ASH 2017

ATLANTA – The bispecific humanized monoclonal antibody emicizumab safely prevents or substantially reduces bleeds in children with hemophilia A with inhibitors that render standard factor VIII replacement therapies ineffective, according to an updated interim analysis of data from the open-label phase 3 HAVEN 2 study.

The findings have life-changing implications for patients and suggest that emicizumab prophylaxis represents a new standard of care for hemophilia A patients with inhibitors, Guy Young, MD, said during a press briefing at the annual meeting of the American Society of Hematology.

Of 57 patients under age 12 years receiving weekly subcutaneous emicizumab (Hemlibra) for bleeding prophylaxis at the data cutoff, 54 (94.7%) had zero treated bleeds, said Dr. Young of the University of Southern California, Los Angeles.

“That’s, honestly, truly remarkable. I mean, most of the time, these patients are bleeding at least on a monthly basis, sometimes more often than that,” he said.

Further, of 23 patients who were treated for at least 12 weeks and had a median efficacy period of 38.1 weeks, 87% had no bleeding events whatsoever (annual bleed rate of 0.2 events vs. a usual annual bleed rate of 1.3 events in patients without inhibitors). The annual treated joint bleed and treated target joint bleed rates each were 0.1, he said.

Overall, only three treated bleeds occurred in the 57 patients, and only one was a spontaneous bleed; one occurred in a joint, one occurred in a muscle, and one occurred in the hip and was classified as “other,” he noted.

The findings expand upon those from a previously reported interim analysis of data on 20 children from the study, which also showed that once-weekly subcutaneous emicizumab prophylaxis prevented or reduced bleeds, and provided clinically meaningful reductions in the annualized bleed rate when compared with prior bypassing agent treatment, Dr Young said.

In that prior analysis of participants aged 2-12 years (or up to 17 years with weight below 40 kg), which was presented in July at the annual meeting of the International Society on Thrombosis and Haemostasis, the data cutoff was Oct. 28, 2016. The current analysis had a May 8, 2017 cutoff, and therefore included about 6 additional months of data.

The treatment, which is given at a dose of 3 mg/kg per week for 4 weeks and then 1.5 mg/kg per week thereafter, was well tolerated. Ten nonserious, treatment-related adverse events occurred, and mainly involved injection site reactions. Serious adverse events occurred in six patients but were mainly related to the disease or to the use of catheters, or were otherwise unrelated to emicizumab. There were no thromboembolic or thrombotic microangiopathy events reported. Mean steady state trough concentrations (approximately 50 mcg/mL) were consistent with the pharmacokinetic profile seen in prior studies in the adolescent/adult population.

Health-related quality of life improvements were considerable, and in many cases, dramatic, Dr. Young said, noting in an interview that, for some patients, the effects were life changing both for the patients and their families. He described one young patient who had experienced scores of debilitating ankle bleeds, but had had no bleeds since he began receiving treatment as part of this study.

Emicizumab, which recently received Food and Drug Administration approval for use in patients of all ages with hemophilia A with inhibitors, bridges factor IXa and factor X to “bring them into proper alignment, which is really what the function of factor VIII is,” he said.

“So, it’s essentially replacing, or mimicking, the function of factor VIII, but without being factor VIII,” he said, explaining that it can be used to treat patients with inhibitors, because the antibodies they develop are specifically to factor VIII.

“This is not factor VIII, it’s just doing the job of factor VIII,” he added.

Studies of emicizumab for hemophilia A without inhibitors are ongoing (HAVEN 3), and could result in expanded indications, he noted.

The primary efficacy results of HAVEN 2 will be reported 52 weeks after the last patient is enrolled. These interim findings, however, demonstrate the potential for weekly subcutaneous injections of emicizumab to safely and conveniently reduce overall disease burden, as well as overall treatment burden in patients with hemophilia A with inhibitors, as these patients previously had to undergo intravenous treatment multiple times per week – and sometimes multiple times per day, he said.

The HAVEN 2 study is sponsored by Hoffman-La Roche. Dr. Young has received honoraria and/or consulting fees from Alnylam, Bayer, Bioverativ, CSL Behring, Genentech/Roche, Kedrion, Novo Nordisk, and Shire.

[email protected]

SOURCE: Young G et al. ASH 2017 Abstract 85.

ATLANTA – The bispecific humanized monoclonal antibody emicizumab safely prevents or substantially reduces bleeds in children with hemophilia A with inhibitors that render standard factor VIII replacement therapies ineffective, according to an updated interim analysis of data from the open-label phase 3 HAVEN 2 study.

The findings have life-changing implications for patients and suggest that emicizumab prophylaxis represents a new standard of care for hemophilia A patients with inhibitors, Guy Young, MD, said during a press briefing at the annual meeting of the American Society of Hematology.

Of 57 patients under age 12 years receiving weekly subcutaneous emicizumab (Hemlibra) for bleeding prophylaxis at the data cutoff, 54 (94.7%) had zero treated bleeds, said Dr. Young of the University of Southern California, Los Angeles.

“That’s, honestly, truly remarkable. I mean, most of the time, these patients are bleeding at least on a monthly basis, sometimes more often than that,” he said.

Further, of 23 patients who were treated for at least 12 weeks and had a median efficacy period of 38.1 weeks, 87% had no bleeding events whatsoever (annual bleed rate of 0.2 events vs. a usual annual bleed rate of 1.3 events in patients without inhibitors). The annual treated joint bleed and treated target joint bleed rates each were 0.1, he said.

Overall, only three treated bleeds occurred in the 57 patients, and only one was a spontaneous bleed; one occurred in a joint, one occurred in a muscle, and one occurred in the hip and was classified as “other,” he noted.

The findings expand upon those from a previously reported interim analysis of data on 20 children from the study, which also showed that once-weekly subcutaneous emicizumab prophylaxis prevented or reduced bleeds, and provided clinically meaningful reductions in the annualized bleed rate when compared with prior bypassing agent treatment, Dr Young said.

In that prior analysis of participants aged 2-12 years (or up to 17 years with weight below 40 kg), which was presented in July at the annual meeting of the International Society on Thrombosis and Haemostasis, the data cutoff was Oct. 28, 2016. The current analysis had a May 8, 2017 cutoff, and therefore included about 6 additional months of data.

The treatment, which is given at a dose of 3 mg/kg per week for 4 weeks and then 1.5 mg/kg per week thereafter, was well tolerated. Ten nonserious, treatment-related adverse events occurred, and mainly involved injection site reactions. Serious adverse events occurred in six patients but were mainly related to the disease or to the use of catheters, or were otherwise unrelated to emicizumab. There were no thromboembolic or thrombotic microangiopathy events reported. Mean steady state trough concentrations (approximately 50 mcg/mL) were consistent with the pharmacokinetic profile seen in prior studies in the adolescent/adult population.

Health-related quality of life improvements were considerable, and in many cases, dramatic, Dr. Young said, noting in an interview that, for some patients, the effects were life changing both for the patients and their families. He described one young patient who had experienced scores of debilitating ankle bleeds, but had had no bleeds since he began receiving treatment as part of this study.

Emicizumab, which recently received Food and Drug Administration approval for use in patients of all ages with hemophilia A with inhibitors, bridges factor IXa and factor X to “bring them into proper alignment, which is really what the function of factor VIII is,” he said.

“So, it’s essentially replacing, or mimicking, the function of factor VIII, but without being factor VIII,” he said, explaining that it can be used to treat patients with inhibitors, because the antibodies they develop are specifically to factor VIII.

“This is not factor VIII, it’s just doing the job of factor VIII,” he added.

Studies of emicizumab for hemophilia A without inhibitors are ongoing (HAVEN 3), and could result in expanded indications, he noted.

The primary efficacy results of HAVEN 2 will be reported 52 weeks after the last patient is enrolled. These interim findings, however, demonstrate the potential for weekly subcutaneous injections of emicizumab to safely and conveniently reduce overall disease burden, as well as overall treatment burden in patients with hemophilia A with inhibitors, as these patients previously had to undergo intravenous treatment multiple times per week – and sometimes multiple times per day, he said.

The HAVEN 2 study is sponsored by Hoffman-La Roche. Dr. Young has received honoraria and/or consulting fees from Alnylam, Bayer, Bioverativ, CSL Behring, Genentech/Roche, Kedrion, Novo Nordisk, and Shire.

[email protected]

SOURCE: Young G et al. ASH 2017 Abstract 85.

ATLANTA – The bispecific humanized monoclonal antibody emicizumab safely prevents or substantially reduces bleeds in children with hemophilia A with inhibitors that render standard factor VIII replacement therapies ineffective, according to an updated interim analysis of data from the open-label phase 3 HAVEN 2 study.

The findings have life-changing implications for patients and suggest that emicizumab prophylaxis represents a new standard of care for hemophilia A patients with inhibitors, Guy Young, MD, said during a press briefing at the annual meeting of the American Society of Hematology.

Of 57 patients under age 12 years receiving weekly subcutaneous emicizumab (Hemlibra) for bleeding prophylaxis at the data cutoff, 54 (94.7%) had zero treated bleeds, said Dr. Young of the University of Southern California, Los Angeles.

“That’s, honestly, truly remarkable. I mean, most of the time, these patients are bleeding at least on a monthly basis, sometimes more often than that,” he said.

Further, of 23 patients who were treated for at least 12 weeks and had a median efficacy period of 38.1 weeks, 87% had no bleeding events whatsoever (annual bleed rate of 0.2 events vs. a usual annual bleed rate of 1.3 events in patients without inhibitors). The annual treated joint bleed and treated target joint bleed rates each were 0.1, he said.

Overall, only three treated bleeds occurred in the 57 patients, and only one was a spontaneous bleed; one occurred in a joint, one occurred in a muscle, and one occurred in the hip and was classified as “other,” he noted.

The findings expand upon those from a previously reported interim analysis of data on 20 children from the study, which also showed that once-weekly subcutaneous emicizumab prophylaxis prevented or reduced bleeds, and provided clinically meaningful reductions in the annualized bleed rate when compared with prior bypassing agent treatment, Dr Young said.

In that prior analysis of participants aged 2-12 years (or up to 17 years with weight below 40 kg), which was presented in July at the annual meeting of the International Society on Thrombosis and Haemostasis, the data cutoff was Oct. 28, 2016. The current analysis had a May 8, 2017 cutoff, and therefore included about 6 additional months of data.

The treatment, which is given at a dose of 3 mg/kg per week for 4 weeks and then 1.5 mg/kg per week thereafter, was well tolerated. Ten nonserious, treatment-related adverse events occurred, and mainly involved injection site reactions. Serious adverse events occurred in six patients but were mainly related to the disease or to the use of catheters, or were otherwise unrelated to emicizumab. There were no thromboembolic or thrombotic microangiopathy events reported. Mean steady state trough concentrations (approximately 50 mcg/mL) were consistent with the pharmacokinetic profile seen in prior studies in the adolescent/adult population.

Health-related quality of life improvements were considerable, and in many cases, dramatic, Dr. Young said, noting in an interview that, for some patients, the effects were life changing both for the patients and their families. He described one young patient who had experienced scores of debilitating ankle bleeds, but had had no bleeds since he began receiving treatment as part of this study.

Emicizumab, which recently received Food and Drug Administration approval for use in patients of all ages with hemophilia A with inhibitors, bridges factor IXa and factor X to “bring them into proper alignment, which is really what the function of factor VIII is,” he said.

“So, it’s essentially replacing, or mimicking, the function of factor VIII, but without being factor VIII,” he said, explaining that it can be used to treat patients with inhibitors, because the antibodies they develop are specifically to factor VIII.

“This is not factor VIII, it’s just doing the job of factor VIII,” he added.

Studies of emicizumab for hemophilia A without inhibitors are ongoing (HAVEN 3), and could result in expanded indications, he noted.

The primary efficacy results of HAVEN 2 will be reported 52 weeks after the last patient is enrolled. These interim findings, however, demonstrate the potential for weekly subcutaneous injections of emicizumab to safely and conveniently reduce overall disease burden, as well as overall treatment burden in patients with hemophilia A with inhibitors, as these patients previously had to undergo intravenous treatment multiple times per week – and sometimes multiple times per day, he said.

The HAVEN 2 study is sponsored by Hoffman-La Roche. Dr. Young has received honoraria and/or consulting fees from Alnylam, Bayer, Bioverativ, CSL Behring, Genentech/Roche, Kedrion, Novo Nordisk, and Shire.

[email protected]

SOURCE: Young G et al. ASH 2017 Abstract 85.

ATLANTA – Voxelotor, an investigational inhibitor of hemoglobin polymerization, demonstrated consistent and sustained improvements in hemoglobin levels in adolescents with sickle cell disease (SCD), according to first results of a phase 2b study.

A hemoglobin response of at least 1 g/dL was achieved in 55% of patients (6 of 11) at 16 weeks, in results of the ongoing open-label, 24-week study presented at the annual meeting of the American Society of Hematology.

The treatment was well tolerated, associated with mostly grade 1-2 adverse events, and also improved patient-reported symptoms, according to Carolyn C. Hoppe, MD, of University of California, San Francisco, Benioff Children’s Hospital.

“These interim results support ongoing clinical evaluation of voxelotor as a potential disease-modifying therapy for adults and children with sickle cell disease,” Dr. Hoppe said at a press conference. “We need therapies to treat this disease and prevent the complications.”

Dr. Hoppe presented data on the first 12 patients in a study designed to assess the safety, pharmacokinetics, and efficacy of voxelotor in adolescent patients with homozygous hemoglobin SS or hemoglobin S beta-0 thalassemia.

All patients except one were already receiving standard care with hydroxyurea, suggesting that the two drugs may provide additive effects, according to investigators.

Treatment with voxelotor was associated with improvements in hemoglobin at 16 weeks, along with improvements in clinical measures of hemolysis – a 34% median reductions in reticulocytes and a 27% reduction in indirect bilirubin, Dr. Hoppe reported.

Patient-reported symptoms improved in 10 of 12 patients, with a median reduction of 94% in total symptom scores (TSS) at week 16, including 5 subjects with a mean TSS of 0.

Voxelotor is designed to address the cause of sickle cell disease, according to Dr. Hoppe, by modulating hemoglobin’s affinity for oxygen, which in turn inhibits hemoglobin polymerization.

“If we can interrupt that early on, we can hopefully disrupt or interrupt the biologic pathways that lead to the consequences of the disease,” she said.

The study is ongoing, as is a phase 3 clinical trial evaluating voxelotor in patients aged 12 years and older with SCD.

Voxelotor was previously known as GBT440

The study was sponsored by Global Blood Therapeutics. Dr. Hoppe reported research funding from and advisory relationships with Global Blood Therapeutics. Several coauthors are employees of the company.

SOURCE: Hoppe C et al. ASH 2017. Abstract 689

ATLANTA – Voxelotor, an investigational inhibitor of hemoglobin polymerization, demonstrated consistent and sustained improvements in hemoglobin levels in adolescents with sickle cell disease (SCD), according to first results of a phase 2b study.

A hemoglobin response of at least 1 g/dL was achieved in 55% of patients (6 of 11) at 16 weeks, in results of the ongoing open-label, 24-week study presented at the annual meeting of the American Society of Hematology.

The treatment was well tolerated, associated with mostly grade 1-2 adverse events, and also improved patient-reported symptoms, according to Carolyn C. Hoppe, MD, of University of California, San Francisco, Benioff Children’s Hospital.

“These interim results support ongoing clinical evaluation of voxelotor as a potential disease-modifying therapy for adults and children with sickle cell disease,” Dr. Hoppe said at a press conference. “We need therapies to treat this disease and prevent the complications.”

Dr. Hoppe presented data on the first 12 patients in a study designed to assess the safety, pharmacokinetics, and efficacy of voxelotor in adolescent patients with homozygous hemoglobin SS or hemoglobin S beta-0 thalassemia.

All patients except one were already receiving standard care with hydroxyurea, suggesting that the two drugs may provide additive effects, according to investigators.

Treatment with voxelotor was associated with improvements in hemoglobin at 16 weeks, along with improvements in clinical measures of hemolysis – a 34% median reductions in reticulocytes and a 27% reduction in indirect bilirubin, Dr. Hoppe reported.

Patient-reported symptoms improved in 10 of 12 patients, with a median reduction of 94% in total symptom scores (TSS) at week 16, including 5 subjects with a mean TSS of 0.

Voxelotor is designed to address the cause of sickle cell disease, according to Dr. Hoppe, by modulating hemoglobin’s affinity for oxygen, which in turn inhibits hemoglobin polymerization.

“If we can interrupt that early on, we can hopefully disrupt or interrupt the biologic pathways that lead to the consequences of the disease,” she said.

The study is ongoing, as is a phase 3 clinical trial evaluating voxelotor in patients aged 12 years and older with SCD.

Voxelotor was previously known as GBT440

The study was sponsored by Global Blood Therapeutics. Dr. Hoppe reported research funding from and advisory relationships with Global Blood Therapeutics. Several coauthors are employees of the company.

SOURCE: Hoppe C et al. ASH 2017. Abstract 689

ATLANTA – Voxelotor, an investigational inhibitor of hemoglobin polymerization, demonstrated consistent and sustained improvements in hemoglobin levels in adolescents with sickle cell disease (SCD), according to first results of a phase 2b study.

A hemoglobin response of at least 1 g/dL was achieved in 55% of patients (6 of 11) at 16 weeks, in results of the ongoing open-label, 24-week study presented at the annual meeting of the American Society of Hematology.

The treatment was well tolerated, associated with mostly grade 1-2 adverse events, and also improved patient-reported symptoms, according to Carolyn C. Hoppe, MD, of University of California, San Francisco, Benioff Children’s Hospital.

“These interim results support ongoing clinical evaluation of voxelotor as a potential disease-modifying therapy for adults and children with sickle cell disease,” Dr. Hoppe said at a press conference. “We need therapies to treat this disease and prevent the complications.”

Dr. Hoppe presented data on the first 12 patients in a study designed to assess the safety, pharmacokinetics, and efficacy of voxelotor in adolescent patients with homozygous hemoglobin SS or hemoglobin S beta-0 thalassemia.

All patients except one were already receiving standard care with hydroxyurea, suggesting that the two drugs may provide additive effects, according to investigators.

Treatment with voxelotor was associated with improvements in hemoglobin at 16 weeks, along with improvements in clinical measures of hemolysis – a 34% median reductions in reticulocytes and a 27% reduction in indirect bilirubin, Dr. Hoppe reported.

Patient-reported symptoms improved in 10 of 12 patients, with a median reduction of 94% in total symptom scores (TSS) at week 16, including 5 subjects with a mean TSS of 0.

Voxelotor is designed to address the cause of sickle cell disease, according to Dr. Hoppe, by modulating hemoglobin’s affinity for oxygen, which in turn inhibits hemoglobin polymerization.

“If we can interrupt that early on, we can hopefully disrupt or interrupt the biologic pathways that lead to the consequences of the disease,” she said.

The study is ongoing, as is a phase 3 clinical trial evaluating voxelotor in patients aged 12 years and older with SCD.

Voxelotor was previously known as GBT440

The study was sponsored by Global Blood Therapeutics. Dr. Hoppe reported research funding from and advisory relationships with Global Blood Therapeutics. Several coauthors are employees of the company.

SOURCE: Hoppe C et al. ASH 2017. Abstract 689

ATLANTA – Matching red cell products to sickle-cell disease (SCD) patients with rare Rh antibodies can be accomplished with a little fancy stem cell footwork and some genetic legerdemain, investigators report.

With the help of CRISPR/Cas9 gene-editing, Stella T. Chou, MD, from Children’s Hospital of Philadelphia and her colleagues have created a panel of red cell reagents customized from induced pluripotent stem cells (iPSCs) to produce a renewable source of red cell reagents and potentially universal infusion products for patients with SCD.

“It has been more than 10 years since iPSCs have been available, but we have yet to see applications for blood diseases that improve how we care for our patients,” Dr. Chou said in a statement. “Using this panel, we would be able to more quickly identify what antibodies the patient has made, informing us what kind of blood we have to give them. It means we’ll be able to improve their ability to be transfused safely and reduce delays in their care.”

Up to half of all patients with SCD who require chronic transfusions may develop antibodies to allogeneic blood products, but identifying inactivating antibodies in a given patient can be both challenging and time consuming, due to a paucity of the appropriate reagent red cells, Dr. Chou and her colleagues reported.

The investigators previously reported that despite receiving transfusions from Rh-matched minority donors, patients with SCD have a high prevalence of red blood cell alloimmunization, and that Rh antibodies are the most common type of antibody in SCD patients, with about 33% of Rh antibodies associated with delayed transfusion reactions (Blood. 2013 Aug 8;122:1062-71; doi: 10.1182/blood-2013-03-490623).

It is both costly and time consuming to genotype donated blood for Rh antigens in order to match a low-antigen product to a specific patient. Instead, the investigators identified a workaround involving reprogramming or genetically engineering iPSCs from donors with rare antigen profiles, with the goal of creating a standard panel of red cell reagents that could reliably and quickly identify SCD patients with complex antibodies.

They used CRISPR/Cas9 gene-editing techniques to modify existing iPSCs to include Rh null cells, other cells lacking all or part of certain high-prevalence Rh antigens, and low prevalence novel antigens.

The investigators then showed that they could induce hematopoietic differentiation of their customized iPSCs through a three-step process and demonstrated that, as they had expected, the engineered antibodies were able to more accurately type Rh in gel card assays than did off-the-shelf commercial assays.

“We have designed a panel of customized iPSCs reprogrammed from rare donors or genetically engineered to express rare blood group antigen phenotypes or combinations that are difficult or impossible to find as donor red cells. Any number of combinations not found in natural populations can be produced and generated in quantities sufficient for reagents,” Dr. Chou said.

They also asserted that iPSC-derived red blood cells (iRBCs) produced from their customized iPSCs could be used with standard blood bank assays as a potential means of streamlining and standardizing the antibody identification process in alloimmunized patients with complex antibody specificities.

“In the future, when technology for scale-up is available, Rh null iRBCs could be used as ‘universal’ donor cells for future therapeutic applications,” the reseachers wrote.

The study was supported by the National Institutes of Health/National Heart Lung and Blood Institute. The authors reported having no conflicts of interest.

SOURCE: Chou S et al. ASH 2017 Abstract 3

ATLANTA – Matching red cell products to sickle-cell disease (SCD) patients with rare Rh antibodies can be accomplished with a little fancy stem cell footwork and some genetic legerdemain, investigators report.

With the help of CRISPR/Cas9 gene-editing, Stella T. Chou, MD, from Children’s Hospital of Philadelphia and her colleagues have created a panel of red cell reagents customized from induced pluripotent stem cells (iPSCs) to produce a renewable source of red cell reagents and potentially universal infusion products for patients with SCD.

“It has been more than 10 years since iPSCs have been available, but we have yet to see applications for blood diseases that improve how we care for our patients,” Dr. Chou said in a statement. “Using this panel, we would be able to more quickly identify what antibodies the patient has made, informing us what kind of blood we have to give them. It means we’ll be able to improve their ability to be transfused safely and reduce delays in their care.”

Up to half of all patients with SCD who require chronic transfusions may develop antibodies to allogeneic blood products, but identifying inactivating antibodies in a given patient can be both challenging and time consuming, due to a paucity of the appropriate reagent red cells, Dr. Chou and her colleagues reported.

The investigators previously reported that despite receiving transfusions from Rh-matched minority donors, patients with SCD have a high prevalence of red blood cell alloimmunization, and that Rh antibodies are the most common type of antibody in SCD patients, with about 33% of Rh antibodies associated with delayed transfusion reactions (Blood. 2013 Aug 8;122:1062-71; doi: 10.1182/blood-2013-03-490623).

It is both costly and time consuming to genotype donated blood for Rh antigens in order to match a low-antigen product to a specific patient. Instead, the investigators identified a workaround involving reprogramming or genetically engineering iPSCs from donors with rare antigen profiles, with the goal of creating a standard panel of red cell reagents that could reliably and quickly identify SCD patients with complex antibodies.

They used CRISPR/Cas9 gene-editing techniques to modify existing iPSCs to include Rh null cells, other cells lacking all or part of certain high-prevalence Rh antigens, and low prevalence novel antigens.

The investigators then showed that they could induce hematopoietic differentiation of their customized iPSCs through a three-step process and demonstrated that, as they had expected, the engineered antibodies were able to more accurately type Rh in gel card assays than did off-the-shelf commercial assays.

“We have designed a panel of customized iPSCs reprogrammed from rare donors or genetically engineered to express rare blood group antigen phenotypes or combinations that are difficult or impossible to find as donor red cells. Any number of combinations not found in natural populations can be produced and generated in quantities sufficient for reagents,” Dr. Chou said.

They also asserted that iPSC-derived red blood cells (iRBCs) produced from their customized iPSCs could be used with standard blood bank assays as a potential means of streamlining and standardizing the antibody identification process in alloimmunized patients with complex antibody specificities.

“In the future, when technology for scale-up is available, Rh null iRBCs could be used as ‘universal’ donor cells for future therapeutic applications,” the reseachers wrote.

The study was supported by the National Institutes of Health/National Heart Lung and Blood Institute. The authors reported having no conflicts of interest.

SOURCE: Chou S et al. ASH 2017 Abstract 3

ATLANTA – Matching red cell products to sickle-cell disease (SCD) patients with rare Rh antibodies can be accomplished with a little fancy stem cell footwork and some genetic legerdemain, investigators report.

With the help of CRISPR/Cas9 gene-editing, Stella T. Chou, MD, from Children’s Hospital of Philadelphia and her colleagues have created a panel of red cell reagents customized from induced pluripotent stem cells (iPSCs) to produce a renewable source of red cell reagents and potentially universal infusion products for patients with SCD.

“It has been more than 10 years since iPSCs have been available, but we have yet to see applications for blood diseases that improve how we care for our patients,” Dr. Chou said in a statement. “Using this panel, we would be able to more quickly identify what antibodies the patient has made, informing us what kind of blood we have to give them. It means we’ll be able to improve their ability to be transfused safely and reduce delays in their care.”

Up to half of all patients with SCD who require chronic transfusions may develop antibodies to allogeneic blood products, but identifying inactivating antibodies in a given patient can be both challenging and time consuming, due to a paucity of the appropriate reagent red cells, Dr. Chou and her colleagues reported.

The investigators previously reported that despite receiving transfusions from Rh-matched minority donors, patients with SCD have a high prevalence of red blood cell alloimmunization, and that Rh antibodies are the most common type of antibody in SCD patients, with about 33% of Rh antibodies associated with delayed transfusion reactions (Blood. 2013 Aug 8;122:1062-71; doi: 10.1182/blood-2013-03-490623).

It is both costly and time consuming to genotype donated blood for Rh antigens in order to match a low-antigen product to a specific patient. Instead, the investigators identified a workaround involving reprogramming or genetically engineering iPSCs from donors with rare antigen profiles, with the goal of creating a standard panel of red cell reagents that could reliably and quickly identify SCD patients with complex antibodies.

They used CRISPR/Cas9 gene-editing techniques to modify existing iPSCs to include Rh null cells, other cells lacking all or part of certain high-prevalence Rh antigens, and low prevalence novel antigens.

The investigators then showed that they could induce hematopoietic differentiation of their customized iPSCs through a three-step process and demonstrated that, as they had expected, the engineered antibodies were able to more accurately type Rh in gel card assays than did off-the-shelf commercial assays.

“We have designed a panel of customized iPSCs reprogrammed from rare donors or genetically engineered to express rare blood group antigen phenotypes or combinations that are difficult or impossible to find as donor red cells. Any number of combinations not found in natural populations can be produced and generated in quantities sufficient for reagents,” Dr. Chou said.

They also asserted that iPSC-derived red blood cells (iRBCs) produced from their customized iPSCs could be used with standard blood bank assays as a potential means of streamlining and standardizing the antibody identification process in alloimmunized patients with complex antibody specificities.

“In the future, when technology for scale-up is available, Rh null iRBCs could be used as ‘universal’ donor cells for future therapeutic applications,” the reseachers wrote.

The study was supported by the National Institutes of Health/National Heart Lung and Blood Institute. The authors reported having no conflicts of interest.

SOURCE: Chou S et al. ASH 2017 Abstract 3

Findings from several studies on marginal zone lymphoma (MZL) will be presented during oral and poster sessions at the annual meeting of the American Society of Hematology, with a focus on evaluating combination treatment approaches.

Some of the MZL treatment–related studies include the assessment of chlorambucil plus rituximab in patients with extranodal marginal zone B-cell lymphoma of mucosa associated lymphoid tissue, the combination of bendamustine with rituximab for first-line treatment of splenic MZL, and the safety and progression-free survival associated with lenalidomide and rituximab in previously untreated patients with MZL.

Other studies consider how to approach refractory disease. One study looks at the use of ibrutinib in patients with relapsed/refractory MZL, and researchers will also present findings from a systematic literature review of the efficacy and safety of various treatments among patients with relapsed/refractory MZL.

Abstract 1506: IELSG-38: A Phase II Study of Chlorambucil in Combination with Rituximab Followed by Maintenance Therapy with Subcutaneous Rituximab in Patients with Extranodal Marginal Zone B-Cell Lymphoma of Mucosa Associated Lymphoid Tissue (MALT) .

Abstract 4062: Bendamustine in Combination with Rituximab as First-Line Treatment of Splenic Marginal Zone Lymphoma (BRISMA). Results of the IELSG-36 Phase II Study.

Abstract 3026: Ibrutinib Therapy in Patients with Relapsed/Refractory Marginal Zone Lymphoma: Analysis by Prior Rituximab Treatment and Baseline Mutations.

Abstract 4040: Safety and Activity of Lenalidomide and Rituximab in Previously Untreated Marginal Zone Lymphoma: Subgroup Analysis and Long-Term Follow-Up of an Open-Label Phase II Trial.

Abstract 2783: Systematic Literature Review of the Clinical Efficacy and Safety of Treatments in the Relapsed/Refractory Setting for Patients with Follicular Lymphoma or Marginal Zone Lymphoma.

[email protected]

Findings from several studies on marginal zone lymphoma (MZL) will be presented during oral and poster sessions at the annual meeting of the American Society of Hematology, with a focus on evaluating combination treatment approaches.

Some of the MZL treatment–related studies include the assessment of chlorambucil plus rituximab in patients with extranodal marginal zone B-cell lymphoma of mucosa associated lymphoid tissue, the combination of bendamustine with rituximab for first-line treatment of splenic MZL, and the safety and progression-free survival associated with lenalidomide and rituximab in previously untreated patients with MZL.

Other studies consider how to approach refractory disease. One study looks at the use of ibrutinib in patients with relapsed/refractory MZL, and researchers will also present findings from a systematic literature review of the efficacy and safety of various treatments among patients with relapsed/refractory MZL.

Abstract 1506: IELSG-38: A Phase II Study of Chlorambucil in Combination with Rituximab Followed by Maintenance Therapy with Subcutaneous Rituximab in Patients with Extranodal Marginal Zone B-Cell Lymphoma of Mucosa Associated Lymphoid Tissue (MALT) .

Abstract 4062: Bendamustine in Combination with Rituximab as First-Line Treatment of Splenic Marginal Zone Lymphoma (BRISMA). Results of the IELSG-36 Phase II Study.

Abstract 3026: Ibrutinib Therapy in Patients with Relapsed/Refractory Marginal Zone Lymphoma: Analysis by Prior Rituximab Treatment and Baseline Mutations.

Abstract 4040: Safety and Activity of Lenalidomide and Rituximab in Previously Untreated Marginal Zone Lymphoma: Subgroup Analysis and Long-Term Follow-Up of an Open-Label Phase II Trial.

Abstract 2783: Systematic Literature Review of the Clinical Efficacy and Safety of Treatments in the Relapsed/Refractory Setting for Patients with Follicular Lymphoma or Marginal Zone Lymphoma.

[email protected]

Findings from several studies on marginal zone lymphoma (MZL) will be presented during oral and poster sessions at the annual meeting of the American Society of Hematology, with a focus on evaluating combination treatment approaches.

Some of the MZL treatment–related studies include the assessment of chlorambucil plus rituximab in patients with extranodal marginal zone B-cell lymphoma of mucosa associated lymphoid tissue, the combination of bendamustine with rituximab for first-line treatment of splenic MZL, and the safety and progression-free survival associated with lenalidomide and rituximab in previously untreated patients with MZL.

Other studies consider how to approach refractory disease. One study looks at the use of ibrutinib in patients with relapsed/refractory MZL, and researchers will also present findings from a systematic literature review of the efficacy and safety of various treatments among patients with relapsed/refractory MZL.

Abstract 1506: IELSG-38: A Phase II Study of Chlorambucil in Combination with Rituximab Followed by Maintenance Therapy with Subcutaneous Rituximab in Patients with Extranodal Marginal Zone B-Cell Lymphoma of Mucosa Associated Lymphoid Tissue (MALT) .

Abstract 4062: Bendamustine in Combination with Rituximab as First-Line Treatment of Splenic Marginal Zone Lymphoma (BRISMA). Results of the IELSG-36 Phase II Study.

Abstract 3026: Ibrutinib Therapy in Patients with Relapsed/Refractory Marginal Zone Lymphoma: Analysis by Prior Rituximab Treatment and Baseline Mutations.

Abstract 4040: Safety and Activity of Lenalidomide and Rituximab in Previously Untreated Marginal Zone Lymphoma: Subgroup Analysis and Long-Term Follow-Up of an Open-Label Phase II Trial.

Abstract 2783: Systematic Literature Review of the Clinical Efficacy and Safety of Treatments in the Relapsed/Refractory Setting for Patients with Follicular Lymphoma or Marginal Zone Lymphoma.

[email protected]

Chimeric antigen receptor (CAR) T-cell therapies are driving ever faster forward, with impressive response rates – including a high level of complete responses – in treatment of patients with lymphomas and multiple myeloma as shown by clinical trial results to be presented at the annual meeting of the American Society of Hematology.

Investigators will be presenting data on the first two CAR T constructs to receive Food and Drug Administration approval, each directed against CD19.
 

ZUMA-1 for non-Hodgkin lymphoma

Long-term follow-up results with the use of axicabtagene ciloleucel (Yescarta; axi-cel) in patients with refractory aggressive non-Hodgkin lymphoma will be presented by Sattva S. Neelapu, MD, of the University of Texas MD Anderson Cancer Center in Houston, on behalf of colleagues in the ZUMA-1 trial (Abstract 578).

At the 2017 European Hematology Association Congress in Madrid, ZUMA-1 investigators reported that axi-cel, an autologous anti-CD19 CAR-T product, was associated with an 82% objective response rate (ORR), including 54% complete responses, in patients with refractory diffuse large B cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma, or transformed follicular lymphoma. The 54% complete response rate was nearly sevenfold higher than that reported for historical controls, according to coinvestigator Yi Lin, MD, PhD, of the Mayo Clinic, Rochester, Minn.

The treatment was generally safe, with 13% of patients experiencing grade 3 or greater cytokine release syndrome (CRS), and 28% having grade 3 or greater neurologic events. The events were generally reversible, and the rates of each declined over time. The use of tocilizumab or steroids to control adverse events did not have a negative effect on responses.

This CAR T-cell construct received FDA approval in October 2017.

At ASH 2017, Dr. Neelapu will present 1-year follow-up data from the trial which will include both data on responses and toxicity, “but also some very interesting information on mechanisms of resistance, whether patients’ tumor cells become CD19 negative, or checkpoint, like PD-L1, positive,” said Kenneth Anderson, MD, of the Dana-Farber Cancer Institute in Boston, who discussed noteworthy abstracts in a media briefing prior to the meeting.
 

JULIET for DLBCL

Data on the use of another anti-CD19 CAR construct, tisagenlecleucel (Kymriah) in adults with relapsed or refractory DLBCL will be presented by Stephen J. Schuster, MD, of the University of Pennsylvania, Philadelphia, on behalf of investigators in the JULIET trial.

At the 2017 European Hematology Association Congress, coinvestigator Gilles Salles, MD, PhD, of the University of Lyon, France, reported an interim analysis from the trial, showing that the CAR T construct was associated with a 59% ORR, consisting of 43% complete responses and 16% partial responses in patients with relapsed or refractory DLBCL. The analysis “confirms the high response rates and durable responses observed in the previous single-center trial,” Dr. Salles said.

Dr. Schuster will present the primary analysis of the global phase 2 pivotal trial at ASH 2017 (Abstract 577), looking at patients who received the product from the U.S. manufacturing site.

As of the data cutoff in March 2017, the best ORR among 81 patients with at least 3 months of follow-up, or earlier discontinuation, was 53.1% with 39.5% complete responses and 13.6% partial responses. For 46 patients evaluable at 6 months, the complete response rate was 30% and partial response rate was 7%.

The response rates were consistent across subgroups, including patients who had previously undergone autologous stem cell transplant and those with double-hit lymphoma (i.e, with mutation in MYC and BCL2 or BCL6).

The responses also appeared to be durable, with the median duration not reached. The 6-month probability of being relapse free was 73.5%. Similarly, median overall survival was not reached; the 6-month probability of overall survival was 64.5%, according to the published abstract.

Adverse events included CRS in 58% of infused patients, with 15% grade 3 and 8% grade 4 in severity. CRS was managed according to protocol with tocilizumab and/or corticosteroids. There were no deaths associated with either the CRS or neurologic toxicities.

“This is a multicenter trial: 27 centers, 10 countries, 4 continents, so it sort of demonstrates to all of us that this technology can be done in an international scope,” Dr. Anderson said.
 

Anti-BCMA for multiple myeloma

CAR T-cells are relative newcomers in the treatment of multiple myeloma, but James N. Kochenderfer, MD, of the National Cancer Institute, Bethesda, Md., will be presenting updated results from a multicenter study of bb2121, a CAR T-cell construct directed against B-cell maturation antigen (BCMA).

BCMA was first described in myeloma in 2004 as a mechanism for the growth and survival of malignant plasma cells. As previously reported, a different anti-BCMA T-cell product induced clinical remissions in 33 of 35 patients with relapsed/refractory multiple myeloma who were treated in an early clinical trial.

With the construct being investigated by Dr. Kochenderfer and colleagues, 21 patients (median 58 years old) with a median of 5 years since a diagnosis of multiple myeloma were infused with bb2121. One-month data on clinical response was available for 18 patients at the time of data cutoff in May 2017 (Abstract 740).

In this heavily pretreated population, the ORR was 89% overall, and was 100% for patients treated with doses of 150 x 10⁶ CAR+ T cells or higher. At this dose range or higher no patients had disease progression at up to 54 weeks after infusion. Of the four patients evaluable for minimal residual disease (MRD), all were MRD negative.

As of the data cut-off there were no dose-limiting toxicities and no treatment-related grade 3 or higher neurotoxicities. CRS was primarily grade 1 or 2 and was reported in 15 of 21 patients. Two patients had grade 3 CRS that resolved in 24 hours, and four patients received tocilizumab (one with steroids) for CRS management.

There was one on-study death, from cardiopulmonary arrest more than 4 months after bb2121 infusion in a patient with an extensive cardiac history. The death was judged to be unrelated to CAR T-cell therapy.

Dr. Kochenderfer will present data and analysis on an additional 5 months of follow-up.

“This abstract demonstrates that again, in patients, this time with myeloma with literally no other option, you can achieve very impressive response,” Dr. Anderson said.

The ZUMA-1 study is funded by Kite Pharma. Dr. Neelapu reported research funding from BMS, Poseida, Merck, Kite Pharma, and Cellectis. He reported consultancy and membership on the board of directors or advisory committees for Merck, Kite Pharma, and Celgene.

The JULIET study is funded by Novartis. Dr. Schuster reported consultancy and research funding from Novartis Pharmaceuticals, Celgene, Genentech, Bristol-Myers Squibb, Janssen R&D, and Gilead. He reported consultancy with Seattle Genetics and Nordic Nanovector, and research funding from Merck.

The multicenter study of bb2121 is sponsored by bluebird bio and Celgene. Dr. Kochenderfer reported research funding from bluebird bio and Kite Pharma. He reported having multiple patents in the CAR field.


Abstract 578 Long-Term Follow-up ZUMA-1: A Pivotal Trial of Axicabtagene Ciloleucel (Axi-Cel; KTE-C19) in Patients with Refractory Aggressive Non-Hodgkin Lymphoma (NHL) will be presented in session 626, Monday, Dec. 11, 2017, at 7:15 a.m.

Abstract 577 Primary Analysis of Juliet: A Global, Pivotal, Phase 2 Trial of CTL019 in Adult Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma will be presented in session 626, Monday, Dec. 11, 2017 at 7:00 a.m.

Abstract 740 Durable Clinical Responses in Heavily Pretreated Patients with Relapsed/Refractory Multiple Myeloma: Updated Results from a Multicenter Study of bb2121 Anti-BCMA CAR T Cell Therapy will be presented in session 653, Monday, Dec. 11, 2017 at 3:00 p.m.

Chimeric antigen receptor (CAR) T-cell therapies are driving ever faster forward, with impressive response rates – including a high level of complete responses – in treatment of patients with lymphomas and multiple myeloma as shown by clinical trial results to be presented at the annual meeting of the American Society of Hematology.

Investigators will be presenting data on the first two CAR T constructs to receive Food and Drug Administration approval, each directed against CD19.
 

ZUMA-1 for non-Hodgkin lymphoma

Long-term follow-up results with the use of axicabtagene ciloleucel (Yescarta; axi-cel) in patients with refractory aggressive non-Hodgkin lymphoma will be presented by Sattva S. Neelapu, MD, of the University of Texas MD Anderson Cancer Center in Houston, on behalf of colleagues in the ZUMA-1 trial (Abstract 578).

At the 2017 European Hematology Association Congress in Madrid, ZUMA-1 investigators reported that axi-cel, an autologous anti-CD19 CAR-T product, was associated with an 82% objective response rate (ORR), including 54% complete responses, in patients with refractory diffuse large B cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma, or transformed follicular lymphoma. The 54% complete response rate was nearly sevenfold higher than that reported for historical controls, according to coinvestigator Yi Lin, MD, PhD, of the Mayo Clinic, Rochester, Minn.

The treatment was generally safe, with 13% of patients experiencing grade 3 or greater cytokine release syndrome (CRS), and 28% having grade 3 or greater neurologic events. The events were generally reversible, and the rates of each declined over time. The use of tocilizumab or steroids to control adverse events did not have a negative effect on responses.

This CAR T-cell construct received FDA approval in October 2017.

At ASH 2017, Dr. Neelapu will present 1-year follow-up data from the trial which will include both data on responses and toxicity, “but also some very interesting information on mechanisms of resistance, whether patients’ tumor cells become CD19 negative, or checkpoint, like PD-L1, positive,” said Kenneth Anderson, MD, of the Dana-Farber Cancer Institute in Boston, who discussed noteworthy abstracts in a media briefing prior to the meeting.
 

JULIET for DLBCL

Data on the use of another anti-CD19 CAR construct, tisagenlecleucel (Kymriah) in adults with relapsed or refractory DLBCL will be presented by Stephen J. Schuster, MD, of the University of Pennsylvania, Philadelphia, on behalf of investigators in the JULIET trial.

At the 2017 European Hematology Association Congress, coinvestigator Gilles Salles, MD, PhD, of the University of Lyon, France, reported an interim analysis from the trial, showing that the CAR T construct was associated with a 59% ORR, consisting of 43% complete responses and 16% partial responses in patients with relapsed or refractory DLBCL. The analysis “confirms the high response rates and durable responses observed in the previous single-center trial,” Dr. Salles said.

Dr. Schuster will present the primary analysis of the global phase 2 pivotal trial at ASH 2017 (Abstract 577), looking at patients who received the product from the U.S. manufacturing site.

As of the data cutoff in March 2017, the best ORR among 81 patients with at least 3 months of follow-up, or earlier discontinuation, was 53.1% with 39.5% complete responses and 13.6% partial responses. For 46 patients evaluable at 6 months, the complete response rate was 30% and partial response rate was 7%.

The response rates were consistent across subgroups, including patients who had previously undergone autologous stem cell transplant and those with double-hit lymphoma (i.e, with mutation in MYC and BCL2 or BCL6).

The responses also appeared to be durable, with the median duration not reached. The 6-month probability of being relapse free was 73.5%. Similarly, median overall survival was not reached; the 6-month probability of overall survival was 64.5%, according to the published abstract.

Adverse events included CRS in 58% of infused patients, with 15% grade 3 and 8% grade 4 in severity. CRS was managed according to protocol with tocilizumab and/or corticosteroids. There were no deaths associated with either the CRS or neurologic toxicities.

“This is a multicenter trial: 27 centers, 10 countries, 4 continents, so it sort of demonstrates to all of us that this technology can be done in an international scope,” Dr. Anderson said.
 

Anti-BCMA for multiple myeloma

CAR T-cells are relative newcomers in the treatment of multiple myeloma, but James N. Kochenderfer, MD, of the National Cancer Institute, Bethesda, Md., will be presenting updated results from a multicenter study of bb2121, a CAR T-cell construct directed against B-cell maturation antigen (BCMA).

BCMA was first described in myeloma in 2004 as a mechanism for the growth and survival of malignant plasma cells. As previously reported, a different anti-BCMA T-cell product induced clinical remissions in 33 of 35 patients with relapsed/refractory multiple myeloma who were treated in an early clinical trial.

With the construct being investigated by Dr. Kochenderfer and colleagues, 21 patients (median 58 years old) with a median of 5 years since a diagnosis of multiple myeloma were infused with bb2121. One-month data on clinical response was available for 18 patients at the time of data cutoff in May 2017 (Abstract 740).

In this heavily pretreated population, the ORR was 89% overall, and was 100% for patients treated with doses of 150 x 10⁶ CAR+ T cells or higher. At this dose range or higher no patients had disease progression at up to 54 weeks after infusion. Of the four patients evaluable for minimal residual disease (MRD), all were MRD negative.

As of the data cut-off there were no dose-limiting toxicities and no treatment-related grade 3 or higher neurotoxicities. CRS was primarily grade 1 or 2 and was reported in 15 of 21 patients. Two patients had grade 3 CRS that resolved in 24 hours, and four patients received tocilizumab (one with steroids) for CRS management.

There was one on-study death, from cardiopulmonary arrest more than 4 months after bb2121 infusion in a patient with an extensive cardiac history. The death was judged to be unrelated to CAR T-cell therapy.

Dr. Kochenderfer will present data and analysis on an additional 5 months of follow-up.

“This abstract demonstrates that again, in patients, this time with myeloma with literally no other option, you can achieve very impressive response,” Dr. Anderson said.

The ZUMA-1 study is funded by Kite Pharma. Dr. Neelapu reported research funding from BMS, Poseida, Merck, Kite Pharma, and Cellectis. He reported consultancy and membership on the board of directors or advisory committees for Merck, Kite Pharma, and Celgene.

The JULIET study is funded by Novartis. Dr. Schuster reported consultancy and research funding from Novartis Pharmaceuticals, Celgene, Genentech, Bristol-Myers Squibb, Janssen R&D, and Gilead. He reported consultancy with Seattle Genetics and Nordic Nanovector, and research funding from Merck.

The multicenter study of bb2121 is sponsored by bluebird bio and Celgene. Dr. Kochenderfer reported research funding from bluebird bio and Kite Pharma. He reported having multiple patents in the CAR field.


Abstract 578 Long-Term Follow-up ZUMA-1: A Pivotal Trial of Axicabtagene Ciloleucel (Axi-Cel; KTE-C19) in Patients with Refractory Aggressive Non-Hodgkin Lymphoma (NHL) will be presented in session 626, Monday, Dec. 11, 2017, at 7:15 a.m.

Abstract 577 Primary Analysis of Juliet: A Global, Pivotal, Phase 2 Trial of CTL019 in Adult Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma will be presented in session 626, Monday, Dec. 11, 2017 at 7:00 a.m.

Abstract 740 Durable Clinical Responses in Heavily Pretreated Patients with Relapsed/Refractory Multiple Myeloma: Updated Results from a Multicenter Study of bb2121 Anti-BCMA CAR T Cell Therapy will be presented in session 653, Monday, Dec. 11, 2017 at 3:00 p.m.

Chimeric antigen receptor (CAR) T-cell therapies are driving ever faster forward, with impressive response rates – including a high level of complete responses – in treatment of patients with lymphomas and multiple myeloma as shown by clinical trial results to be presented at the annual meeting of the American Society of Hematology.

Investigators will be presenting data on the first two CAR T constructs to receive Food and Drug Administration approval, each directed against CD19.
 

ZUMA-1 for non-Hodgkin lymphoma

Long-term follow-up results with the use of axicabtagene ciloleucel (Yescarta; axi-cel) in patients with refractory aggressive non-Hodgkin lymphoma will be presented by Sattva S. Neelapu, MD, of the University of Texas MD Anderson Cancer Center in Houston, on behalf of colleagues in the ZUMA-1 trial (Abstract 578).

At the 2017 European Hematology Association Congress in Madrid, ZUMA-1 investigators reported that axi-cel, an autologous anti-CD19 CAR-T product, was associated with an 82% objective response rate (ORR), including 54% complete responses, in patients with refractory diffuse large B cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma, or transformed follicular lymphoma. The 54% complete response rate was nearly sevenfold higher than that reported for historical controls, according to coinvestigator Yi Lin, MD, PhD, of the Mayo Clinic, Rochester, Minn.

The treatment was generally safe, with 13% of patients experiencing grade 3 or greater cytokine release syndrome (CRS), and 28% having grade 3 or greater neurologic events. The events were generally reversible, and the rates of each declined over time. The use of tocilizumab or steroids to control adverse events did not have a negative effect on responses.

This CAR T-cell construct received FDA approval in October 2017.

At ASH 2017, Dr. Neelapu will present 1-year follow-up data from the trial which will include both data on responses and toxicity, “but also some very interesting information on mechanisms of resistance, whether patients’ tumor cells become CD19 negative, or checkpoint, like PD-L1, positive,” said Kenneth Anderson, MD, of the Dana-Farber Cancer Institute in Boston, who discussed noteworthy abstracts in a media briefing prior to the meeting.
 

JULIET for DLBCL

Data on the use of another anti-CD19 CAR construct, tisagenlecleucel (Kymriah) in adults with relapsed or refractory DLBCL will be presented by Stephen J. Schuster, MD, of the University of Pennsylvania, Philadelphia, on behalf of investigators in the JULIET trial.

At the 2017 European Hematology Association Congress, coinvestigator Gilles Salles, MD, PhD, of the University of Lyon, France, reported an interim analysis from the trial, showing that the CAR T construct was associated with a 59% ORR, consisting of 43% complete responses and 16% partial responses in patients with relapsed or refractory DLBCL. The analysis “confirms the high response rates and durable responses observed in the previous single-center trial,” Dr. Salles said.

Dr. Schuster will present the primary analysis of the global phase 2 pivotal trial at ASH 2017 (Abstract 577), looking at patients who received the product from the U.S. manufacturing site.

As of the data cutoff in March 2017, the best ORR among 81 patients with at least 3 months of follow-up, or earlier discontinuation, was 53.1% with 39.5% complete responses and 13.6% partial responses. For 46 patients evaluable at 6 months, the complete response rate was 30% and partial response rate was 7%.

The response rates were consistent across subgroups, including patients who had previously undergone autologous stem cell transplant and those with double-hit lymphoma (i.e, with mutation in MYC and BCL2 or BCL6).

The responses also appeared to be durable, with the median duration not reached. The 6-month probability of being relapse free was 73.5%. Similarly, median overall survival was not reached; the 6-month probability of overall survival was 64.5%, according to the published abstract.

Adverse events included CRS in 58% of infused patients, with 15% grade 3 and 8% grade 4 in severity. CRS was managed according to protocol with tocilizumab and/or corticosteroids. There were no deaths associated with either the CRS or neurologic toxicities.

“This is a multicenter trial: 27 centers, 10 countries, 4 continents, so it sort of demonstrates to all of us that this technology can be done in an international scope,” Dr. Anderson said.
 

Anti-BCMA for multiple myeloma

CAR T-cells are relative newcomers in the treatment of multiple myeloma, but James N. Kochenderfer, MD, of the National Cancer Institute, Bethesda, Md., will be presenting updated results from a multicenter study of bb2121, a CAR T-cell construct directed against B-cell maturation antigen (BCMA).

BCMA was first described in myeloma in 2004 as a mechanism for the growth and survival of malignant plasma cells. As previously reported, a different anti-BCMA T-cell product induced clinical remissions in 33 of 35 patients with relapsed/refractory multiple myeloma who were treated in an early clinical trial.

With the construct being investigated by Dr. Kochenderfer and colleagues, 21 patients (median 58 years old) with a median of 5 years since a diagnosis of multiple myeloma were infused with bb2121. One-month data on clinical response was available for 18 patients at the time of data cutoff in May 2017 (Abstract 740).

In this heavily pretreated population, the ORR was 89% overall, and was 100% for patients treated with doses of 150 x 10⁶ CAR+ T cells or higher. At this dose range or higher no patients had disease progression at up to 54 weeks after infusion. Of the four patients evaluable for minimal residual disease (MRD), all were MRD negative.

As of the data cut-off there were no dose-limiting toxicities and no treatment-related grade 3 or higher neurotoxicities. CRS was primarily grade 1 or 2 and was reported in 15 of 21 patients. Two patients had grade 3 CRS that resolved in 24 hours, and four patients received tocilizumab (one with steroids) for CRS management.

There was one on-study death, from cardiopulmonary arrest more than 4 months after bb2121 infusion in a patient with an extensive cardiac history. The death was judged to be unrelated to CAR T-cell therapy.

Dr. Kochenderfer will present data and analysis on an additional 5 months of follow-up.

“This abstract demonstrates that again, in patients, this time with myeloma with literally no other option, you can achieve very impressive response,” Dr. Anderson said.

The ZUMA-1 study is funded by Kite Pharma. Dr. Neelapu reported research funding from BMS, Poseida, Merck, Kite Pharma, and Cellectis. He reported consultancy and membership on the board of directors or advisory committees for Merck, Kite Pharma, and Celgene.

The JULIET study is funded by Novartis. Dr. Schuster reported consultancy and research funding from Novartis Pharmaceuticals, Celgene, Genentech, Bristol-Myers Squibb, Janssen R&D, and Gilead. He reported consultancy with Seattle Genetics and Nordic Nanovector, and research funding from Merck.

The multicenter study of bb2121 is sponsored by bluebird bio and Celgene. Dr. Kochenderfer reported research funding from bluebird bio and Kite Pharma. He reported having multiple patents in the CAR field.


Abstract 578 Long-Term Follow-up ZUMA-1: A Pivotal Trial of Axicabtagene Ciloleucel (Axi-Cel; KTE-C19) in Patients with Refractory Aggressive Non-Hodgkin Lymphoma (NHL) will be presented in session 626, Monday, Dec. 11, 2017, at 7:15 a.m.

Abstract 577 Primary Analysis of Juliet: A Global, Pivotal, Phase 2 Trial of CTL019 in Adult Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma will be presented in session 626, Monday, Dec. 11, 2017 at 7:00 a.m.

Abstract 740 Durable Clinical Responses in Heavily Pretreated Patients with Relapsed/Refractory Multiple Myeloma: Updated Results from a Multicenter Study of bb2121 Anti-BCMA CAR T Cell Therapy will be presented in session 653, Monday, Dec. 11, 2017 at 3:00 p.m.

Advances in the treatment of chronic lymphocytic leukemia (CLL), multiple myeloma, venous thromboembolism (VTE), and acquired thrombotic thrombocytopenic purpura will headline the late-breaking trials session at this year’s annual meeting of the American Society of Hematology in Atlanta.

In a preplanned interim analysis of data from 389 patients in the randomized phase III Murano trial, venetoclax and rituximab therapy proved “superior to the standard of care and well tolerated, and a major advance in the management of [relapsed/refractory] CLL,” ASH President Kenneth C. Anderson, MD said during a premeeting preview session for the media.

In Murano, venetoclax plus rituximab bettered bendamustine plus rituximab in progression-free survival, overall survival, overall and complete response rates, and number of patients achieving minimal residual disease (MRD) negativity, said Dr. Anderson, who is also director of the Lebow Institute for Myeloma Therapeutics and Jerome Lipper Myeloma Center at Dana-Farber Cancer Institute, Boston.

The results were consistent in all risk subsets, including patients who had high-risk disease by virtue of chromosome 17p deletion, according Dr. Anderson.

In another late-breaking randomized phase III study, known as ALCYONE, adding the CD38-targeting monoclonal antibody daratumumab to standard therapy with bortezomib, melphalan, and prednisone (VMP) resulted in a “doubling” of progression-free survival in patients who had newly diagnosed multiple myeloma and were ineligible for transplantation, he reported.

In the trial of more than 700 patients, daratumumab plus VMP as initial treatment for nontransplant patients was well tolerated and improved outcomes, including overall response rate and the percent of patients who achieved MRD negative status.

“As we saw in CLL, so it’s true in this abstract in myeloma: this is a very major advance,” Dr. Anderson said.

Also during the preview session, ASH Secretary Robert A. Brodsky, MD, discussed the randomized, phase III HERCULES study results, which showed that patients with acquired thrombotic thrombocytopenic purpura (TTP) may benefit when caplacizumab is added to standard therapy. Caplacizumab targets the A1 domain of von Willebrand factor, which inhibits interaction between ultra-large von Willebrand factor and platelets.

In the trial, 145 patients were randomized to receive either plasma exchange alone or plasma exchange and caplacizumab.

Preliminary results suggest “this was a very positive trial” with a primary endpoint of time to platelet response that “greatly favored the caplacizumab arm,” said Dr. Brodsky, professor of medicine and oncology and director of the division of hematology at Johns Hopkins University, Baltimore. “Even the secondary composite endpoint of death, recurrence, and/or major thromboembolic events was much improved with caplacizumab, so this is a very positive trial and potentially a game-changing drug for the management of TTP, which can be very challenging.”

Dr. Brodsky also discussed the Hokusai VTE-Cancer Study, a randomized, open-label, blinded outcome assessment trial that showed the oral factor Xa inhibitor edoxaban was noninferior to subcutaneous dalteparin for the prevention of cancer-associated venous thromboembolism.

With more than 1,000 patients enrolled in 114 centers, the Hokusai VTE-Cancer Study had a primary outcome of the composite of the first recurrent VTE or major bleeding event during follow-up. The primary outcome occurred in 12.8% of patients in the edoxaban group, compared with 13.5% of patients in the dalteparin group (P = .0056 for noninferiority), according to the preliminary published results.

The key question addressed by the trial is whether a newer oral anticoagulant, edoxaban, can substitute for the older, subcutaneously administered low-molecular-weight heparin, dalteparin. The results “confirmed that a newer oral anticoagulant is at least as good and as safe as the low molecular weight heparin,” allowing patients the convenience of an oral therapy, Dr. Brodsky noted.

This year’s late-breaking abstracts at ASH are:

LBA-1 Results of the Randomized, Double-Blind, Placebo-Controlled, Phase III Hercules Study of Caplacizumab in Patients with Acquired Thrombotic Thrombocytopenic Purpura.

LBA-2 Venetoclax Plus Rituximab Is Superior to Bendamustine Plus Rituximab in Patients with Relapsed/ Refractory Chronic Lymphocytic Leukemia - Results from Pre-Planned Interim Analysis of the Randomized Phase III Murano Study.

LBA-3 Mutations in SRP54 Gene Cause Severe Primary Neutropenia As Well As Shwachman-Diamond-like Syndrome.

LBA-4 Phase III Randomized Study of Daratumumab Plus Bortezomib, Melphalan, and Prednisone (D-VMP) Versus Bortezomib, Melphalan, and Prednisone (VMP) in Newly Diagnosed Multiple Myeloma (NDMM) Patients (Pts) Ineligible for Transplant (ALCYONE).

LBA-5 Prospective Molecular MRD Detection By NGS: A Powerful Independent Predictor for Relapse and Survival in Adults with Newly Diagnosed AML.

LBA-6 A Randomized, Open-Label, Blinded Outcome Assessment Trial Evaluating the Efficacy and Safety of LMWH/Edoxaban Versus Dalteparin for Venous Thromboembolism Associated with Cancer: Hokusai VTE-Cancer Study

Advances in the treatment of chronic lymphocytic leukemia (CLL), multiple myeloma, venous thromboembolism (VTE), and acquired thrombotic thrombocytopenic purpura will headline the late-breaking trials session at this year’s annual meeting of the American Society of Hematology in Atlanta.

In a preplanned interim analysis of data from 389 patients in the randomized phase III Murano trial, venetoclax and rituximab therapy proved “superior to the standard of care and well tolerated, and a major advance in the management of [relapsed/refractory] CLL,” ASH President Kenneth C. Anderson, MD said during a premeeting preview session for the media.

In Murano, venetoclax plus rituximab bettered bendamustine plus rituximab in progression-free survival, overall survival, overall and complete response rates, and number of patients achieving minimal residual disease (MRD) negativity, said Dr. Anderson, who is also director of the Lebow Institute for Myeloma Therapeutics and Jerome Lipper Myeloma Center at Dana-Farber Cancer Institute, Boston.

The results were consistent in all risk subsets, including patients who had high-risk disease by virtue of chromosome 17p deletion, according Dr. Anderson.

In another late-breaking randomized phase III study, known as ALCYONE, adding the CD38-targeting monoclonal antibody daratumumab to standard therapy with bortezomib, melphalan, and prednisone (VMP) resulted in a “doubling” of progression-free survival in patients who had newly diagnosed multiple myeloma and were ineligible for transplantation, he reported.

In the trial of more than 700 patients, daratumumab plus VMP as initial treatment for nontransplant patients was well tolerated and improved outcomes, including overall response rate and the percent of patients who achieved MRD negative status.

“As we saw in CLL, so it’s true in this abstract in myeloma: this is a very major advance,” Dr. Anderson said.

Also during the preview session, ASH Secretary Robert A. Brodsky, MD, discussed the randomized, phase III HERCULES study results, which showed that patients with acquired thrombotic thrombocytopenic purpura (TTP) may benefit when caplacizumab is added to standard therapy. Caplacizumab targets the A1 domain of von Willebrand factor, which inhibits interaction between ultra-large von Willebrand factor and platelets.

In the trial, 145 patients were randomized to receive either plasma exchange alone or plasma exchange and caplacizumab.

Preliminary results suggest “this was a very positive trial” with a primary endpoint of time to platelet response that “greatly favored the caplacizumab arm,” said Dr. Brodsky, professor of medicine and oncology and director of the division of hematology at Johns Hopkins University, Baltimore. “Even the secondary composite endpoint of death, recurrence, and/or major thromboembolic events was much improved with caplacizumab, so this is a very positive trial and potentially a game-changing drug for the management of TTP, which can be very challenging.”

Dr. Brodsky also discussed the Hokusai VTE-Cancer Study, a randomized, open-label, blinded outcome assessment trial that showed the oral factor Xa inhibitor edoxaban was noninferior to subcutaneous dalteparin for the prevention of cancer-associated venous thromboembolism.

With more than 1,000 patients enrolled in 114 centers, the Hokusai VTE-Cancer Study had a primary outcome of the composite of the first recurrent VTE or major bleeding event during follow-up. The primary outcome occurred in 12.8% of patients in the edoxaban group, compared with 13.5% of patients in the dalteparin group (P = .0056 for noninferiority), according to the preliminary published results.

The key question addressed by the trial is whether a newer oral anticoagulant, edoxaban, can substitute for the older, subcutaneously administered low-molecular-weight heparin, dalteparin. The results “confirmed that a newer oral anticoagulant is at least as good and as safe as the low molecular weight heparin,” allowing patients the convenience of an oral therapy, Dr. Brodsky noted.

This year’s late-breaking abstracts at ASH are:

LBA-1 Results of the Randomized, Double-Blind, Placebo-Controlled, Phase III Hercules Study of Caplacizumab in Patients with Acquired Thrombotic Thrombocytopenic Purpura.

LBA-2 Venetoclax Plus Rituximab Is Superior to Bendamustine Plus Rituximab in Patients with Relapsed/ Refractory Chronic Lymphocytic Leukemia - Results from Pre-Planned Interim Analysis of the Randomized Phase III Murano Study.

LBA-3 Mutations in SRP54 Gene Cause Severe Primary Neutropenia As Well As Shwachman-Diamond-like Syndrome.

LBA-4 Phase III Randomized Study of Daratumumab Plus Bortezomib, Melphalan, and Prednisone (D-VMP) Versus Bortezomib, Melphalan, and Prednisone (VMP) in Newly Diagnosed Multiple Myeloma (NDMM) Patients (Pts) Ineligible for Transplant (ALCYONE).

LBA-5 Prospective Molecular MRD Detection By NGS: A Powerful Independent Predictor for Relapse and Survival in Adults with Newly Diagnosed AML.

LBA-6 A Randomized, Open-Label, Blinded Outcome Assessment Trial Evaluating the Efficacy and Safety of LMWH/Edoxaban Versus Dalteparin for Venous Thromboembolism Associated with Cancer: Hokusai VTE-Cancer Study

Advances in the treatment of chronic lymphocytic leukemia (CLL), multiple myeloma, venous thromboembolism (VTE), and acquired thrombotic thrombocytopenic purpura will headline the late-breaking trials session at this year’s annual meeting of the American Society of Hematology in Atlanta.

In a preplanned interim analysis of data from 389 patients in the randomized phase III Murano trial, venetoclax and rituximab therapy proved “superior to the standard of care and well tolerated, and a major advance in the management of [relapsed/refractory] CLL,” ASH President Kenneth C. Anderson, MD said during a premeeting preview session for the media.

In Murano, venetoclax plus rituximab bettered bendamustine plus rituximab in progression-free survival, overall survival, overall and complete response rates, and number of patients achieving minimal residual disease (MRD) negativity, said Dr. Anderson, who is also director of the Lebow Institute for Myeloma Therapeutics and Jerome Lipper Myeloma Center at Dana-Farber Cancer Institute, Boston.

The results were consistent in all risk subsets, including patients who had high-risk disease by virtue of chromosome 17p deletion, according Dr. Anderson.

In another late-breaking randomized phase III study, known as ALCYONE, adding the CD38-targeting monoclonal antibody daratumumab to standard therapy with bortezomib, melphalan, and prednisone (VMP) resulted in a “doubling” of progression-free survival in patients who had newly diagnosed multiple myeloma and were ineligible for transplantation, he reported.

In the trial of more than 700 patients, daratumumab plus VMP as initial treatment for nontransplant patients was well tolerated and improved outcomes, including overall response rate and the percent of patients who achieved MRD negative status.

“As we saw in CLL, so it’s true in this abstract in myeloma: this is a very major advance,” Dr. Anderson said.

Also during the preview session, ASH Secretary Robert A. Brodsky, MD, discussed the randomized, phase III HERCULES study results, which showed that patients with acquired thrombotic thrombocytopenic purpura (TTP) may benefit when caplacizumab is added to standard therapy. Caplacizumab targets the A1 domain of von Willebrand factor, which inhibits interaction between ultra-large von Willebrand factor and platelets.

In the trial, 145 patients were randomized to receive either plasma exchange alone or plasma exchange and caplacizumab.

Preliminary results suggest “this was a very positive trial” with a primary endpoint of time to platelet response that “greatly favored the caplacizumab arm,” said Dr. Brodsky, professor of medicine and oncology and director of the division of hematology at Johns Hopkins University, Baltimore. “Even the secondary composite endpoint of death, recurrence, and/or major thromboembolic events was much improved with caplacizumab, so this is a very positive trial and potentially a game-changing drug for the management of TTP, which can be very challenging.”

Dr. Brodsky also discussed the Hokusai VTE-Cancer Study, a randomized, open-label, blinded outcome assessment trial that showed the oral factor Xa inhibitor edoxaban was noninferior to subcutaneous dalteparin for the prevention of cancer-associated venous thromboembolism.

With more than 1,000 patients enrolled in 114 centers, the Hokusai VTE-Cancer Study had a primary outcome of the composite of the first recurrent VTE or major bleeding event during follow-up. The primary outcome occurred in 12.8% of patients in the edoxaban group, compared with 13.5% of patients in the dalteparin group (P = .0056 for noninferiority), according to the preliminary published results.

The key question addressed by the trial is whether a newer oral anticoagulant, edoxaban, can substitute for the older, subcutaneously administered low-molecular-weight heparin, dalteparin. The results “confirmed that a newer oral anticoagulant is at least as good and as safe as the low molecular weight heparin,” allowing patients the convenience of an oral therapy, Dr. Brodsky noted.

This year’s late-breaking abstracts at ASH are:

LBA-1 Results of the Randomized, Double-Blind, Placebo-Controlled, Phase III Hercules Study of Caplacizumab in Patients with Acquired Thrombotic Thrombocytopenic Purpura.

LBA-2 Venetoclax Plus Rituximab Is Superior to Bendamustine Plus Rituximab in Patients with Relapsed/ Refractory Chronic Lymphocytic Leukemia - Results from Pre-Planned Interim Analysis of the Randomized Phase III Murano Study.

LBA-3 Mutations in SRP54 Gene Cause Severe Primary Neutropenia As Well As Shwachman-Diamond-like Syndrome.

LBA-4 Phase III Randomized Study of Daratumumab Plus Bortezomib, Melphalan, and Prednisone (D-VMP) Versus Bortezomib, Melphalan, and Prednisone (VMP) in Newly Diagnosed Multiple Myeloma (NDMM) Patients (Pts) Ineligible for Transplant (ALCYONE).

LBA-5 Prospective Molecular MRD Detection By NGS: A Powerful Independent Predictor for Relapse and Survival in Adults with Newly Diagnosed AML.

LBA-6 A Randomized, Open-Label, Blinded Outcome Assessment Trial Evaluating the Efficacy and Safety of LMWH/Edoxaban Versus Dalteparin for Venous Thromboembolism Associated with Cancer: Hokusai VTE-Cancer Study