Cellular Therapy

Unintentional transduction of a single leukemic B cell appears to have induced resistance to CTL019 (tisagenlecleucel, Kymriah) therapy, a recent case study suggests.

Courtesy Penn Medicine

A total of 9 months after receiving a seemingly successful CD19-targeted chimeric antigen receptor (CAR) T-cell (CTL019; tisagenlecleucel) infusion, a 20-year-old man with B-cell acute lymphoblastic leukemia (B-ALL) had a frank relapse, with more than 90% bone marrow infiltration of CAR-transduced B-cell leukemia cells. Further investigation showed that the CAR gene had unintentionally been added to a solitary leukemic B cell during the CAR T-cell manufacturing process, reported Marco Ruella, MD, of the University of Pennsylvania, Philadelphia.

“The transduction of a single leukemic cell with an anti-CD19 CAR lentivirus during CTL019 manufacturing is sufficient to mediate resistance through masking of the CD19 epitope. This is a rare event, as this is the only case out of 369 patients reported worldwide at the time of publication. ... These findings illustrate the need for improved manufacturing technologies that can purge residual contaminating tumor cells from engineered T cells,” the authors wrote in Nature Medicine.

The findings also confirm the cancer stem cell hypothesis in humans, “given that clonal analysis indicated that the relapse and subsequent death of the patient were attributed to the progeny of a single leukemic blast cell with extensive replicative capacity, both in culture and in vivo,” they wrote.

Initially, “the infused CTL019 cells displayed the typical pattern of in vivo engraftment and expansion by CAR19-specific flow cytometry, followed by decline to an undetectable level in the peripheral blood” of the affected patient, the authors wrote. “The expansion and contraction phases and long-term persistence of CAR T cells were confirmed via qPCR using CAR-specific primers.” The patient was in complete remission at day 28.

However, they added, routine peripheral blood monitoring with quantitative polymerase chain reaction for CAR-specific sequences identified “the emergence of a second expansion phase of CAR cells starting at day 252, which did not correlate with re-expansion of CAR + T cells by flow cytometry.” Frank relapse soon followed.

Analysis confirmed “that the lack of detection of CD19 by flow cytometry was due to CAR19 binding in cis to CD19 on the surface of leukemic blasts, thus masking the epitope from detection by standard flow cytometry,” the authors wrote.

Study funding was provided by Bristol-Myers Squibb, Novartis, the National Institutes of Health, and others. Dr. Ruella and several of his colleagues work under a research collaboration involving the University of Pennsylvania and the Novartis Institutes of Biomedical Research and are inventors of intellectual property licensed by the University of Pennsylvania to Novartis.

SOURCE: Ruella M et al. Nat Med. 2018 Oct 1. doi: 10.1038/s41591-018-0201-9.

Unintentional transduction of a single leukemic B cell appears to have induced resistance to CTL019 (tisagenlecleucel, Kymriah) therapy, a recent case study suggests.

Courtesy Penn Medicine

A total of 9 months after receiving a seemingly successful CD19-targeted chimeric antigen receptor (CAR) T-cell (CTL019; tisagenlecleucel) infusion, a 20-year-old man with B-cell acute lymphoblastic leukemia (B-ALL) had a frank relapse, with more than 90% bone marrow infiltration of CAR-transduced B-cell leukemia cells. Further investigation showed that the CAR gene had unintentionally been added to a solitary leukemic B cell during the CAR T-cell manufacturing process, reported Marco Ruella, MD, of the University of Pennsylvania, Philadelphia.

“The transduction of a single leukemic cell with an anti-CD19 CAR lentivirus during CTL019 manufacturing is sufficient to mediate resistance through masking of the CD19 epitope. This is a rare event, as this is the only case out of 369 patients reported worldwide at the time of publication. ... These findings illustrate the need for improved manufacturing technologies that can purge residual contaminating tumor cells from engineered T cells,” the authors wrote in Nature Medicine.

The findings also confirm the cancer stem cell hypothesis in humans, “given that clonal analysis indicated that the relapse and subsequent death of the patient were attributed to the progeny of a single leukemic blast cell with extensive replicative capacity, both in culture and in vivo,” they wrote.

Initially, “the infused CTL019 cells displayed the typical pattern of in vivo engraftment and expansion by CAR19-specific flow cytometry, followed by decline to an undetectable level in the peripheral blood” of the affected patient, the authors wrote. “The expansion and contraction phases and long-term persistence of CAR T cells were confirmed via qPCR using CAR-specific primers.” The patient was in complete remission at day 28.

However, they added, routine peripheral blood monitoring with quantitative polymerase chain reaction for CAR-specific sequences identified “the emergence of a second expansion phase of CAR cells starting at day 252, which did not correlate with re-expansion of CAR + T cells by flow cytometry.” Frank relapse soon followed.

Analysis confirmed “that the lack of detection of CD19 by flow cytometry was due to CAR19 binding in cis to CD19 on the surface of leukemic blasts, thus masking the epitope from detection by standard flow cytometry,” the authors wrote.

Study funding was provided by Bristol-Myers Squibb, Novartis, the National Institutes of Health, and others. Dr. Ruella and several of his colleagues work under a research collaboration involving the University of Pennsylvania and the Novartis Institutes of Biomedical Research and are inventors of intellectual property licensed by the University of Pennsylvania to Novartis.

SOURCE: Ruella M et al. Nat Med. 2018 Oct 1. doi: 10.1038/s41591-018-0201-9.

Unintentional transduction of a single leukemic B cell appears to have induced resistance to CTL019 (tisagenlecleucel, Kymriah) therapy, a recent case study suggests.

Courtesy Penn Medicine

A total of 9 months after receiving a seemingly successful CD19-targeted chimeric antigen receptor (CAR) T-cell (CTL019; tisagenlecleucel) infusion, a 20-year-old man with B-cell acute lymphoblastic leukemia (B-ALL) had a frank relapse, with more than 90% bone marrow infiltration of CAR-transduced B-cell leukemia cells. Further investigation showed that the CAR gene had unintentionally been added to a solitary leukemic B cell during the CAR T-cell manufacturing process, reported Marco Ruella, MD, of the University of Pennsylvania, Philadelphia.

“The transduction of a single leukemic cell with an anti-CD19 CAR lentivirus during CTL019 manufacturing is sufficient to mediate resistance through masking of the CD19 epitope. This is a rare event, as this is the only case out of 369 patients reported worldwide at the time of publication. ... These findings illustrate the need for improved manufacturing technologies that can purge residual contaminating tumor cells from engineered T cells,” the authors wrote in Nature Medicine.

The findings also confirm the cancer stem cell hypothesis in humans, “given that clonal analysis indicated that the relapse and subsequent death of the patient were attributed to the progeny of a single leukemic blast cell with extensive replicative capacity, both in culture and in vivo,” they wrote.

Initially, “the infused CTL019 cells displayed the typical pattern of in vivo engraftment and expansion by CAR19-specific flow cytometry, followed by decline to an undetectable level in the peripheral blood” of the affected patient, the authors wrote. “The expansion and contraction phases and long-term persistence of CAR T cells were confirmed via qPCR using CAR-specific primers.” The patient was in complete remission at day 28.

However, they added, routine peripheral blood monitoring with quantitative polymerase chain reaction for CAR-specific sequences identified “the emergence of a second expansion phase of CAR cells starting at day 252, which did not correlate with re-expansion of CAR + T cells by flow cytometry.” Frank relapse soon followed.

Analysis confirmed “that the lack of detection of CD19 by flow cytometry was due to CAR19 binding in cis to CD19 on the surface of leukemic blasts, thus masking the epitope from detection by standard flow cytometry,” the authors wrote.

Study funding was provided by Bristol-Myers Squibb, Novartis, the National Institutes of Health, and others. Dr. Ruella and several of his colleagues work under a research collaboration involving the University of Pennsylvania and the Novartis Institutes of Biomedical Research and are inventors of intellectual property licensed by the University of Pennsylvania to Novartis.

SOURCE: Ruella M et al. Nat Med. 2018 Oct 1. doi: 10.1038/s41591-018-0201-9.

For patients who undergo allogeneic hematopoietic stem cell transplant (allo-HSCT) with intensive antibiotics, a subsequent autologous fecal transplant (auto-FMT) can restore intestinal microbiota, a recent study found.

Courtesy Memorial Sloan Kettering Cancer Center

Loss of normal gut bacteria after allo-HSCT and antibiotics is a common occurrence and known risk factor for graft-versus-host disease (GVHD) and intestinal infection.

“Overall, patients who lose gut microbiota diversity at the time of hematopoietic stem cell engraftment have higher rates of transplant-related death,” reported Ying Taur, MD, of the Memorial Sloan Kettering Cancer Center in New York, and his colleagues. “We explored whether the microbiota could be restored in allo-HSCT patients through the use of auto-FMT.”

Allo-HSCT patients are immune suppressed for months after engraftment, so safety concerns led the investigators to use auto-FMT rather than a fecal transplant from another individual. The complex population of viruses, fungi, archaea, bacteria, and protozoa that inhabit the human gut remains poorly understood, as does the infectious potential of a heterologous fecal donor.

“Despite remarkable advances in recent years, current technologies are incapable of comprehensively determining fecal composition,” the authors wrote in Science Translational Medicine.

The study involved 25 patients undergoing allo-HSCT with intensive antibiotic therapy. Prior to engraftment, fecal samples were collected from all patients and analyzed for composition and diversity, measured by inverse Simpson index.

Samples were then frozen and stored. Fecal analysis also was performed after engraftment, and again after the auto-FMT time point. Auto-FMT was performed in 14 patients; 11 patients served as controls and did not receive treatment. Patients were followed for 1 year.

The investigators found that all of the patients who underwent auto-FMT recovered their pre–allo-HSCT microbiota composition and diversity, compared with none of the controls (P less than .0001). Further analysis showed that auto-FMT increased diversity (inverse Simpson index) by 64%, compared with 38% in controls.

“We have demonstrated the potential of auto-FMT as a clinical intervention to restore intestinal microbiota diversity to levels deemed safe in patients, thereby reversing the disruptive effects of broad-spectrum antibiotic treatment for patients undergoing allo-HSCT transplant,” the investigators concluded.

Study funding was provided by the Leonard Tow Foundation and the Memorial Sloan Kettering’s Center for Microbes, Inflammation, and Cancer. The authors reported financial relationships with Merck, AbbVie, Nektar Therapeutics, Novartis, and others.

SOURCE: Taur Y et al. Sci Transl Med. 2018 Sep 26. doi: 10.1126/scitranslmed.aap9489.

For patients who undergo allogeneic hematopoietic stem cell transplant (allo-HSCT) with intensive antibiotics, a subsequent autologous fecal transplant (auto-FMT) can restore intestinal microbiota, a recent study found.

Courtesy Memorial Sloan Kettering Cancer Center

Loss of normal gut bacteria after allo-HSCT and antibiotics is a common occurrence and known risk factor for graft-versus-host disease (GVHD) and intestinal infection.

“Overall, patients who lose gut microbiota diversity at the time of hematopoietic stem cell engraftment have higher rates of transplant-related death,” reported Ying Taur, MD, of the Memorial Sloan Kettering Cancer Center in New York, and his colleagues. “We explored whether the microbiota could be restored in allo-HSCT patients through the use of auto-FMT.”

Allo-HSCT patients are immune suppressed for months after engraftment, so safety concerns led the investigators to use auto-FMT rather than a fecal transplant from another individual. The complex population of viruses, fungi, archaea, bacteria, and protozoa that inhabit the human gut remains poorly understood, as does the infectious potential of a heterologous fecal donor.

“Despite remarkable advances in recent years, current technologies are incapable of comprehensively determining fecal composition,” the authors wrote in Science Translational Medicine.

The study involved 25 patients undergoing allo-HSCT with intensive antibiotic therapy. Prior to engraftment, fecal samples were collected from all patients and analyzed for composition and diversity, measured by inverse Simpson index.

Samples were then frozen and stored. Fecal analysis also was performed after engraftment, and again after the auto-FMT time point. Auto-FMT was performed in 14 patients; 11 patients served as controls and did not receive treatment. Patients were followed for 1 year.

The investigators found that all of the patients who underwent auto-FMT recovered their pre–allo-HSCT microbiota composition and diversity, compared with none of the controls (P less than .0001). Further analysis showed that auto-FMT increased diversity (inverse Simpson index) by 64%, compared with 38% in controls.

“We have demonstrated the potential of auto-FMT as a clinical intervention to restore intestinal microbiota diversity to levels deemed safe in patients, thereby reversing the disruptive effects of broad-spectrum antibiotic treatment for patients undergoing allo-HSCT transplant,” the investigators concluded.

Study funding was provided by the Leonard Tow Foundation and the Memorial Sloan Kettering’s Center for Microbes, Inflammation, and Cancer. The authors reported financial relationships with Merck, AbbVie, Nektar Therapeutics, Novartis, and others.

SOURCE: Taur Y et al. Sci Transl Med. 2018 Sep 26. doi: 10.1126/scitranslmed.aap9489.

For patients who undergo allogeneic hematopoietic stem cell transplant (allo-HSCT) with intensive antibiotics, a subsequent autologous fecal transplant (auto-FMT) can restore intestinal microbiota, a recent study found.

Courtesy Memorial Sloan Kettering Cancer Center

Loss of normal gut bacteria after allo-HSCT and antibiotics is a common occurrence and known risk factor for graft-versus-host disease (GVHD) and intestinal infection.

“Overall, patients who lose gut microbiota diversity at the time of hematopoietic stem cell engraftment have higher rates of transplant-related death,” reported Ying Taur, MD, of the Memorial Sloan Kettering Cancer Center in New York, and his colleagues. “We explored whether the microbiota could be restored in allo-HSCT patients through the use of auto-FMT.”

Allo-HSCT patients are immune suppressed for months after engraftment, so safety concerns led the investigators to use auto-FMT rather than a fecal transplant from another individual. The complex population of viruses, fungi, archaea, bacteria, and protozoa that inhabit the human gut remains poorly understood, as does the infectious potential of a heterologous fecal donor.

“Despite remarkable advances in recent years, current technologies are incapable of comprehensively determining fecal composition,” the authors wrote in Science Translational Medicine.

The study involved 25 patients undergoing allo-HSCT with intensive antibiotic therapy. Prior to engraftment, fecal samples were collected from all patients and analyzed for composition and diversity, measured by inverse Simpson index.

Samples were then frozen and stored. Fecal analysis also was performed after engraftment, and again after the auto-FMT time point. Auto-FMT was performed in 14 patients; 11 patients served as controls and did not receive treatment. Patients were followed for 1 year.

The investigators found that all of the patients who underwent auto-FMT recovered their pre–allo-HSCT microbiota composition and diversity, compared with none of the controls (P less than .0001). Further analysis showed that auto-FMT increased diversity (inverse Simpson index) by 64%, compared with 38% in controls.

“We have demonstrated the potential of auto-FMT as a clinical intervention to restore intestinal microbiota diversity to levels deemed safe in patients, thereby reversing the disruptive effects of broad-spectrum antibiotic treatment for patients undergoing allo-HSCT transplant,” the investigators concluded.

Study funding was provided by the Leonard Tow Foundation and the Memorial Sloan Kettering’s Center for Microbes, Inflammation, and Cancer. The authors reported financial relationships with Merck, AbbVie, Nektar Therapeutics, Novartis, and others.

SOURCE: Taur Y et al. Sci Transl Med. 2018 Sep 26. doi: 10.1126/scitranslmed.aap9489.

NEW YORK – The cell therapy landscape increasingly involves strategies beyond chimeric antigen receptor (CAR) T-cell therapy, but those studies still predominate among investigational trials, according to Frederick L. Locke, MD, of Moffitt Cancer Center in Tampa.

Researchers are looking at CAR T-cell therapy for earlier lines of treatment, especially in patients with aggressive lymphomas, Dr. Locke said at the annual congress on Hematologic Malignancies held by the National Comprehensive Cancer Network.

Of 753 trials examining cell therapies and listed at ClinicalTrials.gov as of March 30, 2018, about half (404) were CAR T-cell therapies. The others included T-cell receptor therapies, tumor infiltrating lymphocyte therapies, dendritic cell vaccines, and natural killer cell–based therapies, according to an article in Nature Reviews.

“The development isn’t just here in the United States,” Dr. Locke said. “It’s really global. We see a lot of activity in Europe, but also in China. We’re seeing medical advances across the world through molecular biology and gene engineering of T cells and other immune cells which can be adoptively transferred into patients.”

That activity includes studies seeking to move CAR T-cell therapy earlier in the treatment paradigm for some diseases, he added. “CAR T-cell therapy in non-Hodgkin lymphoma is really beginning a paradigm shift, at least in my mind.”

Several large, randomized trials that are now comparing CD19 CAR T-cell therapy with second-line standard-of-care therapies for patients with aggressive B-cell lymphomas. Among those trials is ZUMA-7, a phase 3, randomized trial comparing axicabtagene ciloleucel with standard-of-care treatment in patients with relapsed or refractory diffuse large B-cell lymphoma.

While prognosis remains poor for relapsed or progressing aggressive B-cell lymphomas treated with chemotherapy, data to date suggest CAR T-cell therapy produces durable, long-term remissions in about 40% of patients at “a year out and counting,” Dr. Locke said.

He presented a proposed treatment algorithm that included R-CHOP chemotherapy up front and CAR T-cell therapy in later lines of treatment, an approach that Dr. Locke speculated could result in a cure rate of perhaps 80% in large-cell lymphomas.

Encouraging longer-term data is emerging, with some patients with aggressive T-cell lymphomas now without recurrence for 5 years or more following a single infusion of CAR T-cell therapy, he said.

Dr. Locke reported a financial disclosure related to Cellular Biomedicine Group.

NEW YORK – The cell therapy landscape increasingly involves strategies beyond chimeric antigen receptor (CAR) T-cell therapy, but those studies still predominate among investigational trials, according to Frederick L. Locke, MD, of Moffitt Cancer Center in Tampa.

Researchers are looking at CAR T-cell therapy for earlier lines of treatment, especially in patients with aggressive lymphomas, Dr. Locke said at the annual congress on Hematologic Malignancies held by the National Comprehensive Cancer Network.

Of 753 trials examining cell therapies and listed at ClinicalTrials.gov as of March 30, 2018, about half (404) were CAR T-cell therapies. The others included T-cell receptor therapies, tumor infiltrating lymphocyte therapies, dendritic cell vaccines, and natural killer cell–based therapies, according to an article in Nature Reviews.

“The development isn’t just here in the United States,” Dr. Locke said. “It’s really global. We see a lot of activity in Europe, but also in China. We’re seeing medical advances across the world through molecular biology and gene engineering of T cells and other immune cells which can be adoptively transferred into patients.”

That activity includes studies seeking to move CAR T-cell therapy earlier in the treatment paradigm for some diseases, he added. “CAR T-cell therapy in non-Hodgkin lymphoma is really beginning a paradigm shift, at least in my mind.”

Several large, randomized trials that are now comparing CD19 CAR T-cell therapy with second-line standard-of-care therapies for patients with aggressive B-cell lymphomas. Among those trials is ZUMA-7, a phase 3, randomized trial comparing axicabtagene ciloleucel with standard-of-care treatment in patients with relapsed or refractory diffuse large B-cell lymphoma.

While prognosis remains poor for relapsed or progressing aggressive B-cell lymphomas treated with chemotherapy, data to date suggest CAR T-cell therapy produces durable, long-term remissions in about 40% of patients at “a year out and counting,” Dr. Locke said.

He presented a proposed treatment algorithm that included R-CHOP chemotherapy up front and CAR T-cell therapy in later lines of treatment, an approach that Dr. Locke speculated could result in a cure rate of perhaps 80% in large-cell lymphomas.

Encouraging longer-term data is emerging, with some patients with aggressive T-cell lymphomas now without recurrence for 5 years or more following a single infusion of CAR T-cell therapy, he said.

Dr. Locke reported a financial disclosure related to Cellular Biomedicine Group.

NEW YORK – The cell therapy landscape increasingly involves strategies beyond chimeric antigen receptor (CAR) T-cell therapy, but those studies still predominate among investigational trials, according to Frederick L. Locke, MD, of Moffitt Cancer Center in Tampa.

Researchers are looking at CAR T-cell therapy for earlier lines of treatment, especially in patients with aggressive lymphomas, Dr. Locke said at the annual congress on Hematologic Malignancies held by the National Comprehensive Cancer Network.

Of 753 trials examining cell therapies and listed at ClinicalTrials.gov as of March 30, 2018, about half (404) were CAR T-cell therapies. The others included T-cell receptor therapies, tumor infiltrating lymphocyte therapies, dendritic cell vaccines, and natural killer cell–based therapies, according to an article in Nature Reviews.

“The development isn’t just here in the United States,” Dr. Locke said. “It’s really global. We see a lot of activity in Europe, but also in China. We’re seeing medical advances across the world through molecular biology and gene engineering of T cells and other immune cells which can be adoptively transferred into patients.”

That activity includes studies seeking to move CAR T-cell therapy earlier in the treatment paradigm for some diseases, he added. “CAR T-cell therapy in non-Hodgkin lymphoma is really beginning a paradigm shift, at least in my mind.”

Several large, randomized trials that are now comparing CD19 CAR T-cell therapy with second-line standard-of-care therapies for patients with aggressive B-cell lymphomas. Among those trials is ZUMA-7, a phase 3, randomized trial comparing axicabtagene ciloleucel with standard-of-care treatment in patients with relapsed or refractory diffuse large B-cell lymphoma.

While prognosis remains poor for relapsed or progressing aggressive B-cell lymphomas treated with chemotherapy, data to date suggest CAR T-cell therapy produces durable, long-term remissions in about 40% of patients at “a year out and counting,” Dr. Locke said.

He presented a proposed treatment algorithm that included R-CHOP chemotherapy up front and CAR T-cell therapy in later lines of treatment, an approach that Dr. Locke speculated could result in a cure rate of perhaps 80% in large-cell lymphomas.

Encouraging longer-term data is emerging, with some patients with aggressive T-cell lymphomas now without recurrence for 5 years or more following a single infusion of CAR T-cell therapy, he said.

Dr. Locke reported a financial disclosure related to Cellular Biomedicine Group.

The National Institute for Health and Care Excellence (NICE) has issued draft guidance recommending against tisagenlecleucel (Kymriah) as a treatment for adults with diffuse large B-cell lymphoma (DLBCL).

Courtesy Novartis

Tisagenlecleucel is a chimeric antigen receptor (CAR) T-cell therapy that was recently approved by the European Commission to treat adults with relapsed or refractory DLBCL who have received two or more lines of systemic therapy.

Tisagenlecleucel is also European Commission–approved to treat patients up to age 25 years who have B-cell acute lymphoblastic leukemia (ALL) that is refractory, in relapse posttransplant, or in second or later relapse.

In September 2018, the National Health Service (NHS) in England announced tisagenlecleucel will be made available for these ALL patients through the Cancer Drugs Fund.

However, in draft guidance issued Sept. 19, NICE recommended against using tisagenlecleucel for adults with relapsed/refractory DLBCL who have received two or more lines of systemic therapy. NICE noted that there is no standard treatment for this patient group, and that salvage chemotherapy is the most common treatment option.

Although the latest results from the JULIET trial suggest tisagenlecleucel can produce responses in patients with relapsed/refractory DLBCL, there are no data comparing tisagenlecleucel with salvage chemotherapy. Additionally, tisagenlecleucel cannot be considered a life-extending treatment at the end of life, according to NICE criteria.

All cost-effectiveness estimates for tisagenlecleucel are above the range NICE normally considers acceptable, and tisagenlecleucel does not meet criteria for inclusion in the Cancer Drugs Fund.

The list price for tisagenlecleucel is 282,000 pounds. However, Novartis, the company developing tisagenlecleucel, has a confidential commercial arrangement with the NHS that lowers the price of tisagenlecleucel for the ALL indication. This arrangement would apply if tisagenlecleucel were recommended for the DLBCL indication.

In August, NICE issued a similar draft guidance document recommending against use of another CAR T-cell therapy, axicabtagene ciloleucel (Yescarta). Axicabtagene ciloleucel is approved in Europe for the treatment of patients with relapsed/refractory DLBCL or primary mediastinal B-cell lymphoma who have received two or more lines of systemic therapy.

[email protected]

The National Institute for Health and Care Excellence (NICE) has issued draft guidance recommending against tisagenlecleucel (Kymriah) as a treatment for adults with diffuse large B-cell lymphoma (DLBCL).

Courtesy Novartis

Tisagenlecleucel is a chimeric antigen receptor (CAR) T-cell therapy that was recently approved by the European Commission to treat adults with relapsed or refractory DLBCL who have received two or more lines of systemic therapy.

Tisagenlecleucel is also European Commission–approved to treat patients up to age 25 years who have B-cell acute lymphoblastic leukemia (ALL) that is refractory, in relapse posttransplant, or in second or later relapse.

In September 2018, the National Health Service (NHS) in England announced tisagenlecleucel will be made available for these ALL patients through the Cancer Drugs Fund.

However, in draft guidance issued Sept. 19, NICE recommended against using tisagenlecleucel for adults with relapsed/refractory DLBCL who have received two or more lines of systemic therapy. NICE noted that there is no standard treatment for this patient group, and that salvage chemotherapy is the most common treatment option.

Although the latest results from the JULIET trial suggest tisagenlecleucel can produce responses in patients with relapsed/refractory DLBCL, there are no data comparing tisagenlecleucel with salvage chemotherapy. Additionally, tisagenlecleucel cannot be considered a life-extending treatment at the end of life, according to NICE criteria.

All cost-effectiveness estimates for tisagenlecleucel are above the range NICE normally considers acceptable, and tisagenlecleucel does not meet criteria for inclusion in the Cancer Drugs Fund.

The list price for tisagenlecleucel is 282,000 pounds. However, Novartis, the company developing tisagenlecleucel, has a confidential commercial arrangement with the NHS that lowers the price of tisagenlecleucel for the ALL indication. This arrangement would apply if tisagenlecleucel were recommended for the DLBCL indication.

In August, NICE issued a similar draft guidance document recommending against use of another CAR T-cell therapy, axicabtagene ciloleucel (Yescarta). Axicabtagene ciloleucel is approved in Europe for the treatment of patients with relapsed/refractory DLBCL or primary mediastinal B-cell lymphoma who have received two or more lines of systemic therapy.

[email protected]

The National Institute for Health and Care Excellence (NICE) has issued draft guidance recommending against tisagenlecleucel (Kymriah) as a treatment for adults with diffuse large B-cell lymphoma (DLBCL).

Courtesy Novartis

Tisagenlecleucel is a chimeric antigen receptor (CAR) T-cell therapy that was recently approved by the European Commission to treat adults with relapsed or refractory DLBCL who have received two or more lines of systemic therapy.

Tisagenlecleucel is also European Commission–approved to treat patients up to age 25 years who have B-cell acute lymphoblastic leukemia (ALL) that is refractory, in relapse posttransplant, or in second or later relapse.

In September 2018, the National Health Service (NHS) in England announced tisagenlecleucel will be made available for these ALL patients through the Cancer Drugs Fund.

However, in draft guidance issued Sept. 19, NICE recommended against using tisagenlecleucel for adults with relapsed/refractory DLBCL who have received two or more lines of systemic therapy. NICE noted that there is no standard treatment for this patient group, and that salvage chemotherapy is the most common treatment option.

Although the latest results from the JULIET trial suggest tisagenlecleucel can produce responses in patients with relapsed/refractory DLBCL, there are no data comparing tisagenlecleucel with salvage chemotherapy. Additionally, tisagenlecleucel cannot be considered a life-extending treatment at the end of life, according to NICE criteria.

All cost-effectiveness estimates for tisagenlecleucel are above the range NICE normally considers acceptable, and tisagenlecleucel does not meet criteria for inclusion in the Cancer Drugs Fund.

The list price for tisagenlecleucel is 282,000 pounds. However, Novartis, the company developing tisagenlecleucel, has a confidential commercial arrangement with the NHS that lowers the price of tisagenlecleucel for the ALL indication. This arrangement would apply if tisagenlecleucel were recommended for the DLBCL indication.

In August, NICE issued a similar draft guidance document recommending against use of another CAR T-cell therapy, axicabtagene ciloleucel (Yescarta). Axicabtagene ciloleucel is approved in Europe for the treatment of patients with relapsed/refractory DLBCL or primary mediastinal B-cell lymphoma who have received two or more lines of systemic therapy.

[email protected]

The cost-effectiveness of tisagenlecleucel (Kymriah) depends on long-term clinical outcomes, which are presently unknown, according to investigators.

Courtesy Stanford University

If the long-term outcomes are more modest than clinical trials suggest, then payers may be unwilling to cover the costly therapy, reported John K. Lin, MD, of the Center for Primary Care and Outcomes Research at Stanford (Calif.) University, and his colleagues. Lowering the price or setting up an outcomes-based pricing structure may be necessary to get insurers to cover the therapy.

Tisagenlecleucel is an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy that was approved by the Food and Drug Administration in August 2017 for relapsed or refractory pediatric B-cell acute lymphoblastic leukemia (ALL). In 2018, the FDA expanded the indication for tisagenlecleucel to include adults with relapsed or refractory large B-cell lymphoma, though outcomes from lymphoma trials are not analyzed in the current study.

At a wholesale acquisition cost of $475,000 per infusion, it is the most expensive existing oncology therapy to date, and can be accompanied by expensive, potentially fatal adverse effects. However, clinical trials suggest that tisagenlecleucel can offer years of relapse-free remission, thereby allowing patients to forgo other expensive therapies such as hematopoietic stem cell transplantation (HSCT).

“Although tisagenlecleucel-induced remission rates are promising, compared with those of established therapies (greater than 80% vs. less than 50%), only short-term follow-up data currently exist,” the investigators wrote in the Journal of Clinical Oncology. “Given the high cost and broad applicability in other malignancies of tisagenlecleucel, a pressing question for policy makers, payers, patients, and clinicians is whether the cost of therapy represents reasonable value.”

The study used a Markov model to assess various long-term clinical outcome rates and cost thresholds of tisagenlecleucel. The lifetime cost of therapy was assessed and compared with costs of existing therapies.

The results showed that a 5-year relapse free survival rate of 40% would make the present cost ($475,000) of tisagenlecleucel economically reasonable. In this scenario, the increased life expectancy would be 12.1 years and would result in an additional 5.07 quality-adjusted life years (QALY) gained at a cost of $61,000 per QALY, compared with blinatumomab.

But if long-term outcomes are less favorable, tisagenlecleucel becomes much less cost effective. A 5-year relapse-free survival rate of 20% would drop increased life expectancy to 3.8 years, resulting in 1.80 QALYs gained and raising the cost to $151,000 per QALY.

“Our results suggest that at tisagenlecleucel’s current price and payment structure, its economic value is uncertain,” the investigators wrote.

They suggested a price drop to $200,000 or $350,000, which would allow the drug to remain cost effective even in a worse-case scenario, in which patients relapse and tisagenlecleucel is a bridge to transplant. Another option is to move to outcomes-based pricing. Making payment conditional on 7 months of remission would make the treatment cost effective, according to the analysis.

“Price reductions of tisagenlecleucel or payment only for longer-term remissions would favorably influence cost-effectiveness, even if long-term clinical outcomes are modest,” the investigators wrote.

The study was funded by a Veterans Affairs Office of Academic Affiliations advanced fellowship in health service and research development, and a National Center for Advancing Translational Science Clinical and Translational Science Award. One of the study coauthors reported consulting and research funding from Novartis.

SOURCE: Lin et al. J Clin Oncol. 2018 Sep 13. doi: 10.1200/JCO.2018.79.0642.

The cost-effectiveness of tisagenlecleucel (Kymriah) depends on long-term clinical outcomes, which are presently unknown, according to investigators.

Courtesy Stanford University

If the long-term outcomes are more modest than clinical trials suggest, then payers may be unwilling to cover the costly therapy, reported John K. Lin, MD, of the Center for Primary Care and Outcomes Research at Stanford (Calif.) University, and his colleagues. Lowering the price or setting up an outcomes-based pricing structure may be necessary to get insurers to cover the therapy.

Tisagenlecleucel is an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy that was approved by the Food and Drug Administration in August 2017 for relapsed or refractory pediatric B-cell acute lymphoblastic leukemia (ALL). In 2018, the FDA expanded the indication for tisagenlecleucel to include adults with relapsed or refractory large B-cell lymphoma, though outcomes from lymphoma trials are not analyzed in the current study.

At a wholesale acquisition cost of $475,000 per infusion, it is the most expensive existing oncology therapy to date, and can be accompanied by expensive, potentially fatal adverse effects. However, clinical trials suggest that tisagenlecleucel can offer years of relapse-free remission, thereby allowing patients to forgo other expensive therapies such as hematopoietic stem cell transplantation (HSCT).

“Although tisagenlecleucel-induced remission rates are promising, compared with those of established therapies (greater than 80% vs. less than 50%), only short-term follow-up data currently exist,” the investigators wrote in the Journal of Clinical Oncology. “Given the high cost and broad applicability in other malignancies of tisagenlecleucel, a pressing question for policy makers, payers, patients, and clinicians is whether the cost of therapy represents reasonable value.”

The study used a Markov model to assess various long-term clinical outcome rates and cost thresholds of tisagenlecleucel. The lifetime cost of therapy was assessed and compared with costs of existing therapies.

The results showed that a 5-year relapse free survival rate of 40% would make the present cost ($475,000) of tisagenlecleucel economically reasonable. In this scenario, the increased life expectancy would be 12.1 years and would result in an additional 5.07 quality-adjusted life years (QALY) gained at a cost of $61,000 per QALY, compared with blinatumomab.

But if long-term outcomes are less favorable, tisagenlecleucel becomes much less cost effective. A 5-year relapse-free survival rate of 20% would drop increased life expectancy to 3.8 years, resulting in 1.80 QALYs gained and raising the cost to $151,000 per QALY.

“Our results suggest that at tisagenlecleucel’s current price and payment structure, its economic value is uncertain,” the investigators wrote.

They suggested a price drop to $200,000 or $350,000, which would allow the drug to remain cost effective even in a worse-case scenario, in which patients relapse and tisagenlecleucel is a bridge to transplant. Another option is to move to outcomes-based pricing. Making payment conditional on 7 months of remission would make the treatment cost effective, according to the analysis.

“Price reductions of tisagenlecleucel or payment only for longer-term remissions would favorably influence cost-effectiveness, even if long-term clinical outcomes are modest,” the investigators wrote.

The study was funded by a Veterans Affairs Office of Academic Affiliations advanced fellowship in health service and research development, and a National Center for Advancing Translational Science Clinical and Translational Science Award. One of the study coauthors reported consulting and research funding from Novartis.

SOURCE: Lin et al. J Clin Oncol. 2018 Sep 13. doi: 10.1200/JCO.2018.79.0642.

The cost-effectiveness of tisagenlecleucel (Kymriah) depends on long-term clinical outcomes, which are presently unknown, according to investigators.

Courtesy Stanford University

If the long-term outcomes are more modest than clinical trials suggest, then payers may be unwilling to cover the costly therapy, reported John K. Lin, MD, of the Center for Primary Care and Outcomes Research at Stanford (Calif.) University, and his colleagues. Lowering the price or setting up an outcomes-based pricing structure may be necessary to get insurers to cover the therapy.

Tisagenlecleucel is an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy that was approved by the Food and Drug Administration in August 2017 for relapsed or refractory pediatric B-cell acute lymphoblastic leukemia (ALL). In 2018, the FDA expanded the indication for tisagenlecleucel to include adults with relapsed or refractory large B-cell lymphoma, though outcomes from lymphoma trials are not analyzed in the current study.

At a wholesale acquisition cost of $475,000 per infusion, it is the most expensive existing oncology therapy to date, and can be accompanied by expensive, potentially fatal adverse effects. However, clinical trials suggest that tisagenlecleucel can offer years of relapse-free remission, thereby allowing patients to forgo other expensive therapies such as hematopoietic stem cell transplantation (HSCT).

“Although tisagenlecleucel-induced remission rates are promising, compared with those of established therapies (greater than 80% vs. less than 50%), only short-term follow-up data currently exist,” the investigators wrote in the Journal of Clinical Oncology. “Given the high cost and broad applicability in other malignancies of tisagenlecleucel, a pressing question for policy makers, payers, patients, and clinicians is whether the cost of therapy represents reasonable value.”

The study used a Markov model to assess various long-term clinical outcome rates and cost thresholds of tisagenlecleucel. The lifetime cost of therapy was assessed and compared with costs of existing therapies.

The results showed that a 5-year relapse free survival rate of 40% would make the present cost ($475,000) of tisagenlecleucel economically reasonable. In this scenario, the increased life expectancy would be 12.1 years and would result in an additional 5.07 quality-adjusted life years (QALY) gained at a cost of $61,000 per QALY, compared with blinatumomab.

But if long-term outcomes are less favorable, tisagenlecleucel becomes much less cost effective. A 5-year relapse-free survival rate of 20% would drop increased life expectancy to 3.8 years, resulting in 1.80 QALYs gained and raising the cost to $151,000 per QALY.

“Our results suggest that at tisagenlecleucel’s current price and payment structure, its economic value is uncertain,” the investigators wrote.

They suggested a price drop to $200,000 or $350,000, which would allow the drug to remain cost effective even in a worse-case scenario, in which patients relapse and tisagenlecleucel is a bridge to transplant. Another option is to move to outcomes-based pricing. Making payment conditional on 7 months of remission would make the treatment cost effective, according to the analysis.

“Price reductions of tisagenlecleucel or payment only for longer-term remissions would favorably influence cost-effectiveness, even if long-term clinical outcomes are modest,” the investigators wrote.

The study was funded by a Veterans Affairs Office of Academic Affiliations advanced fellowship in health service and research development, and a National Center for Advancing Translational Science Clinical and Translational Science Award. One of the study coauthors reported consulting and research funding from Novartis.

SOURCE: Lin et al. J Clin Oncol. 2018 Sep 13. doi: 10.1200/JCO.2018.79.0642.

Early results from a phase 1 trial suggest the chimeric antigen receptor (CAR) T-cell therapy P-BCMA-101 can produce responses in patients with relapsed/refractory multiple myeloma.

All 11 patients treated have experienced some clinical response, with 8 patients achieving a partial response (PR) or better.

The most common adverse events were neutropenia and thrombocytopenia. One patient was suspected to have cytokine release syndrome (CRS), but the condition resolved without use of tocilizumab or steroids.

These results were presented at the 2018 CAR-TCR Summit by Eric Ostertag, MD, PhD, chief executive officer of Poseida Therapeutics Inc., the company developing P-BCMA-101.

Dr. Ostertag presented data on 11 patients with heavily pretreated multiple myeloma. They had a median of six prior therapies. The median age was 60 years, and most of the patients were considered high risk.

Prior to receiving P-BCMA-101, patients received conditioning with fludarabine (30 mg/m²) and cyclophosphamide (300 mg/m²) for 3 days.

Patients were then treated across three dose groups with average CAR T-cell doses of 51 x 10⁶ (n = 3), 152 x 10⁶ (n = 7), and 430 x 10⁶ (n = 1).

As of Aug. 10, 2018, all 11 patients were still on study.

There were no dose-limiting toxicities. Eight patients developed neutropenia, and five had thrombocytopenia.

Researchers suspected CRS in one patient, but the condition resolved without tocilizumab or steroid treatment. There was no neurotoxicity reported, and none of the patients required admission to an intensive care unit.

All patients showed improvement in biomarkers following treatment.

Ten patients were evaluable for response by International Myeloma Working Group criteria. Seven of these patients achieved at least a PR, including very good partial responses (VGPRs) and stringent complete response (CR).

The eleventh patient also responded to treatment, but this patient has oligosecretory disease and was evaluable only by PET. The patient had a near-CR by PET.

Poseida Therapeutics would not disclose additional details regarding how many patients achieved a PR, VGPR, or CR, but the company plans to release more information on response at an upcoming meeting.

“The latest data results show that P-BCMA-101 induces deep responses in a heavily pretreated population with relapsed/refractory multiple myeloma, with some patients reaching VGPR and even stringent CR at early efficacy assessments,” Dr. Ostertag said.

This study (NCT03288493) is funded by the California Institute for Regenerative Medicine and Poseida Therapeutics.

[email protected]

Early results from a phase 1 trial suggest the chimeric antigen receptor (CAR) T-cell therapy P-BCMA-101 can produce responses in patients with relapsed/refractory multiple myeloma.

All 11 patients treated have experienced some clinical response, with 8 patients achieving a partial response (PR) or better.

The most common adverse events were neutropenia and thrombocytopenia. One patient was suspected to have cytokine release syndrome (CRS), but the condition resolved without use of tocilizumab or steroids.

These results were presented at the 2018 CAR-TCR Summit by Eric Ostertag, MD, PhD, chief executive officer of Poseida Therapeutics Inc., the company developing P-BCMA-101.

Dr. Ostertag presented data on 11 patients with heavily pretreated multiple myeloma. They had a median of six prior therapies. The median age was 60 years, and most of the patients were considered high risk.

Prior to receiving P-BCMA-101, patients received conditioning with fludarabine (30 mg/m²) and cyclophosphamide (300 mg/m²) for 3 days.

Patients were then treated across three dose groups with average CAR T-cell doses of 51 x 10⁶ (n = 3), 152 x 10⁶ (n = 7), and 430 x 10⁶ (n = 1).

As of Aug. 10, 2018, all 11 patients were still on study.

There were no dose-limiting toxicities. Eight patients developed neutropenia, and five had thrombocytopenia.

Researchers suspected CRS in one patient, but the condition resolved without tocilizumab or steroid treatment. There was no neurotoxicity reported, and none of the patients required admission to an intensive care unit.

All patients showed improvement in biomarkers following treatment.

Ten patients were evaluable for response by International Myeloma Working Group criteria. Seven of these patients achieved at least a PR, including very good partial responses (VGPRs) and stringent complete response (CR).

The eleventh patient also responded to treatment, but this patient has oligosecretory disease and was evaluable only by PET. The patient had a near-CR by PET.

Poseida Therapeutics would not disclose additional details regarding how many patients achieved a PR, VGPR, or CR, but the company plans to release more information on response at an upcoming meeting.

“The latest data results show that P-BCMA-101 induces deep responses in a heavily pretreated population with relapsed/refractory multiple myeloma, with some patients reaching VGPR and even stringent CR at early efficacy assessments,” Dr. Ostertag said.

This study (NCT03288493) is funded by the California Institute for Regenerative Medicine and Poseida Therapeutics.

[email protected]

Early results from a phase 1 trial suggest the chimeric antigen receptor (CAR) T-cell therapy P-BCMA-101 can produce responses in patients with relapsed/refractory multiple myeloma.

All 11 patients treated have experienced some clinical response, with 8 patients achieving a partial response (PR) or better.

The most common adverse events were neutropenia and thrombocytopenia. One patient was suspected to have cytokine release syndrome (CRS), but the condition resolved without use of tocilizumab or steroids.

These results were presented at the 2018 CAR-TCR Summit by Eric Ostertag, MD, PhD, chief executive officer of Poseida Therapeutics Inc., the company developing P-BCMA-101.

Dr. Ostertag presented data on 11 patients with heavily pretreated multiple myeloma. They had a median of six prior therapies. The median age was 60 years, and most of the patients were considered high risk.

Prior to receiving P-BCMA-101, patients received conditioning with fludarabine (30 mg/m²) and cyclophosphamide (300 mg/m²) for 3 days.

Patients were then treated across three dose groups with average CAR T-cell doses of 51 x 10⁶ (n = 3), 152 x 10⁶ (n = 7), and 430 x 10⁶ (n = 1).

As of Aug. 10, 2018, all 11 patients were still on study.

There were no dose-limiting toxicities. Eight patients developed neutropenia, and five had thrombocytopenia.

Researchers suspected CRS in one patient, but the condition resolved without tocilizumab or steroid treatment. There was no neurotoxicity reported, and none of the patients required admission to an intensive care unit.

All patients showed improvement in biomarkers following treatment.

Ten patients were evaluable for response by International Myeloma Working Group criteria. Seven of these patients achieved at least a PR, including very good partial responses (VGPRs) and stringent complete response (CR).

The eleventh patient also responded to treatment, but this patient has oligosecretory disease and was evaluable only by PET. The patient had a near-CR by PET.

Poseida Therapeutics would not disclose additional details regarding how many patients achieved a PR, VGPR, or CR, but the company plans to release more information on response at an upcoming meeting.

“The latest data results show that P-BCMA-101 induces deep responses in a heavily pretreated population with relapsed/refractory multiple myeloma, with some patients reaching VGPR and even stringent CR at early efficacy assessments,” Dr. Ostertag said.

This study (NCT03288493) is funded by the California Institute for Regenerative Medicine and Poseida Therapeutics.

[email protected]

The National Health Service (NHS) of England has announced that tisagenlecleucel (Kymriah), a chimeric antigen receptor (CAR) T-cell therapy, will soon be available for certain leukemia patients.

Courtesy Novartis

Tisagenlecleucel will be available through the Cancer Drugs Fund, and patients could potentially begin receiving the treatment within weeks.

NHS England struck a deal with Novartis to lower the price of tisagenlecleucel, which costs around £282,000 per patient at its full list price. The discount offered to the NHS is confidential.

Tisagenlecleucel was recently approved by the European Commission (EC) to treat patients up to 25 years of age who have B-cell acute lymphoblastic leukemia (ALL) that is refractory, in relapse post transplant, or in second or later relapse.

The EC also approved tisagenlecleucel to treat adults with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who have received two or more lines of systemic therapy.

However, tisagenlecleucel will be available only for ALL patients in England, at least initially. A decision has not been made regarding funding for tisagenlecleucel in DLBCL, and Novartis previously decided to launch tisagenlecleucel in ALL first.

“It’s fantastic news for children and young people with this form of leukemia that CAR T-cell therapy will be made available on the NHS, making them the first in Europe to have routine access to this exciting new type of immunotherapy,” said Charles Swanton, Cancer Research UK’s chief clinician.

The first three NHS hospitals to go through the international accreditation process for the provision of tisagenlecleucel are in London, Manchester, and Newcastle. Subject to passing accreditation requirements, the first treatments could begin in a matter of weeks.

Another CAR T-cell therapy, axicabtagene ciloleucel (Yescarta), has not fared as well as in England. The National Institute for Health and Care Excellence (NICE) recently issued draft guidance recommending against the use of axicabtagene ciloleucel in England.

Axicabtagene ciloleucel was approved by the EC to treat patients with relapsed/refractory DLBCL or primary mediastinal B-cell lymphoma who have received two or more lines of systemic therapy. However, NICE said it isn’t clear how much of a benefit axicabtagene ciloleucel may provide over salvage chemotherapy. NICE also said the price of axicabtagene ciloleucel is too high for the therapy to be considered a cost-effective use of NHS resources, and the therapy does not meet the criteria for inclusion in the Cancer Drugs Fund.

[email protected]

The National Health Service (NHS) of England has announced that tisagenlecleucel (Kymriah), a chimeric antigen receptor (CAR) T-cell therapy, will soon be available for certain leukemia patients.

Courtesy Novartis

Tisagenlecleucel will be available through the Cancer Drugs Fund, and patients could potentially begin receiving the treatment within weeks.

NHS England struck a deal with Novartis to lower the price of tisagenlecleucel, which costs around £282,000 per patient at its full list price. The discount offered to the NHS is confidential.

Tisagenlecleucel was recently approved by the European Commission (EC) to treat patients up to 25 years of age who have B-cell acute lymphoblastic leukemia (ALL) that is refractory, in relapse post transplant, or in second or later relapse.

The EC also approved tisagenlecleucel to treat adults with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who have received two or more lines of systemic therapy.

However, tisagenlecleucel will be available only for ALL patients in England, at least initially. A decision has not been made regarding funding for tisagenlecleucel in DLBCL, and Novartis previously decided to launch tisagenlecleucel in ALL first.

“It’s fantastic news for children and young people with this form of leukemia that CAR T-cell therapy will be made available on the NHS, making them the first in Europe to have routine access to this exciting new type of immunotherapy,” said Charles Swanton, Cancer Research UK’s chief clinician.

The first three NHS hospitals to go through the international accreditation process for the provision of tisagenlecleucel are in London, Manchester, and Newcastle. Subject to passing accreditation requirements, the first treatments could begin in a matter of weeks.

Another CAR T-cell therapy, axicabtagene ciloleucel (Yescarta), has not fared as well as in England. The National Institute for Health and Care Excellence (NICE) recently issued draft guidance recommending against the use of axicabtagene ciloleucel in England.

Axicabtagene ciloleucel was approved by the EC to treat patients with relapsed/refractory DLBCL or primary mediastinal B-cell lymphoma who have received two or more lines of systemic therapy. However, NICE said it isn’t clear how much of a benefit axicabtagene ciloleucel may provide over salvage chemotherapy. NICE also said the price of axicabtagene ciloleucel is too high for the therapy to be considered a cost-effective use of NHS resources, and the therapy does not meet the criteria for inclusion in the Cancer Drugs Fund.

[email protected]

The National Health Service (NHS) of England has announced that tisagenlecleucel (Kymriah), a chimeric antigen receptor (CAR) T-cell therapy, will soon be available for certain leukemia patients.

Courtesy Novartis

Tisagenlecleucel will be available through the Cancer Drugs Fund, and patients could potentially begin receiving the treatment within weeks.

NHS England struck a deal with Novartis to lower the price of tisagenlecleucel, which costs around £282,000 per patient at its full list price. The discount offered to the NHS is confidential.

Tisagenlecleucel was recently approved by the European Commission (EC) to treat patients up to 25 years of age who have B-cell acute lymphoblastic leukemia (ALL) that is refractory, in relapse post transplant, or in second or later relapse.

The EC also approved tisagenlecleucel to treat adults with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who have received two or more lines of systemic therapy.

However, tisagenlecleucel will be available only for ALL patients in England, at least initially. A decision has not been made regarding funding for tisagenlecleucel in DLBCL, and Novartis previously decided to launch tisagenlecleucel in ALL first.

“It’s fantastic news for children and young people with this form of leukemia that CAR T-cell therapy will be made available on the NHS, making them the first in Europe to have routine access to this exciting new type of immunotherapy,” said Charles Swanton, Cancer Research UK’s chief clinician.

The first three NHS hospitals to go through the international accreditation process for the provision of tisagenlecleucel are in London, Manchester, and Newcastle. Subject to passing accreditation requirements, the first treatments could begin in a matter of weeks.

Another CAR T-cell therapy, axicabtagene ciloleucel (Yescarta), has not fared as well as in England. The National Institute for Health and Care Excellence (NICE) recently issued draft guidance recommending against the use of axicabtagene ciloleucel in England.

Axicabtagene ciloleucel was approved by the EC to treat patients with relapsed/refractory DLBCL or primary mediastinal B-cell lymphoma who have received two or more lines of systemic therapy. However, NICE said it isn’t clear how much of a benefit axicabtagene ciloleucel may provide over salvage chemotherapy. NICE also said the price of axicabtagene ciloleucel is too high for the therapy to be considered a cost-effective use of NHS resources, and the therapy does not meet the criteria for inclusion in the Cancer Drugs Fund.

[email protected]

Drugmakers and physician groups expressed concern about connecting patient reported outcomes (PRO) to coverage decisions for chimeric antigen receptor T-cell therapy (CAR T) at a recent Medicare meeting.

copyright roobcio/Thinkstock

Despite these objections, members of the Medicare Evidence Development and Coverage Advisory Committee (MEDCAC) generally expressed confidence in the use of PROs in a series of votes about PRO instruments’ use in cancer care trials.

MEDCAC opened a national coverage analysis in May 2018 at the request of UnitedHealthcare. The insurer had asked the Centers for Medicare & Medicaid Services to clarify the circumstances for coverage of the new CAR T therapies.

In presentations at an Aug. 22 MEDCAC meeting, representatives from the two manufacturers that have approved CAR T treatments on the market cautioned against using PROs in the context of coverage decisions, even though both companies used PRO data in their clinical trials and are collecting it in the postmarketing period.

“While Kite recognizes the importance of PROs in ... clinical trials, the PRO CAR T science, where these instruments are most appropriate for CAR T, remains a still to be determined and still is evolving and still quite early in the developments,” said William Go, MD, PhD, vice president of clinical development at Kite Pharmaceuticals, a Gilead company.

Despite PROs playing an active role in the ongoing development and clinical trials that Kite is running, in the context of CAR T, “we feel PROs are not quite ready for real-world coverage decisions at this time,” Dr. Go said.

A representative from Novartis agreed. “It is important to clearly define research objectives when considering whether to collect patient reported outcomes data, particularly given the burden associated with advanced disease experienced by the patients that are likely to receive this therapy,” Ilia Ferrusi, PhD, associate director, HEOR (CAR T Therapy), U.S. Oncology, Novartis, told the panel.

She noted that Novartis experienced challenges collecting PRO data, which resulted in risks to data quality and interpretation. “This could very well be amplified in larger trials or in real-world practice.”

The presenters’ comments were echoed by written comments submitted to the CMS prior to the MEDCAC meeting.

The American Society for Blood and Marrow Transplantation (ASBMT), despite supporting the collection of patient-reported outcomes, particularly in oncology, “strongly objects to any mechanism that would tie patient access or provider reimbursement to the reporting of PROs, especially in the case of CAR T therapy,” the organization said in a letter to the CMS.

Optimal PRO instruments and time points “are currently unknown” as the PROs used today were developed around chemotherapy use.

“Mandating the use of a current instrument or set of outcomes through NCD [national coverage determination] or CED [coverage with evidence development] will set a course of collecting data that is very likely to be inaccurate and inadequate,” they said.

The ASBMT also noted there is significant heterogeneity in the CAR T constructs and associated disease indications. “Products will utilize different scientific constructs and the time frames for clinical response and/or potential onset of toxicities may differ for each construct, which will challenge the establishment of set time points for data collection.”

And while presentations and comments focused on PROs in the context of CAR T, conversation and voting on the use of PROs was in the broader context of oncology clinical trials, not specific to CAR T, changing the nature of the debate and calling into question the point of the meeting and how it will inform the national coverage determination on CAR T specifically.

The June 15 meeting announcement published in the Federal Register stated that the advisory committee “will specifically focus on appraisal of evidence-based PRO assessments to provide information that impacts patients, their providers, and caregivers after a CAR T-cell therapy intervention for the patient’s cancer.”

However, the committee was asked to evaluate evidence on a number of potential PRO instruments in the broader context of oncology clinical trials without a cancer-specific or treatment-specific context, leading to a debate over how different types of cancer will have different kinds of PRO assessments related to them.

The CMS is expected to make a national coverage decision on CAR T-cell therapy by Feb. 16, 2019.

[email protected]

Drugmakers and physician groups expressed concern about connecting patient reported outcomes (PRO) to coverage decisions for chimeric antigen receptor T-cell therapy (CAR T) at a recent Medicare meeting.

copyright roobcio/Thinkstock

Despite these objections, members of the Medicare Evidence Development and Coverage Advisory Committee (MEDCAC) generally expressed confidence in the use of PROs in a series of votes about PRO instruments’ use in cancer care trials.

MEDCAC opened a national coverage analysis in May 2018 at the request of UnitedHealthcare. The insurer had asked the Centers for Medicare & Medicaid Services to clarify the circumstances for coverage of the new CAR T therapies.

In presentations at an Aug. 22 MEDCAC meeting, representatives from the two manufacturers that have approved CAR T treatments on the market cautioned against using PROs in the context of coverage decisions, even though both companies used PRO data in their clinical trials and are collecting it in the postmarketing period.

“While Kite recognizes the importance of PROs in ... clinical trials, the PRO CAR T science, where these instruments are most appropriate for CAR T, remains a still to be determined and still is evolving and still quite early in the developments,” said William Go, MD, PhD, vice president of clinical development at Kite Pharmaceuticals, a Gilead company.

Despite PROs playing an active role in the ongoing development and clinical trials that Kite is running, in the context of CAR T, “we feel PROs are not quite ready for real-world coverage decisions at this time,” Dr. Go said.

A representative from Novartis agreed. “It is important to clearly define research objectives when considering whether to collect patient reported outcomes data, particularly given the burden associated with advanced disease experienced by the patients that are likely to receive this therapy,” Ilia Ferrusi, PhD, associate director, HEOR (CAR T Therapy), U.S. Oncology, Novartis, told the panel.

She noted that Novartis experienced challenges collecting PRO data, which resulted in risks to data quality and interpretation. “This could very well be amplified in larger trials or in real-world practice.”

The presenters’ comments were echoed by written comments submitted to the CMS prior to the MEDCAC meeting.

The American Society for Blood and Marrow Transplantation (ASBMT), despite supporting the collection of patient-reported outcomes, particularly in oncology, “strongly objects to any mechanism that would tie patient access or provider reimbursement to the reporting of PROs, especially in the case of CAR T therapy,” the organization said in a letter to the CMS.

Optimal PRO instruments and time points “are currently unknown” as the PROs used today were developed around chemotherapy use.

“Mandating the use of a current instrument or set of outcomes through NCD [national coverage determination] or CED [coverage with evidence development] will set a course of collecting data that is very likely to be inaccurate and inadequate,” they said.

The ASBMT also noted there is significant heterogeneity in the CAR T constructs and associated disease indications. “Products will utilize different scientific constructs and the time frames for clinical response and/or potential onset of toxicities may differ for each construct, which will challenge the establishment of set time points for data collection.”

And while presentations and comments focused on PROs in the context of CAR T, conversation and voting on the use of PROs was in the broader context of oncology clinical trials, not specific to CAR T, changing the nature of the debate and calling into question the point of the meeting and how it will inform the national coverage determination on CAR T specifically.

The June 15 meeting announcement published in the Federal Register stated that the advisory committee “will specifically focus on appraisal of evidence-based PRO assessments to provide information that impacts patients, their providers, and caregivers after a CAR T-cell therapy intervention for the patient’s cancer.”

However, the committee was asked to evaluate evidence on a number of potential PRO instruments in the broader context of oncology clinical trials without a cancer-specific or treatment-specific context, leading to a debate over how different types of cancer will have different kinds of PRO assessments related to them.

The CMS is expected to make a national coverage decision on CAR T-cell therapy by Feb. 16, 2019.

[email protected]

Drugmakers and physician groups expressed concern about connecting patient reported outcomes (PRO) to coverage decisions for chimeric antigen receptor T-cell therapy (CAR T) at a recent Medicare meeting.

copyright roobcio/Thinkstock

Despite these objections, members of the Medicare Evidence Development and Coverage Advisory Committee (MEDCAC) generally expressed confidence in the use of PROs in a series of votes about PRO instruments’ use in cancer care trials.

MEDCAC opened a national coverage analysis in May 2018 at the request of UnitedHealthcare. The insurer had asked the Centers for Medicare & Medicaid Services to clarify the circumstances for coverage of the new CAR T therapies.

In presentations at an Aug. 22 MEDCAC meeting, representatives from the two manufacturers that have approved CAR T treatments on the market cautioned against using PROs in the context of coverage decisions, even though both companies used PRO data in their clinical trials and are collecting it in the postmarketing period.

“While Kite recognizes the importance of PROs in ... clinical trials, the PRO CAR T science, where these instruments are most appropriate for CAR T, remains a still to be determined and still is evolving and still quite early in the developments,” said William Go, MD, PhD, vice president of clinical development at Kite Pharmaceuticals, a Gilead company.

Despite PROs playing an active role in the ongoing development and clinical trials that Kite is running, in the context of CAR T, “we feel PROs are not quite ready for real-world coverage decisions at this time,” Dr. Go said.

A representative from Novartis agreed. “It is important to clearly define research objectives when considering whether to collect patient reported outcomes data, particularly given the burden associated with advanced disease experienced by the patients that are likely to receive this therapy,” Ilia Ferrusi, PhD, associate director, HEOR (CAR T Therapy), U.S. Oncology, Novartis, told the panel.

She noted that Novartis experienced challenges collecting PRO data, which resulted in risks to data quality and interpretation. “This could very well be amplified in larger trials or in real-world practice.”

The presenters’ comments were echoed by written comments submitted to the CMS prior to the MEDCAC meeting.

The American Society for Blood and Marrow Transplantation (ASBMT), despite supporting the collection of patient-reported outcomes, particularly in oncology, “strongly objects to any mechanism that would tie patient access or provider reimbursement to the reporting of PROs, especially in the case of CAR T therapy,” the organization said in a letter to the CMS.

Optimal PRO instruments and time points “are currently unknown” as the PROs used today were developed around chemotherapy use.

“Mandating the use of a current instrument or set of outcomes through NCD [national coverage determination] or CED [coverage with evidence development] will set a course of collecting data that is very likely to be inaccurate and inadequate,” they said.

The ASBMT also noted there is significant heterogeneity in the CAR T constructs and associated disease indications. “Products will utilize different scientific constructs and the time frames for clinical response and/or potential onset of toxicities may differ for each construct, which will challenge the establishment of set time points for data collection.”

And while presentations and comments focused on PROs in the context of CAR T, conversation and voting on the use of PROs was in the broader context of oncology clinical trials, not specific to CAR T, changing the nature of the debate and calling into question the point of the meeting and how it will inform the national coverage determination on CAR T specifically.

The June 15 meeting announcement published in the Federal Register stated that the advisory committee “will specifically focus on appraisal of evidence-based PRO assessments to provide information that impacts patients, their providers, and caregivers after a CAR T-cell therapy intervention for the patient’s cancer.”

However, the committee was asked to evaluate evidence on a number of potential PRO instruments in the broader context of oncology clinical trials without a cancer-specific or treatment-specific context, leading to a debate over how different types of cancer will have different kinds of PRO assessments related to them.

The CMS is expected to make a national coverage decision on CAR T-cell therapy by Feb. 16, 2019.

[email protected]

Contrary to what might be expected, chimeric antigen receptor (CAR) T cells with stronger signaling capabilities were less effective against lymphoma cells in a mouse model, investigators reported.

Intracellular signaling strength was a key determinant of T cell fate in the study, which was published in the journal Science Signaling.

By contrast, CAR signaling pathways could not be predicted solely by the costimulatory domains used to construct the receptor, investigators said.

Based on those findings, tailoring CAR design based on signal strength might improve the efficacy and reduce the toxicity of CAR T-cell therapy, according to Alexander Salter, an MD/PhD student at Fred Hutchinson Cancer Research Center, Seattle, Wash.

In a press conference, Mr. Salter described results of the study, which used mass spectrometry to evaluate CARs encoding CD28 or 4-1BB costimulatory domains in primary human T cells.

While CARs with CD28 domains elicited more robust intracellular signaling than those with 4-1BB domains, there was considerable overlap in activation of T cell signaling pathways, Mr. Salter said.

That overlap was somewhat surprising, according to Mr. Salter, since researchers have generally assumed that CARs with CD28 and 4-1BB costimulatory domains will primarily signal through those respective pathways.

“No matter what costimulatory domain was encoded by the receptor, both CARs… activated both CD28 and 41BB signaling pathways,” Mr. Salter said.

The major determinant of efficacy in the study turned out to be not the domain used to construct the receptor, but the speed and strength of signaling, he added. In particular, the CARs that evoked stronger signals also had increased T cell dysfunction, decreasing their potency in the mouse lymphoma model.

The T cells with a CD28 CAR had very strong initial antitumor function that quickly waned in the mouse model of lymphoma; by contrast, the “slower burning” 4-1BB CAR signal led to T cells that better retained their function in vivo and were associated with longer median survival in the model, he said.

Those findings suggest tailoring CAR design based on signal strength may improve clinical efficacy and reduce toxicity.

As part of the study, Mr. Salter and his co-investigators were able to modify the CAR CD28 domain to make the signaling of the CD28 CARs less intense. “This is a modification that we think should be considered in future CAR design,” Mr. Salter said.

While the alterations in the CD28 signaling domain were able to reduce levels of cytokines produced by T cells, the study was primarily designed to look at the efficacy, noted Stanley Riddell, MD, scientific director of the Immunotherapy Integrated Research Center at Fred Hutchinson Cancer Research Center.

“Our models were not set up to address the question of toxicity, so we can’t directly say this would translate to what we would see in patients,” Dr. Riddell said during the press conference. “But I think we gleaned a lot of insights as to why cytokines are produced at greater or lesser levels with various CAR designs, and insights as to how to redesign these receptors to lower the levels of cytokines they make without compromising their ability to kill.”

Dr. Riddell is a founder, shareholder, and scientific advisor of Juno Therapeutics, and together with Mr. Salter, he has filed a patent application on the use of mutant CD28 CARs for cellular therapy. Co-author Raphael Gottardo, PhD, also with Fred Hutchinson Cancer Research Center, is a consultant for Juno Therapeutics. No other competing interests were reported.

SOURCE: Salter AI et al., Sci Signal. 2018 Aug 21;11. pii:eaat6753.

Contrary to what might be expected, chimeric antigen receptor (CAR) T cells with stronger signaling capabilities were less effective against lymphoma cells in a mouse model, investigators reported.

Intracellular signaling strength was a key determinant of T cell fate in the study, which was published in the journal Science Signaling.

By contrast, CAR signaling pathways could not be predicted solely by the costimulatory domains used to construct the receptor, investigators said.

Based on those findings, tailoring CAR design based on signal strength might improve the efficacy and reduce the toxicity of CAR T-cell therapy, according to Alexander Salter, an MD/PhD student at Fred Hutchinson Cancer Research Center, Seattle, Wash.

In a press conference, Mr. Salter described results of the study, which used mass spectrometry to evaluate CARs encoding CD28 or 4-1BB costimulatory domains in primary human T cells.

While CARs with CD28 domains elicited more robust intracellular signaling than those with 4-1BB domains, there was considerable overlap in activation of T cell signaling pathways, Mr. Salter said.

That overlap was somewhat surprising, according to Mr. Salter, since researchers have generally assumed that CARs with CD28 and 4-1BB costimulatory domains will primarily signal through those respective pathways.

“No matter what costimulatory domain was encoded by the receptor, both CARs… activated both CD28 and 41BB signaling pathways,” Mr. Salter said.

The major determinant of efficacy in the study turned out to be not the domain used to construct the receptor, but the speed and strength of signaling, he added. In particular, the CARs that evoked stronger signals also had increased T cell dysfunction, decreasing their potency in the mouse lymphoma model.

The T cells with a CD28 CAR had very strong initial antitumor function that quickly waned in the mouse model of lymphoma; by contrast, the “slower burning” 4-1BB CAR signal led to T cells that better retained their function in vivo and were associated with longer median survival in the model, he said.

Those findings suggest tailoring CAR design based on signal strength may improve clinical efficacy and reduce toxicity.

As part of the study, Mr. Salter and his co-investigators were able to modify the CAR CD28 domain to make the signaling of the CD28 CARs less intense. “This is a modification that we think should be considered in future CAR design,” Mr. Salter said.

While the alterations in the CD28 signaling domain were able to reduce levels of cytokines produced by T cells, the study was primarily designed to look at the efficacy, noted Stanley Riddell, MD, scientific director of the Immunotherapy Integrated Research Center at Fred Hutchinson Cancer Research Center.

“Our models were not set up to address the question of toxicity, so we can’t directly say this would translate to what we would see in patients,” Dr. Riddell said during the press conference. “But I think we gleaned a lot of insights as to why cytokines are produced at greater or lesser levels with various CAR designs, and insights as to how to redesign these receptors to lower the levels of cytokines they make without compromising their ability to kill.”

Dr. Riddell is a founder, shareholder, and scientific advisor of Juno Therapeutics, and together with Mr. Salter, he has filed a patent application on the use of mutant CD28 CARs for cellular therapy. Co-author Raphael Gottardo, PhD, also with Fred Hutchinson Cancer Research Center, is a consultant for Juno Therapeutics. No other competing interests were reported.

SOURCE: Salter AI et al., Sci Signal. 2018 Aug 21;11. pii:eaat6753.

Contrary to what might be expected, chimeric antigen receptor (CAR) T cells with stronger signaling capabilities were less effective against lymphoma cells in a mouse model, investigators reported.

Intracellular signaling strength was a key determinant of T cell fate in the study, which was published in the journal Science Signaling.

By contrast, CAR signaling pathways could not be predicted solely by the costimulatory domains used to construct the receptor, investigators said.

Based on those findings, tailoring CAR design based on signal strength might improve the efficacy and reduce the toxicity of CAR T-cell therapy, according to Alexander Salter, an MD/PhD student at Fred Hutchinson Cancer Research Center, Seattle, Wash.

In a press conference, Mr. Salter described results of the study, which used mass spectrometry to evaluate CARs encoding CD28 or 4-1BB costimulatory domains in primary human T cells.

While CARs with CD28 domains elicited more robust intracellular signaling than those with 4-1BB domains, there was considerable overlap in activation of T cell signaling pathways, Mr. Salter said.

That overlap was somewhat surprising, according to Mr. Salter, since researchers have generally assumed that CARs with CD28 and 4-1BB costimulatory domains will primarily signal through those respective pathways.

“No matter what costimulatory domain was encoded by the receptor, both CARs… activated both CD28 and 41BB signaling pathways,” Mr. Salter said.

The major determinant of efficacy in the study turned out to be not the domain used to construct the receptor, but the speed and strength of signaling, he added. In particular, the CARs that evoked stronger signals also had increased T cell dysfunction, decreasing their potency in the mouse lymphoma model.

The T cells with a CD28 CAR had very strong initial antitumor function that quickly waned in the mouse model of lymphoma; by contrast, the “slower burning” 4-1BB CAR signal led to T cells that better retained their function in vivo and were associated with longer median survival in the model, he said.

Those findings suggest tailoring CAR design based on signal strength may improve clinical efficacy and reduce toxicity.

As part of the study, Mr. Salter and his co-investigators were able to modify the CAR CD28 domain to make the signaling of the CD28 CARs less intense. “This is a modification that we think should be considered in future CAR design,” Mr. Salter said.

While the alterations in the CD28 signaling domain were able to reduce levels of cytokines produced by T cells, the study was primarily designed to look at the efficacy, noted Stanley Riddell, MD, scientific director of the Immunotherapy Integrated Research Center at Fred Hutchinson Cancer Research Center.

“Our models were not set up to address the question of toxicity, so we can’t directly say this would translate to what we would see in patients,” Dr. Riddell said during the press conference. “But I think we gleaned a lot of insights as to why cytokines are produced at greater or lesser levels with various CAR designs, and insights as to how to redesign these receptors to lower the levels of cytokines they make without compromising their ability to kill.”

Dr. Riddell is a founder, shareholder, and scientific advisor of Juno Therapeutics, and together with Mr. Salter, he has filed a patent application on the use of mutant CD28 CARs for cellular therapy. Co-author Raphael Gottardo, PhD, also with Fred Hutchinson Cancer Research Center, is a consultant for Juno Therapeutics. No other competing interests were reported.

SOURCE: Salter AI et al., Sci Signal. 2018 Aug 21;11. pii:eaat6753.

Medical associations are expressing disappointment at the new payment scheme put forward by the Centers for Medicare & Medicaid Services for inpatient administration of two chimeric antigen receptor (CAR) T-cell therapies, calling the reimbursement insufficient for use of the expensive medications.

Courtesy Novartis

Under its Aug. 17 final rule, CMS will now categorize 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 assign 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 begins in October 2018.

CMS also approved a temporary New Technology Add-On Payment (NTAP) for use of the therapies with a maximum threshold of $186,500, according to the rule.

According to the American Society of Hematology (ASH), this payment structure is an improvement, but it hardly covers the cost of the products, nor does it account for full hospitalization costs. ASH noted that the revised MS-DRG 016 has a base payment rate of $36,000 and that the maximum NTAP payment ($186,500) is only about half of the cost for a CAR T-cell product.

“ASH is concerned that this final policy may impede access to care to this cutting-edge therapy because hospitals and academic medical centers that provide this personalized treatment will simply not be able to withstand the negative financial impact,” the society said in a statement. “While this final policy represents an improvement over current CAR T therapy reimbursement rates, ASH believes patient access to care will be jeopardized as providers and hospitals will not be able to afford to deliver the therapy at this reimbursement rate, particularly as other CAR T products receive FDA [Food and Drug Administration] approval.”

ASH and the American Society for Blood and Marrow Transplantation (ASBMT) had strongly urged CMS to develop a site-neutral, equitable payment structure that would have allowed providers to recover more product acquisition costs from CAR T-cell therapies. In its final rule, CMS stated that it was too early to develop a novel payment structure for CAR T-cell treatments and that more research is needed before such changes are made. The agency noted that in May CMS opened a national coverage determination analysis on CAR T-cell therapy for Medicare patients with advanced cancer, which is expected to be completed by May 2019.

“[CMS] is soliciting public comment … on key design considerations for developing a potential model that would test private market strategies and introduce competition to improve quality of care for beneficiaries,” the agency said in the rule. “Given the relative newness of CAR T-cell therapy, the potential model, and our request for feedback on this model approach, we believe it would be premature to adopt changes to our existing payment mechanisms.”

The payment outline by CMS is essentially the bare minimum it could have extended to CAR T-cell therapies for 2019, said Stephanie Farnia, director of health policy and strategic relations for the ASBMT.

“[ASBMT] and a number of stakeholders have been very clear in our comment letters that that would not be enough and the reasons why,” Ms. Farnia said in an interview. “It’s not going to be sufficient to cover the cost of care or the product.”

The rule also fails to address the cancer centers that are exempt from the DRG payment system, Ms. Farnia said. Eleven centers are excluded from the payment system because of past legislation that excludes exclusive cancer hospitals that do not provide noncancer services. The exempt cancer centers cannot receive additional money for new or expensive drugs and therefore will not gain any financial relief from the CAR T-cell therapy payment changes in the CMS final rule.

ASH officials plan to follow up with congressional leaders to identify ways to improve future CAR T-cell therapy payments, including a potential legislative solution. An ASH spokesperson declined to elaborate on its ideal legislative remedy.

Hospital administrators and physicians will need to have difficult conversations in the upcoming year about whether treating patients with CAR T-cell therapies is worth the cost deficits, Ms. Farnia said.

“Everyone was really counting on it being a different reimbursement scenario for the upcoming fiscal year, and it is, but again, it’s that bare minimum difference,” Ms. Farnia said. “I think a number of programs are going to be taking a look at their financial experience thus far and comparing that to the reimbursement and deciding on if they [should] continue to offer it and how to do that.”

In April 2018, 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.

However, physicians have raised concerns that even if the drugs are first administered in the outpatient setting, inpatient care is likely to occur with CAR T-cell therapies because some patients will need to be admitted in order to be monitored for serious side effects. In such cases, all payments will become part of the inpatient stay under CMS’s 3-day payment window rule.

Medical associations are expressing disappointment at the new payment scheme put forward by the Centers for Medicare & Medicaid Services for inpatient administration of two chimeric antigen receptor (CAR) T-cell therapies, calling the reimbursement insufficient for use of the expensive medications.

Courtesy Novartis

Under its Aug. 17 final rule, CMS will now categorize 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 assign 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 begins in October 2018.

CMS also approved a temporary New Technology Add-On Payment (NTAP) for use of the therapies with a maximum threshold of $186,500, according to the rule.

According to the American Society of Hematology (ASH), this payment structure is an improvement, but it hardly covers the cost of the products, nor does it account for full hospitalization costs. ASH noted that the revised MS-DRG 016 has a base payment rate of $36,000 and that the maximum NTAP payment ($186,500) is only about half of the cost for a CAR T-cell product.

“ASH is concerned that this final policy may impede access to care to this cutting-edge therapy because hospitals and academic medical centers that provide this personalized treatment will simply not be able to withstand the negative financial impact,” the society said in a statement. “While this final policy represents an improvement over current CAR T therapy reimbursement rates, ASH believes patient access to care will be jeopardized as providers and hospitals will not be able to afford to deliver the therapy at this reimbursement rate, particularly as other CAR T products receive FDA [Food and Drug Administration] approval.”

ASH and the American Society for Blood and Marrow Transplantation (ASBMT) had strongly urged CMS to develop a site-neutral, equitable payment structure that would have allowed providers to recover more product acquisition costs from CAR T-cell therapies. In its final rule, CMS stated that it was too early to develop a novel payment structure for CAR T-cell treatments and that more research is needed before such changes are made. The agency noted that in May CMS opened a national coverage determination analysis on CAR T-cell therapy for Medicare patients with advanced cancer, which is expected to be completed by May 2019.

“[CMS] is soliciting public comment … on key design considerations for developing a potential model that would test private market strategies and introduce competition to improve quality of care for beneficiaries,” the agency said in the rule. “Given the relative newness of CAR T-cell therapy, the potential model, and our request for feedback on this model approach, we believe it would be premature to adopt changes to our existing payment mechanisms.”

The payment outline by CMS is essentially the bare minimum it could have extended to CAR T-cell therapies for 2019, said Stephanie Farnia, director of health policy and strategic relations for the ASBMT.

“[ASBMT] and a number of stakeholders have been very clear in our comment letters that that would not be enough and the reasons why,” Ms. Farnia said in an interview. “It’s not going to be sufficient to cover the cost of care or the product.”

The rule also fails to address the cancer centers that are exempt from the DRG payment system, Ms. Farnia said. Eleven centers are excluded from the payment system because of past legislation that excludes exclusive cancer hospitals that do not provide noncancer services. The exempt cancer centers cannot receive additional money for new or expensive drugs and therefore will not gain any financial relief from the CAR T-cell therapy payment changes in the CMS final rule.

ASH officials plan to follow up with congressional leaders to identify ways to improve future CAR T-cell therapy payments, including a potential legislative solution. An ASH spokesperson declined to elaborate on its ideal legislative remedy.

Hospital administrators and physicians will need to have difficult conversations in the upcoming year about whether treating patients with CAR T-cell therapies is worth the cost deficits, Ms. Farnia said.

“Everyone was really counting on it being a different reimbursement scenario for the upcoming fiscal year, and it is, but again, it’s that bare minimum difference,” Ms. Farnia said. “I think a number of programs are going to be taking a look at their financial experience thus far and comparing that to the reimbursement and deciding on if they [should] continue to offer it and how to do that.”

In April 2018, 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.

However, physicians have raised concerns that even if the drugs are first administered in the outpatient setting, inpatient care is likely to occur with CAR T-cell therapies because some patients will need to be admitted in order to be monitored for serious side effects. In such cases, all payments will become part of the inpatient stay under CMS’s 3-day payment window rule.

Medical associations are expressing disappointment at the new payment scheme put forward by the Centers for Medicare & Medicaid Services for inpatient administration of two chimeric antigen receptor (CAR) T-cell therapies, calling the reimbursement insufficient for use of the expensive medications.

Courtesy Novartis

Under its Aug. 17 final rule, CMS will now categorize 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 assign 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 begins in October 2018.

CMS also approved a temporary New Technology Add-On Payment (NTAP) for use of the therapies with a maximum threshold of $186,500, according to the rule.

According to the American Society of Hematology (ASH), this payment structure is an improvement, but it hardly covers the cost of the products, nor does it account for full hospitalization costs. ASH noted that the revised MS-DRG 016 has a base payment rate of $36,000 and that the maximum NTAP payment ($186,500) is only about half of the cost for a CAR T-cell product.

“ASH is concerned that this final policy may impede access to care to this cutting-edge therapy because hospitals and academic medical centers that provide this personalized treatment will simply not be able to withstand the negative financial impact,” the society said in a statement. “While this final policy represents an improvement over current CAR T therapy reimbursement rates, ASH believes patient access to care will be jeopardized as providers and hospitals will not be able to afford to deliver the therapy at this reimbursement rate, particularly as other CAR T products receive FDA [Food and Drug Administration] approval.”

ASH and the American Society for Blood and Marrow Transplantation (ASBMT) had strongly urged CMS to develop a site-neutral, equitable payment structure that would have allowed providers to recover more product acquisition costs from CAR T-cell therapies. In its final rule, CMS stated that it was too early to develop a novel payment structure for CAR T-cell treatments and that more research is needed before such changes are made. The agency noted that in May CMS opened a national coverage determination analysis on CAR T-cell therapy for Medicare patients with advanced cancer, which is expected to be completed by May 2019.

“[CMS] is soliciting public comment … on key design considerations for developing a potential model that would test private market strategies and introduce competition to improve quality of care for beneficiaries,” the agency said in the rule. “Given the relative newness of CAR T-cell therapy, the potential model, and our request for feedback on this model approach, we believe it would be premature to adopt changes to our existing payment mechanisms.”

The payment outline by CMS is essentially the bare minimum it could have extended to CAR T-cell therapies for 2019, said Stephanie Farnia, director of health policy and strategic relations for the ASBMT.

“[ASBMT] and a number of stakeholders have been very clear in our comment letters that that would not be enough and the reasons why,” Ms. Farnia said in an interview. “It’s not going to be sufficient to cover the cost of care or the product.”

The rule also fails to address the cancer centers that are exempt from the DRG payment system, Ms. Farnia said. Eleven centers are excluded from the payment system because of past legislation that excludes exclusive cancer hospitals that do not provide noncancer services. The exempt cancer centers cannot receive additional money for new or expensive drugs and therefore will not gain any financial relief from the CAR T-cell therapy payment changes in the CMS final rule.

ASH officials plan to follow up with congressional leaders to identify ways to improve future CAR T-cell therapy payments, including a potential legislative solution. An ASH spokesperson declined to elaborate on its ideal legislative remedy.

Hospital administrators and physicians will need to have difficult conversations in the upcoming year about whether treating patients with CAR T-cell therapies is worth the cost deficits, Ms. Farnia said.

“Everyone was really counting on it being a different reimbursement scenario for the upcoming fiscal year, and it is, but again, it’s that bare minimum difference,” Ms. Farnia said. “I think a number of programs are going to be taking a look at their financial experience thus far and comparing that to the reimbursement and deciding on if they [should] continue to offer it and how to do that.”

In April 2018, 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.

However, physicians have raised concerns that even if the drugs are first administered in the outpatient setting, inpatient care is likely to occur with CAR T-cell therapies because some patients will need to be admitted in order to be monitored for serious side effects. In such cases, all payments will become part of the inpatient stay under CMS’s 3-day payment window rule.