Cellular Therapy

CHICAGO – A low intensity chemotherapy regimen may be the best approach to bridge patients waiting for chimeric antigen receptor (CAR) T-cell therapy, according to a retrospective analysis of adults with acute lymphoblastic leukemia (ALL).

Investigators found that high intensity bridging regimens provided no clear outcome benefit, but did produce a greater number of infections.

But the decision on the type of regimen is very much dependent on the individual patient, Karlo Perica, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York, said at the annual meeting of the American Society of Clinical Oncology.

Mary Ellen Schneider/MDedge News

Dr. Perica and his colleagues at Memorial Sloan Kettering examined the effectiveness and toxicity of bridging therapies provided to relapsed or refractory ALL patients waiting to receive CD19 CAR T-cell therapy as part of a phase 1 trial (N Engl J Med. 2018 Feb 1;378[5]:449-59).

Bridging therapy was defined as any therapy given from leukapheresis to cell infusion.

The low-intensity regimens included POMP (6-mercaptopurine, vincristine, methotrexate, and prednisone, or combinations), liposomal vincristine, mini-hyper CVD (reduced cyclophosphamide, dexamethasone, methotrexate, Ara-C), blinatumomab, inotuzumab, oral tyrosine kinase inhibitor-based regimens, or hydroxyurea.

The high-intensity regimens included hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone), high-dose cytarabine, attenuated FLAG/FLAG-IDA (reduced fludarabine, cytarabine, G-CSF plus or minus idarubicin), and pediatric-type induction.

Of the 53 patients who were ultimately infused with CAR T cells, 19 received some type of high intensity regimen, 29 received low intensity regimens, and 5 received no bridging treatment. The group overall was heavily pretreated. Nearly a third of the low intensity and no bridging patients and 42% of the high intensity patients had previously undergone transplant. More than 40% of the low intensity and no bridging patients and about a quarter of the high intensity bridging group had four or more prior lines of therapy.

The use of high intensity bridging therapy was not associated with improved overall response or relapse-free survival to CAR T-cell therapy, the investigators reported. In a subgroup with 23 high disease burden patients with greater than 20% blasts, there was no difference in MRD-negative complete response by intensity (75% versus 60%, Fisher’s P = .65).

High intensity bridging was also not associated with successful CAR T-cell infusion, versus low intensity regimens (63% versus 79%, P greater than .05) or a combined endpoint of CAR T-cell infusion plus transplant or alternative treatment (80% versus 86%, P greater than .05).

In terms of toxicity, the high intensity bridging regimens were associated with a higher rate of grade 3 or 4 infections – 15 versus 11 infections (Fisher’s P = .002). But there was no association with post-infusion grade 3 or 4 cytokine release syndrome or neurotoxicity.

Dr. Perica said the results reflect that the real goal of bridging is not to reduce disease burden but instead to successfully bring patients to the next phase of their treatment. “The goal of the bridging therapy is to get the patient to the CAR infusion,” he said.

Due to the retrospective nature of the study, Dr. Perica said he can’t recommend any single bridging regimen and he emphasized that the decisions are patient-specific.

The original study was funded by several foundations and Juno Therapeutics. Dr. Perica reported royalties from technology licensed to Neximmune.

[email protected]

SOURCE: Perica K et al. ASCO 2019, Abstract 2520.

CHICAGO – A low intensity chemotherapy regimen may be the best approach to bridge patients waiting for chimeric antigen receptor (CAR) T-cell therapy, according to a retrospective analysis of adults with acute lymphoblastic leukemia (ALL).

Investigators found that high intensity bridging regimens provided no clear outcome benefit, but did produce a greater number of infections.

But the decision on the type of regimen is very much dependent on the individual patient, Karlo Perica, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York, said at the annual meeting of the American Society of Clinical Oncology.

Mary Ellen Schneider/MDedge News

Dr. Perica and his colleagues at Memorial Sloan Kettering examined the effectiveness and toxicity of bridging therapies provided to relapsed or refractory ALL patients waiting to receive CD19 CAR T-cell therapy as part of a phase 1 trial (N Engl J Med. 2018 Feb 1;378[5]:449-59).

Bridging therapy was defined as any therapy given from leukapheresis to cell infusion.

The low-intensity regimens included POMP (6-mercaptopurine, vincristine, methotrexate, and prednisone, or combinations), liposomal vincristine, mini-hyper CVD (reduced cyclophosphamide, dexamethasone, methotrexate, Ara-C), blinatumomab, inotuzumab, oral tyrosine kinase inhibitor-based regimens, or hydroxyurea.

The high-intensity regimens included hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone), high-dose cytarabine, attenuated FLAG/FLAG-IDA (reduced fludarabine, cytarabine, G-CSF plus or minus idarubicin), and pediatric-type induction.

Of the 53 patients who were ultimately infused with CAR T cells, 19 received some type of high intensity regimen, 29 received low intensity regimens, and 5 received no bridging treatment. The group overall was heavily pretreated. Nearly a third of the low intensity and no bridging patients and 42% of the high intensity patients had previously undergone transplant. More than 40% of the low intensity and no bridging patients and about a quarter of the high intensity bridging group had four or more prior lines of therapy.

The use of high intensity bridging therapy was not associated with improved overall response or relapse-free survival to CAR T-cell therapy, the investigators reported. In a subgroup with 23 high disease burden patients with greater than 20% blasts, there was no difference in MRD-negative complete response by intensity (75% versus 60%, Fisher’s P = .65).

High intensity bridging was also not associated with successful CAR T-cell infusion, versus low intensity regimens (63% versus 79%, P greater than .05) or a combined endpoint of CAR T-cell infusion plus transplant or alternative treatment (80% versus 86%, P greater than .05).

In terms of toxicity, the high intensity bridging regimens were associated with a higher rate of grade 3 or 4 infections – 15 versus 11 infections (Fisher’s P = .002). But there was no association with post-infusion grade 3 or 4 cytokine release syndrome or neurotoxicity.

Dr. Perica said the results reflect that the real goal of bridging is not to reduce disease burden but instead to successfully bring patients to the next phase of their treatment. “The goal of the bridging therapy is to get the patient to the CAR infusion,” he said.

Due to the retrospective nature of the study, Dr. Perica said he can’t recommend any single bridging regimen and he emphasized that the decisions are patient-specific.

The original study was funded by several foundations and Juno Therapeutics. Dr. Perica reported royalties from technology licensed to Neximmune.

[email protected]

SOURCE: Perica K et al. ASCO 2019, Abstract 2520.

CHICAGO – A low intensity chemotherapy regimen may be the best approach to bridge patients waiting for chimeric antigen receptor (CAR) T-cell therapy, according to a retrospective analysis of adults with acute lymphoblastic leukemia (ALL).

Investigators found that high intensity bridging regimens provided no clear outcome benefit, but did produce a greater number of infections.

But the decision on the type of regimen is very much dependent on the individual patient, Karlo Perica, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York, said at the annual meeting of the American Society of Clinical Oncology.

Mary Ellen Schneider/MDedge News

Dr. Perica and his colleagues at Memorial Sloan Kettering examined the effectiveness and toxicity of bridging therapies provided to relapsed or refractory ALL patients waiting to receive CD19 CAR T-cell therapy as part of a phase 1 trial (N Engl J Med. 2018 Feb 1;378[5]:449-59).

Bridging therapy was defined as any therapy given from leukapheresis to cell infusion.

The low-intensity regimens included POMP (6-mercaptopurine, vincristine, methotrexate, and prednisone, or combinations), liposomal vincristine, mini-hyper CVD (reduced cyclophosphamide, dexamethasone, methotrexate, Ara-C), blinatumomab, inotuzumab, oral tyrosine kinase inhibitor-based regimens, or hydroxyurea.

The high-intensity regimens included hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone), high-dose cytarabine, attenuated FLAG/FLAG-IDA (reduced fludarabine, cytarabine, G-CSF plus or minus idarubicin), and pediatric-type induction.

Of the 53 patients who were ultimately infused with CAR T cells, 19 received some type of high intensity regimen, 29 received low intensity regimens, and 5 received no bridging treatment. The group overall was heavily pretreated. Nearly a third of the low intensity and no bridging patients and 42% of the high intensity patients had previously undergone transplant. More than 40% of the low intensity and no bridging patients and about a quarter of the high intensity bridging group had four or more prior lines of therapy.

The use of high intensity bridging therapy was not associated with improved overall response or relapse-free survival to CAR T-cell therapy, the investigators reported. In a subgroup with 23 high disease burden patients with greater than 20% blasts, there was no difference in MRD-negative complete response by intensity (75% versus 60%, Fisher’s P = .65).

High intensity bridging was also not associated with successful CAR T-cell infusion, versus low intensity regimens (63% versus 79%, P greater than .05) or a combined endpoint of CAR T-cell infusion plus transplant or alternative treatment (80% versus 86%, P greater than .05).

In terms of toxicity, the high intensity bridging regimens were associated with a higher rate of grade 3 or 4 infections – 15 versus 11 infections (Fisher’s P = .002). But there was no association with post-infusion grade 3 or 4 cytokine release syndrome or neurotoxicity.

Dr. Perica said the results reflect that the real goal of bridging is not to reduce disease burden but instead to successfully bring patients to the next phase of their treatment. “The goal of the bridging therapy is to get the patient to the CAR infusion,” he said.

Due to the retrospective nature of the study, Dr. Perica said he can’t recommend any single bridging regimen and he emphasized that the decisions are patient-specific.

The original study was funded by several foundations and Juno Therapeutics. Dr. Perica reported royalties from technology licensed to Neximmune.

[email protected]

SOURCE: Perica K et al. ASCO 2019, Abstract 2520.

The Food and Drug Administration has approved Jafaki (ruxolitinib) for treatment of steroid-refractory acute graft-versus-host disease (GVHD) in adult and pediatric patients 12 years and older.

Ruxolitinib will be made available to appropriate patients immediately, according to a statement from Incyte, which markets the drug. The company noted that ruxolitinib is the first FDA-approved treatment for this indication.

The approval is based on data from the open-label, single-arm, multicenter REACH1 trial, which studied ruxolitinib in combination with corticosteroids. The 71 patients in the trial had grade 2-4 acute GVHD after allogeneic hematopoietic stem cell transplant; of these patients, 49 were refractory to steroids alone, 12 had received at least two prior therapies for GVHD, and 10 did not otherwise meet the FDA definition of steroid refractory.

The trial’s primary endpoints were day-28 overall response rate and response duration. Among the 49 patients with steroid only–refractory GVHD, the overall response rate was 100% for grade 2 GVHD, 40.7% for grade 3, and 44.4% for grade 4. Median response duration was 16 days. For all 49 of these patients, the overall response rate was 57%, and the complete response rate was 31%.

Among all 71 participants, the most frequently reported adverse reactions were infections (55%) and edema (51%); anemia (71%), thrombocytopenia (75%), and neutropenia (58%) were the most common laboratory abnormalities.

[email protected]

The Food and Drug Administration has approved Jafaki (ruxolitinib) for treatment of steroid-refractory acute graft-versus-host disease (GVHD) in adult and pediatric patients 12 years and older.

Ruxolitinib will be made available to appropriate patients immediately, according to a statement from Incyte, which markets the drug. The company noted that ruxolitinib is the first FDA-approved treatment for this indication.

The approval is based on data from the open-label, single-arm, multicenter REACH1 trial, which studied ruxolitinib in combination with corticosteroids. The 71 patients in the trial had grade 2-4 acute GVHD after allogeneic hematopoietic stem cell transplant; of these patients, 49 were refractory to steroids alone, 12 had received at least two prior therapies for GVHD, and 10 did not otherwise meet the FDA definition of steroid refractory.

The trial’s primary endpoints were day-28 overall response rate and response duration. Among the 49 patients with steroid only–refractory GVHD, the overall response rate was 100% for grade 2 GVHD, 40.7% for grade 3, and 44.4% for grade 4. Median response duration was 16 days. For all 49 of these patients, the overall response rate was 57%, and the complete response rate was 31%.

Among all 71 participants, the most frequently reported adverse reactions were infections (55%) and edema (51%); anemia (71%), thrombocytopenia (75%), and neutropenia (58%) were the most common laboratory abnormalities.

[email protected]

The Food and Drug Administration has approved Jafaki (ruxolitinib) for treatment of steroid-refractory acute graft-versus-host disease (GVHD) in adult and pediatric patients 12 years and older.

Ruxolitinib will be made available to appropriate patients immediately, according to a statement from Incyte, which markets the drug. The company noted that ruxolitinib is the first FDA-approved treatment for this indication.

The approval is based on data from the open-label, single-arm, multicenter REACH1 trial, which studied ruxolitinib in combination with corticosteroids. The 71 patients in the trial had grade 2-4 acute GVHD after allogeneic hematopoietic stem cell transplant; of these patients, 49 were refractory to steroids alone, 12 had received at least two prior therapies for GVHD, and 10 did not otherwise meet the FDA definition of steroid refractory.

The trial’s primary endpoints were day-28 overall response rate and response duration. Among the 49 patients with steroid only–refractory GVHD, the overall response rate was 100% for grade 2 GVHD, 40.7% for grade 3, and 44.4% for grade 4. Median response duration was 16 days. For all 49 of these patients, the overall response rate was 57%, and the complete response rate was 31%.

Among all 71 participants, the most frequently reported adverse reactions were infections (55%) and edema (51%); anemia (71%), thrombocytopenia (75%), and neutropenia (58%) were the most common laboratory abnormalities.

[email protected]

Hospitals could get a payment bump for administering chimeric antigen receptor (CAR) T-cell therapies under a proposed rule issued by the Centers for Medicare & Medicaid Services.

Penn Medicine

The proposal calls for raising the new technology add-on payment (NTAP) associated with the therapies from 50% of the technology to 65%, an increase from $186,500 to $242,450.

Beginning with discharges on Oct. 1, 2019, if discharge costs involving a new medical service or technology exceed the full Medicare Severity Diagnosis-Related Group (DRG) payment, Medicare would make an add-on payment of either 65% of the cost of the new medical service or technology, or 65% of the amount by which the costs of the case exceed the standard DRG payment, whichever is less.

Roy Silverstein, MD, president of the American Society of Hematology, said the group was pleased that the CMS is examining its existing payment policies to identify more realistic ways to account for the costs of administering CAR T-cell therapies.

“While ASH had originally suggested a higher [new technology] payment, any increase is an improvement,” Dr. Silverstein said in a statement. “While the proposal from CMS is promising, it is not a one-stop solution for making CAR T more accessible to patients. Just as these therapies are innovative, it is going to take some innovation on the part of CMS to develop a plan that equitably compensates providers and institutions so that offering the therapy is sustainable.”

The agency’s proposal follows an August 2018 final rule by the CMS that set a new payment scheme for inpatient administration of two CAR T-cell therapies. The rule categorized CAR T-cell therapies under the umbrella of the renamed Medicare Severity–Diagnosis Related Groups (MS-DRG) 016 – Autologous Bone Marrow Transplant with CC/MCC or T-cell Immunotherapy – and assigned ICD-10 PCS procedure codes XW033C3 and XW043C3 to the use of axicabtagene ciloleucel (Yescarta) and tisagenlecleucel (Kymriah) in the inpatient setting for fiscal year 2019, which began in October 2018.

In April 2018, the CMS announced payment rates for outpatient administration of the two drugs, settling on $395,380 for axicabtagene ciloleucel and $500,839 for tisagenlecleucel. The two medications have list prices of $373,000 and $475,000, respectively.

In February 2019, the CMS also proposed to cover CAR T-cell therapy for cancer patients participating in clinical trials that study the treatment’s effectiveness. A final decision on the proposal is expected in May 2019.

In the current proposal, the CMS acknowledged requests calling for the agency to create a new MS-DRG for procedures involving CAR T-cell therapies to improve payment in the inpatient setting. However, the agency declined to create a new MS-DRG for CAR T-cell cases, writing that the move is premature given the relative newness of CAR T-cell therapy and the agency’s proposal to continue new technology add-on payments for fiscal 2020 for Kymriah and Yescarta.

However, the agency is requesting public comments on whether, in light of additional experience with billing and payment for cases involving CAR T-cell therapies to Medicare patients, the CMS should consider using a specific cost-to-charge ratio for ICD-10-PCS procedure codes used to report the performance of procedures involving CAR T-cell therapies.

Comments on the proposed rule will be accepted until June 24.

[email protected]

Hospitals could get a payment bump for administering chimeric antigen receptor (CAR) T-cell therapies under a proposed rule issued by the Centers for Medicare & Medicaid Services.

Penn Medicine

The proposal calls for raising the new technology add-on payment (NTAP) associated with the therapies from 50% of the technology to 65%, an increase from $186,500 to $242,450.

Beginning with discharges on Oct. 1, 2019, if discharge costs involving a new medical service or technology exceed the full Medicare Severity Diagnosis-Related Group (DRG) payment, Medicare would make an add-on payment of either 65% of the cost of the new medical service or technology, or 65% of the amount by which the costs of the case exceed the standard DRG payment, whichever is less.

Roy Silverstein, MD, president of the American Society of Hematology, said the group was pleased that the CMS is examining its existing payment policies to identify more realistic ways to account for the costs of administering CAR T-cell therapies.

“While ASH had originally suggested a higher [new technology] payment, any increase is an improvement,” Dr. Silverstein said in a statement. “While the proposal from CMS is promising, it is not a one-stop solution for making CAR T more accessible to patients. Just as these therapies are innovative, it is going to take some innovation on the part of CMS to develop a plan that equitably compensates providers and institutions so that offering the therapy is sustainable.”

The agency’s proposal follows an August 2018 final rule by the CMS that set a new payment scheme for inpatient administration of two CAR T-cell therapies. The rule categorized CAR T-cell therapies under the umbrella of the renamed Medicare Severity–Diagnosis Related Groups (MS-DRG) 016 – Autologous Bone Marrow Transplant with CC/MCC or T-cell Immunotherapy – and assigned ICD-10 PCS procedure codes XW033C3 and XW043C3 to the use of axicabtagene ciloleucel (Yescarta) and tisagenlecleucel (Kymriah) in the inpatient setting for fiscal year 2019, which began in October 2018.

In April 2018, the CMS announced payment rates for outpatient administration of the two drugs, settling on $395,380 for axicabtagene ciloleucel and $500,839 for tisagenlecleucel. The two medications have list prices of $373,000 and $475,000, respectively.

In February 2019, the CMS also proposed to cover CAR T-cell therapy for cancer patients participating in clinical trials that study the treatment’s effectiveness. A final decision on the proposal is expected in May 2019.

In the current proposal, the CMS acknowledged requests calling for the agency to create a new MS-DRG for procedures involving CAR T-cell therapies to improve payment in the inpatient setting. However, the agency declined to create a new MS-DRG for CAR T-cell cases, writing that the move is premature given the relative newness of CAR T-cell therapy and the agency’s proposal to continue new technology add-on payments for fiscal 2020 for Kymriah and Yescarta.

However, the agency is requesting public comments on whether, in light of additional experience with billing and payment for cases involving CAR T-cell therapies to Medicare patients, the CMS should consider using a specific cost-to-charge ratio for ICD-10-PCS procedure codes used to report the performance of procedures involving CAR T-cell therapies.

Comments on the proposed rule will be accepted until June 24.

[email protected]

Hospitals could get a payment bump for administering chimeric antigen receptor (CAR) T-cell therapies under a proposed rule issued by the Centers for Medicare & Medicaid Services.

Penn Medicine

The proposal calls for raising the new technology add-on payment (NTAP) associated with the therapies from 50% of the technology to 65%, an increase from $186,500 to $242,450.

Beginning with discharges on Oct. 1, 2019, if discharge costs involving a new medical service or technology exceed the full Medicare Severity Diagnosis-Related Group (DRG) payment, Medicare would make an add-on payment of either 65% of the cost of the new medical service or technology, or 65% of the amount by which the costs of the case exceed the standard DRG payment, whichever is less.

Roy Silverstein, MD, president of the American Society of Hematology, said the group was pleased that the CMS is examining its existing payment policies to identify more realistic ways to account for the costs of administering CAR T-cell therapies.

“While ASH had originally suggested a higher [new technology] payment, any increase is an improvement,” Dr. Silverstein said in a statement. “While the proposal from CMS is promising, it is not a one-stop solution for making CAR T more accessible to patients. Just as these therapies are innovative, it is going to take some innovation on the part of CMS to develop a plan that equitably compensates providers and institutions so that offering the therapy is sustainable.”

The agency’s proposal follows an August 2018 final rule by the CMS that set a new payment scheme for inpatient administration of two CAR T-cell therapies. The rule categorized CAR T-cell therapies under the umbrella of the renamed Medicare Severity–Diagnosis Related Groups (MS-DRG) 016 – Autologous Bone Marrow Transplant with CC/MCC or T-cell Immunotherapy – and assigned ICD-10 PCS procedure codes XW033C3 and XW043C3 to the use of axicabtagene ciloleucel (Yescarta) and tisagenlecleucel (Kymriah) in the inpatient setting for fiscal year 2019, which began in October 2018.

In April 2018, the CMS announced payment rates for outpatient administration of the two drugs, settling on $395,380 for axicabtagene ciloleucel and $500,839 for tisagenlecleucel. The two medications have list prices of $373,000 and $475,000, respectively.

In February 2019, the CMS also proposed to cover CAR T-cell therapy for cancer patients participating in clinical trials that study the treatment’s effectiveness. A final decision on the proposal is expected in May 2019.

In the current proposal, the CMS acknowledged requests calling for the agency to create a new MS-DRG for procedures involving CAR T-cell therapies to improve payment in the inpatient setting. However, the agency declined to create a new MS-DRG for CAR T-cell cases, writing that the move is premature given the relative newness of CAR T-cell therapy and the agency’s proposal to continue new technology add-on payments for fiscal 2020 for Kymriah and Yescarta.

However, the agency is requesting public comments on whether, in light of additional experience with billing and payment for cases involving CAR T-cell therapies to Medicare patients, the CMS should consider using a specific cost-to-charge ratio for ICD-10-PCS procedure codes used to report the performance of procedures involving CAR T-cell therapies.

Comments on the proposed rule will be accepted until June 24.

[email protected]

The National Institutes of Health has released an amended guideline on research involving gene therapy.

As part of the streamlining process, the Recombinant DNA Advisory Committee has been renamed as the Novel and Exceptional Technology and Research Advisory Committee to better align with the committee’s original intention – following and providing advice on safety and ethical issues associated with emerging biotechnologies, according to a statement from Francis S. Collins, MD, PhD, director of the NIH.

We previously covered this story; find our coverage at the link below.

[email protected]

The National Institutes of Health has released an amended guideline on research involving gene therapy.

As part of the streamlining process, the Recombinant DNA Advisory Committee has been renamed as the Novel and Exceptional Technology and Research Advisory Committee to better align with the committee’s original intention – following and providing advice on safety and ethical issues associated with emerging biotechnologies, according to a statement from Francis S. Collins, MD, PhD, director of the NIH.

We previously covered this story; find our coverage at the link below.

[email protected]

The National Institutes of Health has released an amended guideline on research involving gene therapy.

As part of the streamlining process, the Recombinant DNA Advisory Committee has been renamed as the Novel and Exceptional Technology and Research Advisory Committee to better align with the committee’s original intention – following and providing advice on safety and ethical issues associated with emerging biotechnologies, according to a statement from Francis S. Collins, MD, PhD, director of the NIH.

We previously covered this story; find our coverage at the link below.

[email protected]

GLASGOW – Constant patient monitoring and early intervention with tocilizumab and steroids are essential to the safe delivery of chimeric antigen receptor (CAR) T-cell therapy in patients with non-Hodgkin lymphoma (NHL), according to a leading expert.

As a clinical researcher at MD Anderson Cancer Center in Houston, Loretta Nastoupil, MD has played an active role in the evolution of CAR T-cell therapy, from early trials to ongoing development of treatment protocols. During a presentation at the annual meeting of the British Society for Haematology, Dr. Nastoupil discussed leading topics in CAR T-cell therapy, with an emphasis on safe delivery.

“[Toxicity] is something we don’t talk about as much as we should, partly because this therapy works and it’s really exciting,” Dr. Nastoupil said. “But the toxicity is not something that I minimize, and it’s very challenging. It’s led us to restructure our inpatient services. It’s led to a lot of sleepless nights. These patients can do very, very well, or they can do very, very poorly in terms of toxicity and I think the most important strategy is recognition and early intervention.”

Monitoring

Early recognition depends on close monitoring, Dr. Nastoupil said, which is carried out by highly trained nursing staff who follow therapy-specific decision algorithms.

“We have nurses that are on the front line,” Dr. Nastoupil said. “They’re the most important group. We have staff that round on [patients] daily, but the nurses are there 24 hours a day. We have a flow sheet where they grade cytokine release syndrome and neurotoxicity every 8 hours, or if there is an acute change in symptoms or toxicity, they’ll do it in real time.”

Dr. Nastoupil said that if these toxicities are detected, intervention is occurring sooner than it did with some of the first patients to receive CAR-T cell therapy.

“Initially there was a lot of fear surrounding anything that would abort the CAR-T cell therapy,” Dr. Nastoupil said. “There was concern that if you were trying to mitigate some of the toxicity you might have a negative impact on efficacy ... [W]ith the first iteration of studies, generally we were waiting until grade 3 or higher cytokine release syndrome before initiating either tocilizumab and/or steroids. As the studies evolved, it started to move into grade 2 toxicity that we started using therapy, mostly because we started to see that those patients were still responding.”

At MD Anderson, these earlier interventions have decreased severity of adverse events.

“It’s rare nowadays to have grade 3 or 4 cytokine release syndrome because we are generally introducing abortive therapy at grade 2,” Dr. Nastoupil said, citing increased use of steroids and tocilizumab.

Currently, no consensus exists for managing these events, partly because clinicians are still learning about best management practices.

“There will be a consensus on management,” Dr. Nastoupil said. “I think that’s needed. The problem is, it will probably evolve as we get more experience with managing these patients. I think there’s been a little hesitation to put something out on paper knowing that a year from now that might change.”

Grading toxicity

In contrast, Dr. Nastoupil said that a consensus has been reached for grading acute toxicity. Of note, fever is now considered an essential element of cytokine release syndrome.

“The first thing we see [with cytokine release syndrome] is fever, generally speaking,” Dr. Nastoupil said. “That will prompt a workup for infection because these patients are going to be neutropenic. And we initiate broad spectrum antimicrobials.”

She said that some patients treated with CAR T-cell therapy have had disseminated fungal infections, so clinicians need to be on the lookout for septic shock.

To assess neurotoxicity, the team at MD Anderson uses an objective scoring system, called “CARTOX.” This helps maintain consistency when facing broadly different neurological presentations.

“There’s such a wide ranging spectrum of patients that are undergoing neurotoxicity you can’t expect someone, even myself, to be consistent when you are trying to tease out how serious it is,” Dr. Nastoupil said.

With CARTOX, nurses can easily score patients and call clinicians with results. Still, this doesn’t eliminate difficulties inherent to managing neurotoxicity, particularly when it is severe.

“I’d say one of the areas that is still very challenging is when [patients with neurotoxicity] are no longer responding,” Dr. Nastoupil said. “You have to be very mindful of seizure activity. We’ve had a couple of patients with status [epilepticus]. You don’t see seizure activity physically, but when you do an EEG, you pick it up.”

Dr. Nastoupil added that most centers are now giving patients prophylactic levetiracetam (Keppra) to lower seizure risk.

Choosing therapy

When selecting between the two therapies currently approved by the Food and Drug Administration – tisagenlecleucel (Kymriah) and axicabtagene ciloleucel (Yescarta) – based on safety, Dr. Nastoupil said that rates of cytokine release syndrome appear similar, but neurotoxicity rates may differ.

“Cytokine release syndrome in my opinion is probably more similar than different in terms of grade 3 or higher because tocilizumab and steroids work quite well in aborting those toxicities,” Dr. Nastoupil said. “But neurotoxicity still sticks out in my mind as the most striking difference, where with axicabtagene you see more grade 3 or higher neurotoxicity, though very, very few deaths as a result of this. But it’s very challenging in terms of management.”

According to Dr. Nastoupil, comparisons between CAR T-cell therapies have been complicated by differences in clinical trial methodologies. However, she offered a general conclusion regarding efficacy.

“[W]hat I’ll tell you, at the end of the day, is [that existing CAR T-cell therapies] all seem to sort of settle out around 30%-40% in terms of durable responses,” Dr. Nastoupil said.

Dr. Nastoupil concluded her presentation with an overview and look to the future.

“I do think [CAR T-cell therapy] is transformative, particularly for our chemo refractory patients,” she said. “There is nothing else like it. The problem right now is that it is only durable in 40% of patients. So can we be better at selecting out patients that are more likely to respond? Does introducing this in earlier lines of therapy increase that fraction of patients that are potentially cured?”

Considering these questions, she said: “We need more patients. We need more data. We need longer follow-up to understand the nuances of this therapy.”

Dr. Nastoupil previously reported financial relationships with Celgene, Genentech, Gilead, Merck, Novartis, Spectrum, and TG Therapeutics.

GLASGOW – Constant patient monitoring and early intervention with tocilizumab and steroids are essential to the safe delivery of chimeric antigen receptor (CAR) T-cell therapy in patients with non-Hodgkin lymphoma (NHL), according to a leading expert.

As a clinical researcher at MD Anderson Cancer Center in Houston, Loretta Nastoupil, MD has played an active role in the evolution of CAR T-cell therapy, from early trials to ongoing development of treatment protocols. During a presentation at the annual meeting of the British Society for Haematology, Dr. Nastoupil discussed leading topics in CAR T-cell therapy, with an emphasis on safe delivery.

“[Toxicity] is something we don’t talk about as much as we should, partly because this therapy works and it’s really exciting,” Dr. Nastoupil said. “But the toxicity is not something that I minimize, and it’s very challenging. It’s led us to restructure our inpatient services. It’s led to a lot of sleepless nights. These patients can do very, very well, or they can do very, very poorly in terms of toxicity and I think the most important strategy is recognition and early intervention.”

Monitoring

Early recognition depends on close monitoring, Dr. Nastoupil said, which is carried out by highly trained nursing staff who follow therapy-specific decision algorithms.

“We have nurses that are on the front line,” Dr. Nastoupil said. “They’re the most important group. We have staff that round on [patients] daily, but the nurses are there 24 hours a day. We have a flow sheet where they grade cytokine release syndrome and neurotoxicity every 8 hours, or if there is an acute change in symptoms or toxicity, they’ll do it in real time.”

Dr. Nastoupil said that if these toxicities are detected, intervention is occurring sooner than it did with some of the first patients to receive CAR-T cell therapy.

“Initially there was a lot of fear surrounding anything that would abort the CAR-T cell therapy,” Dr. Nastoupil said. “There was concern that if you were trying to mitigate some of the toxicity you might have a negative impact on efficacy ... [W]ith the first iteration of studies, generally we were waiting until grade 3 or higher cytokine release syndrome before initiating either tocilizumab and/or steroids. As the studies evolved, it started to move into grade 2 toxicity that we started using therapy, mostly because we started to see that those patients were still responding.”

At MD Anderson, these earlier interventions have decreased severity of adverse events.

“It’s rare nowadays to have grade 3 or 4 cytokine release syndrome because we are generally introducing abortive therapy at grade 2,” Dr. Nastoupil said, citing increased use of steroids and tocilizumab.

Currently, no consensus exists for managing these events, partly because clinicians are still learning about best management practices.

“There will be a consensus on management,” Dr. Nastoupil said. “I think that’s needed. The problem is, it will probably evolve as we get more experience with managing these patients. I think there’s been a little hesitation to put something out on paper knowing that a year from now that might change.”

Grading toxicity

In contrast, Dr. Nastoupil said that a consensus has been reached for grading acute toxicity. Of note, fever is now considered an essential element of cytokine release syndrome.

“The first thing we see [with cytokine release syndrome] is fever, generally speaking,” Dr. Nastoupil said. “That will prompt a workup for infection because these patients are going to be neutropenic. And we initiate broad spectrum antimicrobials.”

She said that some patients treated with CAR T-cell therapy have had disseminated fungal infections, so clinicians need to be on the lookout for septic shock.

To assess neurotoxicity, the team at MD Anderson uses an objective scoring system, called “CARTOX.” This helps maintain consistency when facing broadly different neurological presentations.

“There’s such a wide ranging spectrum of patients that are undergoing neurotoxicity you can’t expect someone, even myself, to be consistent when you are trying to tease out how serious it is,” Dr. Nastoupil said.

With CARTOX, nurses can easily score patients and call clinicians with results. Still, this doesn’t eliminate difficulties inherent to managing neurotoxicity, particularly when it is severe.

“I’d say one of the areas that is still very challenging is when [patients with neurotoxicity] are no longer responding,” Dr. Nastoupil said. “You have to be very mindful of seizure activity. We’ve had a couple of patients with status [epilepticus]. You don’t see seizure activity physically, but when you do an EEG, you pick it up.”

Dr. Nastoupil added that most centers are now giving patients prophylactic levetiracetam (Keppra) to lower seizure risk.

Choosing therapy

When selecting between the two therapies currently approved by the Food and Drug Administration – tisagenlecleucel (Kymriah) and axicabtagene ciloleucel (Yescarta) – based on safety, Dr. Nastoupil said that rates of cytokine release syndrome appear similar, but neurotoxicity rates may differ.

“Cytokine release syndrome in my opinion is probably more similar than different in terms of grade 3 or higher because tocilizumab and steroids work quite well in aborting those toxicities,” Dr. Nastoupil said. “But neurotoxicity still sticks out in my mind as the most striking difference, where with axicabtagene you see more grade 3 or higher neurotoxicity, though very, very few deaths as a result of this. But it’s very challenging in terms of management.”

According to Dr. Nastoupil, comparisons between CAR T-cell therapies have been complicated by differences in clinical trial methodologies. However, she offered a general conclusion regarding efficacy.

“[W]hat I’ll tell you, at the end of the day, is [that existing CAR T-cell therapies] all seem to sort of settle out around 30%-40% in terms of durable responses,” Dr. Nastoupil said.

Dr. Nastoupil concluded her presentation with an overview and look to the future.

“I do think [CAR T-cell therapy] is transformative, particularly for our chemo refractory patients,” she said. “There is nothing else like it. The problem right now is that it is only durable in 40% of patients. So can we be better at selecting out patients that are more likely to respond? Does introducing this in earlier lines of therapy increase that fraction of patients that are potentially cured?”

Considering these questions, she said: “We need more patients. We need more data. We need longer follow-up to understand the nuances of this therapy.”

Dr. Nastoupil previously reported financial relationships with Celgene, Genentech, Gilead, Merck, Novartis, Spectrum, and TG Therapeutics.

GLASGOW – Constant patient monitoring and early intervention with tocilizumab and steroids are essential to the safe delivery of chimeric antigen receptor (CAR) T-cell therapy in patients with non-Hodgkin lymphoma (NHL), according to a leading expert.

As a clinical researcher at MD Anderson Cancer Center in Houston, Loretta Nastoupil, MD has played an active role in the evolution of CAR T-cell therapy, from early trials to ongoing development of treatment protocols. During a presentation at the annual meeting of the British Society for Haematology, Dr. Nastoupil discussed leading topics in CAR T-cell therapy, with an emphasis on safe delivery.

“[Toxicity] is something we don’t talk about as much as we should, partly because this therapy works and it’s really exciting,” Dr. Nastoupil said. “But the toxicity is not something that I minimize, and it’s very challenging. It’s led us to restructure our inpatient services. It’s led to a lot of sleepless nights. These patients can do very, very well, or they can do very, very poorly in terms of toxicity and I think the most important strategy is recognition and early intervention.”

Monitoring

Early recognition depends on close monitoring, Dr. Nastoupil said, which is carried out by highly trained nursing staff who follow therapy-specific decision algorithms.

“We have nurses that are on the front line,” Dr. Nastoupil said. “They’re the most important group. We have staff that round on [patients] daily, but the nurses are there 24 hours a day. We have a flow sheet where they grade cytokine release syndrome and neurotoxicity every 8 hours, or if there is an acute change in symptoms or toxicity, they’ll do it in real time.”

Dr. Nastoupil said that if these toxicities are detected, intervention is occurring sooner than it did with some of the first patients to receive CAR-T cell therapy.

“Initially there was a lot of fear surrounding anything that would abort the CAR-T cell therapy,” Dr. Nastoupil said. “There was concern that if you were trying to mitigate some of the toxicity you might have a negative impact on efficacy ... [W]ith the first iteration of studies, generally we were waiting until grade 3 or higher cytokine release syndrome before initiating either tocilizumab and/or steroids. As the studies evolved, it started to move into grade 2 toxicity that we started using therapy, mostly because we started to see that those patients were still responding.”

At MD Anderson, these earlier interventions have decreased severity of adverse events.

“It’s rare nowadays to have grade 3 or 4 cytokine release syndrome because we are generally introducing abortive therapy at grade 2,” Dr. Nastoupil said, citing increased use of steroids and tocilizumab.

Currently, no consensus exists for managing these events, partly because clinicians are still learning about best management practices.

“There will be a consensus on management,” Dr. Nastoupil said. “I think that’s needed. The problem is, it will probably evolve as we get more experience with managing these patients. I think there’s been a little hesitation to put something out on paper knowing that a year from now that might change.”

Grading toxicity

In contrast, Dr. Nastoupil said that a consensus has been reached for grading acute toxicity. Of note, fever is now considered an essential element of cytokine release syndrome.

“The first thing we see [with cytokine release syndrome] is fever, generally speaking,” Dr. Nastoupil said. “That will prompt a workup for infection because these patients are going to be neutropenic. And we initiate broad spectrum antimicrobials.”

She said that some patients treated with CAR T-cell therapy have had disseminated fungal infections, so clinicians need to be on the lookout for septic shock.

To assess neurotoxicity, the team at MD Anderson uses an objective scoring system, called “CARTOX.” This helps maintain consistency when facing broadly different neurological presentations.

“There’s such a wide ranging spectrum of patients that are undergoing neurotoxicity you can’t expect someone, even myself, to be consistent when you are trying to tease out how serious it is,” Dr. Nastoupil said.

With CARTOX, nurses can easily score patients and call clinicians with results. Still, this doesn’t eliminate difficulties inherent to managing neurotoxicity, particularly when it is severe.

“I’d say one of the areas that is still very challenging is when [patients with neurotoxicity] are no longer responding,” Dr. Nastoupil said. “You have to be very mindful of seizure activity. We’ve had a couple of patients with status [epilepticus]. You don’t see seizure activity physically, but when you do an EEG, you pick it up.”

Dr. Nastoupil added that most centers are now giving patients prophylactic levetiracetam (Keppra) to lower seizure risk.

Choosing therapy

When selecting between the two therapies currently approved by the Food and Drug Administration – tisagenlecleucel (Kymriah) and axicabtagene ciloleucel (Yescarta) – based on safety, Dr. Nastoupil said that rates of cytokine release syndrome appear similar, but neurotoxicity rates may differ.

“Cytokine release syndrome in my opinion is probably more similar than different in terms of grade 3 or higher because tocilizumab and steroids work quite well in aborting those toxicities,” Dr. Nastoupil said. “But neurotoxicity still sticks out in my mind as the most striking difference, where with axicabtagene you see more grade 3 or higher neurotoxicity, though very, very few deaths as a result of this. But it’s very challenging in terms of management.”

According to Dr. Nastoupil, comparisons between CAR T-cell therapies have been complicated by differences in clinical trial methodologies. However, she offered a general conclusion regarding efficacy.

“[W]hat I’ll tell you, at the end of the day, is [that existing CAR T-cell therapies] all seem to sort of settle out around 30%-40% in terms of durable responses,” Dr. Nastoupil said.

Dr. Nastoupil concluded her presentation with an overview and look to the future.

“I do think [CAR T-cell therapy] is transformative, particularly for our chemo refractory patients,” she said. “There is nothing else like it. The problem right now is that it is only durable in 40% of patients. So can we be better at selecting out patients that are more likely to respond? Does introducing this in earlier lines of therapy increase that fraction of patients that are potentially cured?”

Considering these questions, she said: “We need more patients. We need more data. We need longer follow-up to understand the nuances of this therapy.”

Dr. Nastoupil previously reported financial relationships with Celgene, Genentech, Gilead, Merck, Novartis, Spectrum, and TG Therapeutics.

For infants with newly diagnosed X-linked severe combined immunodeficiency (SCID-X1), lentiviral gene therapy and targeted busulfan conditioning successfully induced multilineage engraftment of transduced cells, researchers reported.

Pogonic/Getty Images

By 3-4 months after infusion, seven of eight patients had normal numbers of CD3+, CD4+, and naive CD4+ T cells; normal counts of natural killer (NK) cells; and vector marking of T cells, B cells, NK cells, myeloid cells, and bone marrow progenitors, Ewelina Mamcarz, MD, of St. Jude Children’s Research Hospital in Memphis, and her associates reported in the New England Journal of Medicine.

The eighth infant at first lacked a sufficient T-cell response but responded to a boost of gene-corrected cells without busulfan conditioning.

By 6-12 months after infusion, IgM levels also had normalized in seven of the eight infants and showed polyclonal patterns without clonal dominance, according to the investigators. Among four infants who were able to stop intravenous immunoglobulin therapy, three responded to vaccinations with tetanus, diphtheria, pertussis, polio, and pneumococcal polysaccharide. Such restoration of humoral immunity “has not been achieved in previously reported trials of gene therapy for infants with newly diagnosed SCID-X1,” wrote the investigators of this dual-center, phase 1/2 study.

X-linked severe combined immunodeficiency – “bubble boy disease” – is characterized by a lack of T cells, NK cells, and B cells, and is caused by mutations in IL2RG. Some 80% of affected infants have no matched sibling donor for hematopoietic stem cell transplantation, and transplantation from other donors can produce an inadequate response and graft-versus-host disease. Prior attempts at gene therapy with gamma-retroviral vectors had led to vector-induced leukemia or had failed to induce humoral immunity or normal NK cell production.

“Our new lentiviral vector gene therapy combined with nonmyeloablative busulfan conditioning has been successful in restoring immunity in five patients 7-23 years of age in whom a previous allogeneic hematopoietic stem cell transplantation for SCID-X1 had failed,” the investigators wrote. “We hypothesized that the combination of this lentiviral vector and low-exposure busulfan administered by means of pharmacokinetic dose targeting would be safe and effective as the primary treatment in infants with newly diagnosed SCID-X1.”

Their protocol included one to two daily intravenous doses of busulfan, targeting a cumulative area under the curve of 22 mg per hr/L. They calculated the first dose by weight and age using a population-based pharmacokinetic model and adjusted the second dose based on first-dose pharmacokinetics.

After a median of 16.4 months, all infants continued to grow normally and cleared previous infections, and there were no unanticipated side effects from bone marrow harvest, busulfan conditioning, or cell infusion.

“It is hoped that durable, complete adaptive immunity will be achieved in the majority of the patients over time,” the researchers wrote.

They continue to follow the patients to assess therapeutic safety, immune durability, and persistence of the transferred gene in hematopoietic and immune cells.

Study funders included the American Lebanese Syrian Associated Charities, the National Institutes of Health, the California Institute of Regenerative Medicine, and the Assisi Foundation of Memphis. St. Jude Children’s Research Hospital has licensed the gene therapy and partnered with Mustang Bio to develop and commercialize it. Dr. Mamcarz reported receiving grant support from the study funders.

SOURCE: Mamcarz E et al. N Engl J Med. 2019; 380:1525-34.

For infants with newly diagnosed X-linked severe combined immunodeficiency (SCID-X1), lentiviral gene therapy and targeted busulfan conditioning successfully induced multilineage engraftment of transduced cells, researchers reported.

Pogonic/Getty Images

By 3-4 months after infusion, seven of eight patients had normal numbers of CD3+, CD4+, and naive CD4+ T cells; normal counts of natural killer (NK) cells; and vector marking of T cells, B cells, NK cells, myeloid cells, and bone marrow progenitors, Ewelina Mamcarz, MD, of St. Jude Children’s Research Hospital in Memphis, and her associates reported in the New England Journal of Medicine.

The eighth infant at first lacked a sufficient T-cell response but responded to a boost of gene-corrected cells without busulfan conditioning.

By 6-12 months after infusion, IgM levels also had normalized in seven of the eight infants and showed polyclonal patterns without clonal dominance, according to the investigators. Among four infants who were able to stop intravenous immunoglobulin therapy, three responded to vaccinations with tetanus, diphtheria, pertussis, polio, and pneumococcal polysaccharide. Such restoration of humoral immunity “has not been achieved in previously reported trials of gene therapy for infants with newly diagnosed SCID-X1,” wrote the investigators of this dual-center, phase 1/2 study.

X-linked severe combined immunodeficiency – “bubble boy disease” – is characterized by a lack of T cells, NK cells, and B cells, and is caused by mutations in IL2RG. Some 80% of affected infants have no matched sibling donor for hematopoietic stem cell transplantation, and transplantation from other donors can produce an inadequate response and graft-versus-host disease. Prior attempts at gene therapy with gamma-retroviral vectors had led to vector-induced leukemia or had failed to induce humoral immunity or normal NK cell production.

“Our new lentiviral vector gene therapy combined with nonmyeloablative busulfan conditioning has been successful in restoring immunity in five patients 7-23 years of age in whom a previous allogeneic hematopoietic stem cell transplantation for SCID-X1 had failed,” the investigators wrote. “We hypothesized that the combination of this lentiviral vector and low-exposure busulfan administered by means of pharmacokinetic dose targeting would be safe and effective as the primary treatment in infants with newly diagnosed SCID-X1.”

Their protocol included one to two daily intravenous doses of busulfan, targeting a cumulative area under the curve of 22 mg per hr/L. They calculated the first dose by weight and age using a population-based pharmacokinetic model and adjusted the second dose based on first-dose pharmacokinetics.

After a median of 16.4 months, all infants continued to grow normally and cleared previous infections, and there were no unanticipated side effects from bone marrow harvest, busulfan conditioning, or cell infusion.

“It is hoped that durable, complete adaptive immunity will be achieved in the majority of the patients over time,” the researchers wrote.

They continue to follow the patients to assess therapeutic safety, immune durability, and persistence of the transferred gene in hematopoietic and immune cells.

Study funders included the American Lebanese Syrian Associated Charities, the National Institutes of Health, the California Institute of Regenerative Medicine, and the Assisi Foundation of Memphis. St. Jude Children’s Research Hospital has licensed the gene therapy and partnered with Mustang Bio to develop and commercialize it. Dr. Mamcarz reported receiving grant support from the study funders.

SOURCE: Mamcarz E et al. N Engl J Med. 2019; 380:1525-34.

For infants with newly diagnosed X-linked severe combined immunodeficiency (SCID-X1), lentiviral gene therapy and targeted busulfan conditioning successfully induced multilineage engraftment of transduced cells, researchers reported.

Pogonic/Getty Images

By 3-4 months after infusion, seven of eight patients had normal numbers of CD3+, CD4+, and naive CD4+ T cells; normal counts of natural killer (NK) cells; and vector marking of T cells, B cells, NK cells, myeloid cells, and bone marrow progenitors, Ewelina Mamcarz, MD, of St. Jude Children’s Research Hospital in Memphis, and her associates reported in the New England Journal of Medicine.

The eighth infant at first lacked a sufficient T-cell response but responded to a boost of gene-corrected cells without busulfan conditioning.

By 6-12 months after infusion, IgM levels also had normalized in seven of the eight infants and showed polyclonal patterns without clonal dominance, according to the investigators. Among four infants who were able to stop intravenous immunoglobulin therapy, three responded to vaccinations with tetanus, diphtheria, pertussis, polio, and pneumococcal polysaccharide. Such restoration of humoral immunity “has not been achieved in previously reported trials of gene therapy for infants with newly diagnosed SCID-X1,” wrote the investigators of this dual-center, phase 1/2 study.

X-linked severe combined immunodeficiency – “bubble boy disease” – is characterized by a lack of T cells, NK cells, and B cells, and is caused by mutations in IL2RG. Some 80% of affected infants have no matched sibling donor for hematopoietic stem cell transplantation, and transplantation from other donors can produce an inadequate response and graft-versus-host disease. Prior attempts at gene therapy with gamma-retroviral vectors had led to vector-induced leukemia or had failed to induce humoral immunity or normal NK cell production.

“Our new lentiviral vector gene therapy combined with nonmyeloablative busulfan conditioning has been successful in restoring immunity in five patients 7-23 years of age in whom a previous allogeneic hematopoietic stem cell transplantation for SCID-X1 had failed,” the investigators wrote. “We hypothesized that the combination of this lentiviral vector and low-exposure busulfan administered by means of pharmacokinetic dose targeting would be safe and effective as the primary treatment in infants with newly diagnosed SCID-X1.”

Their protocol included one to two daily intravenous doses of busulfan, targeting a cumulative area under the curve of 22 mg per hr/L. They calculated the first dose by weight and age using a population-based pharmacokinetic model and adjusted the second dose based on first-dose pharmacokinetics.

After a median of 16.4 months, all infants continued to grow normally and cleared previous infections, and there were no unanticipated side effects from bone marrow harvest, busulfan conditioning, or cell infusion.

“It is hoped that durable, complete adaptive immunity will be achieved in the majority of the patients over time,” the researchers wrote.

They continue to follow the patients to assess therapeutic safety, immune durability, and persistence of the transferred gene in hematopoietic and immune cells.

Study funders included the American Lebanese Syrian Associated Charities, the National Institutes of Health, the California Institute of Regenerative Medicine, and the Assisi Foundation of Memphis. St. Jude Children’s Research Hospital has licensed the gene therapy and partnered with Mustang Bio to develop and commercialize it. Dr. Mamcarz reported receiving grant support from the study funders.

SOURCE: Mamcarz E et al. N Engl J Med. 2019; 380:1525-34.

HOUSTON – Cytokine release syndrome and neurotoxicity frequently occur with CD19-directed chimeric antigen receptor (CAR) T-cell immunotherapies, but targetable factors for mitigating the risk and effects of these complications are emerging, according to Cameron Turtle, MBBS, PhD.

Novartis

These factors include infused CAR T-cell dose, bone marrow disease burden, immune response, and the lymphodepletion regimen used, Dr. Turtle, of Fred Hutchinson Cancer Research Center, Seattle, said at the Transplantation & Cellular Therapies Meetings. This list is based on an analysis of several studies that included a total of 195 patients with B-cell malignancies who were treated with defined-composition CD19 CAR T cells.

In a 2016 study included in the analysis, for instance, Dr. Turtle and his colleagues found that CD19 CAR T cells administered to adults with B-cell acute lymphoblastic leukemia (B-ALL) after lymphodepletion chemotherapy were “remarkably potent.” Remission was achieved in 27 of 29 patients (J Clin Invest. 2016 Jun 1;126[6]:2123-38).

However, the study also established that high CAR T-cell doses and tumor burden increased the risk of severe cytokine release syndrome (CRS) and neurotoxicity, Dr. Turtle said at the meeting, held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research. At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).

“Importantly, we identified serum biomarkers that allow testing of early intervention strategies in the patients who have the highest risk of toxicity,” he said.

Dr. Turtle explained that significantly higher peak interleuken-6 (IL-6) and interferon (IFN)-gamma levels were seen after CAR T-cell infusion in patients with high bone marrow tumor burden and in patients requiring treatment in an intensive care unit (ICU).


ICU care correlated with a higher percentage of bone marrow blasts before lymphodepletion chemotherapy, he added.

Elevations of serum C-reactive protein (CRP) and ferritin also correlated with bone marrow disease burden and with the occurrence of severe CRS requiring ICU care, he said, noting that ferritin and CRP levels declined after tocilizumab or corticosteroid therapy.

In addition, all patients in the study who developed neurotoxicity had evidence of CRS. Peak levels of IL-6, IFN-gamma, ferritin, and CRP were significantly higher in those who developed grade 3 or higher neurotoxicity. Further, serum IL-6 and IFN-gamma concentrations on day 1 after infusion were significantly higher in those who required ICU care and in those who subsequently developed grade 4 neurotoxicity than in patients who developed grade 3 neurotoxicity.

Multivariate analysis indicated that serum IL-6 concentration of more than 30 pg/mL on day 1 and the total number of CD19+ cells in bone marrow before therapy were independent predictors of subsequent development of grade 3 or higher neurotoxicity.

Notably, serum IL-6 of more than 30 pg/mL on day 1 identified all patients in the study who subsequently developed grade 4 or higher neurotoxicity, Dr. Turtle and his colleagues noted.

“The findings suggested that evaluation of serum IL-6 concentration early after CAR T-cell infusion might be useful for identifying patients at high risk of severe neurotoxicity and to evaluate early intervention approaches,” he said.

Neurotoxicity

In a 2017 study from Juliane Gust, MD, PhD, and her colleagues, bone marrow disease burden, lymphodepletion regimen, and CAR T-cell dose were found to be significantly associated with neurotoxicity during multivariate analysis (Cancer Discov. 2017 Dec;7[12]:1404-19).

Patients with severe neurotoxicity in that study demonstrated evidence of endothelial activation, including disseminated intravascular coagulation, capillary leak, and increased blood-brain barrier permeability – with the latter leading to a failure to protect the cerebrospinal fluid from high concentrations of systemic cytokines, including IFN-gamma. These high levels of cytokines may cause vascular pericyte activation and stress, Dr. Turtle explained.

Patients who subsequently developed grade 4 or higher neurotoxicity had higher pretreatment levels of endothelial activation biomarkers.

CRS

In another 2017 study, from Kevin A. Hay, MD, and his colleagues, similar factors were found to be associated with CRS (Blood. 2017 Nov 23;130[21]:2295-306).

Multivariable analysis identified high marrow tumor burden, lymphodepletion using cyclophosphamide and fludarabine, higher CAR T-cell dose, thrombocytopenia before lymphodepletion, and manufacturing of CAR T cells without selection of CD8+ central memory T cells as independent predictors of CRS.

Severe CRS was characterized by hemodynamic instability, capillary leak, and consumptive coagulopathy. As in the study by Dr. Gust and her colleagues, biomarkers of endothelial activation, including angiopoietin-2 and von Willebrand factor, were increased during severe CRS and before lymphodepletion in patients who subsequently developed CRS.
 

Potential modifications

The findings to date suggest that risk stratification, prophylaxis, early intervention and therapeutic intervention are among potential strategies for mitigating the risk of CD19-directed CAR T toxicity, Dr. Turtle said. Steroids, tocilizumab, siltuximab, anakinra, anti-GM-CSF, small molecules, plasma exchange, angiopoietin-1, and hypertransfusion are among candidates under consideration for such interventions, he noted.

Other approaches that have been tested in small studies, and which may reduce toxicity and improve the therapeutic index of CD19 CAR T-cell therapy for B-ALL, include split dosing and risk-adapted dosing.

“These approaches do appear to mitigate toxicity, but larger studies are needed to confirm that treatment efficacy is maintained,” Dr. Turtle said.

Toxicity prediction and early intervention to maintain the CAR T-cell dose while avoiding grade 4 or greater toxicities would be helpful and is within reach, he said, noting that the findings by Dr. Hay and his colleagues led to the development of “day-1 cytokine combination algorithms that predict grade 4-5 CRS and could direct preemptive intervention.”

One algorithm based on three cytokines had high sensitivity and specificity, but would require screening of all patients.

Early intervention in patients in whom toxicity is predicted has not been extensively evaluated in clinical studies, he said.

Dr. Hay and his colleagues did, however, develop a “classification tree model of early intervention strategies” using their findings.

A complicating factor in predicting risk and intervening is that each CAR T-cell product is associated with differing levels of toxicity risk. The varying rates of toxicity suggest that promising approaches for addressing CAR T toxicity require validation for each product with respect to cutpoints, efficacy, and maintenance of response, Dr. Turtle said.

“The findings to date are encouraging and show that potentially targetable factors for mitigating the toxicity of CAR T-cell therapy can be identified,” he said. “But clinical studies have yet to convincingly establish the best approach.”

Dr. Turtle has served on advisory boards for Juno/Celgene, Kite/Gilead, Novartis, Precision Biosciences, Eureka Therapeutics, Caribou Biosciences, Nektar Therapeutics, Humanigen, and Aptevo; has intellectual property rights licensed to Juno; has stock options with Precision Biosciences, Eureka Therapeutics, and Caribou Biosciences; and has received research funding from Juno and Nektar Therapeutics.

[email protected]

HOUSTON – Cytokine release syndrome and neurotoxicity frequently occur with CD19-directed chimeric antigen receptor (CAR) T-cell immunotherapies, but targetable factors for mitigating the risk and effects of these complications are emerging, according to Cameron Turtle, MBBS, PhD.

Novartis

These factors include infused CAR T-cell dose, bone marrow disease burden, immune response, and the lymphodepletion regimen used, Dr. Turtle, of Fred Hutchinson Cancer Research Center, Seattle, said at the Transplantation & Cellular Therapies Meetings. This list is based on an analysis of several studies that included a total of 195 patients with B-cell malignancies who were treated with defined-composition CD19 CAR T cells.

In a 2016 study included in the analysis, for instance, Dr. Turtle and his colleagues found that CD19 CAR T cells administered to adults with B-cell acute lymphoblastic leukemia (B-ALL) after lymphodepletion chemotherapy were “remarkably potent.” Remission was achieved in 27 of 29 patients (J Clin Invest. 2016 Jun 1;126[6]:2123-38).

However, the study also established that high CAR T-cell doses and tumor burden increased the risk of severe cytokine release syndrome (CRS) and neurotoxicity, Dr. Turtle said at the meeting, held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research. At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).

“Importantly, we identified serum biomarkers that allow testing of early intervention strategies in the patients who have the highest risk of toxicity,” he said.

Dr. Turtle explained that significantly higher peak interleuken-6 (IL-6) and interferon (IFN)-gamma levels were seen after CAR T-cell infusion in patients with high bone marrow tumor burden and in patients requiring treatment in an intensive care unit (ICU).


ICU care correlated with a higher percentage of bone marrow blasts before lymphodepletion chemotherapy, he added.

Elevations of serum C-reactive protein (CRP) and ferritin also correlated with bone marrow disease burden and with the occurrence of severe CRS requiring ICU care, he said, noting that ferritin and CRP levels declined after tocilizumab or corticosteroid therapy.

In addition, all patients in the study who developed neurotoxicity had evidence of CRS. Peak levels of IL-6, IFN-gamma, ferritin, and CRP were significantly higher in those who developed grade 3 or higher neurotoxicity. Further, serum IL-6 and IFN-gamma concentrations on day 1 after infusion were significantly higher in those who required ICU care and in those who subsequently developed grade 4 neurotoxicity than in patients who developed grade 3 neurotoxicity.

Multivariate analysis indicated that serum IL-6 concentration of more than 30 pg/mL on day 1 and the total number of CD19+ cells in bone marrow before therapy were independent predictors of subsequent development of grade 3 or higher neurotoxicity.

Notably, serum IL-6 of more than 30 pg/mL on day 1 identified all patients in the study who subsequently developed grade 4 or higher neurotoxicity, Dr. Turtle and his colleagues noted.

“The findings suggested that evaluation of serum IL-6 concentration early after CAR T-cell infusion might be useful for identifying patients at high risk of severe neurotoxicity and to evaluate early intervention approaches,” he said.

Neurotoxicity

In a 2017 study from Juliane Gust, MD, PhD, and her colleagues, bone marrow disease burden, lymphodepletion regimen, and CAR T-cell dose were found to be significantly associated with neurotoxicity during multivariate analysis (Cancer Discov. 2017 Dec;7[12]:1404-19).

Patients with severe neurotoxicity in that study demonstrated evidence of endothelial activation, including disseminated intravascular coagulation, capillary leak, and increased blood-brain barrier permeability – with the latter leading to a failure to protect the cerebrospinal fluid from high concentrations of systemic cytokines, including IFN-gamma. These high levels of cytokines may cause vascular pericyte activation and stress, Dr. Turtle explained.

Patients who subsequently developed grade 4 or higher neurotoxicity had higher pretreatment levels of endothelial activation biomarkers.

CRS

In another 2017 study, from Kevin A. Hay, MD, and his colleagues, similar factors were found to be associated with CRS (Blood. 2017 Nov 23;130[21]:2295-306).

Multivariable analysis identified high marrow tumor burden, lymphodepletion using cyclophosphamide and fludarabine, higher CAR T-cell dose, thrombocytopenia before lymphodepletion, and manufacturing of CAR T cells without selection of CD8+ central memory T cells as independent predictors of CRS.

Severe CRS was characterized by hemodynamic instability, capillary leak, and consumptive coagulopathy. As in the study by Dr. Gust and her colleagues, biomarkers of endothelial activation, including angiopoietin-2 and von Willebrand factor, were increased during severe CRS and before lymphodepletion in patients who subsequently developed CRS.
 

Potential modifications

The findings to date suggest that risk stratification, prophylaxis, early intervention and therapeutic intervention are among potential strategies for mitigating the risk of CD19-directed CAR T toxicity, Dr. Turtle said. Steroids, tocilizumab, siltuximab, anakinra, anti-GM-CSF, small molecules, plasma exchange, angiopoietin-1, and hypertransfusion are among candidates under consideration for such interventions, he noted.

Other approaches that have been tested in small studies, and which may reduce toxicity and improve the therapeutic index of CD19 CAR T-cell therapy for B-ALL, include split dosing and risk-adapted dosing.

“These approaches do appear to mitigate toxicity, but larger studies are needed to confirm that treatment efficacy is maintained,” Dr. Turtle said.

Toxicity prediction and early intervention to maintain the CAR T-cell dose while avoiding grade 4 or greater toxicities would be helpful and is within reach, he said, noting that the findings by Dr. Hay and his colleagues led to the development of “day-1 cytokine combination algorithms that predict grade 4-5 CRS and could direct preemptive intervention.”

One algorithm based on three cytokines had high sensitivity and specificity, but would require screening of all patients.

Early intervention in patients in whom toxicity is predicted has not been extensively evaluated in clinical studies, he said.

Dr. Hay and his colleagues did, however, develop a “classification tree model of early intervention strategies” using their findings.

A complicating factor in predicting risk and intervening is that each CAR T-cell product is associated with differing levels of toxicity risk. The varying rates of toxicity suggest that promising approaches for addressing CAR T toxicity require validation for each product with respect to cutpoints, efficacy, and maintenance of response, Dr. Turtle said.

“The findings to date are encouraging and show that potentially targetable factors for mitigating the toxicity of CAR T-cell therapy can be identified,” he said. “But clinical studies have yet to convincingly establish the best approach.”

Dr. Turtle has served on advisory boards for Juno/Celgene, Kite/Gilead, Novartis, Precision Biosciences, Eureka Therapeutics, Caribou Biosciences, Nektar Therapeutics, Humanigen, and Aptevo; has intellectual property rights licensed to Juno; has stock options with Precision Biosciences, Eureka Therapeutics, and Caribou Biosciences; and has received research funding from Juno and Nektar Therapeutics.

[email protected]

HOUSTON – Cytokine release syndrome and neurotoxicity frequently occur with CD19-directed chimeric antigen receptor (CAR) T-cell immunotherapies, but targetable factors for mitigating the risk and effects of these complications are emerging, according to Cameron Turtle, MBBS, PhD.

Novartis

These factors include infused CAR T-cell dose, bone marrow disease burden, immune response, and the lymphodepletion regimen used, Dr. Turtle, of Fred Hutchinson Cancer Research Center, Seattle, said at the Transplantation & Cellular Therapies Meetings. This list is based on an analysis of several studies that included a total of 195 patients with B-cell malignancies who were treated with defined-composition CD19 CAR T cells.

In a 2016 study included in the analysis, for instance, Dr. Turtle and his colleagues found that CD19 CAR T cells administered to adults with B-cell acute lymphoblastic leukemia (B-ALL) after lymphodepletion chemotherapy were “remarkably potent.” Remission was achieved in 27 of 29 patients (J Clin Invest. 2016 Jun 1;126[6]:2123-38).

However, the study also established that high CAR T-cell doses and tumor burden increased the risk of severe cytokine release syndrome (CRS) and neurotoxicity, Dr. Turtle said at the meeting, held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research. At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).

“Importantly, we identified serum biomarkers that allow testing of early intervention strategies in the patients who have the highest risk of toxicity,” he said.

Dr. Turtle explained that significantly higher peak interleuken-6 (IL-6) and interferon (IFN)-gamma levels were seen after CAR T-cell infusion in patients with high bone marrow tumor burden and in patients requiring treatment in an intensive care unit (ICU).


ICU care correlated with a higher percentage of bone marrow blasts before lymphodepletion chemotherapy, he added.

Elevations of serum C-reactive protein (CRP) and ferritin also correlated with bone marrow disease burden and with the occurrence of severe CRS requiring ICU care, he said, noting that ferritin and CRP levels declined after tocilizumab or corticosteroid therapy.

In addition, all patients in the study who developed neurotoxicity had evidence of CRS. Peak levels of IL-6, IFN-gamma, ferritin, and CRP were significantly higher in those who developed grade 3 or higher neurotoxicity. Further, serum IL-6 and IFN-gamma concentrations on day 1 after infusion were significantly higher in those who required ICU care and in those who subsequently developed grade 4 neurotoxicity than in patients who developed grade 3 neurotoxicity.

Multivariate analysis indicated that serum IL-6 concentration of more than 30 pg/mL on day 1 and the total number of CD19+ cells in bone marrow before therapy were independent predictors of subsequent development of grade 3 or higher neurotoxicity.

Notably, serum IL-6 of more than 30 pg/mL on day 1 identified all patients in the study who subsequently developed grade 4 or higher neurotoxicity, Dr. Turtle and his colleagues noted.

“The findings suggested that evaluation of serum IL-6 concentration early after CAR T-cell infusion might be useful for identifying patients at high risk of severe neurotoxicity and to evaluate early intervention approaches,” he said.

Neurotoxicity

In a 2017 study from Juliane Gust, MD, PhD, and her colleagues, bone marrow disease burden, lymphodepletion regimen, and CAR T-cell dose were found to be significantly associated with neurotoxicity during multivariate analysis (Cancer Discov. 2017 Dec;7[12]:1404-19).

Patients with severe neurotoxicity in that study demonstrated evidence of endothelial activation, including disseminated intravascular coagulation, capillary leak, and increased blood-brain barrier permeability – with the latter leading to a failure to protect the cerebrospinal fluid from high concentrations of systemic cytokines, including IFN-gamma. These high levels of cytokines may cause vascular pericyte activation and stress, Dr. Turtle explained.

Patients who subsequently developed grade 4 or higher neurotoxicity had higher pretreatment levels of endothelial activation biomarkers.

CRS

In another 2017 study, from Kevin A. Hay, MD, and his colleagues, similar factors were found to be associated with CRS (Blood. 2017 Nov 23;130[21]:2295-306).

Multivariable analysis identified high marrow tumor burden, lymphodepletion using cyclophosphamide and fludarabine, higher CAR T-cell dose, thrombocytopenia before lymphodepletion, and manufacturing of CAR T cells without selection of CD8+ central memory T cells as independent predictors of CRS.

Severe CRS was characterized by hemodynamic instability, capillary leak, and consumptive coagulopathy. As in the study by Dr. Gust and her colleagues, biomarkers of endothelial activation, including angiopoietin-2 and von Willebrand factor, were increased during severe CRS and before lymphodepletion in patients who subsequently developed CRS.
 

Potential modifications

The findings to date suggest that risk stratification, prophylaxis, early intervention and therapeutic intervention are among potential strategies for mitigating the risk of CD19-directed CAR T toxicity, Dr. Turtle said. Steroids, tocilizumab, siltuximab, anakinra, anti-GM-CSF, small molecules, plasma exchange, angiopoietin-1, and hypertransfusion are among candidates under consideration for such interventions, he noted.

Other approaches that have been tested in small studies, and which may reduce toxicity and improve the therapeutic index of CD19 CAR T-cell therapy for B-ALL, include split dosing and risk-adapted dosing.

“These approaches do appear to mitigate toxicity, but larger studies are needed to confirm that treatment efficacy is maintained,” Dr. Turtle said.

Toxicity prediction and early intervention to maintain the CAR T-cell dose while avoiding grade 4 or greater toxicities would be helpful and is within reach, he said, noting that the findings by Dr. Hay and his colleagues led to the development of “day-1 cytokine combination algorithms that predict grade 4-5 CRS and could direct preemptive intervention.”

One algorithm based on three cytokines had high sensitivity and specificity, but would require screening of all patients.

Early intervention in patients in whom toxicity is predicted has not been extensively evaluated in clinical studies, he said.

Dr. Hay and his colleagues did, however, develop a “classification tree model of early intervention strategies” using their findings.

A complicating factor in predicting risk and intervening is that each CAR T-cell product is associated with differing levels of toxicity risk. The varying rates of toxicity suggest that promising approaches for addressing CAR T toxicity require validation for each product with respect to cutpoints, efficacy, and maintenance of response, Dr. Turtle said.

“The findings to date are encouraging and show that potentially targetable factors for mitigating the toxicity of CAR T-cell therapy can be identified,” he said. “But clinical studies have yet to convincingly establish the best approach.”

Dr. Turtle has served on advisory boards for Juno/Celgene, Kite/Gilead, Novartis, Precision Biosciences, Eureka Therapeutics, Caribou Biosciences, Nektar Therapeutics, Humanigen, and Aptevo; has intellectual property rights licensed to Juno; has stock options with Precision Biosciences, Eureka Therapeutics, and Caribou Biosciences; and has received research funding from Juno and Nektar Therapeutics.

[email protected]

NEWPORT BEACH, CALIF. – Preclinical research has revealed workarounds that may make chimeric antigen receptor (CAR) T-cell therapy feasible for patients with T-cell malignancies.

Researchers have found that using allogeneic cells for CAR T-cell therapy can eliminate contamination by malignant T cells, and editing those allogeneic T cells to delete the target antigen and the T-cell receptor alpha chain (TRAC) can prevent fratricide and graft-versus-host disease (GVHD).

Additionally, an interleukin-7 molecule called NT-I7 has been shown to enhance CAR T-cell proliferation, differentiation, and tumor killing in a mouse model of a T-cell malignancy.

John F. DiPersio, MD, PhD, of Washington University in St. Louis, described this work in a presentation at the Acute Leukemia Forum of Hemedicus.
 

Obstacles to development

“The primary obstacle for targeting T-cell malignancies with a T cell is that all of the targets that are on the [malignant] T cells are also expressed on the normal T cells,” Dr. DiPersio said. “So when you put a CAR into a normal T cell, it just kills itself. It’s called fratricide.”

A second issue that has limited development is that the phenotype of the malignant T cell in the blood is similar to a normal T cell, so they can’t be separated, he explained.

“So if you were to do anything to a normal T cell, you would also be doing it, in theory, to the malignant T cell – in theory, making it resistant to therapy,” he said.

A third obstacle, which has been seen in patients with B-cell malignancies as well, is the inability to harvest enough T cells to generate effective CAR T-cell therapy.

And a fourth obstacle is that T cells from patients with malignancies may not function normally because they have been exposed to prior therapies.

Dr. DiPersio and his colleagues believe these obstacles can be overcome by creating CAR T-cell therapies using T cells derived from healthy donors or cord blood, using gene editing to remove the target antigen and TRAC, and using NT-I7 to enhance the efficacy of these universal, “off-the-shelf” CAR T cells.

The researchers have tested these theories, and achieved successes, in preclinical models. The team is now planning a clinical trial in patients at Washington University. Dr. DiPersio and his colleagues also created a company called WUGEN that will develop the universal CAR T-cell therapies if the initial proof-of-principle trial proves successful.
 

UCART7

One of the universal CAR T-cell therapies Dr. DiPersio and his colleagues have tested is UCART7, which targets CD7. Dr. DiPersio noted that CD7 is expressed on 98% of T-cell acute lymphoblastic leukemias (T-ALLs), 24% of acute myeloid leukemias, natural killer (NK) cells, and T cells.

The researchers created UCART7 by using CRISPR/Cas9 to delete CD7 and TRAC from allogeneic T cells and following this with lentiviral transduction with a third-generation CD7-CAR. The team found a way to delete both TRAC and CD7 in a single day with 95% efficiency, Dr. DiPersio noted.

“Knocking out CD7 doesn’t seem to have any impact on the expansion or trafficking of these T cells in vivo,” Dr. DiPersio said. “So we think that deleting that target in a normal T cell will not affect its overall ability to kill a target when we put a CAR into those T cells.”

In fact, the researchers’ experiments showed that UCART7 can kill T-ALL cells in vitro and target primary T-ALL in vivo without inducing GVHD (Leukemia. 2018 Sep;32[9]:1970-83.)
 

UCART2 and NT-I7

Dr. DiPersio and his colleagues have also tested UCART2, an allogeneic CAR T-cell therapy in which CD2 and TRAC are deleted. The therapy targets CD2 because this antigen is expressed on T-ALL and other T-cell and NK-cell malignancies. Experiments showed that UCART2 targets T-cell malignancies, including T-ALL and cutaneous T-cell lymphoma, in vitro.

The researchers also tested UCART2 in a mouse model of Sézary syndrome. In these experiments, UCART2 was combined with NT-I7.

NT-I7 enhanced the proliferation, persistence, and tumor killing ability of UCART2. Sézary mice that received UCART2 and NT-I7 had “virtually no tumor burden,” according to researchers, and survived longer than mice treated with UCART2 alone (Blood. 2018;132:340).

Dr. DiPersio noted that there was no cytokine release syndrome because these were immunodeficient mice. However, cytokine release syndrome may be a side effect of NT-I7 in patients as NT-I7 induces rapid expansion of CAR T cells.

Dr. DiPersio reported ownership and investment in WUGEN and Magenta Therapeutics. He also has relationships with Cellworks Group, Tioma Therapeutics, RiverVest Venture Partners, Bioline, Asterias Biotherapeutics, Amphivena Therapeutics, Bluebird Bio, Celgene, Incyte, NeoImuneTech, and MacroGenics.

The Acute Leukemia Forum is organized by Hemedicus, which is owned by the same company as this news organization.

[email protected]

NEWPORT BEACH, CALIF. – Preclinical research has revealed workarounds that may make chimeric antigen receptor (CAR) T-cell therapy feasible for patients with T-cell malignancies.

Researchers have found that using allogeneic cells for CAR T-cell therapy can eliminate contamination by malignant T cells, and editing those allogeneic T cells to delete the target antigen and the T-cell receptor alpha chain (TRAC) can prevent fratricide and graft-versus-host disease (GVHD).

Additionally, an interleukin-7 molecule called NT-I7 has been shown to enhance CAR T-cell proliferation, differentiation, and tumor killing in a mouse model of a T-cell malignancy.

John F. DiPersio, MD, PhD, of Washington University in St. Louis, described this work in a presentation at the Acute Leukemia Forum of Hemedicus.
 

Obstacles to development

“The primary obstacle for targeting T-cell malignancies with a T cell is that all of the targets that are on the [malignant] T cells are also expressed on the normal T cells,” Dr. DiPersio said. “So when you put a CAR into a normal T cell, it just kills itself. It’s called fratricide.”

A second issue that has limited development is that the phenotype of the malignant T cell in the blood is similar to a normal T cell, so they can’t be separated, he explained.

“So if you were to do anything to a normal T cell, you would also be doing it, in theory, to the malignant T cell – in theory, making it resistant to therapy,” he said.

A third obstacle, which has been seen in patients with B-cell malignancies as well, is the inability to harvest enough T cells to generate effective CAR T-cell therapy.

And a fourth obstacle is that T cells from patients with malignancies may not function normally because they have been exposed to prior therapies.

Dr. DiPersio and his colleagues believe these obstacles can be overcome by creating CAR T-cell therapies using T cells derived from healthy donors or cord blood, using gene editing to remove the target antigen and TRAC, and using NT-I7 to enhance the efficacy of these universal, “off-the-shelf” CAR T cells.

The researchers have tested these theories, and achieved successes, in preclinical models. The team is now planning a clinical trial in patients at Washington University. Dr. DiPersio and his colleagues also created a company called WUGEN that will develop the universal CAR T-cell therapies if the initial proof-of-principle trial proves successful.
 

UCART7

One of the universal CAR T-cell therapies Dr. DiPersio and his colleagues have tested is UCART7, which targets CD7. Dr. DiPersio noted that CD7 is expressed on 98% of T-cell acute lymphoblastic leukemias (T-ALLs), 24% of acute myeloid leukemias, natural killer (NK) cells, and T cells.

The researchers created UCART7 by using CRISPR/Cas9 to delete CD7 and TRAC from allogeneic T cells and following this with lentiviral transduction with a third-generation CD7-CAR. The team found a way to delete both TRAC and CD7 in a single day with 95% efficiency, Dr. DiPersio noted.

“Knocking out CD7 doesn’t seem to have any impact on the expansion or trafficking of these T cells in vivo,” Dr. DiPersio said. “So we think that deleting that target in a normal T cell will not affect its overall ability to kill a target when we put a CAR into those T cells.”

In fact, the researchers’ experiments showed that UCART7 can kill T-ALL cells in vitro and target primary T-ALL in vivo without inducing GVHD (Leukemia. 2018 Sep;32[9]:1970-83.)
 

UCART2 and NT-I7

Dr. DiPersio and his colleagues have also tested UCART2, an allogeneic CAR T-cell therapy in which CD2 and TRAC are deleted. The therapy targets CD2 because this antigen is expressed on T-ALL and other T-cell and NK-cell malignancies. Experiments showed that UCART2 targets T-cell malignancies, including T-ALL and cutaneous T-cell lymphoma, in vitro.

The researchers also tested UCART2 in a mouse model of Sézary syndrome. In these experiments, UCART2 was combined with NT-I7.

NT-I7 enhanced the proliferation, persistence, and tumor killing ability of UCART2. Sézary mice that received UCART2 and NT-I7 had “virtually no tumor burden,” according to researchers, and survived longer than mice treated with UCART2 alone (Blood. 2018;132:340).

Dr. DiPersio noted that there was no cytokine release syndrome because these were immunodeficient mice. However, cytokine release syndrome may be a side effect of NT-I7 in patients as NT-I7 induces rapid expansion of CAR T cells.

Dr. DiPersio reported ownership and investment in WUGEN and Magenta Therapeutics. He also has relationships with Cellworks Group, Tioma Therapeutics, RiverVest Venture Partners, Bioline, Asterias Biotherapeutics, Amphivena Therapeutics, Bluebird Bio, Celgene, Incyte, NeoImuneTech, and MacroGenics.

The Acute Leukemia Forum is organized by Hemedicus, which is owned by the same company as this news organization.

[email protected]

NEWPORT BEACH, CALIF. – Preclinical research has revealed workarounds that may make chimeric antigen receptor (CAR) T-cell therapy feasible for patients with T-cell malignancies.

Researchers have found that using allogeneic cells for CAR T-cell therapy can eliminate contamination by malignant T cells, and editing those allogeneic T cells to delete the target antigen and the T-cell receptor alpha chain (TRAC) can prevent fratricide and graft-versus-host disease (GVHD).

Additionally, an interleukin-7 molecule called NT-I7 has been shown to enhance CAR T-cell proliferation, differentiation, and tumor killing in a mouse model of a T-cell malignancy.

John F. DiPersio, MD, PhD, of Washington University in St. Louis, described this work in a presentation at the Acute Leukemia Forum of Hemedicus.
 

Obstacles to development

“The primary obstacle for targeting T-cell malignancies with a T cell is that all of the targets that are on the [malignant] T cells are also expressed on the normal T cells,” Dr. DiPersio said. “So when you put a CAR into a normal T cell, it just kills itself. It’s called fratricide.”

A second issue that has limited development is that the phenotype of the malignant T cell in the blood is similar to a normal T cell, so they can’t be separated, he explained.

“So if you were to do anything to a normal T cell, you would also be doing it, in theory, to the malignant T cell – in theory, making it resistant to therapy,” he said.

A third obstacle, which has been seen in patients with B-cell malignancies as well, is the inability to harvest enough T cells to generate effective CAR T-cell therapy.

And a fourth obstacle is that T cells from patients with malignancies may not function normally because they have been exposed to prior therapies.

Dr. DiPersio and his colleagues believe these obstacles can be overcome by creating CAR T-cell therapies using T cells derived from healthy donors or cord blood, using gene editing to remove the target antigen and TRAC, and using NT-I7 to enhance the efficacy of these universal, “off-the-shelf” CAR T cells.

The researchers have tested these theories, and achieved successes, in preclinical models. The team is now planning a clinical trial in patients at Washington University. Dr. DiPersio and his colleagues also created a company called WUGEN that will develop the universal CAR T-cell therapies if the initial proof-of-principle trial proves successful.
 

UCART7

One of the universal CAR T-cell therapies Dr. DiPersio and his colleagues have tested is UCART7, which targets CD7. Dr. DiPersio noted that CD7 is expressed on 98% of T-cell acute lymphoblastic leukemias (T-ALLs), 24% of acute myeloid leukemias, natural killer (NK) cells, and T cells.

The researchers created UCART7 by using CRISPR/Cas9 to delete CD7 and TRAC from allogeneic T cells and following this with lentiviral transduction with a third-generation CD7-CAR. The team found a way to delete both TRAC and CD7 in a single day with 95% efficiency, Dr. DiPersio noted.

“Knocking out CD7 doesn’t seem to have any impact on the expansion or trafficking of these T cells in vivo,” Dr. DiPersio said. “So we think that deleting that target in a normal T cell will not affect its overall ability to kill a target when we put a CAR into those T cells.”

In fact, the researchers’ experiments showed that UCART7 can kill T-ALL cells in vitro and target primary T-ALL in vivo without inducing GVHD (Leukemia. 2018 Sep;32[9]:1970-83.)
 

UCART2 and NT-I7

Dr. DiPersio and his colleagues have also tested UCART2, an allogeneic CAR T-cell therapy in which CD2 and TRAC are deleted. The therapy targets CD2 because this antigen is expressed on T-ALL and other T-cell and NK-cell malignancies. Experiments showed that UCART2 targets T-cell malignancies, including T-ALL and cutaneous T-cell lymphoma, in vitro.

The researchers also tested UCART2 in a mouse model of Sézary syndrome. In these experiments, UCART2 was combined with NT-I7.

NT-I7 enhanced the proliferation, persistence, and tumor killing ability of UCART2. Sézary mice that received UCART2 and NT-I7 had “virtually no tumor burden,” according to researchers, and survived longer than mice treated with UCART2 alone (Blood. 2018;132:340).

Dr. DiPersio noted that there was no cytokine release syndrome because these were immunodeficient mice. However, cytokine release syndrome may be a side effect of NT-I7 in patients as NT-I7 induces rapid expansion of CAR T cells.

Dr. DiPersio reported ownership and investment in WUGEN and Magenta Therapeutics. He also has relationships with Cellworks Group, Tioma Therapeutics, RiverVest Venture Partners, Bioline, Asterias Biotherapeutics, Amphivena Therapeutics, Bluebird Bio, Celgene, Incyte, NeoImuneTech, and MacroGenics.

The Acute Leukemia Forum is organized by Hemedicus, which is owned by the same company as this news organization.

[email protected]

High rates of relapse and toxicities among infants who undergo allogeneic hematopoietic cell transplant (allo-HCT) contribute to survival rates that have remained largely unchanged from 2000-2014, based on a retrospective study of almost 2,500 cases.

Although survival rates improved from 2000 to 2004 among children aged 1 and younger who underwent allo-HCT for nonmalignant conditions, rates plateaued thereafter, reported lead author Suhag H. Parikh, MD, of Duke University Medical Center in Durham, North Carolina, and his colleagues. Still more disappointing, survival rates for infants with malignant conditions remained relatively flat throughout the 15-year study period.

For adult patients, allo-HCT survival rates have improved over time, but data for infants are rare. This is a concerning blind spot because infants are a particularly vulnerable population in the transplant setting.

Courtesy Duke Health

“Infants may be at higher risk for toxicities than adults,” the investigators wrote in JAMA Pediatrics. “Although children are considered to have better tolerance to high-intensity or myeloablative conditioning regimens and perhaps better immune reconstitution owing to a functional thymus, infants may be at higher risk of transplant-associated complications.”

The present study involved 2,498 infants,1 year old or younger (median age 7 months), who underwent allo-HCT for malignant or nonmalignant conditions between 2000 and 2014. Information was drawn from The Center for International Blood and Marrow Transplant Research (CIBMTR), which consists of data from more than 450 transplant centers across the world.

The investigators assessed overall survival trends among infants undergoing allo-HCT; in addition, they analyzed factors contributing to mortality and rates of two major organ toxicities: sinusoidal obstruction syndrome and idiopathic pneumonia syndrome. Cases were divided into 2 cohorts: malignant and nonmalignant. Time-analysis was divided into three periods: 2000-2004, 2005-2009, and 2010-2014.

Overall, the results were disheartening. Survival trends were generally flat during the 15-year study period, and some outcomes actually worsened over time. As a small highlight, infants with nonmalignant disease had improved survival when comparing the second and third time period with the first time period (HR, 0.77; P = .007); however, this trend fell flat after 2004. Three-year overall survival rates for infants with nonmalignant disease from least recent to most recent time period, were 65.0%, 72.0%, and 74.0%.

Survival was poorer with malignant conditions, with 3-year overall survival rates of 54.8%, 64.6%, and 58.9% from least recent to most recent time period. This trend was associated with a worsening relapse rate, which increased from 19% to 36% from 2000 to 2014.

Also, toxicities were relatively common. Sinusoidal obstruction syndrome occurred in 32% of infants with malignant disease and in 13% with nonmalignant conditions. The rate of interstitial pneumonia syndrome at 100 days post-transplant was 5% across all patients.

Optimal supportive care and donor/graft selection might improve outcomes, as could reduced-intensity/nonmyeloablative conditioning regimens rather than total body irradiation, according to the researchers.

Changes in practice for disease subgroups may be warranted, based on the improved survival rate seen for infants with nonmalignant disease, which was mostly driven by better outcomes in patients with severe combined immunodeficiency, a disease subgroup that has had newborn-screening programs since 2008. Judging by the trends, such programs are truly making a difference, the researchers wrote.

The study was funded by the National Cancer Institute (NCI); the National Heart, Lung and Blood Institute (NHLBI); Health Resources and Services Administration; the Office of Naval Research; and a number of private pharmaceutical companies. The investigators reported financial relationships with Sangamo Therapeutics, Mallinckrodt, Takeda, Jazz, and others.

SOURCE: Parikh et al. JAMA Peds. 2019 March 18. doi: 10.1001/jamapediatrics.2019.0081.

High rates of relapse and toxicities among infants who undergo allogeneic hematopoietic cell transplant (allo-HCT) contribute to survival rates that have remained largely unchanged from 2000-2014, based on a retrospective study of almost 2,500 cases.

Although survival rates improved from 2000 to 2004 among children aged 1 and younger who underwent allo-HCT for nonmalignant conditions, rates plateaued thereafter, reported lead author Suhag H. Parikh, MD, of Duke University Medical Center in Durham, North Carolina, and his colleagues. Still more disappointing, survival rates for infants with malignant conditions remained relatively flat throughout the 15-year study period.

For adult patients, allo-HCT survival rates have improved over time, but data for infants are rare. This is a concerning blind spot because infants are a particularly vulnerable population in the transplant setting.

Courtesy Duke Health

“Infants may be at higher risk for toxicities than adults,” the investigators wrote in JAMA Pediatrics. “Although children are considered to have better tolerance to high-intensity or myeloablative conditioning regimens and perhaps better immune reconstitution owing to a functional thymus, infants may be at higher risk of transplant-associated complications.”

The present study involved 2,498 infants,1 year old or younger (median age 7 months), who underwent allo-HCT for malignant or nonmalignant conditions between 2000 and 2014. Information was drawn from The Center for International Blood and Marrow Transplant Research (CIBMTR), which consists of data from more than 450 transplant centers across the world.

The investigators assessed overall survival trends among infants undergoing allo-HCT; in addition, they analyzed factors contributing to mortality and rates of two major organ toxicities: sinusoidal obstruction syndrome and idiopathic pneumonia syndrome. Cases were divided into 2 cohorts: malignant and nonmalignant. Time-analysis was divided into three periods: 2000-2004, 2005-2009, and 2010-2014.

Overall, the results were disheartening. Survival trends were generally flat during the 15-year study period, and some outcomes actually worsened over time. As a small highlight, infants with nonmalignant disease had improved survival when comparing the second and third time period with the first time period (HR, 0.77; P = .007); however, this trend fell flat after 2004. Three-year overall survival rates for infants with nonmalignant disease from least recent to most recent time period, were 65.0%, 72.0%, and 74.0%.

Survival was poorer with malignant conditions, with 3-year overall survival rates of 54.8%, 64.6%, and 58.9% from least recent to most recent time period. This trend was associated with a worsening relapse rate, which increased from 19% to 36% from 2000 to 2014.

Also, toxicities were relatively common. Sinusoidal obstruction syndrome occurred in 32% of infants with malignant disease and in 13% with nonmalignant conditions. The rate of interstitial pneumonia syndrome at 100 days post-transplant was 5% across all patients.

Optimal supportive care and donor/graft selection might improve outcomes, as could reduced-intensity/nonmyeloablative conditioning regimens rather than total body irradiation, according to the researchers.

Changes in practice for disease subgroups may be warranted, based on the improved survival rate seen for infants with nonmalignant disease, which was mostly driven by better outcomes in patients with severe combined immunodeficiency, a disease subgroup that has had newborn-screening programs since 2008. Judging by the trends, such programs are truly making a difference, the researchers wrote.

The study was funded by the National Cancer Institute (NCI); the National Heart, Lung and Blood Institute (NHLBI); Health Resources and Services Administration; the Office of Naval Research; and a number of private pharmaceutical companies. The investigators reported financial relationships with Sangamo Therapeutics, Mallinckrodt, Takeda, Jazz, and others.

SOURCE: Parikh et al. JAMA Peds. 2019 March 18. doi: 10.1001/jamapediatrics.2019.0081.

High rates of relapse and toxicities among infants who undergo allogeneic hematopoietic cell transplant (allo-HCT) contribute to survival rates that have remained largely unchanged from 2000-2014, based on a retrospective study of almost 2,500 cases.

Although survival rates improved from 2000 to 2004 among children aged 1 and younger who underwent allo-HCT for nonmalignant conditions, rates plateaued thereafter, reported lead author Suhag H. Parikh, MD, of Duke University Medical Center in Durham, North Carolina, and his colleagues. Still more disappointing, survival rates for infants with malignant conditions remained relatively flat throughout the 15-year study period.

For adult patients, allo-HCT survival rates have improved over time, but data for infants are rare. This is a concerning blind spot because infants are a particularly vulnerable population in the transplant setting.

Courtesy Duke Health

“Infants may be at higher risk for toxicities than adults,” the investigators wrote in JAMA Pediatrics. “Although children are considered to have better tolerance to high-intensity or myeloablative conditioning regimens and perhaps better immune reconstitution owing to a functional thymus, infants may be at higher risk of transplant-associated complications.”

The present study involved 2,498 infants,1 year old or younger (median age 7 months), who underwent allo-HCT for malignant or nonmalignant conditions between 2000 and 2014. Information was drawn from The Center for International Blood and Marrow Transplant Research (CIBMTR), which consists of data from more than 450 transplant centers across the world.

The investigators assessed overall survival trends among infants undergoing allo-HCT; in addition, they analyzed factors contributing to mortality and rates of two major organ toxicities: sinusoidal obstruction syndrome and idiopathic pneumonia syndrome. Cases were divided into 2 cohorts: malignant and nonmalignant. Time-analysis was divided into three periods: 2000-2004, 2005-2009, and 2010-2014.

Overall, the results were disheartening. Survival trends were generally flat during the 15-year study period, and some outcomes actually worsened over time. As a small highlight, infants with nonmalignant disease had improved survival when comparing the second and third time period with the first time period (HR, 0.77; P = .007); however, this trend fell flat after 2004. Three-year overall survival rates for infants with nonmalignant disease from least recent to most recent time period, were 65.0%, 72.0%, and 74.0%.

Survival was poorer with malignant conditions, with 3-year overall survival rates of 54.8%, 64.6%, and 58.9% from least recent to most recent time period. This trend was associated with a worsening relapse rate, which increased from 19% to 36% from 2000 to 2014.

Also, toxicities were relatively common. Sinusoidal obstruction syndrome occurred in 32% of infants with malignant disease and in 13% with nonmalignant conditions. The rate of interstitial pneumonia syndrome at 100 days post-transplant was 5% across all patients.

Optimal supportive care and donor/graft selection might improve outcomes, as could reduced-intensity/nonmyeloablative conditioning regimens rather than total body irradiation, according to the researchers.

Changes in practice for disease subgroups may be warranted, based on the improved survival rate seen for infants with nonmalignant disease, which was mostly driven by better outcomes in patients with severe combined immunodeficiency, a disease subgroup that has had newborn-screening programs since 2008. Judging by the trends, such programs are truly making a difference, the researchers wrote.

The study was funded by the National Cancer Institute (NCI); the National Heart, Lung and Blood Institute (NHLBI); Health Resources and Services Administration; the Office of Naval Research; and a number of private pharmaceutical companies. The investigators reported financial relationships with Sangamo Therapeutics, Mallinckrodt, Takeda, Jazz, and others.

SOURCE: Parikh et al. JAMA Peds. 2019 March 18. doi: 10.1001/jamapediatrics.2019.0081.

HOUSTON – Acute lymphoblastic leukemia patients with measurable residual disease (MRD) negativity prior to hematopoietic cell transplantation achieve better outcomes than do those who are MRD positive, particularly when total body irradiation (TBI)–based conditioning is used, a large retrospective study suggests.

Of 2,780 ALL patients who underwent hematopoietic cell transplantation (HCT) in first or second complete remission (CR), and who were included in the study, 1,816 were MRD negative before transplantation and 964 were MRD positive.

Overall, with follow-up of 40-44 months, MRD positivity was a significant independent predictor of lower overall survival (OS; hazard ratio, 1.19), leukemia-free survival (LFS; HR, 1.26), and higher relapse incidence (RI; 1.51), Arnon Nagler, MD, reported at the Transplantation & Cellular Therapy Meetings.

Conditioning was TBI-based in 76% of the patients; when these patients were compared with those who received chemotherapy-based conditioning, they were found to have better OS, LFS, and RI (HRs, 0.75, 0.70, and 0.60, respectively), said Dr. Nagler, director of both the division of hematology and the bone marrow transplantation and cord blood bank at the Chaim Sheba Medical Center, Tel-Hashomer, and professor of medicine at Tel Aviv University, both in Israel.

“There was no significant interaction between the MRD status and the conditioning,” he said.


On multivariate analysis, MRD positivity was found to be associated with lower OS and LFS (HRs, 1.26 and 1.3), and higher RI (HR, 1.53) in the TBI group, and with higher RI (HR 1.58) in the chemotherapy group, he said. There was no significant association between MRD and other outcomes in this last cohort, he added, noting that TBI-based conditioning was associated with improved OS, LFS, and RI in both MRD-negative and MRD-positive patients.

“MRD is an extremely important prognostic factor for ALL,” he said, noting that its prognostic value in this setting has been established in multiple studies, and that MRD measured at the end of induction is increasingly used to guide further therapy.

However, although MRD detectable immediately before HCT is known to be associated with poor outcomes, it has been unclear if – or to what extent – this differs with different types of conditioning, he added.

“So the aim of this study was to explore if MRD detectable before allogeneic HCT for ALL is associated with different outcomes in adult patients receiving myeloablative conditioning, either TBI or chemotherapy based,” he said at the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research.

At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).

Patients included in the analysis had a median age of 38 years and underwent HCT between 2000 and 2017 using sibling or unrelated 9/10 or 10/10 matched donors. None received blinatumomab or inotuzumab, Dr. Nagler said, adding that more patients are likely to achieve MRD negativity with these agents.

It will be interesting to see if the prognostic value of MRD will remain as strong with the new agents, and if TBI will be “a strong factor in overall survival and disease-free survival” with modern immunotherapy, he concluded.

The study was conducted on behalf of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT).

Dr. Nagler reported having no relevant financial disclosures.

[email protected]

SOURCE: Nagler A et al. TCT 2019, Abstract 7.

HOUSTON – Acute lymphoblastic leukemia patients with measurable residual disease (MRD) negativity prior to hematopoietic cell transplantation achieve better outcomes than do those who are MRD positive, particularly when total body irradiation (TBI)–based conditioning is used, a large retrospective study suggests.

Of 2,780 ALL patients who underwent hematopoietic cell transplantation (HCT) in first or second complete remission (CR), and who were included in the study, 1,816 were MRD negative before transplantation and 964 were MRD positive.

Overall, with follow-up of 40-44 months, MRD positivity was a significant independent predictor of lower overall survival (OS; hazard ratio, 1.19), leukemia-free survival (LFS; HR, 1.26), and higher relapse incidence (RI; 1.51), Arnon Nagler, MD, reported at the Transplantation & Cellular Therapy Meetings.

Conditioning was TBI-based in 76% of the patients; when these patients were compared with those who received chemotherapy-based conditioning, they were found to have better OS, LFS, and RI (HRs, 0.75, 0.70, and 0.60, respectively), said Dr. Nagler, director of both the division of hematology and the bone marrow transplantation and cord blood bank at the Chaim Sheba Medical Center, Tel-Hashomer, and professor of medicine at Tel Aviv University, both in Israel.

“There was no significant interaction between the MRD status and the conditioning,” he said.


On multivariate analysis, MRD positivity was found to be associated with lower OS and LFS (HRs, 1.26 and 1.3), and higher RI (HR, 1.53) in the TBI group, and with higher RI (HR 1.58) in the chemotherapy group, he said. There was no significant association between MRD and other outcomes in this last cohort, he added, noting that TBI-based conditioning was associated with improved OS, LFS, and RI in both MRD-negative and MRD-positive patients.

“MRD is an extremely important prognostic factor for ALL,” he said, noting that its prognostic value in this setting has been established in multiple studies, and that MRD measured at the end of induction is increasingly used to guide further therapy.

However, although MRD detectable immediately before HCT is known to be associated with poor outcomes, it has been unclear if – or to what extent – this differs with different types of conditioning, he added.

“So the aim of this study was to explore if MRD detectable before allogeneic HCT for ALL is associated with different outcomes in adult patients receiving myeloablative conditioning, either TBI or chemotherapy based,” he said at the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research.

At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).

Patients included in the analysis had a median age of 38 years and underwent HCT between 2000 and 2017 using sibling or unrelated 9/10 or 10/10 matched donors. None received blinatumomab or inotuzumab, Dr. Nagler said, adding that more patients are likely to achieve MRD negativity with these agents.

It will be interesting to see if the prognostic value of MRD will remain as strong with the new agents, and if TBI will be “a strong factor in overall survival and disease-free survival” with modern immunotherapy, he concluded.

The study was conducted on behalf of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT).

Dr. Nagler reported having no relevant financial disclosures.

[email protected]

SOURCE: Nagler A et al. TCT 2019, Abstract 7.

HOUSTON – Acute lymphoblastic leukemia patients with measurable residual disease (MRD) negativity prior to hematopoietic cell transplantation achieve better outcomes than do those who are MRD positive, particularly when total body irradiation (TBI)–based conditioning is used, a large retrospective study suggests.

Of 2,780 ALL patients who underwent hematopoietic cell transplantation (HCT) in first or second complete remission (CR), and who were included in the study, 1,816 were MRD negative before transplantation and 964 were MRD positive.

Overall, with follow-up of 40-44 months, MRD positivity was a significant independent predictor of lower overall survival (OS; hazard ratio, 1.19), leukemia-free survival (LFS; HR, 1.26), and higher relapse incidence (RI; 1.51), Arnon Nagler, MD, reported at the Transplantation & Cellular Therapy Meetings.

Conditioning was TBI-based in 76% of the patients; when these patients were compared with those who received chemotherapy-based conditioning, they were found to have better OS, LFS, and RI (HRs, 0.75, 0.70, and 0.60, respectively), said Dr. Nagler, director of both the division of hematology and the bone marrow transplantation and cord blood bank at the Chaim Sheba Medical Center, Tel-Hashomer, and professor of medicine at Tel Aviv University, both in Israel.

“There was no significant interaction between the MRD status and the conditioning,” he said.


On multivariate analysis, MRD positivity was found to be associated with lower OS and LFS (HRs, 1.26 and 1.3), and higher RI (HR, 1.53) in the TBI group, and with higher RI (HR 1.58) in the chemotherapy group, he said. There was no significant association between MRD and other outcomes in this last cohort, he added, noting that TBI-based conditioning was associated with improved OS, LFS, and RI in both MRD-negative and MRD-positive patients.

“MRD is an extremely important prognostic factor for ALL,” he said, noting that its prognostic value in this setting has been established in multiple studies, and that MRD measured at the end of induction is increasingly used to guide further therapy.

However, although MRD detectable immediately before HCT is known to be associated with poor outcomes, it has been unclear if – or to what extent – this differs with different types of conditioning, he added.

“So the aim of this study was to explore if MRD detectable before allogeneic HCT for ALL is associated with different outcomes in adult patients receiving myeloablative conditioning, either TBI or chemotherapy based,” he said at the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research.

At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).

Patients included in the analysis had a median age of 38 years and underwent HCT between 2000 and 2017 using sibling or unrelated 9/10 or 10/10 matched donors. None received blinatumomab or inotuzumab, Dr. Nagler said, adding that more patients are likely to achieve MRD negativity with these agents.

It will be interesting to see if the prognostic value of MRD will remain as strong with the new agents, and if TBI will be “a strong factor in overall survival and disease-free survival” with modern immunotherapy, he concluded.

The study was conducted on behalf of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT).

Dr. Nagler reported having no relevant financial disclosures.

[email protected]

SOURCE: Nagler A et al. TCT 2019, Abstract 7.