to Dr. Bishop, the total doses of cyclophosphamide and fludarabine in BELINDA were 900 mg/m2 and 75 mg/m2, respectively, while in the other two trials, doses were 1,500 mg/m² and 90 mg/m², respectively.

Lymphodepleting chemotherapy is “extremely important” in the success of CAR T-cell therapeutic approaches, he noted at the press conference.

Dr. Bishop reported receiving consultancy fees from Arcellx, Autolus Therapeutics, Bristol-Myers Squibb, CRISPR, Kite/Gilead, and Novartis. He also reported research funding from Bristol-Myers Squibb and Kite/Gilead.

Tisagenlecleucel failed to outperform standard of care treatment when given as a second-line treatment for certain patients with relapsed/refractory aggressive non-Hodgkin lymphomas, according to results of a randomized, phase 3 trial.

The chimeric antigen receptor (CAR) T-cell therapy did not improve event-free survival (EFS) in this phase 3 BELINDA study, potentially because of study design decisions or imbalances in relevant patient characteristics, according to the study investigators.

Despite the negative result, insights from this study will inform the development of future clinical trials of CAR T-cell therapy, said BELINDA investigator Michael R. Bishop, MD, of the David and Etta Jonas Center for Cellular Therapy, University of Chicago.

Findings of BELINDA, presented at the annual meeting of the American Society of Hematology, stand in contrast to two other high-profile CAR T-cell therapy studies also presented at the meeting. Those other studies demonstrated significant improvements in EFS in the second-line treatment of large B-cell lymphomas.

“All of us are excited to see that the other two trials were positive, and we were hoping that ours would be as well, but there are significant differences in the trial design,” Dr. Bishop said in a press conference held at the ASH meeting.

Tisagenlecleucel (tisa-cel), an anti-CD19 CAR T-cell therapy, is already approved by the Food and Drug Administration for the treatment of patients with relapsed or refractory large B-cell lymphomas after at least two other lines of systemic therapy.

The aim of the pivotal phase 3, randomized, multicenter BELINDA study was to evaluate tisa-cel earlier in the course of treatment for patients with more aggressive disease, according to Dr. Bishop.

About two-thirds of non-Hodgkin lymphoma patients will be cured with first-line treatment. However, very poor outcomes are seen among patients with disease that does not respond to the initial treatment or that reoccurs shortly afterward, Dr. Bishop said.

The standard of care approach for those patients is second-line therapy, he noted, usually with combination chemoimmunotherapy, followed by autologous stem cell transplant if the disease responds to chemotherapy.

“Unfortunately, only a minority of those patients will be found to have chemotherapy-sensitive disease and be able to go on to autologous stem cell transplantation,” Dr. Bishop said. “And even in that subgroup of patients, the outcomes are relatively poor.”

Accordingly, the phase 3 BELINDA study enrolled patients with aggressive non-Hodgkin lymphomas that either did not respond to first-line treatment or that reoccurred within 12 months.

The primary endpoint of the study was EFS, defined as the time from randomization to either stable or progressive disease at or after a week 12 assessment or to any-cause death at any time.

While that primary endpoint was not met for tisa-cel versus standard of care therapy, two other randomized, phase 3 studies presented at the ASH meeting did demonstrate that CAR T-cell therapy extended EFS when given as a second-line lymphoma treatment.

In the randomized, phase 3 ZUMA-7 trial, axicabtagene ciloleucel (axi-cel) significantly improved EFS versus standard of care in the treatment of patients with large B-cell lymphoma refractory to or relapsed within 12 months of adequate first-line therapy, according to investigators.

Similarly, the investigators said that treatment with lisocabtagene maraleucel (liso-cel) led to a significant improvement in EFS in TRANSFORM, a randomized, phase 3 clinical trial that enrolled patients with large B-cell lymphoma that was refractory to first-line therapy or else relapsed within 12 months of that treatment.

“It’s very possible that either or both the patient characteristics and the study design is what led to the difference in the top-line study results,” lymphoma specialist Andrew M. Evens, DO, said in an interview.

There were substantial differences between the studies in terms of what was allowed as optional bridging therapy and salvage therapy, according to Dr. Evens, associate director for clinical services and director of the lymphoma program at Rutgers Cancer Institute in New Brunswick, N.J.

“In ZUMA-7, they only allowed steroids as bridging therapy,” said Dr. Evens, who was not an investigator on any of the three second-line CAR T-cell studies.

In the BELINDA study, optional platinum-based chemotherapy bridging treatment allowed in one arm of the study could have potentially delayed tisa-cel infusion until after the week 6 assessment, study investigators reported in their ASH meeting abstract.

Differences in lymphodepleting therapy prior to CAR T-cell therapy could have also played a role. According to Dr. Bishop, the total doses of cyclophosphamide and fludarabine in BELINDA were 900 mg/m2 and 75 mg/m2, respectively, while in the other two trials, doses were 1,500 mg/m² and 90 mg/m², respectively.

Lymphodepleting chemotherapy is “extremely important” in the success of CAR T-cell therapeutic approaches, he noted at the press conference.

Dr. Bishop reported receiving consultancy fees from Arcellx, Autolus Therapeutics, Bristol-Myers Squibb, CRISPR, Kite/Gilead, and Novartis. He also reported research funding from Bristol-Myers Squibb and Kite/Gilead.

Tisagenlecleucel failed to outperform standard of care treatment when given as a second-line treatment for certain patients with relapsed/refractory aggressive non-Hodgkin lymphomas, according to results of a randomized, phase 3 trial.

The chimeric antigen receptor (CAR) T-cell therapy did not improve event-free survival (EFS) in this phase 3 BELINDA study, potentially because of study design decisions or imbalances in relevant patient characteristics, according to the study investigators.

Despite the negative result, insights from this study will inform the development of future clinical trials of CAR T-cell therapy, said BELINDA investigator Michael R. Bishop, MD, of the David and Etta Jonas Center for Cellular Therapy, University of Chicago.

Findings of BELINDA, presented at the annual meeting of the American Society of Hematology, stand in contrast to two other high-profile CAR T-cell therapy studies also presented at the meeting. Those other studies demonstrated significant improvements in EFS in the second-line treatment of large B-cell lymphomas.

“All of us are excited to see that the other two trials were positive, and we were hoping that ours would be as well, but there are significant differences in the trial design,” Dr. Bishop said in a press conference held at the ASH meeting.

Tisagenlecleucel (tisa-cel), an anti-CD19 CAR T-cell therapy, is already approved by the Food and Drug Administration for the treatment of patients with relapsed or refractory large B-cell lymphomas after at least two other lines of systemic therapy.

The aim of the pivotal phase 3, randomized, multicenter BELINDA study was to evaluate tisa-cel earlier in the course of treatment for patients with more aggressive disease, according to Dr. Bishop.

About two-thirds of non-Hodgkin lymphoma patients will be cured with first-line treatment. However, very poor outcomes are seen among patients with disease that does not respond to the initial treatment or that reoccurs shortly afterward, Dr. Bishop said.

The standard of care approach for those patients is second-line therapy, he noted, usually with combination chemoimmunotherapy, followed by autologous stem cell transplant if the disease responds to chemotherapy.

“Unfortunately, only a minority of those patients will be found to have chemotherapy-sensitive disease and be able to go on to autologous stem cell transplantation,” Dr. Bishop said. “And even in that subgroup of patients, the outcomes are relatively poor.”

Accordingly, the phase 3 BELINDA study enrolled patients with aggressive non-Hodgkin lymphomas that either did not respond to first-line treatment or that reoccurred within 12 months.

The primary endpoint of the study was EFS, defined as the time from randomization to either stable or progressive disease at or after a week 12 assessment or to any-cause death at any time.

While that primary endpoint was not met for tisa-cel versus standard of care therapy, two other randomized, phase 3 studies presented at the ASH meeting did demonstrate that CAR T-cell therapy extended EFS when given as a second-line lymphoma treatment.

In the randomized, phase 3 ZUMA-7 trial, axicabtagene ciloleucel (axi-cel) significantly improved EFS versus standard of care in the treatment of patients with large B-cell lymphoma refractory to or relapsed within 12 months of adequate first-line therapy, according to investigators.

Similarly, the investigators said that treatment with lisocabtagene maraleucel (liso-cel) led to a significant improvement in EFS in TRANSFORM, a randomized, phase 3 clinical trial that enrolled patients with large B-cell lymphoma that was refractory to first-line therapy or else relapsed within 12 months of that treatment.

“It’s very possible that either or both the patient characteristics and the study design is what led to the difference in the top-line study results,” lymphoma specialist Andrew M. Evens, DO, said in an interview.

There were substantial differences between the studies in terms of what was allowed as optional bridging therapy and salvage therapy, according to Dr. Evens, associate director for clinical services and director of the lymphoma program at Rutgers Cancer Institute in New Brunswick, N.J.

“In ZUMA-7, they only allowed steroids as bridging therapy,” said Dr. Evens, who was not an investigator on any of the three second-line CAR T-cell studies.

In the BELINDA study, optional platinum-based chemotherapy bridging treatment allowed in one arm of the study could have potentially delayed tisa-cel infusion until after the week 6 assessment, study investigators reported in their ASH meeting abstract.

Differences in lymphodepleting therapy prior to CAR T-cell therapy could have also played a role. According to Dr. Bishop, the total doses of cyclophosphamide and fludarabine in BELINDA were 900 mg/m2 and 75 mg/m2, respectively, while in the other two trials, doses were 1,500 mg/m² and 90 mg/m², respectively.

Lymphodepleting chemotherapy is “extremely important” in the success of CAR T-cell therapeutic approaches, he noted at the press conference.

Dr. Bishop reported receiving consultancy fees from Arcellx, Autolus Therapeutics, Bristol-Myers Squibb, CRISPR, Kite/Gilead, and Novartis. He also reported research funding from Bristol-Myers Squibb and Kite/Gilead.

ATLANTA – Older patients with acute lymphoblastic leukemia positive for the Philadelphia chromosome (Ph+ALL) are often not fit enough to withstand intensive chemotherapy and stem cell transplants, but remissions with alternative therapies are usually short lived.

Now, results from an ongoing study suggest that the combination of the tyrosine kinase inhibitor (TKI) dastatinib (Sprycel) with the bispecific T-cell engager (BiTE) blinatumomab (Blincyto), together with prednisone, may significantly improve remission rates and prolong both progression-free and overall survival among older and/or less fit patients with Ph+ALL.

The new results were reported by investigators in the SWOG Cancer Research Network and come from a cohort of 25 patients with a median age of 73 years with newly diagnosed Ph+ALL or ALL with dasatinib-sensitive fusions of mutations (Ph-like ALL).

Nearly all (23 of 25 patients, 92%) had complete remissions, and 5 of 16 patients for whom minimal residual disease (MRD) data were available were MRD negative at day 28, said Anjali Advani, MD, from the Cleveland Clinic.

At a median follow-up of 1.7 years, the estimated 3-year disease-free survival rate was 80%, and the estimated overall survival rate was 85%, the investigators reported in a poster presentation at the annual meeting of the American Society of Hematology.

“I think the biggest question will be longer-term follow-up. We clearly see high remission rates in this population, but the issue is whether in these elderly patients who are not candidates for chemo we can prolong remission by the addition of other treatments, such as blinatumomab,” she said in an interview with this news organization.

“The follow-up is reasonable at this point, and as we get longer follow-up, if the current 3-year survival estimates hold up, that would be very encouraging,” she said.
 

Early promise

A leukemia specialist who was not involved in the study told this news organization that the results are promising, but added that it’s too early to make definitive judgments about the efficacy of the combination.

“People have used just a tyrosine kinase inhibitor and prednisone in these patients and gotten remissions, but they just don’t last,” said Peter Emanuel, MD, from CHI St. Vincent Infirmary in Little Rock, Ark.

“The promise with this approach is that you’re getting a longer-lasting remission – maybe not a cure, but a longer-lasting remission – without having to use intensive chemotherapy,” he said.

“It’s still a pretty small study, so I think this is going to require a bigger trial, looking at more patients, but it’s certainly very encouraging and very promising,” he added.

Hanno Hock, MD, PhD, a leukemia researcher at the Mass General Cancer Center in Boston, said in an interview that “the whole idea here is to add this newer agent, blinatumomab, to make those good initial responses more durable, and it looks like it is able to do that with very impressive initial data,” he said.

“The caveat is that this is still early, and one needs to wait and see how it all pans out, but it’s very well tolerated, and definitely the next logical step in trying to offer something to people who cannot tolerate more aggressive therapy such as transplant,” Dr. Hock added.
 

Study results

The new results come from a feasibility cohort of patients enrolled in the SWOG S1318 trial, which studied blinatumomab plus chemotherapy and prednisone in older patients with Ph-ALL, as well as blinatumomab, dasatinib, and prednisone in older adults with Ph+ ALL.

Patients 65 and older with newly diagnosed or relapsed/refractory Ph+ALL or Ph-like ALL and no central nervous system disease were eligible for the arm of the trial described here. All patients with data reported in this analysis had newly diagnosed ALL.

Patients first received a single induction cycle of dasatinib and prednisone and were then evaluated for response. Patients with a complete remission (CR) or CR with incomplete recovery of blood counts (CRi) would then undergo prednisone tapering while continuing dasatinib until day 84. Patients without a CR or CRi at day 28 who had remissions by day 56 then also continued dasatinib until day 84.

Those patients still in remission at day 84 went on to three cycles of blinatumomab and dasatinib, followed by dasatinib and prednisone maintenance until unacceptable toxicity or disease progression. Patients may remain on maintenance for up to 10 years after registration.

Patients who do not have a CR or CRi by day 84 can receive reinduction with up to two total cycles of blinatumomab, with those who get a remission moving on to the blinatumomab/ dasatinib combination and those who do not going off protocol.

Of the 25 patients, 23 had a CR following dasatinib/prednisone induction. As noted, 5 of 16 patients evaluable for MRD were MRD negative.

Four patients did not receive postremission therapy, two because of adverse events, one who went on to transplant, and one because of insurance issues.

In a safety review early in the study, 4 of 12 evaluable patients were found to have dose-limiting toxicities, including one case each of grade 3 dyspnea and gastrointestinal pain (in a single patient), hypertension, dyspnea, and hyperglycemia.

These adverse events were deemed acceptable by both U.S. Food and Drug Administration and National Cancer Institute reviewers, and this arm of the study was allowed to continue, Dr. Advani noted.

The study was funded by grants from the National Institutes of Health. Dr. Advani disclosed financial relationships with several companies. Dr. Emanuel and Dr. Hock have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

ATLANTA – Older patients with acute lymphoblastic leukemia positive for the Philadelphia chromosome (Ph+ALL) are often not fit enough to withstand intensive chemotherapy and stem cell transplants, but remissions with alternative therapies are usually short lived.

Now, results from an ongoing study suggest that the combination of the tyrosine kinase inhibitor (TKI) dastatinib (Sprycel) with the bispecific T-cell engager (BiTE) blinatumomab (Blincyto), together with prednisone, may significantly improve remission rates and prolong both progression-free and overall survival among older and/or less fit patients with Ph+ALL.

The new results were reported by investigators in the SWOG Cancer Research Network and come from a cohort of 25 patients with a median age of 73 years with newly diagnosed Ph+ALL or ALL with dasatinib-sensitive fusions of mutations (Ph-like ALL).

Nearly all (23 of 25 patients, 92%) had complete remissions, and 5 of 16 patients for whom minimal residual disease (MRD) data were available were MRD negative at day 28, said Anjali Advani, MD, from the Cleveland Clinic.

At a median follow-up of 1.7 years, the estimated 3-year disease-free survival rate was 80%, and the estimated overall survival rate was 85%, the investigators reported in a poster presentation at the annual meeting of the American Society of Hematology.

“I think the biggest question will be longer-term follow-up. We clearly see high remission rates in this population, but the issue is whether in these elderly patients who are not candidates for chemo we can prolong remission by the addition of other treatments, such as blinatumomab,” she said in an interview with this news organization.

“The follow-up is reasonable at this point, and as we get longer follow-up, if the current 3-year survival estimates hold up, that would be very encouraging,” she said.
 

Early promise

A leukemia specialist who was not involved in the study told this news organization that the results are promising, but added that it’s too early to make definitive judgments about the efficacy of the combination.

“People have used just a tyrosine kinase inhibitor and prednisone in these patients and gotten remissions, but they just don’t last,” said Peter Emanuel, MD, from CHI St. Vincent Infirmary in Little Rock, Ark.

“The promise with this approach is that you’re getting a longer-lasting remission – maybe not a cure, but a longer-lasting remission – without having to use intensive chemotherapy,” he said.

“It’s still a pretty small study, so I think this is going to require a bigger trial, looking at more patients, but it’s certainly very encouraging and very promising,” he added.

Hanno Hock, MD, PhD, a leukemia researcher at the Mass General Cancer Center in Boston, said in an interview that “the whole idea here is to add this newer agent, blinatumomab, to make those good initial responses more durable, and it looks like it is able to do that with very impressive initial data,” he said.

“The caveat is that this is still early, and one needs to wait and see how it all pans out, but it’s very well tolerated, and definitely the next logical step in trying to offer something to people who cannot tolerate more aggressive therapy such as transplant,” Dr. Hock added.
 

Study results

The new results come from a feasibility cohort of patients enrolled in the SWOG S1318 trial, which studied blinatumomab plus chemotherapy and prednisone in older patients with Ph-ALL, as well as blinatumomab, dasatinib, and prednisone in older adults with Ph+ ALL.

Patients 65 and older with newly diagnosed or relapsed/refractory Ph+ALL or Ph-like ALL and no central nervous system disease were eligible for the arm of the trial described here. All patients with data reported in this analysis had newly diagnosed ALL.

Patients first received a single induction cycle of dasatinib and prednisone and were then evaluated for response. Patients with a complete remission (CR) or CR with incomplete recovery of blood counts (CRi) would then undergo prednisone tapering while continuing dasatinib until day 84. Patients without a CR or CRi at day 28 who had remissions by day 56 then also continued dasatinib until day 84.

Those patients still in remission at day 84 went on to three cycles of blinatumomab and dasatinib, followed by dasatinib and prednisone maintenance until unacceptable toxicity or disease progression. Patients may remain on maintenance for up to 10 years after registration.

Patients who do not have a CR or CRi by day 84 can receive reinduction with up to two total cycles of blinatumomab, with those who get a remission moving on to the blinatumomab/ dasatinib combination and those who do not going off protocol.

Of the 25 patients, 23 had a CR following dasatinib/prednisone induction. As noted, 5 of 16 patients evaluable for MRD were MRD negative.

Four patients did not receive postremission therapy, two because of adverse events, one who went on to transplant, and one because of insurance issues.

In a safety review early in the study, 4 of 12 evaluable patients were found to have dose-limiting toxicities, including one case each of grade 3 dyspnea and gastrointestinal pain (in a single patient), hypertension, dyspnea, and hyperglycemia.

These adverse events were deemed acceptable by both U.S. Food and Drug Administration and National Cancer Institute reviewers, and this arm of the study was allowed to continue, Dr. Advani noted.

The study was funded by grants from the National Institutes of Health. Dr. Advani disclosed financial relationships with several companies. Dr. Emanuel and Dr. Hock have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

ATLANTA – Older patients with acute lymphoblastic leukemia positive for the Philadelphia chromosome (Ph+ALL) are often not fit enough to withstand intensive chemotherapy and stem cell transplants, but remissions with alternative therapies are usually short lived.

Now, results from an ongoing study suggest that the combination of the tyrosine kinase inhibitor (TKI) dastatinib (Sprycel) with the bispecific T-cell engager (BiTE) blinatumomab (Blincyto), together with prednisone, may significantly improve remission rates and prolong both progression-free and overall survival among older and/or less fit patients with Ph+ALL.

The new results were reported by investigators in the SWOG Cancer Research Network and come from a cohort of 25 patients with a median age of 73 years with newly diagnosed Ph+ALL or ALL with dasatinib-sensitive fusions of mutations (Ph-like ALL).

Nearly all (23 of 25 patients, 92%) had complete remissions, and 5 of 16 patients for whom minimal residual disease (MRD) data were available were MRD negative at day 28, said Anjali Advani, MD, from the Cleveland Clinic.

At a median follow-up of 1.7 years, the estimated 3-year disease-free survival rate was 80%, and the estimated overall survival rate was 85%, the investigators reported in a poster presentation at the annual meeting of the American Society of Hematology.

“I think the biggest question will be longer-term follow-up. We clearly see high remission rates in this population, but the issue is whether in these elderly patients who are not candidates for chemo we can prolong remission by the addition of other treatments, such as blinatumomab,” she said in an interview with this news organization.

“The follow-up is reasonable at this point, and as we get longer follow-up, if the current 3-year survival estimates hold up, that would be very encouraging,” she said.
 

Early promise

A leukemia specialist who was not involved in the study told this news organization that the results are promising, but added that it’s too early to make definitive judgments about the efficacy of the combination.

“People have used just a tyrosine kinase inhibitor and prednisone in these patients and gotten remissions, but they just don’t last,” said Peter Emanuel, MD, from CHI St. Vincent Infirmary in Little Rock, Ark.

“The promise with this approach is that you’re getting a longer-lasting remission – maybe not a cure, but a longer-lasting remission – without having to use intensive chemotherapy,” he said.

“It’s still a pretty small study, so I think this is going to require a bigger trial, looking at more patients, but it’s certainly very encouraging and very promising,” he added.

Hanno Hock, MD, PhD, a leukemia researcher at the Mass General Cancer Center in Boston, said in an interview that “the whole idea here is to add this newer agent, blinatumomab, to make those good initial responses more durable, and it looks like it is able to do that with very impressive initial data,” he said.

“The caveat is that this is still early, and one needs to wait and see how it all pans out, but it’s very well tolerated, and definitely the next logical step in trying to offer something to people who cannot tolerate more aggressive therapy such as transplant,” Dr. Hock added.
 

Study results

The new results come from a feasibility cohort of patients enrolled in the SWOG S1318 trial, which studied blinatumomab plus chemotherapy and prednisone in older patients with Ph-ALL, as well as blinatumomab, dasatinib, and prednisone in older adults with Ph+ ALL.

Patients 65 and older with newly diagnosed or relapsed/refractory Ph+ALL or Ph-like ALL and no central nervous system disease were eligible for the arm of the trial described here. All patients with data reported in this analysis had newly diagnosed ALL.

Patients first received a single induction cycle of dasatinib and prednisone and were then evaluated for response. Patients with a complete remission (CR) or CR with incomplete recovery of blood counts (CRi) would then undergo prednisone tapering while continuing dasatinib until day 84. Patients without a CR or CRi at day 28 who had remissions by day 56 then also continued dasatinib until day 84.

Those patients still in remission at day 84 went on to three cycles of blinatumomab and dasatinib, followed by dasatinib and prednisone maintenance until unacceptable toxicity or disease progression. Patients may remain on maintenance for up to 10 years after registration.

Patients who do not have a CR or CRi by day 84 can receive reinduction with up to two total cycles of blinatumomab, with those who get a remission moving on to the blinatumomab/ dasatinib combination and those who do not going off protocol.

Of the 25 patients, 23 had a CR following dasatinib/prednisone induction. As noted, 5 of 16 patients evaluable for MRD were MRD negative.

Four patients did not receive postremission therapy, two because of adverse events, one who went on to transplant, and one because of insurance issues.

In a safety review early in the study, 4 of 12 evaluable patients were found to have dose-limiting toxicities, including one case each of grade 3 dyspnea and gastrointestinal pain (in a single patient), hypertension, dyspnea, and hyperglycemia.

These adverse events were deemed acceptable by both U.S. Food and Drug Administration and National Cancer Institute reviewers, and this arm of the study was allowed to continue, Dr. Advani noted.

The study was funded by grants from the National Institutes of Health. Dr. Advani disclosed financial relationships with several companies. Dr. Emanuel and Dr. Hock have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Nearly every patient with a myeloid malignancy seroconverted against COVID-19 after their second dose of the Moderna vaccine in a review of 46 patients at the Moffitt Cancer Center in Tampa, Fla.

Factors including age, gender, race, disease status, lower-intensity active treatment, baseline neutrophil and lymphocyte counts, and past history of stem cell transplant had no effects on seroconversion in the study, which, despite its small numbers, is one of the largest series to date among patients with myeloid cancers. The findings were reported at the annual meeting of the American Society of Hematology.

COVID vaccination “appears to induce a strong antibody response” in patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), unlike with B-cell malignancies. “It indicates we should be aggressive about vaccinating such patients,” said senior investigator Jeffrey Lancet, MD, a blood cancer specialist at Moffitt, when he presented the findings at the meeting.

Presentation moderator Laura Michaelis, MD, a hematologist-oncologist at the Medical College of Wisconsin, Milwaukee, agreed.

The “strong antibody response in this group,” coupled with its high risk for severe COVID, “confirm the importance of these patients getting vaccinated,” she said.

Thirty patients with AML and 16 with MDS were included in the review. Most patients were in remission at the time of vaccination, but a third were in active treatment, including six on hypomethylating agents, six on targeted therapies, two on luspatercept, and one on lenalidomide. Thirty-two patients (69.6%) were a median of 17 months past allogeneic stem cell transplant.

Overall, 69.6% of patients developed IgG against spike proteins after the first shot and 95.7% of patients after the second dose, with a large increase in titer levels from the first to the second dose, from a mean of 315 AU/mL to 3,806.5 AU/mL following the second dose.

“Lab and clinical variables did not affect the antibody positivity rate after the second dose,” but patients on steroids and other immunosuppressants seemed less likely to respond to the first shot, Dr. Lancet said.

The study, conducted in early 2021, did not include acutely ill patients or those undergoing cheomotherapy induction and other aggressive treatments, because such patients were not being vaccinated at Moffitt during the study period.

The investigators measured anti-spike IgG by ELISA at baseline, then again about a month after the first shot and a month after the second shot.

Side effects were common and typically mild, including injection site pain, fatigue, headache, and arm swelling. Two patients with AML relapsed after vaccination.

Patients were a median of 68 years old when they were vaccinated; 58.7% were men; and almost all of the subjects were White. The median time from diagnosis to the first shot was 2 years.

The next step in the project is to study the timing of vaccination and response to it among patients on aggressive treatment and to perform neutralizing antibody assays to correlate IgG response with protection from COVID.

No funding was reported for the study. Investigators had numerous industry ties, including Dr. Lancet, a consultant for Celgene/BMS, Millenium Pharma/Takeda, AbbVie, and other firms. Dr. Michaelis didn’t have any disclosures.

[email protected]

Nearly every patient with a myeloid malignancy seroconverted against COVID-19 after their second dose of the Moderna vaccine in a review of 46 patients at the Moffitt Cancer Center in Tampa, Fla.

Factors including age, gender, race, disease status, lower-intensity active treatment, baseline neutrophil and lymphocyte counts, and past history of stem cell transplant had no effects on seroconversion in the study, which, despite its small numbers, is one of the largest series to date among patients with myeloid cancers. The findings were reported at the annual meeting of the American Society of Hematology.

COVID vaccination “appears to induce a strong antibody response” in patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), unlike with B-cell malignancies. “It indicates we should be aggressive about vaccinating such patients,” said senior investigator Jeffrey Lancet, MD, a blood cancer specialist at Moffitt, when he presented the findings at the meeting.

Presentation moderator Laura Michaelis, MD, a hematologist-oncologist at the Medical College of Wisconsin, Milwaukee, agreed.

The “strong antibody response in this group,” coupled with its high risk for severe COVID, “confirm the importance of these patients getting vaccinated,” she said.

Thirty patients with AML and 16 with MDS were included in the review. Most patients were in remission at the time of vaccination, but a third were in active treatment, including six on hypomethylating agents, six on targeted therapies, two on luspatercept, and one on lenalidomide. Thirty-two patients (69.6%) were a median of 17 months past allogeneic stem cell transplant.

Overall, 69.6% of patients developed IgG against spike proteins after the first shot and 95.7% of patients after the second dose, with a large increase in titer levels from the first to the second dose, from a mean of 315 AU/mL to 3,806.5 AU/mL following the second dose.

“Lab and clinical variables did not affect the antibody positivity rate after the second dose,” but patients on steroids and other immunosuppressants seemed less likely to respond to the first shot, Dr. Lancet said.

The study, conducted in early 2021, did not include acutely ill patients or those undergoing cheomotherapy induction and other aggressive treatments, because such patients were not being vaccinated at Moffitt during the study period.

The investigators measured anti-spike IgG by ELISA at baseline, then again about a month after the first shot and a month after the second shot.

Side effects were common and typically mild, including injection site pain, fatigue, headache, and arm swelling. Two patients with AML relapsed after vaccination.

Patients were a median of 68 years old when they were vaccinated; 58.7% were men; and almost all of the subjects were White. The median time from diagnosis to the first shot was 2 years.

The next step in the project is to study the timing of vaccination and response to it among patients on aggressive treatment and to perform neutralizing antibody assays to correlate IgG response with protection from COVID.

No funding was reported for the study. Investigators had numerous industry ties, including Dr. Lancet, a consultant for Celgene/BMS, Millenium Pharma/Takeda, AbbVie, and other firms. Dr. Michaelis didn’t have any disclosures.

[email protected]

Nearly every patient with a myeloid malignancy seroconverted against COVID-19 after their second dose of the Moderna vaccine in a review of 46 patients at the Moffitt Cancer Center in Tampa, Fla.

Factors including age, gender, race, disease status, lower-intensity active treatment, baseline neutrophil and lymphocyte counts, and past history of stem cell transplant had no effects on seroconversion in the study, which, despite its small numbers, is one of the largest series to date among patients with myeloid cancers. The findings were reported at the annual meeting of the American Society of Hematology.

COVID vaccination “appears to induce a strong antibody response” in patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), unlike with B-cell malignancies. “It indicates we should be aggressive about vaccinating such patients,” said senior investigator Jeffrey Lancet, MD, a blood cancer specialist at Moffitt, when he presented the findings at the meeting.

Presentation moderator Laura Michaelis, MD, a hematologist-oncologist at the Medical College of Wisconsin, Milwaukee, agreed.

The “strong antibody response in this group,” coupled with its high risk for severe COVID, “confirm the importance of these patients getting vaccinated,” she said.

Thirty patients with AML and 16 with MDS were included in the review. Most patients were in remission at the time of vaccination, but a third were in active treatment, including six on hypomethylating agents, six on targeted therapies, two on luspatercept, and one on lenalidomide. Thirty-two patients (69.6%) were a median of 17 months past allogeneic stem cell transplant.

Overall, 69.6% of patients developed IgG against spike proteins after the first shot and 95.7% of patients after the second dose, with a large increase in titer levels from the first to the second dose, from a mean of 315 AU/mL to 3,806.5 AU/mL following the second dose.

“Lab and clinical variables did not affect the antibody positivity rate after the second dose,” but patients on steroids and other immunosuppressants seemed less likely to respond to the first shot, Dr. Lancet said.

The study, conducted in early 2021, did not include acutely ill patients or those undergoing cheomotherapy induction and other aggressive treatments, because such patients were not being vaccinated at Moffitt during the study period.

The investigators measured anti-spike IgG by ELISA at baseline, then again about a month after the first shot and a month after the second shot.

Side effects were common and typically mild, including injection site pain, fatigue, headache, and arm swelling. Two patients with AML relapsed after vaccination.

Patients were a median of 68 years old when they were vaccinated; 58.7% were men; and almost all of the subjects were White. The median time from diagnosis to the first shot was 2 years.

The next step in the project is to study the timing of vaccination and response to it among patients on aggressive treatment and to perform neutralizing antibody assays to correlate IgG response with protection from COVID.

No funding was reported for the study. Investigators had numerous industry ties, including Dr. Lancet, a consultant for Celgene/BMS, Millenium Pharma/Takeda, AbbVie, and other firms. Dr. Michaelis didn’t have any disclosures.

[email protected]

Factors associated with the worst COVID-19-related outcomes for patients with acute leukemias and myelodysplastic syndromes include neutropenia, pre-COVID-19 prognosis, and deferral of ICU care, results of an American Society of Hematology (ASH) COVID-19 registry study suggest.

Rates of severe COVID-19 were significantly higher among patients who had active disease or neutropenia at the time of their COVID-19 diagnosis. Mortality related to COVID-19 was linked to neutropenia, primary disease prognosis of less than 6 months, and deferral of recommended ICU care, study results show.

By contrast, mortality was not associated with active primary disease or its treatment, according to researcher Pinkal Desai, MD, MPH.

Taken together, these findings provide preliminary evidence to support the use of aggressive supportive treatment of COVID-19 in patients with acute leukemias and myelodysplastic syndromes, said Dr. Desai, a hematologist-oncologist with Weill Cornell Medicine and NewYork-Presbyterian in New York.

“If desired by patients, aggressive support for hospitalized patients with COVID-19 is appropriate, regardless of remission status, given the results of our study,” Dr. Desai said in a press conference during the annual meeting of the American Society of Hematology.

In non-cancer patient populations, advanced age and cytopenias have been associated with mortality related to COVID-19, Dr. Desai said. Likewise, patients with acute leukemias and myelodysplastic syndrome are generally older and have disease- or treatment-related cytopenias, which might affect the severity of and mortality from COVID-19, she added.

With that concern in mind, Dr. Desai and co-investigators looked at predictors of severe COVID-19 disease and death among patients in the ASH Research Collaborative (ASH RC) COVID-19 Registry for Hematology.

This registry was started in the early days of the pandemic to provide real-time observational COVID-19 data to clinicians, according to an ASH news release.

The analysis by Dr. Desai and co-authors included 257 patients with COVID-19 as determined by their physician, including 135 with a primary diagnosis of acute myeloid leukemia, 82 with acute lymphocytic leukemia, and 40 with myelodysplastic syndromes. Sixty percent of the patients were hospitalized due to COVID-19.

At the time of COVID-19 diagnosis, 46% of patients were in remission, and 44% had active disease, according to the report.

Both neutropenia and active disease status at COVID-19 diagnosis were linked to severe COVID-19, defined as ICU admission due to a COVID-19-related reason, according to results of multivariable analysis. Among patients with severe COVID-19, 67% had active disease, meaning just 33% were in remission, Dr. Desai noted.

In multivariable analysis, two factors were significantly associated with mortality, she added: having an estimated pre-COVID-19 prognosis from the primary disease of less than 6 months, and deferral of ICU care when it was recommended to the patient.

Mortality was 21% overall, higher than would be expected in a non-cancer population, Dr. Desai said. For patients with COVID-19 requiring hospitalization, the mortality rate was 34% and for those patients who did go to the ICU, the mortality rate was 68%.

By contrast, there was no significant association between mortality and active disease as compared to disease in remission, Dr. Desai noted in her presentation. Likewise, mortality was not associated with active treatment at the time of COVID-19 diagnosis as compared to no treatment.

The Leukemia & Lymphoma Society

Gwen Nichols, MD, executive vice president and chief medical officer of the Leukemia & Lymphoma Society, New York, said those are reassuring data for patients with acute leukemias and myelodysplastic syndromes and their healthcare providers.

“From our point of view, it helps us say, ‘do not stop your treatment because of worries about COVID-19—it’s more important that you treat your cancer,” Dr. Nichols said in an interview. “We now know we can help people through COVID-19, and I think this is just really important data to back that up,” she added.

Dr. Desai provided disclosures related to Agios, Kura Oncology, and Bristol Myers Squibb (consultancy), and to Janssen R&D and Astex (research funding).

Factors associated with the worst COVID-19-related outcomes for patients with acute leukemias and myelodysplastic syndromes include neutropenia, pre-COVID-19 prognosis, and deferral of ICU care, results of an American Society of Hematology (ASH) COVID-19 registry study suggest.

Rates of severe COVID-19 were significantly higher among patients who had active disease or neutropenia at the time of their COVID-19 diagnosis. Mortality related to COVID-19 was linked to neutropenia, primary disease prognosis of less than 6 months, and deferral of recommended ICU care, study results show.

By contrast, mortality was not associated with active primary disease or its treatment, according to researcher Pinkal Desai, MD, MPH.

Taken together, these findings provide preliminary evidence to support the use of aggressive supportive treatment of COVID-19 in patients with acute leukemias and myelodysplastic syndromes, said Dr. Desai, a hematologist-oncologist with Weill Cornell Medicine and NewYork-Presbyterian in New York.

“If desired by patients, aggressive support for hospitalized patients with COVID-19 is appropriate, regardless of remission status, given the results of our study,” Dr. Desai said in a press conference during the annual meeting of the American Society of Hematology.

In non-cancer patient populations, advanced age and cytopenias have been associated with mortality related to COVID-19, Dr. Desai said. Likewise, patients with acute leukemias and myelodysplastic syndrome are generally older and have disease- or treatment-related cytopenias, which might affect the severity of and mortality from COVID-19, she added.

With that concern in mind, Dr. Desai and co-investigators looked at predictors of severe COVID-19 disease and death among patients in the ASH Research Collaborative (ASH RC) COVID-19 Registry for Hematology.

This registry was started in the early days of the pandemic to provide real-time observational COVID-19 data to clinicians, according to an ASH news release.

The analysis by Dr. Desai and co-authors included 257 patients with COVID-19 as determined by their physician, including 135 with a primary diagnosis of acute myeloid leukemia, 82 with acute lymphocytic leukemia, and 40 with myelodysplastic syndromes. Sixty percent of the patients were hospitalized due to COVID-19.

At the time of COVID-19 diagnosis, 46% of patients were in remission, and 44% had active disease, according to the report.

Both neutropenia and active disease status at COVID-19 diagnosis were linked to severe COVID-19, defined as ICU admission due to a COVID-19-related reason, according to results of multivariable analysis. Among patients with severe COVID-19, 67% had active disease, meaning just 33% were in remission, Dr. Desai noted.

In multivariable analysis, two factors were significantly associated with mortality, she added: having an estimated pre-COVID-19 prognosis from the primary disease of less than 6 months, and deferral of ICU care when it was recommended to the patient.

Mortality was 21% overall, higher than would be expected in a non-cancer population, Dr. Desai said. For patients with COVID-19 requiring hospitalization, the mortality rate was 34% and for those patients who did go to the ICU, the mortality rate was 68%.

By contrast, there was no significant association between mortality and active disease as compared to disease in remission, Dr. Desai noted in her presentation. Likewise, mortality was not associated with active treatment at the time of COVID-19 diagnosis as compared to no treatment.

The Leukemia & Lymphoma Society

Gwen Nichols, MD, executive vice president and chief medical officer of the Leukemia & Lymphoma Society, New York, said those are reassuring data for patients with acute leukemias and myelodysplastic syndromes and their healthcare providers.

“From our point of view, it helps us say, ‘do not stop your treatment because of worries about COVID-19—it’s more important that you treat your cancer,” Dr. Nichols said in an interview. “We now know we can help people through COVID-19, and I think this is just really important data to back that up,” she added.

Dr. Desai provided disclosures related to Agios, Kura Oncology, and Bristol Myers Squibb (consultancy), and to Janssen R&D and Astex (research funding).

Factors associated with the worst COVID-19-related outcomes for patients with acute leukemias and myelodysplastic syndromes include neutropenia, pre-COVID-19 prognosis, and deferral of ICU care, results of an American Society of Hematology (ASH) COVID-19 registry study suggest.

Rates of severe COVID-19 were significantly higher among patients who had active disease or neutropenia at the time of their COVID-19 diagnosis. Mortality related to COVID-19 was linked to neutropenia, primary disease prognosis of less than 6 months, and deferral of recommended ICU care, study results show.

By contrast, mortality was not associated with active primary disease or its treatment, according to researcher Pinkal Desai, MD, MPH.

Taken together, these findings provide preliminary evidence to support the use of aggressive supportive treatment of COVID-19 in patients with acute leukemias and myelodysplastic syndromes, said Dr. Desai, a hematologist-oncologist with Weill Cornell Medicine and NewYork-Presbyterian in New York.

“If desired by patients, aggressive support for hospitalized patients with COVID-19 is appropriate, regardless of remission status, given the results of our study,” Dr. Desai said in a press conference during the annual meeting of the American Society of Hematology.

In non-cancer patient populations, advanced age and cytopenias have been associated with mortality related to COVID-19, Dr. Desai said. Likewise, patients with acute leukemias and myelodysplastic syndrome are generally older and have disease- or treatment-related cytopenias, which might affect the severity of and mortality from COVID-19, she added.

With that concern in mind, Dr. Desai and co-investigators looked at predictors of severe COVID-19 disease and death among patients in the ASH Research Collaborative (ASH RC) COVID-19 Registry for Hematology.

This registry was started in the early days of the pandemic to provide real-time observational COVID-19 data to clinicians, according to an ASH news release.

The analysis by Dr. Desai and co-authors included 257 patients with COVID-19 as determined by their physician, including 135 with a primary diagnosis of acute myeloid leukemia, 82 with acute lymphocytic leukemia, and 40 with myelodysplastic syndromes. Sixty percent of the patients were hospitalized due to COVID-19.

At the time of COVID-19 diagnosis, 46% of patients were in remission, and 44% had active disease, according to the report.

Both neutropenia and active disease status at COVID-19 diagnosis were linked to severe COVID-19, defined as ICU admission due to a COVID-19-related reason, according to results of multivariable analysis. Among patients with severe COVID-19, 67% had active disease, meaning just 33% were in remission, Dr. Desai noted.

In multivariable analysis, two factors were significantly associated with mortality, she added: having an estimated pre-COVID-19 prognosis from the primary disease of less than 6 months, and deferral of ICU care when it was recommended to the patient.

Mortality was 21% overall, higher than would be expected in a non-cancer population, Dr. Desai said. For patients with COVID-19 requiring hospitalization, the mortality rate was 34% and for those patients who did go to the ICU, the mortality rate was 68%.

By contrast, there was no significant association between mortality and active disease as compared to disease in remission, Dr. Desai noted in her presentation. Likewise, mortality was not associated with active treatment at the time of COVID-19 diagnosis as compared to no treatment.

The Leukemia & Lymphoma Society

Gwen Nichols, MD, executive vice president and chief medical officer of the Leukemia & Lymphoma Society, New York, said those are reassuring data for patients with acute leukemias and myelodysplastic syndromes and their healthcare providers.

“From our point of view, it helps us say, ‘do not stop your treatment because of worries about COVID-19—it’s more important that you treat your cancer,” Dr. Nichols said in an interview. “We now know we can help people through COVID-19, and I think this is just really important data to back that up,” she added.

Dr. Desai provided disclosures related to Agios, Kura Oncology, and Bristol Myers Squibb (consultancy), and to Janssen R&D and Astex (research funding).

In patients with transfusion-dependent beta-thalassemia, a single gene therapy infusion is capable of yielding durable transfusion independence and substantial improvements in iron overload, an investigator reported at the annual meeting of the American Society of Hematology.

Among patients who received betibeglogene autotemcel (beti-cel) in a phase 3 trial and enrolled in a long-term follow-up study, nearly 90% achieved durable transfusion independence, according to Alexis A. Thompson, MD, MPH, of the hematology section at the Ann & Robert H. Lurie Children’s Hospital of Chicago.

The median duration of ongoing transfusion independence was nearly 3 years as of this report, which Dr. Thompson described in a press conference at the meeting.

In a subanalysis of this international study, Dr. Thompson and co-investigators reported that in patients who achieve transfusion independence, chelation reduced iron, and iron markers stabilized even after chelation was stopped.

Beyond 2 years post-infusion, no adverse events related to the drug product were seen. This suggested that the therapy has a favorable long-term safety profile, according to Dr. Thompson.

“At this point, we believe that beti-cel is potentially curative for patients with TDT [transfusion-dependent beta-thalassemia],” Dr. Thompson said in the press conference.

This study answers one of the major outstanding questions about beti-cel and iron metabolism, according to Arielle L. Langer, MD, MPH, an instructor in medicine at Harvard Medical School and attending physician for adult thalassemia patients at Brigham and Women’s and Dana Farber Cancer Institute, both in Boston.

“Seeing the restoration of iron metabolism, it really takes us a step closer to really thinking the term ‘cure’ might truly apply,” Dr. Langer said in an interview.

Dr. Langer said she looks forward to “very long-term outcomes” of beti-cel-treated patients to see whether endocrinopathies and other long-term sequelae of TDT are also abated.

“This [study] is a great intermediate point, but really, when we think about how thalassemia harms and kills our patients, we really sometimes measure that in decades,” she said.

Beta-thalassemia is caused by mutations in the beta-globin gene, resulting in reduced levels of hemoglobin. Patients with TDT, the most serious form of the disease, have severe anemia and are often dependent on red blood cell transfusions from infancy onward, Dr. Thompson said.

With chronic transfusions needed to maintain hemoglobin levels, TDT patients inevitably experience iron overload, which can lead to organ damage and can be fatal. Consequently, patients will require lifelong iron chelation therapy, she added.

Beti-cel, an investigational ex vivo gene addition therapy currently under review by the U.S. Food and Drug Administration, involves adding functional copies of a modified form of the beta-globin gene into a patient’s own hematopoietic stem cells. Once those cells are reinfused, patients may produce adult hemoglobin at levels that eliminate the need for transfusions, according to Dr. Thompson.

At the meeting, Dr. Thompson reported on patients from two phase 1/2 and two phase 3 beti-cel clinical trials who subsequently enrolled in LTF-303, a 13-year follow-up study of the gene therapy’s safety and efficacy.

A total of 57 patients were included in this report, making it the largest gene therapy program to date in any blood disorder, according to Dr. Thompson. Before receiving beti-cel, the patients, who had a broad range of thalassemia genotypes, were receiving between 10 and almost 40 red blood cell transfusions per year, she reported.

Patients ranged in age from 5 to 35 years. The median age in the phase 1/2 studies was 20 years, while in the phase 3 studies it was 15 years.

“The early experience in the phase 1/2 trials allowed us to be more comfortable with enrolling more children, and that has actually helped us to understand safety and efficacy and children in the phase 3 setting,” Dr. Thompson said.

Fertility preservation measures had been undertaken by about 59% of patients from the phase 1/2 studies and 71% of patients from the phase 3 studies, the data show.

Among patients from the phase 3 beti-cel studies who could be evaluated, 31 out of 35 (or 89%) achieved durable transfusion independence, according to the investigator.

The median duration of ongoing transfusion independence was 32 months, with a range of about 18 to 49 months, she added.

Dr. Thompson also reported a subanalysis intended to assess iron status in 16 patients who restarted and then stopped chelation. That subanalysis demonstrated iron reduction in response to chelation, and then stabilization of iron markers after chelation was stopped. Post-gene therapy chelation led to reductions in liver iron concentration and serum ferritin that remained relatively stable after chelation was stopped, she said.

Serious adverse events occurred in eight patients in the long-term follow-up study. However, adverse events related to beti-cel have been absent beyond 2 years post-infusion, according to Dr. Thompson, who added that there have been no reported cases of replication-competent lentivirus, no clonal expansion, no insertional oncogenesis, and no malignancies observed.

“Very reassuringly, there have been 2 male patients, one of whom underwent fertility preservation, who report having healthy children with their partners,” she added.

Dr. Thompson provided disclosures related to Baxalta, Biomarin, bluebird bio, Inc., Celgene/BMS, CRISPR Therapeutics, Vertex, Editas, Graphite Bio, Novartis, Agios, Beam, and Global Blood Therapeutics.
 

In patients with transfusion-dependent beta-thalassemia, a single gene therapy infusion is capable of yielding durable transfusion independence and substantial improvements in iron overload, an investigator reported at the annual meeting of the American Society of Hematology.

Among patients who received betibeglogene autotemcel (beti-cel) in a phase 3 trial and enrolled in a long-term follow-up study, nearly 90% achieved durable transfusion independence, according to Alexis A. Thompson, MD, MPH, of the hematology section at the Ann & Robert H. Lurie Children’s Hospital of Chicago.

The median duration of ongoing transfusion independence was nearly 3 years as of this report, which Dr. Thompson described in a press conference at the meeting.

In a subanalysis of this international study, Dr. Thompson and co-investigators reported that in patients who achieve transfusion independence, chelation reduced iron, and iron markers stabilized even after chelation was stopped.

Beyond 2 years post-infusion, no adverse events related to the drug product were seen. This suggested that the therapy has a favorable long-term safety profile, according to Dr. Thompson.

“At this point, we believe that beti-cel is potentially curative for patients with TDT [transfusion-dependent beta-thalassemia],” Dr. Thompson said in the press conference.

This study answers one of the major outstanding questions about beti-cel and iron metabolism, according to Arielle L. Langer, MD, MPH, an instructor in medicine at Harvard Medical School and attending physician for adult thalassemia patients at Brigham and Women’s and Dana Farber Cancer Institute, both in Boston.

“Seeing the restoration of iron metabolism, it really takes us a step closer to really thinking the term ‘cure’ might truly apply,” Dr. Langer said in an interview.

Dr. Langer said she looks forward to “very long-term outcomes” of beti-cel-treated patients to see whether endocrinopathies and other long-term sequelae of TDT are also abated.

“This [study] is a great intermediate point, but really, when we think about how thalassemia harms and kills our patients, we really sometimes measure that in decades,” she said.

Beta-thalassemia is caused by mutations in the beta-globin gene, resulting in reduced levels of hemoglobin. Patients with TDT, the most serious form of the disease, have severe anemia and are often dependent on red blood cell transfusions from infancy onward, Dr. Thompson said.

With chronic transfusions needed to maintain hemoglobin levels, TDT patients inevitably experience iron overload, which can lead to organ damage and can be fatal. Consequently, patients will require lifelong iron chelation therapy, she added.

Beti-cel, an investigational ex vivo gene addition therapy currently under review by the U.S. Food and Drug Administration, involves adding functional copies of a modified form of the beta-globin gene into a patient’s own hematopoietic stem cells. Once those cells are reinfused, patients may produce adult hemoglobin at levels that eliminate the need for transfusions, according to Dr. Thompson.

At the meeting, Dr. Thompson reported on patients from two phase 1/2 and two phase 3 beti-cel clinical trials who subsequently enrolled in LTF-303, a 13-year follow-up study of the gene therapy’s safety and efficacy.

A total of 57 patients were included in this report, making it the largest gene therapy program to date in any blood disorder, according to Dr. Thompson. Before receiving beti-cel, the patients, who had a broad range of thalassemia genotypes, were receiving between 10 and almost 40 red blood cell transfusions per year, she reported.

Patients ranged in age from 5 to 35 years. The median age in the phase 1/2 studies was 20 years, while in the phase 3 studies it was 15 years.

“The early experience in the phase 1/2 trials allowed us to be more comfortable with enrolling more children, and that has actually helped us to understand safety and efficacy and children in the phase 3 setting,” Dr. Thompson said.

Fertility preservation measures had been undertaken by about 59% of patients from the phase 1/2 studies and 71% of patients from the phase 3 studies, the data show.

Among patients from the phase 3 beti-cel studies who could be evaluated, 31 out of 35 (or 89%) achieved durable transfusion independence, according to the investigator.

The median duration of ongoing transfusion independence was 32 months, with a range of about 18 to 49 months, she added.

Dr. Thompson also reported a subanalysis intended to assess iron status in 16 patients who restarted and then stopped chelation. That subanalysis demonstrated iron reduction in response to chelation, and then stabilization of iron markers after chelation was stopped. Post-gene therapy chelation led to reductions in liver iron concentration and serum ferritin that remained relatively stable after chelation was stopped, she said.

Serious adverse events occurred in eight patients in the long-term follow-up study. However, adverse events related to beti-cel have been absent beyond 2 years post-infusion, according to Dr. Thompson, who added that there have been no reported cases of replication-competent lentivirus, no clonal expansion, no insertional oncogenesis, and no malignancies observed.

“Very reassuringly, there have been 2 male patients, one of whom underwent fertility preservation, who report having healthy children with their partners,” she added.

Dr. Thompson provided disclosures related to Baxalta, Biomarin, bluebird bio, Inc., Celgene/BMS, CRISPR Therapeutics, Vertex, Editas, Graphite Bio, Novartis, Agios, Beam, and Global Blood Therapeutics.
 

In patients with transfusion-dependent beta-thalassemia, a single gene therapy infusion is capable of yielding durable transfusion independence and substantial improvements in iron overload, an investigator reported at the annual meeting of the American Society of Hematology.

Among patients who received betibeglogene autotemcel (beti-cel) in a phase 3 trial and enrolled in a long-term follow-up study, nearly 90% achieved durable transfusion independence, according to Alexis A. Thompson, MD, MPH, of the hematology section at the Ann & Robert H. Lurie Children’s Hospital of Chicago.

The median duration of ongoing transfusion independence was nearly 3 years as of this report, which Dr. Thompson described in a press conference at the meeting.

In a subanalysis of this international study, Dr. Thompson and co-investigators reported that in patients who achieve transfusion independence, chelation reduced iron, and iron markers stabilized even after chelation was stopped.

Beyond 2 years post-infusion, no adverse events related to the drug product were seen. This suggested that the therapy has a favorable long-term safety profile, according to Dr. Thompson.

“At this point, we believe that beti-cel is potentially curative for patients with TDT [transfusion-dependent beta-thalassemia],” Dr. Thompson said in the press conference.

This study answers one of the major outstanding questions about beti-cel and iron metabolism, according to Arielle L. Langer, MD, MPH, an instructor in medicine at Harvard Medical School and attending physician for adult thalassemia patients at Brigham and Women’s and Dana Farber Cancer Institute, both in Boston.

“Seeing the restoration of iron metabolism, it really takes us a step closer to really thinking the term ‘cure’ might truly apply,” Dr. Langer said in an interview.

Dr. Langer said she looks forward to “very long-term outcomes” of beti-cel-treated patients to see whether endocrinopathies and other long-term sequelae of TDT are also abated.

“This [study] is a great intermediate point, but really, when we think about how thalassemia harms and kills our patients, we really sometimes measure that in decades,” she said.

Beta-thalassemia is caused by mutations in the beta-globin gene, resulting in reduced levels of hemoglobin. Patients with TDT, the most serious form of the disease, have severe anemia and are often dependent on red blood cell transfusions from infancy onward, Dr. Thompson said.

With chronic transfusions needed to maintain hemoglobin levels, TDT patients inevitably experience iron overload, which can lead to organ damage and can be fatal. Consequently, patients will require lifelong iron chelation therapy, she added.

Beti-cel, an investigational ex vivo gene addition therapy currently under review by the U.S. Food and Drug Administration, involves adding functional copies of a modified form of the beta-globin gene into a patient’s own hematopoietic stem cells. Once those cells are reinfused, patients may produce adult hemoglobin at levels that eliminate the need for transfusions, according to Dr. Thompson.

At the meeting, Dr. Thompson reported on patients from two phase 1/2 and two phase 3 beti-cel clinical trials who subsequently enrolled in LTF-303, a 13-year follow-up study of the gene therapy’s safety and efficacy.

A total of 57 patients were included in this report, making it the largest gene therapy program to date in any blood disorder, according to Dr. Thompson. Before receiving beti-cel, the patients, who had a broad range of thalassemia genotypes, were receiving between 10 and almost 40 red blood cell transfusions per year, she reported.

Patients ranged in age from 5 to 35 years. The median age in the phase 1/2 studies was 20 years, while in the phase 3 studies it was 15 years.

“The early experience in the phase 1/2 trials allowed us to be more comfortable with enrolling more children, and that has actually helped us to understand safety and efficacy and children in the phase 3 setting,” Dr. Thompson said.

Fertility preservation measures had been undertaken by about 59% of patients from the phase 1/2 studies and 71% of patients from the phase 3 studies, the data show.

Among patients from the phase 3 beti-cel studies who could be evaluated, 31 out of 35 (or 89%) achieved durable transfusion independence, according to the investigator.

The median duration of ongoing transfusion independence was 32 months, with a range of about 18 to 49 months, she added.

Dr. Thompson also reported a subanalysis intended to assess iron status in 16 patients who restarted and then stopped chelation. That subanalysis demonstrated iron reduction in response to chelation, and then stabilization of iron markers after chelation was stopped. Post-gene therapy chelation led to reductions in liver iron concentration and serum ferritin that remained relatively stable after chelation was stopped, she said.

Serious adverse events occurred in eight patients in the long-term follow-up study. However, adverse events related to beti-cel have been absent beyond 2 years post-infusion, according to Dr. Thompson, who added that there have been no reported cases of replication-competent lentivirus, no clonal expansion, no insertional oncogenesis, and no malignancies observed.

“Very reassuringly, there have been 2 male patients, one of whom underwent fertility preservation, who report having healthy children with their partners,” she added.

Dr. Thompson provided disclosures related to Baxalta, Biomarin, bluebird bio, Inc., Celgene/BMS, CRISPR Therapeutics, Vertex, Editas, Graphite Bio, Novartis, Agios, Beam, and Global Blood Therapeutics.
 

Background: DOACs have largely replaced VKAs as first-line therapy for venous thromboembolism in patients with adequate renal function. However, there is concern in APS that DOACs may have higher rates of recurrent thrombosis than VKAs when treating thromboembolism.

The DOAC arm was not proven to be noninferior with respect to the primary outcome of thrombotic events. The higher risk of stroke in this group suggests the need for caution in using DOACs in this population.

Bottom line: DOACs have a higher risk of stroke than VKAs in patients with APS without a significant difference in rate of a major bleed.

Citation: Ordi-Ros J et. al. Rivaroxaban versus vitamin K antagonist in antiphospholipid syndrome. Ann Intern Med. 2019;171(10):685-94. doi: 10.7326/M19-0291.

Dr. Portnoy is a hospitalist in the Division of Hospital Medicine, Mount Sinai Health System, New York.

Background: DOACs have largely replaced VKAs as first-line therapy for venous thromboembolism in patients with adequate renal function. However, there is concern in APS that DOACs may have higher rates of recurrent thrombosis than VKAs when treating thromboembolism.

The DOAC arm was not proven to be noninferior with respect to the primary outcome of thrombotic events. The higher risk of stroke in this group suggests the need for caution in using DOACs in this population.

Bottom line: DOACs have a higher risk of stroke than VKAs in patients with APS without a significant difference in rate of a major bleed.

Citation: Ordi-Ros J et. al. Rivaroxaban versus vitamin K antagonist in antiphospholipid syndrome. Ann Intern Med. 2019;171(10):685-94. doi: 10.7326/M19-0291.

Dr. Portnoy is a hospitalist in the Division of Hospital Medicine, Mount Sinai Health System, New York.

Background: DOACs have largely replaced VKAs as first-line therapy for venous thromboembolism in patients with adequate renal function. However, there is concern in APS that DOACs may have higher rates of recurrent thrombosis than VKAs when treating thromboembolism.

The DOAC arm was not proven to be noninferior with respect to the primary outcome of thrombotic events. The higher risk of stroke in this group suggests the need for caution in using DOACs in this population.

Bottom line: DOACs have a higher risk of stroke than VKAs in patients with APS without a significant difference in rate of a major bleed.

Citation: Ordi-Ros J et. al. Rivaroxaban versus vitamin K antagonist in antiphospholipid syndrome. Ann Intern Med. 2019;171(10):685-94. doi: 10.7326/M19-0291.

Dr. Portnoy is a hospitalist in the Division of Hospital Medicine, Mount Sinai Health System, New York.

Background: Over 6 million Americans are prescribed anticoagulation; however, available anticoagulation options for patients with concomitant renal impairment are limited. Until recently, warfarin was the only recommended option because of a lack of data to support the use of alternative agents in such patients. This study evaluates the safety and effectiveness of apixaban, compared with warfarin, in patients with severe renal dysfunction.

The main limitation is the retrospective observational design, which may have introduced confounding variables that were not accounted for in the analyses. The study also did not account for patient nonadherence to medication.

Bottom line: Apixaban is a reasonable alternative to warfarin in patients with severe renal impairment.

Citation: Hanni C et al. Outcomes associated with apixaban vs. warfarin in patients with renal dysfunction. Blood Adv. 2020;4(11): 2366-71. doi: 10.1182/bloodadvances.2019000972.

Dr. Narayan is a hospitalist in the Division of Hospital Medicine, Mount Sinai Health System, New York.

Background: Over 6 million Americans are prescribed anticoagulation; however, available anticoagulation options for patients with concomitant renal impairment are limited. Until recently, warfarin was the only recommended option because of a lack of data to support the use of alternative agents in such patients. This study evaluates the safety and effectiveness of apixaban, compared with warfarin, in patients with severe renal dysfunction.

The main limitation is the retrospective observational design, which may have introduced confounding variables that were not accounted for in the analyses. The study also did not account for patient nonadherence to medication.

Bottom line: Apixaban is a reasonable alternative to warfarin in patients with severe renal impairment.

Citation: Hanni C et al. Outcomes associated with apixaban vs. warfarin in patients with renal dysfunction. Blood Adv. 2020;4(11): 2366-71. doi: 10.1182/bloodadvances.2019000972.

Dr. Narayan is a hospitalist in the Division of Hospital Medicine, Mount Sinai Health System, New York.

Background: Over 6 million Americans are prescribed anticoagulation; however, available anticoagulation options for patients with concomitant renal impairment are limited. Until recently, warfarin was the only recommended option because of a lack of data to support the use of alternative agents in such patients. This study evaluates the safety and effectiveness of apixaban, compared with warfarin, in patients with severe renal dysfunction.

The main limitation is the retrospective observational design, which may have introduced confounding variables that were not accounted for in the analyses. The study also did not account for patient nonadherence to medication.

Bottom line: Apixaban is a reasonable alternative to warfarin in patients with severe renal impairment.

Citation: Hanni C et al. Outcomes associated with apixaban vs. warfarin in patients with renal dysfunction. Blood Adv. 2020;4(11): 2366-71. doi: 10.1182/bloodadvances.2019000972.

Dr. Narayan is a hospitalist in the Division of Hospital Medicine, Mount Sinai Health System, New York.

Apixaban appears to be safer and more effective than rivaroxaban for reducing risk of venous thromboembolism and bleeding, based on new research.

Recurrent venous thromboembolism (VTE) – a composite of pulmonary embolism and deep vein thrombosis – was the primary effectiveness outcome in the retrospective analysis of new-user data from almost 40,000 patients, which was published in Annals of Internal Medicine. Safety was evaluated through a composite of intracranial and gastrointestinal bleeding.

After a median follow-up of 102 days in the apixaban group and 105 days in the rivaroxaban group, apixaban demonstrated superiority for both primary outcomes.

These real-world findings may guide selection of initial anticoagulant therapy, reported lead author Ghadeer K. Dawwas, PhD, MSc, MBA, of the University of Pennsylvania, Philadelphia, and colleagues.

“Randomized clinical trials comparing apixaban with rivaroxaban in patients with VTE are under way (for example, COBRRA (NCT03266783),” the investigators wrote. “Until the results from these trials become available (The estimated completion date for COBRRA is December 2023.), observational studies that use existing data can provide evidence on the effectiveness and safety of these alternatives to inform clinical practice.”

In the new research, apixaban was associated with a 23% lower rate of recurrent VTE (hazard ratio, 0.77; 95% confidence interval, 0.69-0.87), including a 15% lower rate of deep vein thrombosis and a 41% lower rate of pulmonary embolism. Apixaban was associated with 40% fewer bleeding events (HR, 0.60; 95% CI, 0.53-0.69]), including a 40% lower rate of GI bleeding and a 46% lower rate of intracranial bleeding.

The study involved 37,236 patients with VTE, all of whom were diagnosed in at least one inpatient encounter and initiated direct oral anticoagulant (DOAC) therapy within 30 days, according to Optum’s deidentified Clinformatics Data Mart Database. Patients were evenly split into apixaban and rivaroxaban groups, with 18,618 individuals in each. Propensity score matching was used to minimize differences in baseline characteristics.

Apixaban was associated with an absolute reduction in recurrent VTE of 0.6% and 1.1% over 2 and 6 months, respectively, as well as reductions in bleeding of 1.1% and 1.5% over the same respective time periods.

The investigators noted that these findings were maintained in various sensitivity and subgroup analyses, including a model in which patients with VTE who had transient risk factors were compared with VTE patients exhibiting chronic risk factors.

“These findings suggest that apixaban has superior effectiveness and safety, compared with rivaroxaban and may provide guidance to clinicians and patients regarding selection of an anticoagulant for treatment of VTE,” Dr. Dawwas and colleagues concluded.

Study may have missed some nuance in possible outcomes, according to vascular surgeon

Thomas Wakefield, MD, a vascular surgeon and a professor of surgery at the University of Michigan Health Frankel Cardiovascular Center, Ann Arbor, generally agreed with the investigators’ conclusion, although he noted that DOAC selection may also be influenced by other considerations.

“The results of this study suggest that, when choosing an agent for an individual patient, apixaban does appear to have an advantage over rivaroxaban related to recurrent VTE and bleeding,” Dr. Wakefield said in an interview. “One must keep in mind that these are not the only factors that are considered when choosing an agent and these are not the only two DOACs available. For example, rivaroxaban is given once per day while apixaban is given twice per day, and rivaroxaban has been shown to be successful in the treatment of other thrombotic disorders.”

Dr. Wakefield also pointed out that the study may have missed some nuance in possible outcomes.

“The current study looked at severe outcomes that resulted in inpatient hospitalization, so the generalization to strictly outpatient treatment and less severe outcomes cannot be inferred,” he said.

Damon E. Houghton, MD, of the department of medicine and a consultant in the department of vascular medicine and hematology at Mayo Clinic, Rochester, Minn., called the study a “very nice analysis,” highlighting the large sample size.

“The results are not a reason to abandon rivaroxaban altogether, but do suggest that, when otherwise appropriate for a patient, apixaban should be the first choice,” Dr. Houghton said in a written comment. “Hopefully this analysis will encourage more payers to create financial incentives that facilitate the use of apixaban in more patients.”

Randomized trial needed, says hematologist

Colleen Edwards, MD, of the departments of medicine, hematology, and medical oncology, at the Icahn School of Medicine at Mount Sinai, New York, had a more guarded view of the findings than Dr. Wakefield and Dr. Houghton.

“[The investigators] certainly seem to be doing a lot of statistical gymnastics in this paper,” Dr. Edwards said in an interview. “They used all kinds of surrogates in place of real data that you would get from a randomized trial.”

For example, Dr. Edwards noted the use of prescription refills as a surrogate for medication adherence, and emphasized that inpatient observational data may not reflect outpatient therapy.

“Inpatients are constantly missing their medicines all the time,” she said. “They’re holding it for procedures, they’re NPO, they’re off the floor, so they missed their medicine. So it’s just a very different patient population than the outpatient population, which is where venous thromboembolism is treated now, by and large.”

Although Dr. Edwards suggested that the findings might guide treatment selection “a little bit,” she noted that insurance constraints and costs play a greater role, and ultimately concluded that a randomized trial is needed to materially alter clinical decision-making.

“I think we really have to wait for randomized trial before we abandon our other choices,” she said.

The investigators disclosed relationships with Merck, Celgene, UCB, and others. Dr. Wakefield reported awaiting disclosures. Dr. Houghton and Dr. Edwards reported no relevant conflicts of interest.

Apixaban appears to be safer and more effective than rivaroxaban for reducing risk of venous thromboembolism and bleeding, based on new research.

Recurrent venous thromboembolism (VTE) – a composite of pulmonary embolism and deep vein thrombosis – was the primary effectiveness outcome in the retrospective analysis of new-user data from almost 40,000 patients, which was published in Annals of Internal Medicine. Safety was evaluated through a composite of intracranial and gastrointestinal bleeding.

After a median follow-up of 102 days in the apixaban group and 105 days in the rivaroxaban group, apixaban demonstrated superiority for both primary outcomes.

These real-world findings may guide selection of initial anticoagulant therapy, reported lead author Ghadeer K. Dawwas, PhD, MSc, MBA, of the University of Pennsylvania, Philadelphia, and colleagues.

“Randomized clinical trials comparing apixaban with rivaroxaban in patients with VTE are under way (for example, COBRRA (NCT03266783),” the investigators wrote. “Until the results from these trials become available (The estimated completion date for COBRRA is December 2023.), observational studies that use existing data can provide evidence on the effectiveness and safety of these alternatives to inform clinical practice.”

In the new research, apixaban was associated with a 23% lower rate of recurrent VTE (hazard ratio, 0.77; 95% confidence interval, 0.69-0.87), including a 15% lower rate of deep vein thrombosis and a 41% lower rate of pulmonary embolism. Apixaban was associated with 40% fewer bleeding events (HR, 0.60; 95% CI, 0.53-0.69]), including a 40% lower rate of GI bleeding and a 46% lower rate of intracranial bleeding.

The study involved 37,236 patients with VTE, all of whom were diagnosed in at least one inpatient encounter and initiated direct oral anticoagulant (DOAC) therapy within 30 days, according to Optum’s deidentified Clinformatics Data Mart Database. Patients were evenly split into apixaban and rivaroxaban groups, with 18,618 individuals in each. Propensity score matching was used to minimize differences in baseline characteristics.

Apixaban was associated with an absolute reduction in recurrent VTE of 0.6% and 1.1% over 2 and 6 months, respectively, as well as reductions in bleeding of 1.1% and 1.5% over the same respective time periods.

The investigators noted that these findings were maintained in various sensitivity and subgroup analyses, including a model in which patients with VTE who had transient risk factors were compared with VTE patients exhibiting chronic risk factors.

“These findings suggest that apixaban has superior effectiveness and safety, compared with rivaroxaban and may provide guidance to clinicians and patients regarding selection of an anticoagulant for treatment of VTE,” Dr. Dawwas and colleagues concluded.

Study may have missed some nuance in possible outcomes, according to vascular surgeon

Thomas Wakefield, MD, a vascular surgeon and a professor of surgery at the University of Michigan Health Frankel Cardiovascular Center, Ann Arbor, generally agreed with the investigators’ conclusion, although he noted that DOAC selection may also be influenced by other considerations.

“The results of this study suggest that, when choosing an agent for an individual patient, apixaban does appear to have an advantage over rivaroxaban related to recurrent VTE and bleeding,” Dr. Wakefield said in an interview. “One must keep in mind that these are not the only factors that are considered when choosing an agent and these are not the only two DOACs available. For example, rivaroxaban is given once per day while apixaban is given twice per day, and rivaroxaban has been shown to be successful in the treatment of other thrombotic disorders.”

Dr. Wakefield also pointed out that the study may have missed some nuance in possible outcomes.

“The current study looked at severe outcomes that resulted in inpatient hospitalization, so the generalization to strictly outpatient treatment and less severe outcomes cannot be inferred,” he said.

Damon E. Houghton, MD, of the department of medicine and a consultant in the department of vascular medicine and hematology at Mayo Clinic, Rochester, Minn., called the study a “very nice analysis,” highlighting the large sample size.

“The results are not a reason to abandon rivaroxaban altogether, but do suggest that, when otherwise appropriate for a patient, apixaban should be the first choice,” Dr. Houghton said in a written comment. “Hopefully this analysis will encourage more payers to create financial incentives that facilitate the use of apixaban in more patients.”

Randomized trial needed, says hematologist

Colleen Edwards, MD, of the departments of medicine, hematology, and medical oncology, at the Icahn School of Medicine at Mount Sinai, New York, had a more guarded view of the findings than Dr. Wakefield and Dr. Houghton.

“[The investigators] certainly seem to be doing a lot of statistical gymnastics in this paper,” Dr. Edwards said in an interview. “They used all kinds of surrogates in place of real data that you would get from a randomized trial.”

For example, Dr. Edwards noted the use of prescription refills as a surrogate for medication adherence, and emphasized that inpatient observational data may not reflect outpatient therapy.

“Inpatients are constantly missing their medicines all the time,” she said. “They’re holding it for procedures, they’re NPO, they’re off the floor, so they missed their medicine. So it’s just a very different patient population than the outpatient population, which is where venous thromboembolism is treated now, by and large.”

Although Dr. Edwards suggested that the findings might guide treatment selection “a little bit,” she noted that insurance constraints and costs play a greater role, and ultimately concluded that a randomized trial is needed to materially alter clinical decision-making.

“I think we really have to wait for randomized trial before we abandon our other choices,” she said.

The investigators disclosed relationships with Merck, Celgene, UCB, and others. Dr. Wakefield reported awaiting disclosures. Dr. Houghton and Dr. Edwards reported no relevant conflicts of interest.

Apixaban appears to be safer and more effective than rivaroxaban for reducing risk of venous thromboembolism and bleeding, based on new research.

Recurrent venous thromboembolism (VTE) – a composite of pulmonary embolism and deep vein thrombosis – was the primary effectiveness outcome in the retrospective analysis of new-user data from almost 40,000 patients, which was published in Annals of Internal Medicine. Safety was evaluated through a composite of intracranial and gastrointestinal bleeding.

After a median follow-up of 102 days in the apixaban group and 105 days in the rivaroxaban group, apixaban demonstrated superiority for both primary outcomes.

These real-world findings may guide selection of initial anticoagulant therapy, reported lead author Ghadeer K. Dawwas, PhD, MSc, MBA, of the University of Pennsylvania, Philadelphia, and colleagues.

“Randomized clinical trials comparing apixaban with rivaroxaban in patients with VTE are under way (for example, COBRRA (NCT03266783),” the investigators wrote. “Until the results from these trials become available (The estimated completion date for COBRRA is December 2023.), observational studies that use existing data can provide evidence on the effectiveness and safety of these alternatives to inform clinical practice.”

In the new research, apixaban was associated with a 23% lower rate of recurrent VTE (hazard ratio, 0.77; 95% confidence interval, 0.69-0.87), including a 15% lower rate of deep vein thrombosis and a 41% lower rate of pulmonary embolism. Apixaban was associated with 40% fewer bleeding events (HR, 0.60; 95% CI, 0.53-0.69]), including a 40% lower rate of GI bleeding and a 46% lower rate of intracranial bleeding.

The study involved 37,236 patients with VTE, all of whom were diagnosed in at least one inpatient encounter and initiated direct oral anticoagulant (DOAC) therapy within 30 days, according to Optum’s deidentified Clinformatics Data Mart Database. Patients were evenly split into apixaban and rivaroxaban groups, with 18,618 individuals in each. Propensity score matching was used to minimize differences in baseline characteristics.

Apixaban was associated with an absolute reduction in recurrent VTE of 0.6% and 1.1% over 2 and 6 months, respectively, as well as reductions in bleeding of 1.1% and 1.5% over the same respective time periods.

The investigators noted that these findings were maintained in various sensitivity and subgroup analyses, including a model in which patients with VTE who had transient risk factors were compared with VTE patients exhibiting chronic risk factors.

“These findings suggest that apixaban has superior effectiveness and safety, compared with rivaroxaban and may provide guidance to clinicians and patients regarding selection of an anticoagulant for treatment of VTE,” Dr. Dawwas and colleagues concluded.

Study may have missed some nuance in possible outcomes, according to vascular surgeon

Thomas Wakefield, MD, a vascular surgeon and a professor of surgery at the University of Michigan Health Frankel Cardiovascular Center, Ann Arbor, generally agreed with the investigators’ conclusion, although he noted that DOAC selection may also be influenced by other considerations.

“The results of this study suggest that, when choosing an agent for an individual patient, apixaban does appear to have an advantage over rivaroxaban related to recurrent VTE and bleeding,” Dr. Wakefield said in an interview. “One must keep in mind that these are not the only factors that are considered when choosing an agent and these are not the only two DOACs available. For example, rivaroxaban is given once per day while apixaban is given twice per day, and rivaroxaban has been shown to be successful in the treatment of other thrombotic disorders.”

Dr. Wakefield also pointed out that the study may have missed some nuance in possible outcomes.

“The current study looked at severe outcomes that resulted in inpatient hospitalization, so the generalization to strictly outpatient treatment and less severe outcomes cannot be inferred,” he said.

Damon E. Houghton, MD, of the department of medicine and a consultant in the department of vascular medicine and hematology at Mayo Clinic, Rochester, Minn., called the study a “very nice analysis,” highlighting the large sample size.

“The results are not a reason to abandon rivaroxaban altogether, but do suggest that, when otherwise appropriate for a patient, apixaban should be the first choice,” Dr. Houghton said in a written comment. “Hopefully this analysis will encourage more payers to create financial incentives that facilitate the use of apixaban in more patients.”

Randomized trial needed, says hematologist

Colleen Edwards, MD, of the departments of medicine, hematology, and medical oncology, at the Icahn School of Medicine at Mount Sinai, New York, had a more guarded view of the findings than Dr. Wakefield and Dr. Houghton.

“[The investigators] certainly seem to be doing a lot of statistical gymnastics in this paper,” Dr. Edwards said in an interview. “They used all kinds of surrogates in place of real data that you would get from a randomized trial.”

For example, Dr. Edwards noted the use of prescription refills as a surrogate for medication adherence, and emphasized that inpatient observational data may not reflect outpatient therapy.

“Inpatients are constantly missing their medicines all the time,” she said. “They’re holding it for procedures, they’re NPO, they’re off the floor, so they missed their medicine. So it’s just a very different patient population than the outpatient population, which is where venous thromboembolism is treated now, by and large.”

Although Dr. Edwards suggested that the findings might guide treatment selection “a little bit,” she noted that insurance constraints and costs play a greater role, and ultimately concluded that a randomized trial is needed to materially alter clinical decision-making.

“I think we really have to wait for randomized trial before we abandon our other choices,” she said.

The investigators disclosed relationships with Merck, Celgene, UCB, and others. Dr. Wakefield reported awaiting disclosures. Dr. Houghton and Dr. Edwards reported no relevant conflicts of interest.

Background: VTE is common in patients with cancer and can lead to serious complications and death. Relatively recently, the use of edoxaban or rivaroxaban was recommended by major guidelines for the treatment of cancer-associated VTE. Previous studies have demonstrated a higher risk of major bleeding when compared with low-molecular-weight heparin. Whether oral apixaban can be safely used in this setting is unknown.

Dr. Hermansen is a hospitalist in the Division of Hospital Medicine, Mount Sinai Health System, New York.

Background: VTE is common in patients with cancer and can lead to serious complications and death. Relatively recently, the use of edoxaban or rivaroxaban was recommended by major guidelines for the treatment of cancer-associated VTE. Previous studies have demonstrated a higher risk of major bleeding when compared with low-molecular-weight heparin. Whether oral apixaban can be safely used in this setting is unknown.

Dr. Hermansen is a hospitalist in the Division of Hospital Medicine, Mount Sinai Health System, New York.

Background: VTE is common in patients with cancer and can lead to serious complications and death. Relatively recently, the use of edoxaban or rivaroxaban was recommended by major guidelines for the treatment of cancer-associated VTE. Previous studies have demonstrated a higher risk of major bleeding when compared with low-molecular-weight heparin. Whether oral apixaban can be safely used in this setting is unknown.

Dr. Hermansen is a hospitalist in the Division of Hospital Medicine, Mount Sinai Health System, New York.

Background: TXA is an anti-fibrinolytic agent that decreases surgical bleeding and reduces death resulting from bleeding in trauma and postpartum hemorrhage. A 2012 Cochrane review suggested a reduction in mortality with use of TXA in patients with GI bleed, but previous trials were small with a high risk of bias.

There was an increase in venous thromboembolism (VTE; deep vein thrombosis or pulmonary embolism) in the TXA group versus the placebo group (0.8% with TXA and 0.4% with placebo; RR, 1.85; 95% CI, 1.15-2.98), as well as an increase in seizure events (0.6% with TXA and 0.4% with placebo; RR, 1.73; 95% CI, 1.03–2.93).

Bottom line: TXA did not reduce mortality risk in patients with upper or lower GI bleeding and should not be used in the routine management of GI bleed.

Citation: Roberts I et al. Effects of a high-dose 24-h infusion of tranexamic acid on death and thromboembolic events in patients with acute gastrointestinal bleeding (HALT-IT): an international randomised, double-blind, placebo-controlled trial. Lancet. 2020;395(10241):1927-1936. doi: 10.1016/S0140-6736(20)30848-5.

Dr. Chung is a hospitalist in the Division of Hospital Medicine, Mount Sinai Health System, New York.

Background: TXA is an anti-fibrinolytic agent that decreases surgical bleeding and reduces death resulting from bleeding in trauma and postpartum hemorrhage. A 2012 Cochrane review suggested a reduction in mortality with use of TXA in patients with GI bleed, but previous trials were small with a high risk of bias.

There was an increase in venous thromboembolism (VTE; deep vein thrombosis or pulmonary embolism) in the TXA group versus the placebo group (0.8% with TXA and 0.4% with placebo; RR, 1.85; 95% CI, 1.15-2.98), as well as an increase in seizure events (0.6% with TXA and 0.4% with placebo; RR, 1.73; 95% CI, 1.03–2.93).

Bottom line: TXA did not reduce mortality risk in patients with upper or lower GI bleeding and should not be used in the routine management of GI bleed.

Citation: Roberts I et al. Effects of a high-dose 24-h infusion of tranexamic acid on death and thromboembolic events in patients with acute gastrointestinal bleeding (HALT-IT): an international randomised, double-blind, placebo-controlled trial. Lancet. 2020;395(10241):1927-1936. doi: 10.1016/S0140-6736(20)30848-5.

Dr. Chung is a hospitalist in the Division of Hospital Medicine, Mount Sinai Health System, New York.

Background: TXA is an anti-fibrinolytic agent that decreases surgical bleeding and reduces death resulting from bleeding in trauma and postpartum hemorrhage. A 2012 Cochrane review suggested a reduction in mortality with use of TXA in patients with GI bleed, but previous trials were small with a high risk of bias.

There was an increase in venous thromboembolism (VTE; deep vein thrombosis or pulmonary embolism) in the TXA group versus the placebo group (0.8% with TXA and 0.4% with placebo; RR, 1.85; 95% CI, 1.15-2.98), as well as an increase in seizure events (0.6% with TXA and 0.4% with placebo; RR, 1.73; 95% CI, 1.03–2.93).

Bottom line: TXA did not reduce mortality risk in patients with upper or lower GI bleeding and should not be used in the routine management of GI bleed.

Citation: Roberts I et al. Effects of a high-dose 24-h infusion of tranexamic acid on death and thromboembolic events in patients with acute gastrointestinal bleeding (HALT-IT): an international randomised, double-blind, placebo-controlled trial. Lancet. 2020;395(10241):1927-1936. doi: 10.1016/S0140-6736(20)30848-5.

Dr. Chung is a hospitalist in the Division of Hospital Medicine, Mount Sinai Health System, New York.