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Gene variants linked to survival after HSCT
New research has revealed a link between rare gene variants and survival after hematopoietic stem cell transplant (HSCT).
Researchers performed exome sequencing in nearly 2500 HSCT recipients and their matched, unrelated donors.
The sequencing revealed several gene variants—in both donors and recipients—that were significantly associated with overall survival (OS), transplant-related mortality (TRM), and disease-related mortality (DRM) after HSCT.
Qianqian Zhu, PhD, of Roswell Park Comprehensive Cancer Center in Buffalo, New York, and her colleagues described these findings in Blood.
The team performed exome sequencing—using the Illumina HumanExome BeadChip—in patients who participated in the DISCOVeRY-BMT study.
This included 2473 HSCT recipients who had acute myeloid leukemia, acute lymphoblastic leukemia, or myelodysplastic syndromes. It also included 2221 donors who were a 10/10 human leukocyte antigen match for each recipient.
The researchers looked at genetic variants in donors and recipients and assessed the variants’ associations with OS, TRM, and DRM.
Variants in recipients
Analyses revealed an increased risk of TRM when there was a mismatch between donors and recipients for a variant in TEX38—rs200092801. The increased risk was even more pronounced when either the recipient or the donor was female.
Among the recipients mismatched with their donors at rs200092801, every female recipient and every recipient with a female donor died from TRM. In comparison, 44% of the male recipients with male donors died from TRM.
The researchers said the rs200092801 variant may prompt the production of a mutant peptide that can be presented by MHC-I molecules to immune cells to trigger downstream immune response and TRM.
Dr Zhu and her colleagues also identified variants that appeared to have a positive impact on TRM and OS.
Recipients who had any of 6 variants in the gene OR51D1 had a decreased risk of TRM and improved OS.
The variants (rs138224979, rs148606808, rs141786655, rs61745314, rs200394876, and rs149135276) were not associated with DRM, so the researchers concluded that the improvement in OS was driven by protection against TRM.
Donor variants linked to OS
Donors had variants in 4 genes—ALPP, EMID1, SLC44A5, and LRP1—that were associated with OS but not TRM or DRM.
The 3 variants identified in ALPP (rs144454460, rs140078460, and rs142493383) were associated with improved OS.
And the 2 variants in SLC44A5 (rs143004355 and rs149696907) were associated with worse OS.
There were 2 variants in EMID1. One was associated with improved OS (rs34772704), and the other was associated with decreased OS (rs139996840).
And there were 27 variants in LRP1. Some had a positive association with OS, and others had a negative association.
Donor variants linked to TRM and DRM
Six variants in the HHAT gene were associated with TRM. Five of the variants appeared to have a protective effect against TRM (rs145455128, rs146916002, rs61744143, rs149597734, and rs145943928). For the other variant (rs141591165), the apparent effect was inconsistent between patient cohorts.
There were 3 variants in LYZL4 associated with DRM. Two were associated with an increased risk of DRM (rs147770623 and rs76947105), and 1 appeared to have a protective effect (rs181886204).
Six variants in NT5E appeared to have a protective effect against DRM (rs200250022, rs200369370, rs41271617, rs200648774, rs144719925, and rs145505137).
The researchers said the variants in NT5E probably reduce the enzyme activity of the gene. This supports preclinical findings showing that targeted blockade of NT5E can slow tumor growth.
“We have just started to uncover the biological relevance of these new and unexpected genes to a patient’s survival after [HSCT],” Dr Zhu said.
“Our findings shed light on new areas that were not considered before, but we need to further replicate and test our findings. We’re hoping that additional studies of this type will continue to discover novel genes leading to improved outcomes for patients.”
New research has revealed a link between rare gene variants and survival after hematopoietic stem cell transplant (HSCT).
Researchers performed exome sequencing in nearly 2500 HSCT recipients and their matched, unrelated donors.
The sequencing revealed several gene variants—in both donors and recipients—that were significantly associated with overall survival (OS), transplant-related mortality (TRM), and disease-related mortality (DRM) after HSCT.
Qianqian Zhu, PhD, of Roswell Park Comprehensive Cancer Center in Buffalo, New York, and her colleagues described these findings in Blood.
The team performed exome sequencing—using the Illumina HumanExome BeadChip—in patients who participated in the DISCOVeRY-BMT study.
This included 2473 HSCT recipients who had acute myeloid leukemia, acute lymphoblastic leukemia, or myelodysplastic syndromes. It also included 2221 donors who were a 10/10 human leukocyte antigen match for each recipient.
The researchers looked at genetic variants in donors and recipients and assessed the variants’ associations with OS, TRM, and DRM.
Variants in recipients
Analyses revealed an increased risk of TRM when there was a mismatch between donors and recipients for a variant in TEX38—rs200092801. The increased risk was even more pronounced when either the recipient or the donor was female.
Among the recipients mismatched with their donors at rs200092801, every female recipient and every recipient with a female donor died from TRM. In comparison, 44% of the male recipients with male donors died from TRM.
The researchers said the rs200092801 variant may prompt the production of a mutant peptide that can be presented by MHC-I molecules to immune cells to trigger downstream immune response and TRM.
Dr Zhu and her colleagues also identified variants that appeared to have a positive impact on TRM and OS.
Recipients who had any of 6 variants in the gene OR51D1 had a decreased risk of TRM and improved OS.
The variants (rs138224979, rs148606808, rs141786655, rs61745314, rs200394876, and rs149135276) were not associated with DRM, so the researchers concluded that the improvement in OS was driven by protection against TRM.
Donor variants linked to OS
Donors had variants in 4 genes—ALPP, EMID1, SLC44A5, and LRP1—that were associated with OS but not TRM or DRM.
The 3 variants identified in ALPP (rs144454460, rs140078460, and rs142493383) were associated with improved OS.
And the 2 variants in SLC44A5 (rs143004355 and rs149696907) were associated with worse OS.
There were 2 variants in EMID1. One was associated with improved OS (rs34772704), and the other was associated with decreased OS (rs139996840).
And there were 27 variants in LRP1. Some had a positive association with OS, and others had a negative association.
Donor variants linked to TRM and DRM
Six variants in the HHAT gene were associated with TRM. Five of the variants appeared to have a protective effect against TRM (rs145455128, rs146916002, rs61744143, rs149597734, and rs145943928). For the other variant (rs141591165), the apparent effect was inconsistent between patient cohorts.
There were 3 variants in LYZL4 associated with DRM. Two were associated with an increased risk of DRM (rs147770623 and rs76947105), and 1 appeared to have a protective effect (rs181886204).
Six variants in NT5E appeared to have a protective effect against DRM (rs200250022, rs200369370, rs41271617, rs200648774, rs144719925, and rs145505137).
The researchers said the variants in NT5E probably reduce the enzyme activity of the gene. This supports preclinical findings showing that targeted blockade of NT5E can slow tumor growth.
“We have just started to uncover the biological relevance of these new and unexpected genes to a patient’s survival after [HSCT],” Dr Zhu said.
“Our findings shed light on new areas that were not considered before, but we need to further replicate and test our findings. We’re hoping that additional studies of this type will continue to discover novel genes leading to improved outcomes for patients.”
New research has revealed a link between rare gene variants and survival after hematopoietic stem cell transplant (HSCT).
Researchers performed exome sequencing in nearly 2500 HSCT recipients and their matched, unrelated donors.
The sequencing revealed several gene variants—in both donors and recipients—that were significantly associated with overall survival (OS), transplant-related mortality (TRM), and disease-related mortality (DRM) after HSCT.
Qianqian Zhu, PhD, of Roswell Park Comprehensive Cancer Center in Buffalo, New York, and her colleagues described these findings in Blood.
The team performed exome sequencing—using the Illumina HumanExome BeadChip—in patients who participated in the DISCOVeRY-BMT study.
This included 2473 HSCT recipients who had acute myeloid leukemia, acute lymphoblastic leukemia, or myelodysplastic syndromes. It also included 2221 donors who were a 10/10 human leukocyte antigen match for each recipient.
The researchers looked at genetic variants in donors and recipients and assessed the variants’ associations with OS, TRM, and DRM.
Variants in recipients
Analyses revealed an increased risk of TRM when there was a mismatch between donors and recipients for a variant in TEX38—rs200092801. The increased risk was even more pronounced when either the recipient or the donor was female.
Among the recipients mismatched with their donors at rs200092801, every female recipient and every recipient with a female donor died from TRM. In comparison, 44% of the male recipients with male donors died from TRM.
The researchers said the rs200092801 variant may prompt the production of a mutant peptide that can be presented by MHC-I molecules to immune cells to trigger downstream immune response and TRM.
Dr Zhu and her colleagues also identified variants that appeared to have a positive impact on TRM and OS.
Recipients who had any of 6 variants in the gene OR51D1 had a decreased risk of TRM and improved OS.
The variants (rs138224979, rs148606808, rs141786655, rs61745314, rs200394876, and rs149135276) were not associated with DRM, so the researchers concluded that the improvement in OS was driven by protection against TRM.
Donor variants linked to OS
Donors had variants in 4 genes—ALPP, EMID1, SLC44A5, and LRP1—that were associated with OS but not TRM or DRM.
The 3 variants identified in ALPP (rs144454460, rs140078460, and rs142493383) were associated with improved OS.
And the 2 variants in SLC44A5 (rs143004355 and rs149696907) were associated with worse OS.
There were 2 variants in EMID1. One was associated with improved OS (rs34772704), and the other was associated with decreased OS (rs139996840).
And there were 27 variants in LRP1. Some had a positive association with OS, and others had a negative association.
Donor variants linked to TRM and DRM
Six variants in the HHAT gene were associated with TRM. Five of the variants appeared to have a protective effect against TRM (rs145455128, rs146916002, rs61744143, rs149597734, and rs145943928). For the other variant (rs141591165), the apparent effect was inconsistent between patient cohorts.
There were 3 variants in LYZL4 associated with DRM. Two were associated with an increased risk of DRM (rs147770623 and rs76947105), and 1 appeared to have a protective effect (rs181886204).
Six variants in NT5E appeared to have a protective effect against DRM (rs200250022, rs200369370, rs41271617, rs200648774, rs144719925, and rs145505137).
The researchers said the variants in NT5E probably reduce the enzyme activity of the gene. This supports preclinical findings showing that targeted blockade of NT5E can slow tumor growth.
“We have just started to uncover the biological relevance of these new and unexpected genes to a patient’s survival after [HSCT],” Dr Zhu said.
“Our findings shed light on new areas that were not considered before, but we need to further replicate and test our findings. We’re hoping that additional studies of this type will continue to discover novel genes leading to improved outcomes for patients.”
Health Canada approves product for adult ALL
Health Canada has approved inotuzumab ozogamicin (Besponsa™) as monotherapy for adults with relapsed or refractory, CD22-positive, B-cell precursor acute lymphoblastic leukemia (ALL).
Inotuzumab ozogamicin is the first and only CD22-directed antibody-drug conjugate approved for this indication.
The product consists of a monoclonal antibody targeting CD22 and a cytotoxic agent known as calicheamicin.
Health Canada’s approval of inotuzumab ozogamicin is based on results from the phase 3 INO-VATE trial, which were published in NEJM in June 2016.
The trial enrolled 326 adults with relapsed or refractory B-cell precursor ALL.
Patients received inotuzumab ozogamicin or 1 of 3 chemotherapy regimens—high-dose cytarabine; cytarabine plus mitoxantrone; or fludarabine, cytarabine, and granulocyte colony-stimulating factor.
The rate of complete remission, including incomplete hematologic recovery, was 80.7% in the inotuzumab arm and 29.4% in the chemotherapy arm (P<0.001). The median duration of remission was 4.6 months and 3.1 months, respectively (P=0.03).
Forty-one percent of patients treated with inotuzumab and 11% of those who received chemotherapy proceeded to stem cell transplant directly after treatment (P<0.001).
The median progression-free survival was 5.0 months in the inotuzumab arm and 1.8 months in the chemotherapy arm (P<0.001).
The median overall survival was 7.7 months and 6.7 months, respectively (P=0.04). This did not meet the prespecified boundary of significance (P=0.0208).
Liver-related adverse events were more common in the inotuzumab arm than the chemotherapy arm. The most frequent of these were increased aspartate aminotransferase level (20% vs 10%), hyperbilirubinemia (15% vs 10%), and increased alanine aminotransferase level (14% vs 11%).
Veno-occlusive liver disease occurred in 11% of patients in the inotuzumab arm and 1% in the chemotherapy arm.
There were 17 deaths during treatment in the inotuzumab arm and 11 in the chemotherapy arm. Four deaths were considered related to inotuzumab, and 2 were deemed related to chemotherapy.
Health Canada has approved inotuzumab ozogamicin (Besponsa™) as monotherapy for adults with relapsed or refractory, CD22-positive, B-cell precursor acute lymphoblastic leukemia (ALL).
Inotuzumab ozogamicin is the first and only CD22-directed antibody-drug conjugate approved for this indication.
The product consists of a monoclonal antibody targeting CD22 and a cytotoxic agent known as calicheamicin.
Health Canada’s approval of inotuzumab ozogamicin is based on results from the phase 3 INO-VATE trial, which were published in NEJM in June 2016.
The trial enrolled 326 adults with relapsed or refractory B-cell precursor ALL.
Patients received inotuzumab ozogamicin or 1 of 3 chemotherapy regimens—high-dose cytarabine; cytarabine plus mitoxantrone; or fludarabine, cytarabine, and granulocyte colony-stimulating factor.
The rate of complete remission, including incomplete hematologic recovery, was 80.7% in the inotuzumab arm and 29.4% in the chemotherapy arm (P<0.001). The median duration of remission was 4.6 months and 3.1 months, respectively (P=0.03).
Forty-one percent of patients treated with inotuzumab and 11% of those who received chemotherapy proceeded to stem cell transplant directly after treatment (P<0.001).
The median progression-free survival was 5.0 months in the inotuzumab arm and 1.8 months in the chemotherapy arm (P<0.001).
The median overall survival was 7.7 months and 6.7 months, respectively (P=0.04). This did not meet the prespecified boundary of significance (P=0.0208).
Liver-related adverse events were more common in the inotuzumab arm than the chemotherapy arm. The most frequent of these were increased aspartate aminotransferase level (20% vs 10%), hyperbilirubinemia (15% vs 10%), and increased alanine aminotransferase level (14% vs 11%).
Veno-occlusive liver disease occurred in 11% of patients in the inotuzumab arm and 1% in the chemotherapy arm.
There were 17 deaths during treatment in the inotuzumab arm and 11 in the chemotherapy arm. Four deaths were considered related to inotuzumab, and 2 were deemed related to chemotherapy.
Health Canada has approved inotuzumab ozogamicin (Besponsa™) as monotherapy for adults with relapsed or refractory, CD22-positive, B-cell precursor acute lymphoblastic leukemia (ALL).
Inotuzumab ozogamicin is the first and only CD22-directed antibody-drug conjugate approved for this indication.
The product consists of a monoclonal antibody targeting CD22 and a cytotoxic agent known as calicheamicin.
Health Canada’s approval of inotuzumab ozogamicin is based on results from the phase 3 INO-VATE trial, which were published in NEJM in June 2016.
The trial enrolled 326 adults with relapsed or refractory B-cell precursor ALL.
Patients received inotuzumab ozogamicin or 1 of 3 chemotherapy regimens—high-dose cytarabine; cytarabine plus mitoxantrone; or fludarabine, cytarabine, and granulocyte colony-stimulating factor.
The rate of complete remission, including incomplete hematologic recovery, was 80.7% in the inotuzumab arm and 29.4% in the chemotherapy arm (P<0.001). The median duration of remission was 4.6 months and 3.1 months, respectively (P=0.03).
Forty-one percent of patients treated with inotuzumab and 11% of those who received chemotherapy proceeded to stem cell transplant directly after treatment (P<0.001).
The median progression-free survival was 5.0 months in the inotuzumab arm and 1.8 months in the chemotherapy arm (P<0.001).
The median overall survival was 7.7 months and 6.7 months, respectively (P=0.04). This did not meet the prespecified boundary of significance (P=0.0208).
Liver-related adverse events were more common in the inotuzumab arm than the chemotherapy arm. The most frequent of these were increased aspartate aminotransferase level (20% vs 10%), hyperbilirubinemia (15% vs 10%), and increased alanine aminotransferase level (14% vs 11%).
Veno-occlusive liver disease occurred in 11% of patients in the inotuzumab arm and 1% in the chemotherapy arm.
There were 17 deaths during treatment in the inotuzumab arm and 11 in the chemotherapy arm. Four deaths were considered related to inotuzumab, and 2 were deemed related to chemotherapy.
Team maps genetic evolution of T-ALL subtype
Single-cell analysis has revealed key genetic events in a type of T-cell acute lymphoblastic leukemia (T-ALL), according to researchers.
The team tracked the branching pattern of evolution in STIL-TAL1-positive T-ALL and identified mutations that may trigger development of the disease.
The researchers believe their findings could be used in minimal residual disease assessments as well as for the development of new targeted drugs.
Caroline Furness, MD, of Institute of Cancer Research in London, UK, and her colleagues described this research in Leukemia.
To determine the sequence of mutational events in STIL-TAL1-positive T-ALL, the researchers examined individual leukemia cells from 19 children and young adults with the disease, as well as 1 cell line with the STIL-TAL1 rearrangement (RPMI 8402).
The team found the STIL-TAL1 gene fusion and inactivation of the CDKN2A gene occurred very early in leukemia development.
The researchers said it was difficult to tell whether STIL-TAL1 fusion or CDKN2A loss are initiating events in this disease, and it isn’t clear which mutational event occurs first.
However, the team believes the STIL-TAL1 fusion is likely a founder or truncal event for this type of leukemia, so targeting the TAL1 regulatory complex could be an effective way to treat the disease.
The researchers also identified mutations in NOTCH1 and PTEN as secondary subclonal events.
Half of the samples examined had errors affecting PTEN, which suggests these events are key to maintaining leukemia growth and survival in STIL-TAL1-positive T-ALL, according to the researchers.
“We need to understand how cancers evolve and unpick which mutations are key to triggering cancer development and which are important for driving its growth and spread,” Dr Furness said.
“Our study uncovered these crucial mutations in a type of leukemia that accounts for around a quarter of cases of T-cell leukemia in children and young adults. This will help us to develop more effective treatments, especially in those children who relapse, and kinder treatments that won’t cause life-long side effects.”
Single-cell analysis has revealed key genetic events in a type of T-cell acute lymphoblastic leukemia (T-ALL), according to researchers.
The team tracked the branching pattern of evolution in STIL-TAL1-positive T-ALL and identified mutations that may trigger development of the disease.
The researchers believe their findings could be used in minimal residual disease assessments as well as for the development of new targeted drugs.
Caroline Furness, MD, of Institute of Cancer Research in London, UK, and her colleagues described this research in Leukemia.
To determine the sequence of mutational events in STIL-TAL1-positive T-ALL, the researchers examined individual leukemia cells from 19 children and young adults with the disease, as well as 1 cell line with the STIL-TAL1 rearrangement (RPMI 8402).
The team found the STIL-TAL1 gene fusion and inactivation of the CDKN2A gene occurred very early in leukemia development.
The researchers said it was difficult to tell whether STIL-TAL1 fusion or CDKN2A loss are initiating events in this disease, and it isn’t clear which mutational event occurs first.
However, the team believes the STIL-TAL1 fusion is likely a founder or truncal event for this type of leukemia, so targeting the TAL1 regulatory complex could be an effective way to treat the disease.
The researchers also identified mutations in NOTCH1 and PTEN as secondary subclonal events.
Half of the samples examined had errors affecting PTEN, which suggests these events are key to maintaining leukemia growth and survival in STIL-TAL1-positive T-ALL, according to the researchers.
“We need to understand how cancers evolve and unpick which mutations are key to triggering cancer development and which are important for driving its growth and spread,” Dr Furness said.
“Our study uncovered these crucial mutations in a type of leukemia that accounts for around a quarter of cases of T-cell leukemia in children and young adults. This will help us to develop more effective treatments, especially in those children who relapse, and kinder treatments that won’t cause life-long side effects.”
Single-cell analysis has revealed key genetic events in a type of T-cell acute lymphoblastic leukemia (T-ALL), according to researchers.
The team tracked the branching pattern of evolution in STIL-TAL1-positive T-ALL and identified mutations that may trigger development of the disease.
The researchers believe their findings could be used in minimal residual disease assessments as well as for the development of new targeted drugs.
Caroline Furness, MD, of Institute of Cancer Research in London, UK, and her colleagues described this research in Leukemia.
To determine the sequence of mutational events in STIL-TAL1-positive T-ALL, the researchers examined individual leukemia cells from 19 children and young adults with the disease, as well as 1 cell line with the STIL-TAL1 rearrangement (RPMI 8402).
The team found the STIL-TAL1 gene fusion and inactivation of the CDKN2A gene occurred very early in leukemia development.
The researchers said it was difficult to tell whether STIL-TAL1 fusion or CDKN2A loss are initiating events in this disease, and it isn’t clear which mutational event occurs first.
However, the team believes the STIL-TAL1 fusion is likely a founder or truncal event for this type of leukemia, so targeting the TAL1 regulatory complex could be an effective way to treat the disease.
The researchers also identified mutations in NOTCH1 and PTEN as secondary subclonal events.
Half of the samples examined had errors affecting PTEN, which suggests these events are key to maintaining leukemia growth and survival in STIL-TAL1-positive T-ALL, according to the researchers.
“We need to understand how cancers evolve and unpick which mutations are key to triggering cancer development and which are important for driving its growth and spread,” Dr Furness said.
“Our study uncovered these crucial mutations in a type of leukemia that accounts for around a quarter of cases of T-cell leukemia in children and young adults. This will help us to develop more effective treatments, especially in those children who relapse, and kinder treatments that won’t cause life-long side effects.”
Ponatinib bests older TKIs against Ph+ALL
Every generation aspires to be better than its predecessors, and for the third-generation tyrosine kinase inhibitor ponatinib (Iclusig), that might just be true, investigators claim.
A retrospective analysis comparing clinical trial outcomes for patients with newly diagnosed acute lymphoblastic leukemia positive for the Philadelphia chromosome (Ph+ALL) suggests that first-line ponatinib offers modestly better complete molecular response (CMR) rates and 3-year overall survival (OS) than either first-generation TKIs such as imatinib (Gleevec) or second-generation agents such as dasatinib (Sprycel) and nilotinib (Tasigna).
“Although only 1 relevant study of ponatinib combined with chemotherapy in Ph+ALL has been reported and our ability to adjust for baseline patient characteristics was limited, the results suggest that ponatinib combined with chemotherapy might represent a more effective front-line treatment option than chemotherapy combined with an earlier generation TKI for patients with newly diagnosed Ph+ALL, including those who cannot or choose not to undergo [stem cell transplant],” wrote Elias Jabbour, MD, of the University of Texas MD Anderson Cancer Center in Houston, and his colleagues.
They based their conclusions on a meta-regression analysis of 25 studies looking at first- or second-generation TKIs and one study of ponatinib as frontline therapy for patients with Ph+ALL. They described their results in Clinical Lymphoma, Myeloma & Leukemia.
The investigators created pooled estimates of outcomes from studies of earlier-generation TKIs plus combination chemotherapy using a random-effects meta-analysis method. For the sole ponatinib study – a single-arm trial of combination chemotherapy plus ponatinib – they used a binomial distribution method to calculate 95% confidence intervals (CI). The method essentially estimates the probability of success or failure of a repeated experiment.
They found that 79% of patients in the ponatinib trial achieved a CMR, compared with 34% of patients treated with earlier generation TKIs plus chemotherapy. This translates into an odds ratio (OR) for CMR with ponatinib of 6.09 (P = .034).
Two-year OS rates were 83% with ponatinib versus 58% for all patients treated with other TKIs. Although the OR (3.70) seemed to run in favor of ponatinib, the difference was not statistically significant (P = .062).
For 3-year OS, however, ponatinib was superior to the pooled data for the other TKIs, at 79% versus 50%, translating into an OR of 4.49 (P = .050).
The authors acknowledged that the study was limited by differences in treatment regimens and centers, and a limited ability to adjust for patient characteristics, due to the study’s reliance on only those covariates published across different studies. Head-to-head comparison trials are needed to confirm their results, they noted.
Nonetheless, “[w]e believe that the improved efficacy of ponatinib combined with chemotherapy for newly diagnosed Ph+ALL might prevent the need for allogeneic SCT,” they wrote.
Ariad Pharmaceuticals funded the study. Dr. Jabbour and three coauthors reported research funding from the company; other study authors reported employment or other financial relationships with Ariad or its parent company Takeda.
SOURCE: Jabbour E et al. Clin Lymphoma Myeloma Leuk. 2018 18(4):257-65.
Every generation aspires to be better than its predecessors, and for the third-generation tyrosine kinase inhibitor ponatinib (Iclusig), that might just be true, investigators claim.
A retrospective analysis comparing clinical trial outcomes for patients with newly diagnosed acute lymphoblastic leukemia positive for the Philadelphia chromosome (Ph+ALL) suggests that first-line ponatinib offers modestly better complete molecular response (CMR) rates and 3-year overall survival (OS) than either first-generation TKIs such as imatinib (Gleevec) or second-generation agents such as dasatinib (Sprycel) and nilotinib (Tasigna).
“Although only 1 relevant study of ponatinib combined with chemotherapy in Ph+ALL has been reported and our ability to adjust for baseline patient characteristics was limited, the results suggest that ponatinib combined with chemotherapy might represent a more effective front-line treatment option than chemotherapy combined with an earlier generation TKI for patients with newly diagnosed Ph+ALL, including those who cannot or choose not to undergo [stem cell transplant],” wrote Elias Jabbour, MD, of the University of Texas MD Anderson Cancer Center in Houston, and his colleagues.
They based their conclusions on a meta-regression analysis of 25 studies looking at first- or second-generation TKIs and one study of ponatinib as frontline therapy for patients with Ph+ALL. They described their results in Clinical Lymphoma, Myeloma & Leukemia.
The investigators created pooled estimates of outcomes from studies of earlier-generation TKIs plus combination chemotherapy using a random-effects meta-analysis method. For the sole ponatinib study – a single-arm trial of combination chemotherapy plus ponatinib – they used a binomial distribution method to calculate 95% confidence intervals (CI). The method essentially estimates the probability of success or failure of a repeated experiment.
They found that 79% of patients in the ponatinib trial achieved a CMR, compared with 34% of patients treated with earlier generation TKIs plus chemotherapy. This translates into an odds ratio (OR) for CMR with ponatinib of 6.09 (P = .034).
Two-year OS rates were 83% with ponatinib versus 58% for all patients treated with other TKIs. Although the OR (3.70) seemed to run in favor of ponatinib, the difference was not statistically significant (P = .062).
For 3-year OS, however, ponatinib was superior to the pooled data for the other TKIs, at 79% versus 50%, translating into an OR of 4.49 (P = .050).
The authors acknowledged that the study was limited by differences in treatment regimens and centers, and a limited ability to adjust for patient characteristics, due to the study’s reliance on only those covariates published across different studies. Head-to-head comparison trials are needed to confirm their results, they noted.
Nonetheless, “[w]e believe that the improved efficacy of ponatinib combined with chemotherapy for newly diagnosed Ph+ALL might prevent the need for allogeneic SCT,” they wrote.
Ariad Pharmaceuticals funded the study. Dr. Jabbour and three coauthors reported research funding from the company; other study authors reported employment or other financial relationships with Ariad or its parent company Takeda.
SOURCE: Jabbour E et al. Clin Lymphoma Myeloma Leuk. 2018 18(4):257-65.
Every generation aspires to be better than its predecessors, and for the third-generation tyrosine kinase inhibitor ponatinib (Iclusig), that might just be true, investigators claim.
A retrospective analysis comparing clinical trial outcomes for patients with newly diagnosed acute lymphoblastic leukemia positive for the Philadelphia chromosome (Ph+ALL) suggests that first-line ponatinib offers modestly better complete molecular response (CMR) rates and 3-year overall survival (OS) than either first-generation TKIs such as imatinib (Gleevec) or second-generation agents such as dasatinib (Sprycel) and nilotinib (Tasigna).
“Although only 1 relevant study of ponatinib combined with chemotherapy in Ph+ALL has been reported and our ability to adjust for baseline patient characteristics was limited, the results suggest that ponatinib combined with chemotherapy might represent a more effective front-line treatment option than chemotherapy combined with an earlier generation TKI for patients with newly diagnosed Ph+ALL, including those who cannot or choose not to undergo [stem cell transplant],” wrote Elias Jabbour, MD, of the University of Texas MD Anderson Cancer Center in Houston, and his colleagues.
They based their conclusions on a meta-regression analysis of 25 studies looking at first- or second-generation TKIs and one study of ponatinib as frontline therapy for patients with Ph+ALL. They described their results in Clinical Lymphoma, Myeloma & Leukemia.
The investigators created pooled estimates of outcomes from studies of earlier-generation TKIs plus combination chemotherapy using a random-effects meta-analysis method. For the sole ponatinib study – a single-arm trial of combination chemotherapy plus ponatinib – they used a binomial distribution method to calculate 95% confidence intervals (CI). The method essentially estimates the probability of success or failure of a repeated experiment.
They found that 79% of patients in the ponatinib trial achieved a CMR, compared with 34% of patients treated with earlier generation TKIs plus chemotherapy. This translates into an odds ratio (OR) for CMR with ponatinib of 6.09 (P = .034).
Two-year OS rates were 83% with ponatinib versus 58% for all patients treated with other TKIs. Although the OR (3.70) seemed to run in favor of ponatinib, the difference was not statistically significant (P = .062).
For 3-year OS, however, ponatinib was superior to the pooled data for the other TKIs, at 79% versus 50%, translating into an OR of 4.49 (P = .050).
The authors acknowledged that the study was limited by differences in treatment regimens and centers, and a limited ability to adjust for patient characteristics, due to the study’s reliance on only those covariates published across different studies. Head-to-head comparison trials are needed to confirm their results, they noted.
Nonetheless, “[w]e believe that the improved efficacy of ponatinib combined with chemotherapy for newly diagnosed Ph+ALL might prevent the need for allogeneic SCT,” they wrote.
Ariad Pharmaceuticals funded the study. Dr. Jabbour and three coauthors reported research funding from the company; other study authors reported employment or other financial relationships with Ariad or its parent company Takeda.
SOURCE: Jabbour E et al. Clin Lymphoma Myeloma Leuk. 2018 18(4):257-65.
FROM CLINICAL LYMPHOMA, MYELOMA & LEUKEMIA
Key clinical point:
Major finding: Complete molecular response rates and 3-year overall survival were better with ponatinib in combination with chemotherapy.
Study details: Meta-regression analysis of 26 studies of TKIs in combination with chemotherapy as first-line therapy for patients with Ph+ALL.
Disclosures: Ariad Pharmaceuticals funded the study. Dr. Jabbour and three coauthors reported research funding from the company; other study authors reported employment or other financial relationships with Ariad or its parent company, Takeda.
Source: Jabbour E et al. Clin Lymphoma Myeloma Leuk. 2018 18(4):257-65.
FDA approves blinatumomab to treat MRD+ BCP-ALL
The US Food and Drug Administration (FDA) has expanded the approved indication for blinatumomab (Blincyto®).
The drug is now approved to treat adults and children with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) in first or second complete remission (CR) with minimal residual disease (MRD) greater than or equal to 0.1%.
Blinatumomab received accelerated approval for this indication because the drug has not yet shown a clinical benefit in these patients.
The FDA’s accelerated approval program allows conditional approval of a drug that fills an unmet medical need for a serious condition.
Accelerated approval is based on surrogate or intermediate endpoints—in this case, MRD response rate and hematologic relapse-free survival (RFS)—that are reasonably likely to predict clinical benefit.
Continued approval of blinatumomab for the aforementioned indication may be contingent upon verification of clinical benefit in confirmatory trials.
“This is the first FDA-approved treatment for patients with MRD-positive ALL,” said Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence.
“Because patients who have MRD are more likely to relapse, having a treatment option that eliminates even very low amounts of residual leukemia cells may help keep the cancer in remission longer. We look forward to furthering our understanding about the reduction in MRD after treatment with Blincyto. Studies are being conducted to assess how Blincyto affects long-term survival outcomes in patients with MRD.”
About blinatumomab
Blinatumomab is a bispecific, CD19-directed, CD3 T-cell engager (BiTE®) antibody construct that binds to CD19 expressed on the surface of cells of B-lineage origin and CD3 expressed on the surface of T cells.
In 2014, the FDA granted blinatumomab accelerated approval to treat adults with Philadelphia chromosome-negative (Ph-) relapsed/refractory BCP-ALL.
In 2016, the FDA granted the therapy accelerated approval for pediatric patients with Ph- relapsed/refractory BCP-ALL.
Last year, the FDA granted blinatumomab full approval for pediatric and adult patients with Ph- or Ph+ relapsed/refractory BCP-ALL.
The FDA-approved prescribing information for blinatumomab includes a boxed warning for cytokine release syndrome and neurologic toxicities. Blinatumomab is also under a risk evaluation and mitigation strategy program in the US.
BLAST study
The new accelerated approval for blinatumomab was supported by results from the phase 2 BLAST study, which were published in Blood in January.
The study enrolled adults with MRD-positive BCP-ALL in complete hematologic remission after 3 or more cycles of intensive chemotherapy.
Patients received continuous intravenous infusions of blinatumomab at 15 μg/m2/day for 4 weeks, followed by 2 weeks off. They received up to 4 cycles of treatment and could undergo hematopoietic stem cell transplant (HSCT) at any time after the first cycle.
In all, there were 116 patients who received at least 1 infusion of blinatumomab. Seventy-six patients went on to HSCT while in continuous CR after cycle 1 (n=27), 2 (n=36), or 3/4 (n=13).
The study’s primary endpoint was the rate of complete MRD response within the first treatment cycle, and 78% of evaluable patients (88/113) achieved this endpoint.
A key secondary endpoint was RFS at 18 months. There were 110 patients evaluable for this endpoint. They all had Ph- BCP-ALL and <5% blasts at baseline.
The estimated RFS at 18 months was 54%, and the median RFS was 18.9 months. The median RFS was 24.6 months for patients treated in first CR and 11.0 months for patients treated in a later CR (P=0.004).
Another key endpoint was overall survival (OS). The median OS was 36.5 months, both for the 110 patients in the RFS analysis and for the entire study population.
In a landmark analysis, complete MRD responders had longer OS than MRD nonresponders—38.9 months and 12.5 months, respectively (P=0.002). And complete MRD responders had longer RFS than nonresponders—23.6 months and 5.7 months, respectively (P=0.002).
All 116 patients who started cycle 1 had at least 1 adverse event (AE). The rate of grade 3 AEs was 33%, and the rate of grade 4 AEs was 27%. These AEs were considered treatment-related in 29% (grade 3) and 22% (grade 4) of patients.
Four (3%) patients developed cytokine release syndrome—2 with grade 1 and 2 with grade 3. All of these events occurred during cycle 1.
Fifty-three percent of patients (n=61) had neurologic events. In most cases (97%, n=59), these events resolved.
There were 2 fatal AEs during the treatment period, both in cycle 1. One of these events—atypical pneumonitis with H1N1 influenza—was considered treatment-related. The other event—subdural hemorrhage—was considered unrelated to treatment.
There were 4 fatal AEs reported after blinatumomab treatment. Two of these deaths—due to multifocal CNS lesions and graft-versus-host disease—occurred in HSCT recipients. The other 2 deaths—due to disease progression and multi-organ failure—occurred in nontransplanted patients after relapse.
The US Food and Drug Administration (FDA) has expanded the approved indication for blinatumomab (Blincyto®).
The drug is now approved to treat adults and children with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) in first or second complete remission (CR) with minimal residual disease (MRD) greater than or equal to 0.1%.
Blinatumomab received accelerated approval for this indication because the drug has not yet shown a clinical benefit in these patients.
The FDA’s accelerated approval program allows conditional approval of a drug that fills an unmet medical need for a serious condition.
Accelerated approval is based on surrogate or intermediate endpoints—in this case, MRD response rate and hematologic relapse-free survival (RFS)—that are reasonably likely to predict clinical benefit.
Continued approval of blinatumomab for the aforementioned indication may be contingent upon verification of clinical benefit in confirmatory trials.
“This is the first FDA-approved treatment for patients with MRD-positive ALL,” said Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence.
“Because patients who have MRD are more likely to relapse, having a treatment option that eliminates even very low amounts of residual leukemia cells may help keep the cancer in remission longer. We look forward to furthering our understanding about the reduction in MRD after treatment with Blincyto. Studies are being conducted to assess how Blincyto affects long-term survival outcomes in patients with MRD.”
About blinatumomab
Blinatumomab is a bispecific, CD19-directed, CD3 T-cell engager (BiTE®) antibody construct that binds to CD19 expressed on the surface of cells of B-lineage origin and CD3 expressed on the surface of T cells.
In 2014, the FDA granted blinatumomab accelerated approval to treat adults with Philadelphia chromosome-negative (Ph-) relapsed/refractory BCP-ALL.
In 2016, the FDA granted the therapy accelerated approval for pediatric patients with Ph- relapsed/refractory BCP-ALL.
Last year, the FDA granted blinatumomab full approval for pediatric and adult patients with Ph- or Ph+ relapsed/refractory BCP-ALL.
The FDA-approved prescribing information for blinatumomab includes a boxed warning for cytokine release syndrome and neurologic toxicities. Blinatumomab is also under a risk evaluation and mitigation strategy program in the US.
BLAST study
The new accelerated approval for blinatumomab was supported by results from the phase 2 BLAST study, which were published in Blood in January.
The study enrolled adults with MRD-positive BCP-ALL in complete hematologic remission after 3 or more cycles of intensive chemotherapy.
Patients received continuous intravenous infusions of blinatumomab at 15 μg/m2/day for 4 weeks, followed by 2 weeks off. They received up to 4 cycles of treatment and could undergo hematopoietic stem cell transplant (HSCT) at any time after the first cycle.
In all, there were 116 patients who received at least 1 infusion of blinatumomab. Seventy-six patients went on to HSCT while in continuous CR after cycle 1 (n=27), 2 (n=36), or 3/4 (n=13).
The study’s primary endpoint was the rate of complete MRD response within the first treatment cycle, and 78% of evaluable patients (88/113) achieved this endpoint.
A key secondary endpoint was RFS at 18 months. There were 110 patients evaluable for this endpoint. They all had Ph- BCP-ALL and <5% blasts at baseline.
The estimated RFS at 18 months was 54%, and the median RFS was 18.9 months. The median RFS was 24.6 months for patients treated in first CR and 11.0 months for patients treated in a later CR (P=0.004).
Another key endpoint was overall survival (OS). The median OS was 36.5 months, both for the 110 patients in the RFS analysis and for the entire study population.
In a landmark analysis, complete MRD responders had longer OS than MRD nonresponders—38.9 months and 12.5 months, respectively (P=0.002). And complete MRD responders had longer RFS than nonresponders—23.6 months and 5.7 months, respectively (P=0.002).
All 116 patients who started cycle 1 had at least 1 adverse event (AE). The rate of grade 3 AEs was 33%, and the rate of grade 4 AEs was 27%. These AEs were considered treatment-related in 29% (grade 3) and 22% (grade 4) of patients.
Four (3%) patients developed cytokine release syndrome—2 with grade 1 and 2 with grade 3. All of these events occurred during cycle 1.
Fifty-three percent of patients (n=61) had neurologic events. In most cases (97%, n=59), these events resolved.
There were 2 fatal AEs during the treatment period, both in cycle 1. One of these events—atypical pneumonitis with H1N1 influenza—was considered treatment-related. The other event—subdural hemorrhage—was considered unrelated to treatment.
There were 4 fatal AEs reported after blinatumomab treatment. Two of these deaths—due to multifocal CNS lesions and graft-versus-host disease—occurred in HSCT recipients. The other 2 deaths—due to disease progression and multi-organ failure—occurred in nontransplanted patients after relapse.
The US Food and Drug Administration (FDA) has expanded the approved indication for blinatumomab (Blincyto®).
The drug is now approved to treat adults and children with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) in first or second complete remission (CR) with minimal residual disease (MRD) greater than or equal to 0.1%.
Blinatumomab received accelerated approval for this indication because the drug has not yet shown a clinical benefit in these patients.
The FDA’s accelerated approval program allows conditional approval of a drug that fills an unmet medical need for a serious condition.
Accelerated approval is based on surrogate or intermediate endpoints—in this case, MRD response rate and hematologic relapse-free survival (RFS)—that are reasonably likely to predict clinical benefit.
Continued approval of blinatumomab for the aforementioned indication may be contingent upon verification of clinical benefit in confirmatory trials.
“This is the first FDA-approved treatment for patients with MRD-positive ALL,” said Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence.
“Because patients who have MRD are more likely to relapse, having a treatment option that eliminates even very low amounts of residual leukemia cells may help keep the cancer in remission longer. We look forward to furthering our understanding about the reduction in MRD after treatment with Blincyto. Studies are being conducted to assess how Blincyto affects long-term survival outcomes in patients with MRD.”
About blinatumomab
Blinatumomab is a bispecific, CD19-directed, CD3 T-cell engager (BiTE®) antibody construct that binds to CD19 expressed on the surface of cells of B-lineage origin and CD3 expressed on the surface of T cells.
In 2014, the FDA granted blinatumomab accelerated approval to treat adults with Philadelphia chromosome-negative (Ph-) relapsed/refractory BCP-ALL.
In 2016, the FDA granted the therapy accelerated approval for pediatric patients with Ph- relapsed/refractory BCP-ALL.
Last year, the FDA granted blinatumomab full approval for pediatric and adult patients with Ph- or Ph+ relapsed/refractory BCP-ALL.
The FDA-approved prescribing information for blinatumomab includes a boxed warning for cytokine release syndrome and neurologic toxicities. Blinatumomab is also under a risk evaluation and mitigation strategy program in the US.
BLAST study
The new accelerated approval for blinatumomab was supported by results from the phase 2 BLAST study, which were published in Blood in January.
The study enrolled adults with MRD-positive BCP-ALL in complete hematologic remission after 3 or more cycles of intensive chemotherapy.
Patients received continuous intravenous infusions of blinatumomab at 15 μg/m2/day for 4 weeks, followed by 2 weeks off. They received up to 4 cycles of treatment and could undergo hematopoietic stem cell transplant (HSCT) at any time after the first cycle.
In all, there were 116 patients who received at least 1 infusion of blinatumomab. Seventy-six patients went on to HSCT while in continuous CR after cycle 1 (n=27), 2 (n=36), or 3/4 (n=13).
The study’s primary endpoint was the rate of complete MRD response within the first treatment cycle, and 78% of evaluable patients (88/113) achieved this endpoint.
A key secondary endpoint was RFS at 18 months. There were 110 patients evaluable for this endpoint. They all had Ph- BCP-ALL and <5% blasts at baseline.
The estimated RFS at 18 months was 54%, and the median RFS was 18.9 months. The median RFS was 24.6 months for patients treated in first CR and 11.0 months for patients treated in a later CR (P=0.004).
Another key endpoint was overall survival (OS). The median OS was 36.5 months, both for the 110 patients in the RFS analysis and for the entire study population.
In a landmark analysis, complete MRD responders had longer OS than MRD nonresponders—38.9 months and 12.5 months, respectively (P=0.002). And complete MRD responders had longer RFS than nonresponders—23.6 months and 5.7 months, respectively (P=0.002).
All 116 patients who started cycle 1 had at least 1 adverse event (AE). The rate of grade 3 AEs was 33%, and the rate of grade 4 AEs was 27%. These AEs were considered treatment-related in 29% (grade 3) and 22% (grade 4) of patients.
Four (3%) patients developed cytokine release syndrome—2 with grade 1 and 2 with grade 3. All of these events occurred during cycle 1.
Fifty-three percent of patients (n=61) had neurologic events. In most cases (97%, n=59), these events resolved.
There were 2 fatal AEs during the treatment period, both in cycle 1. One of these events—atypical pneumonitis with H1N1 influenza—was considered treatment-related. The other event—subdural hemorrhage—was considered unrelated to treatment.
There were 4 fatal AEs reported after blinatumomab treatment. Two of these deaths—due to multifocal CNS lesions and graft-versus-host disease—occurred in HSCT recipients. The other 2 deaths—due to disease progression and multi-organ failure—occurred in nontransplanted patients after relapse.
Disease, genetics contribute to neurocognitive decline in ALL
Chemotherapeutic agents have been associated with neurocognitive side effects in survivors of pediatric acute lymphoblastic leukemia (ALL).
Now, researchers have found evidence to suggest that genetics and ALL itself can increase the risk for long-term problems with attention, organization, and related neurocognitive skills.
The researchers reported these findings in JAMA Oncology.
The team evaluated patients enrolled in the Total XV St. Jude clinical trial, analyzing the cerebrospinal fluid (CSF) of 235 pediatric ALL patients treated with chemotherapy alone.
The CSF had been collected at 5 times before and during treatment (between 2000 and 2010). The analysis included neurocognitive testing and brain imaging of 138 ALL survivors who were at least 8 years old and 5 years from their cancer diagnosis.
The researchers found that, even before treatment began, some patients had proteins in their CSF that suggested injury to glial cells.
“This was a surprise,” said study author Kevin Krull, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.
“Until now, we had not suspected that leukemia by itself or the inflammatory response to the disease may lead to changes that leave ALL survivors at risk for problems with executive functioning and processing speed later.”
Previously, researchers had assumed neurocognitive problems were a side effect of ALL therapy, particularly treatment with methotrexate.
So finding elevated biomarkers in the CSF of some patients during methotrexate treatment was not surprising, but, previously, little was known about the neurotoxic mechanism involved. The biomarkers identified were indicative of injury to neurons, axons, and glial cells.
The researchers checked patients’ CSF for 5 proteins and other biomarkers of brain cell damage related to treatment with either high-dose intravenous methotrexate or intrathecal methotrexate.
The biomarkers were present early on but changed and varied throughout treatment. For example, biomarkers of demyelination were present in some patients newly diagnosed with ALL and then decreased during treatment.
Others, including biomarkers of inflammation and neuronal damage, increased as treatment progressed.
Overall, methotrexate treatment was associated with biomarkers that signaled as much as a 70% increased risk for reduced neurocognitive functioning in long-term ALL survivors.
The researchers also looked for evidence that genetic variation might influence the susceptibility of pediatric ALL patients to methotrexate injury.
The team checked patients’ DNA for 42 gene variants known to influence drug metabolism, neurodevelopment, and oxidative stress.
The analysis identified a variant of the COMT gene that was associated with higher biomarker levels following methotrexate treatment. The gene encodes instructions for a protein involved in processing the neurotransmitter dopamine in the frontal regions of the brain.
“Dopamine is the primary neurotransmitter in executive functioning,” Dr Krull noted. “This suggests that 2 independent processes might be coming together in some patients that influence their risk for diminished executive functioning.”
“Taken together, the results suggest that survivors’ neurocognitive deficits are multifactorial and reflect a complex interaction among genetics, treatment intensity, and other factors. Monitoring CSF biomarkers and screening for genetic mediators of brain injury may help identify and intervene with survivors at risk for neurocognitive problems.”
Chemotherapeutic agents have been associated with neurocognitive side effects in survivors of pediatric acute lymphoblastic leukemia (ALL).
Now, researchers have found evidence to suggest that genetics and ALL itself can increase the risk for long-term problems with attention, organization, and related neurocognitive skills.
The researchers reported these findings in JAMA Oncology.
The team evaluated patients enrolled in the Total XV St. Jude clinical trial, analyzing the cerebrospinal fluid (CSF) of 235 pediatric ALL patients treated with chemotherapy alone.
The CSF had been collected at 5 times before and during treatment (between 2000 and 2010). The analysis included neurocognitive testing and brain imaging of 138 ALL survivors who were at least 8 years old and 5 years from their cancer diagnosis.
The researchers found that, even before treatment began, some patients had proteins in their CSF that suggested injury to glial cells.
“This was a surprise,” said study author Kevin Krull, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.
“Until now, we had not suspected that leukemia by itself or the inflammatory response to the disease may lead to changes that leave ALL survivors at risk for problems with executive functioning and processing speed later.”
Previously, researchers had assumed neurocognitive problems were a side effect of ALL therapy, particularly treatment with methotrexate.
So finding elevated biomarkers in the CSF of some patients during methotrexate treatment was not surprising, but, previously, little was known about the neurotoxic mechanism involved. The biomarkers identified were indicative of injury to neurons, axons, and glial cells.
The researchers checked patients’ CSF for 5 proteins and other biomarkers of brain cell damage related to treatment with either high-dose intravenous methotrexate or intrathecal methotrexate.
The biomarkers were present early on but changed and varied throughout treatment. For example, biomarkers of demyelination were present in some patients newly diagnosed with ALL and then decreased during treatment.
Others, including biomarkers of inflammation and neuronal damage, increased as treatment progressed.
Overall, methotrexate treatment was associated with biomarkers that signaled as much as a 70% increased risk for reduced neurocognitive functioning in long-term ALL survivors.
The researchers also looked for evidence that genetic variation might influence the susceptibility of pediatric ALL patients to methotrexate injury.
The team checked patients’ DNA for 42 gene variants known to influence drug metabolism, neurodevelopment, and oxidative stress.
The analysis identified a variant of the COMT gene that was associated with higher biomarker levels following methotrexate treatment. The gene encodes instructions for a protein involved in processing the neurotransmitter dopamine in the frontal regions of the brain.
“Dopamine is the primary neurotransmitter in executive functioning,” Dr Krull noted. “This suggests that 2 independent processes might be coming together in some patients that influence their risk for diminished executive functioning.”
“Taken together, the results suggest that survivors’ neurocognitive deficits are multifactorial and reflect a complex interaction among genetics, treatment intensity, and other factors. Monitoring CSF biomarkers and screening for genetic mediators of brain injury may help identify and intervene with survivors at risk for neurocognitive problems.”
Chemotherapeutic agents have been associated with neurocognitive side effects in survivors of pediatric acute lymphoblastic leukemia (ALL).
Now, researchers have found evidence to suggest that genetics and ALL itself can increase the risk for long-term problems with attention, organization, and related neurocognitive skills.
The researchers reported these findings in JAMA Oncology.
The team evaluated patients enrolled in the Total XV St. Jude clinical trial, analyzing the cerebrospinal fluid (CSF) of 235 pediatric ALL patients treated with chemotherapy alone.
The CSF had been collected at 5 times before and during treatment (between 2000 and 2010). The analysis included neurocognitive testing and brain imaging of 138 ALL survivors who were at least 8 years old and 5 years from their cancer diagnosis.
The researchers found that, even before treatment began, some patients had proteins in their CSF that suggested injury to glial cells.
“This was a surprise,” said study author Kevin Krull, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.
“Until now, we had not suspected that leukemia by itself or the inflammatory response to the disease may lead to changes that leave ALL survivors at risk for problems with executive functioning and processing speed later.”
Previously, researchers had assumed neurocognitive problems were a side effect of ALL therapy, particularly treatment with methotrexate.
So finding elevated biomarkers in the CSF of some patients during methotrexate treatment was not surprising, but, previously, little was known about the neurotoxic mechanism involved. The biomarkers identified were indicative of injury to neurons, axons, and glial cells.
The researchers checked patients’ CSF for 5 proteins and other biomarkers of brain cell damage related to treatment with either high-dose intravenous methotrexate or intrathecal methotrexate.
The biomarkers were present early on but changed and varied throughout treatment. For example, biomarkers of demyelination were present in some patients newly diagnosed with ALL and then decreased during treatment.
Others, including biomarkers of inflammation and neuronal damage, increased as treatment progressed.
Overall, methotrexate treatment was associated with biomarkers that signaled as much as a 70% increased risk for reduced neurocognitive functioning in long-term ALL survivors.
The researchers also looked for evidence that genetic variation might influence the susceptibility of pediatric ALL patients to methotrexate injury.
The team checked patients’ DNA for 42 gene variants known to influence drug metabolism, neurodevelopment, and oxidative stress.
The analysis identified a variant of the COMT gene that was associated with higher biomarker levels following methotrexate treatment. The gene encodes instructions for a protein involved in processing the neurotransmitter dopamine in the frontal regions of the brain.
“Dopamine is the primary neurotransmitter in executive functioning,” Dr Krull noted. “This suggests that 2 independent processes might be coming together in some patients that influence their risk for diminished executive functioning.”
“Taken together, the results suggest that survivors’ neurocognitive deficits are multifactorial and reflect a complex interaction among genetics, treatment intensity, and other factors. Monitoring CSF biomarkers and screening for genetic mediators of brain injury may help identify and intervene with survivors at risk for neurocognitive problems.”
FDA expands indication for blinatumomab in treating ALL
The Food and Drug Administration has granted accelerated who are in remission but still have minimal residual disease (MRD).
This is the first FDA-approved treatment for those with MRD, the FDA said in a statement.
The current approval was based on a single-arm clinical trial of 86 patients in first or second complete remission who had detectable MRD in at least 1 out of 1,000 cells in their bone marrow. Undetectable MRD was achieved by 70 patients after one cycle of blinatumomab treatment. More than half of the patients remained alive and in remission for at least 22.3 months, the FDA said.
Common side effects include bacterial and pathogen-unspecified infections, pyrexia, headache, infusion-related reactions, neutropenia, anemia, febrile neutropenia, and thrombocytopenia. The drug carries a boxed warning about cytokine release syndrome at the start of the first treatment. The FDA also warns that children weighing less than 22 kg should receive the drug prepared with preservative-free saline because of the risk of serious adverse reactions in pediatric patients from a benzyl alcohol preservative.
Blinatumomab is marketed as Blincyto by Amgen.
The Food and Drug Administration has granted accelerated who are in remission but still have minimal residual disease (MRD).
This is the first FDA-approved treatment for those with MRD, the FDA said in a statement.
The current approval was based on a single-arm clinical trial of 86 patients in first or second complete remission who had detectable MRD in at least 1 out of 1,000 cells in their bone marrow. Undetectable MRD was achieved by 70 patients after one cycle of blinatumomab treatment. More than half of the patients remained alive and in remission for at least 22.3 months, the FDA said.
Common side effects include bacterial and pathogen-unspecified infections, pyrexia, headache, infusion-related reactions, neutropenia, anemia, febrile neutropenia, and thrombocytopenia. The drug carries a boxed warning about cytokine release syndrome at the start of the first treatment. The FDA also warns that children weighing less than 22 kg should receive the drug prepared with preservative-free saline because of the risk of serious adverse reactions in pediatric patients from a benzyl alcohol preservative.
Blinatumomab is marketed as Blincyto by Amgen.
The Food and Drug Administration has granted accelerated who are in remission but still have minimal residual disease (MRD).
This is the first FDA-approved treatment for those with MRD, the FDA said in a statement.
The current approval was based on a single-arm clinical trial of 86 patients in first or second complete remission who had detectable MRD in at least 1 out of 1,000 cells in their bone marrow. Undetectable MRD was achieved by 70 patients after one cycle of blinatumomab treatment. More than half of the patients remained alive and in remission for at least 22.3 months, the FDA said.
Common side effects include bacterial and pathogen-unspecified infections, pyrexia, headache, infusion-related reactions, neutropenia, anemia, febrile neutropenia, and thrombocytopenia. The drug carries a boxed warning about cytokine release syndrome at the start of the first treatment. The FDA also warns that children weighing less than 22 kg should receive the drug prepared with preservative-free saline because of the risk of serious adverse reactions in pediatric patients from a benzyl alcohol preservative.
Blinatumomab is marketed as Blincyto by Amgen.
UCART19 can bridge to transplant in adults
LISBON—Preliminary data from a phase 1 trial suggest UCART19 can serve as a bridge to transplant in adults with relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL).
This “universal,” donor-derived, chimeric antigen receptor (CAR) T-cell therapy produced complete responses (CRs) in 6 of 9 patients treated.
Five of the patients who were negative for minimal residual disease (MRD) proceeded to allogeneic hematopoietic stem cell transplant (allo-HSCT).
Two of the 5 patients were still alive and in MRD-negative remission at last follow-up, but 1 had relapsed and 2 died.
A total of 4 patients died in this trial—1 from a dose-limiting toxicity (DLT), 1 from progressive disease, 1 from infection, and 1 from pulmonary hemorrhage.
“These early results for UCART19 are very encouraging, both in terms of manageable safety and the impressive complete molecular remission rate in these hard-to-treat adult patients with R/R B-ALL,” said principal investigator Reuben Benjamin, MBBS, PhD, a consultant hematologist at King’s College London in the UK.
Dr Benjamin presented these results, from the CALM trial, at the 44th Annual Meeting of the EBMT (abstract OS10-4*).
The CALM trial is sponsored by Servier. In 2015, Servier acquired exclusive rights from Cellectis for UCART19, which is being co-developed by Servier and Pfizer.
Patients and treatment
Dr Benjamin presented results in 9 patients with R/R B-ALL who had a median age of 23 (range, 18-49).
All patients had morphological disease or an MRD level of at least 1 x 10-3 (via flow cytometry and/or qPCR) at baseline. The median disease burden was 8% (range, 0-95).
Four patients had received 1 to 3 prior therapies, and 5 had received 4 or more prior treatments. Six patients had prior inotuzumab ozogamicin, 2 had prior blinatumomab, and 7 had prior allo-HSCT. The median time to relapse after allo-HSCT was 5.9 months (range, 4.1-11).
Patients underwent lymphodepletion with fludarabine, cyclophosphamide, and alemtuzumab (n=8) or fludarabine and cyclophosphamide (n=1).
They received UCART19 at 2 dose levels—6 x 106 total cells (n=6) or 6 to 8 x 107 total cells (n=3).
Toxicity
There were 2 DLTs, 1 at each dose level. At the lower dose, the DLT was grade 4 cytokine release syndrome (CRS) associated with grade 5 neutropenic sepsis. The patient with this DLT died at day 15 post-infusion.
At the higher dose level, the DLT was grade 4 prolonged cytopenia associated with infection and pulmonary hemorrhage. This patient died at day 82 post-infusion, 19 days after undergoing allo-HSCT.
In all, 8 patients had CRS. One patient had grade 1, 6 had grade 2, and 1 had grade 4 CRS. Seven patients had complete resolution of CRS.
Two patients had neurotoxic events, both grade 1.
Three patients had prolonged cytopenia, all grade 4. This was defined as persistent neutropenia and/or thrombocytopenia beyond day 42 after UCART19 infusion, except if the patient had >5% bone marrow blasts.
Two patients had neutropenic sepsis, grade 4 and grade 5.
Three patients had cytomegalovirus infection, all grade 2. Two patients had adenovirus infection, grade 1 and grade 3.
One patient had grade 1 acute cutaneous graft-versus-host disease.
Efficacy
Six of 9 patients achieved a CR, and 5 were MRD-negative by flow cytometry or qPCR. All 5 patients proceeded to allo-HSCT.
After transplant, 2 patients were still MRD-negative at 8 months, 1 patient relapsed after 6 months, and 2 patients died while MRD-negative. The deaths were due to infection and pulmonary hemorrhage.
Two other deaths were due to a DLT (neutropenic sepsis associated with CRS) and progressive disease.
Of the 5 patients who are alive, 2 are still MRD-negative after allo-HSCT. One of these patients relapsed after the first UCART19 infusion, received a second infusion, and achieved an MRD-negative CR that enabled transplant.
The remaining 3 patients who are still alive did not undergo transplant. One of these patients relapsed after achieving MRD-positive remission, and 1 relapsed after MRD-negative remission. The third patient relapsed and received a second UCART19 infusion. This patient has yet to respond to the second infusion but has minimal follow-up.
Recruitment in this study is ongoing at the higher dose level—6 to 8 x 107 total cells.
*Data in the abstract were updated in the presentation.
LISBON—Preliminary data from a phase 1 trial suggest UCART19 can serve as a bridge to transplant in adults with relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL).
This “universal,” donor-derived, chimeric antigen receptor (CAR) T-cell therapy produced complete responses (CRs) in 6 of 9 patients treated.
Five of the patients who were negative for minimal residual disease (MRD) proceeded to allogeneic hematopoietic stem cell transplant (allo-HSCT).
Two of the 5 patients were still alive and in MRD-negative remission at last follow-up, but 1 had relapsed and 2 died.
A total of 4 patients died in this trial—1 from a dose-limiting toxicity (DLT), 1 from progressive disease, 1 from infection, and 1 from pulmonary hemorrhage.
“These early results for UCART19 are very encouraging, both in terms of manageable safety and the impressive complete molecular remission rate in these hard-to-treat adult patients with R/R B-ALL,” said principal investigator Reuben Benjamin, MBBS, PhD, a consultant hematologist at King’s College London in the UK.
Dr Benjamin presented these results, from the CALM trial, at the 44th Annual Meeting of the EBMT (abstract OS10-4*).
The CALM trial is sponsored by Servier. In 2015, Servier acquired exclusive rights from Cellectis for UCART19, which is being co-developed by Servier and Pfizer.
Patients and treatment
Dr Benjamin presented results in 9 patients with R/R B-ALL who had a median age of 23 (range, 18-49).
All patients had morphological disease or an MRD level of at least 1 x 10-3 (via flow cytometry and/or qPCR) at baseline. The median disease burden was 8% (range, 0-95).
Four patients had received 1 to 3 prior therapies, and 5 had received 4 or more prior treatments. Six patients had prior inotuzumab ozogamicin, 2 had prior blinatumomab, and 7 had prior allo-HSCT. The median time to relapse after allo-HSCT was 5.9 months (range, 4.1-11).
Patients underwent lymphodepletion with fludarabine, cyclophosphamide, and alemtuzumab (n=8) or fludarabine and cyclophosphamide (n=1).
They received UCART19 at 2 dose levels—6 x 106 total cells (n=6) or 6 to 8 x 107 total cells (n=3).
Toxicity
There were 2 DLTs, 1 at each dose level. At the lower dose, the DLT was grade 4 cytokine release syndrome (CRS) associated with grade 5 neutropenic sepsis. The patient with this DLT died at day 15 post-infusion.
At the higher dose level, the DLT was grade 4 prolonged cytopenia associated with infection and pulmonary hemorrhage. This patient died at day 82 post-infusion, 19 days after undergoing allo-HSCT.
In all, 8 patients had CRS. One patient had grade 1, 6 had grade 2, and 1 had grade 4 CRS. Seven patients had complete resolution of CRS.
Two patients had neurotoxic events, both grade 1.
Three patients had prolonged cytopenia, all grade 4. This was defined as persistent neutropenia and/or thrombocytopenia beyond day 42 after UCART19 infusion, except if the patient had >5% bone marrow blasts.
Two patients had neutropenic sepsis, grade 4 and grade 5.
Three patients had cytomegalovirus infection, all grade 2. Two patients had adenovirus infection, grade 1 and grade 3.
One patient had grade 1 acute cutaneous graft-versus-host disease.
Efficacy
Six of 9 patients achieved a CR, and 5 were MRD-negative by flow cytometry or qPCR. All 5 patients proceeded to allo-HSCT.
After transplant, 2 patients were still MRD-negative at 8 months, 1 patient relapsed after 6 months, and 2 patients died while MRD-negative. The deaths were due to infection and pulmonary hemorrhage.
Two other deaths were due to a DLT (neutropenic sepsis associated with CRS) and progressive disease.
Of the 5 patients who are alive, 2 are still MRD-negative after allo-HSCT. One of these patients relapsed after the first UCART19 infusion, received a second infusion, and achieved an MRD-negative CR that enabled transplant.
The remaining 3 patients who are still alive did not undergo transplant. One of these patients relapsed after achieving MRD-positive remission, and 1 relapsed after MRD-negative remission. The third patient relapsed and received a second UCART19 infusion. This patient has yet to respond to the second infusion but has minimal follow-up.
Recruitment in this study is ongoing at the higher dose level—6 to 8 x 107 total cells.
*Data in the abstract were updated in the presentation.
LISBON—Preliminary data from a phase 1 trial suggest UCART19 can serve as a bridge to transplant in adults with relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL).
This “universal,” donor-derived, chimeric antigen receptor (CAR) T-cell therapy produced complete responses (CRs) in 6 of 9 patients treated.
Five of the patients who were negative for minimal residual disease (MRD) proceeded to allogeneic hematopoietic stem cell transplant (allo-HSCT).
Two of the 5 patients were still alive and in MRD-negative remission at last follow-up, but 1 had relapsed and 2 died.
A total of 4 patients died in this trial—1 from a dose-limiting toxicity (DLT), 1 from progressive disease, 1 from infection, and 1 from pulmonary hemorrhage.
“These early results for UCART19 are very encouraging, both in terms of manageable safety and the impressive complete molecular remission rate in these hard-to-treat adult patients with R/R B-ALL,” said principal investigator Reuben Benjamin, MBBS, PhD, a consultant hematologist at King’s College London in the UK.
Dr Benjamin presented these results, from the CALM trial, at the 44th Annual Meeting of the EBMT (abstract OS10-4*).
The CALM trial is sponsored by Servier. In 2015, Servier acquired exclusive rights from Cellectis for UCART19, which is being co-developed by Servier and Pfizer.
Patients and treatment
Dr Benjamin presented results in 9 patients with R/R B-ALL who had a median age of 23 (range, 18-49).
All patients had morphological disease or an MRD level of at least 1 x 10-3 (via flow cytometry and/or qPCR) at baseline. The median disease burden was 8% (range, 0-95).
Four patients had received 1 to 3 prior therapies, and 5 had received 4 or more prior treatments. Six patients had prior inotuzumab ozogamicin, 2 had prior blinatumomab, and 7 had prior allo-HSCT. The median time to relapse after allo-HSCT was 5.9 months (range, 4.1-11).
Patients underwent lymphodepletion with fludarabine, cyclophosphamide, and alemtuzumab (n=8) or fludarabine and cyclophosphamide (n=1).
They received UCART19 at 2 dose levels—6 x 106 total cells (n=6) or 6 to 8 x 107 total cells (n=3).
Toxicity
There were 2 DLTs, 1 at each dose level. At the lower dose, the DLT was grade 4 cytokine release syndrome (CRS) associated with grade 5 neutropenic sepsis. The patient with this DLT died at day 15 post-infusion.
At the higher dose level, the DLT was grade 4 prolonged cytopenia associated with infection and pulmonary hemorrhage. This patient died at day 82 post-infusion, 19 days after undergoing allo-HSCT.
In all, 8 patients had CRS. One patient had grade 1, 6 had grade 2, and 1 had grade 4 CRS. Seven patients had complete resolution of CRS.
Two patients had neurotoxic events, both grade 1.
Three patients had prolonged cytopenia, all grade 4. This was defined as persistent neutropenia and/or thrombocytopenia beyond day 42 after UCART19 infusion, except if the patient had >5% bone marrow blasts.
Two patients had neutropenic sepsis, grade 4 and grade 5.
Three patients had cytomegalovirus infection, all grade 2. Two patients had adenovirus infection, grade 1 and grade 3.
One patient had grade 1 acute cutaneous graft-versus-host disease.
Efficacy
Six of 9 patients achieved a CR, and 5 were MRD-negative by flow cytometry or qPCR. All 5 patients proceeded to allo-HSCT.
After transplant, 2 patients were still MRD-negative at 8 months, 1 patient relapsed after 6 months, and 2 patients died while MRD-negative. The deaths were due to infection and pulmonary hemorrhage.
Two other deaths were due to a DLT (neutropenic sepsis associated with CRS) and progressive disease.
Of the 5 patients who are alive, 2 are still MRD-negative after allo-HSCT. One of these patients relapsed after the first UCART19 infusion, received a second infusion, and achieved an MRD-negative CR that enabled transplant.
The remaining 3 patients who are still alive did not undergo transplant. One of these patients relapsed after achieving MRD-positive remission, and 1 relapsed after MRD-negative remission. The third patient relapsed and received a second UCART19 infusion. This patient has yet to respond to the second infusion but has minimal follow-up.
Recruitment in this study is ongoing at the higher dose level—6 to 8 x 107 total cells.
*Data in the abstract were updated in the presentation.
Phase 1 results with UCART19 in kids
LISBON—Early results from a phase 1, pediatric trial of UCART19 expand upon results observed in children who received the therapy via a compassionate use program.
Two patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL) received UCART19, a “universal,” donor-derived chimeric antigen receptor (CAR) T-cell therapy, via the program.
Both achieved remission and were still alive at last follow-up, more than 2 years after proceeding to transplant.
In the phase 1 trial, 5 of 6 B-ALL patients have achieved remission and gone on to transplant.
Three of the patients are still alive, and 2 are still negative for minimal residual disease (MRD) at 10 months and 11 months after UCART19 infusion.
However, 2 patients died of progression, and 1 died of transplant-related complications.
Paul Veys, MBBS, of Great Ormond Street Hospital (GOSH) in London, UK, presented these results, from the PALL trial, at the 44th Annual Meeting of the EBMT (abstract OS18-5*).
The trial is sponsored by Servier. In 2015, Servier acquired exclusive rights from Cellectis for UCART19, which is being co-developed by Servier and Pfizer.
Prior experience
Researchers previously reported results with UCART19 in 2 infants with relapsed/refractory B-ALL who had exhausted all other treatment options and received UCART19 via a compassionate use program.
Both patients achieved remission after UCART19 and proceeded to allogeneic hematopoietic stem cell transplant (allo-HSCT).
When these results were published, in January 2017, both patients were still alive and leukemia-free at last follow-up—12 months and 18 months after UCART19 infusion.
Dr Veys provided an update, noting that these patients were still alive and in remission at 24 months and 30 months after allo-HSCT.
Phase 1 patients and treatment
Thus far, the phase 1 trial has enrolled and treated 6 patients with relapsed B-ALL. They had a median age of 3.75 (range, 0.8-16.4).
All patients had morphological disease or an MRD level of at least 1 x 10-3 (via flow cytometry and/or qPCR) at baseline.
One patient had received 1 prior therapy, 2 had 3 prior therapies, and 3 had 4 or more prior therapies. Two patients had prior inotuzumab ozogamicin, and 2 had prior allo-HSCT. Both had relapsed within 6 months of allo-HSCT.
Five patients had less than 10% bone marrow blasts prior to lymphodepletion, and 1 had greater than 50% blasts.
Patients underwent lymphodepletion with fludarabine, cyclophosphamide, and alemtuzumab (n=5) or fludarabine and cyclophosphamide (n=1).
The patients received UCART19 at doses of 2 x 107 total cells or 1.1 to 2.3 x 106 cells/kg.
Toxicity
All 6 patients developed cytokine release syndrome (CRS), including grade 1 (n=1), grade 2 (n=4), and grade 3 (n-1) CRS. However, all 6 cases resolved completely.
Three patients had neurotoxic events, 2 grade 1 and 1 grade 2. One patient had grade 3 febrile neutropenia.
Three patients had grade 4 prolonged cytopenia. This was defined as persistent neutropenia and/or thrombocytopenia beyond day 42 after UCART19 infusion, except if the patient had >5% bone marrow blasts.
One patient had grade 1 adenovirus infection, 1 had grade 3 cytomegalovirus infection, 2 had grade 3 BK virus hemorrhagic cystitis, and 1 had grade 4 metapneumovirus infection.
One patient had grade 1 acute cutaneous graft-versus-host disease.
Efficacy
All 6 patients achieved a complete response at day 28 to 42 after UCART19 infusion. Five patients achieved MRD negativity according to flow cytometry, and 3 were MRD-negative according to PCR.
The 5 flow-MRD-negative patients went on to receive an allo-HSCT between 49 days and 62 days after UCART19 infusion. Conditioning consisted of total body irradiation and fludarabine, with or without cyclophosphamide and antithymocyte globulin. All of these patients received a dose of rituximab as well, which was intended to target any remaining UCART19 cells.
Two patients relapsed 3 months after transplant and died at 7 months and 8 months after UCART19 infusion. One of these patients was CD19-, and 1 was CD19+, but both were MRD-positive by PCR prior to receiving their transplant.
A third patient died 2.5 months after allo-HSCT from transplant-related complications, including thrombotic microangiopathy, BK hemorrhagic cystitis, and nephritis.
The remaining 3 patients are still alive at 1.5 months, 10 months, and 11 months after UCART19 infusion. Two are still MRD-negative, and 1 is MRD-positive. The MRD-positive patient has not undergone allo-HSCT.
*Data in the abstract were updated in the presentation.
LISBON—Early results from a phase 1, pediatric trial of UCART19 expand upon results observed in children who received the therapy via a compassionate use program.
Two patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL) received UCART19, a “universal,” donor-derived chimeric antigen receptor (CAR) T-cell therapy, via the program.
Both achieved remission and were still alive at last follow-up, more than 2 years after proceeding to transplant.
In the phase 1 trial, 5 of 6 B-ALL patients have achieved remission and gone on to transplant.
Three of the patients are still alive, and 2 are still negative for minimal residual disease (MRD) at 10 months and 11 months after UCART19 infusion.
However, 2 patients died of progression, and 1 died of transplant-related complications.
Paul Veys, MBBS, of Great Ormond Street Hospital (GOSH) in London, UK, presented these results, from the PALL trial, at the 44th Annual Meeting of the EBMT (abstract OS18-5*).
The trial is sponsored by Servier. In 2015, Servier acquired exclusive rights from Cellectis for UCART19, which is being co-developed by Servier and Pfizer.
Prior experience
Researchers previously reported results with UCART19 in 2 infants with relapsed/refractory B-ALL who had exhausted all other treatment options and received UCART19 via a compassionate use program.
Both patients achieved remission after UCART19 and proceeded to allogeneic hematopoietic stem cell transplant (allo-HSCT).
When these results were published, in January 2017, both patients were still alive and leukemia-free at last follow-up—12 months and 18 months after UCART19 infusion.
Dr Veys provided an update, noting that these patients were still alive and in remission at 24 months and 30 months after allo-HSCT.
Phase 1 patients and treatment
Thus far, the phase 1 trial has enrolled and treated 6 patients with relapsed B-ALL. They had a median age of 3.75 (range, 0.8-16.4).
All patients had morphological disease or an MRD level of at least 1 x 10-3 (via flow cytometry and/or qPCR) at baseline.
One patient had received 1 prior therapy, 2 had 3 prior therapies, and 3 had 4 or more prior therapies. Two patients had prior inotuzumab ozogamicin, and 2 had prior allo-HSCT. Both had relapsed within 6 months of allo-HSCT.
Five patients had less than 10% bone marrow blasts prior to lymphodepletion, and 1 had greater than 50% blasts.
Patients underwent lymphodepletion with fludarabine, cyclophosphamide, and alemtuzumab (n=5) or fludarabine and cyclophosphamide (n=1).
The patients received UCART19 at doses of 2 x 107 total cells or 1.1 to 2.3 x 106 cells/kg.
Toxicity
All 6 patients developed cytokine release syndrome (CRS), including grade 1 (n=1), grade 2 (n=4), and grade 3 (n-1) CRS. However, all 6 cases resolved completely.
Three patients had neurotoxic events, 2 grade 1 and 1 grade 2. One patient had grade 3 febrile neutropenia.
Three patients had grade 4 prolonged cytopenia. This was defined as persistent neutropenia and/or thrombocytopenia beyond day 42 after UCART19 infusion, except if the patient had >5% bone marrow blasts.
One patient had grade 1 adenovirus infection, 1 had grade 3 cytomegalovirus infection, 2 had grade 3 BK virus hemorrhagic cystitis, and 1 had grade 4 metapneumovirus infection.
One patient had grade 1 acute cutaneous graft-versus-host disease.
Efficacy
All 6 patients achieved a complete response at day 28 to 42 after UCART19 infusion. Five patients achieved MRD negativity according to flow cytometry, and 3 were MRD-negative according to PCR.
The 5 flow-MRD-negative patients went on to receive an allo-HSCT between 49 days and 62 days after UCART19 infusion. Conditioning consisted of total body irradiation and fludarabine, with or without cyclophosphamide and antithymocyte globulin. All of these patients received a dose of rituximab as well, which was intended to target any remaining UCART19 cells.
Two patients relapsed 3 months after transplant and died at 7 months and 8 months after UCART19 infusion. One of these patients was CD19-, and 1 was CD19+, but both were MRD-positive by PCR prior to receiving their transplant.
A third patient died 2.5 months after allo-HSCT from transplant-related complications, including thrombotic microangiopathy, BK hemorrhagic cystitis, and nephritis.
The remaining 3 patients are still alive at 1.5 months, 10 months, and 11 months after UCART19 infusion. Two are still MRD-negative, and 1 is MRD-positive. The MRD-positive patient has not undergone allo-HSCT.
*Data in the abstract were updated in the presentation.
LISBON—Early results from a phase 1, pediatric trial of UCART19 expand upon results observed in children who received the therapy via a compassionate use program.
Two patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL) received UCART19, a “universal,” donor-derived chimeric antigen receptor (CAR) T-cell therapy, via the program.
Both achieved remission and were still alive at last follow-up, more than 2 years after proceeding to transplant.
In the phase 1 trial, 5 of 6 B-ALL patients have achieved remission and gone on to transplant.
Three of the patients are still alive, and 2 are still negative for minimal residual disease (MRD) at 10 months and 11 months after UCART19 infusion.
However, 2 patients died of progression, and 1 died of transplant-related complications.
Paul Veys, MBBS, of Great Ormond Street Hospital (GOSH) in London, UK, presented these results, from the PALL trial, at the 44th Annual Meeting of the EBMT (abstract OS18-5*).
The trial is sponsored by Servier. In 2015, Servier acquired exclusive rights from Cellectis for UCART19, which is being co-developed by Servier and Pfizer.
Prior experience
Researchers previously reported results with UCART19 in 2 infants with relapsed/refractory B-ALL who had exhausted all other treatment options and received UCART19 via a compassionate use program.
Both patients achieved remission after UCART19 and proceeded to allogeneic hematopoietic stem cell transplant (allo-HSCT).
When these results were published, in January 2017, both patients were still alive and leukemia-free at last follow-up—12 months and 18 months after UCART19 infusion.
Dr Veys provided an update, noting that these patients were still alive and in remission at 24 months and 30 months after allo-HSCT.
Phase 1 patients and treatment
Thus far, the phase 1 trial has enrolled and treated 6 patients with relapsed B-ALL. They had a median age of 3.75 (range, 0.8-16.4).
All patients had morphological disease or an MRD level of at least 1 x 10-3 (via flow cytometry and/or qPCR) at baseline.
One patient had received 1 prior therapy, 2 had 3 prior therapies, and 3 had 4 or more prior therapies. Two patients had prior inotuzumab ozogamicin, and 2 had prior allo-HSCT. Both had relapsed within 6 months of allo-HSCT.
Five patients had less than 10% bone marrow blasts prior to lymphodepletion, and 1 had greater than 50% blasts.
Patients underwent lymphodepletion with fludarabine, cyclophosphamide, and alemtuzumab (n=5) or fludarabine and cyclophosphamide (n=1).
The patients received UCART19 at doses of 2 x 107 total cells or 1.1 to 2.3 x 106 cells/kg.
Toxicity
All 6 patients developed cytokine release syndrome (CRS), including grade 1 (n=1), grade 2 (n=4), and grade 3 (n-1) CRS. However, all 6 cases resolved completely.
Three patients had neurotoxic events, 2 grade 1 and 1 grade 2. One patient had grade 3 febrile neutropenia.
Three patients had grade 4 prolonged cytopenia. This was defined as persistent neutropenia and/or thrombocytopenia beyond day 42 after UCART19 infusion, except if the patient had >5% bone marrow blasts.
One patient had grade 1 adenovirus infection, 1 had grade 3 cytomegalovirus infection, 2 had grade 3 BK virus hemorrhagic cystitis, and 1 had grade 4 metapneumovirus infection.
One patient had grade 1 acute cutaneous graft-versus-host disease.
Efficacy
All 6 patients achieved a complete response at day 28 to 42 after UCART19 infusion. Five patients achieved MRD negativity according to flow cytometry, and 3 were MRD-negative according to PCR.
The 5 flow-MRD-negative patients went on to receive an allo-HSCT between 49 days and 62 days after UCART19 infusion. Conditioning consisted of total body irradiation and fludarabine, with or without cyclophosphamide and antithymocyte globulin. All of these patients received a dose of rituximab as well, which was intended to target any remaining UCART19 cells.
Two patients relapsed 3 months after transplant and died at 7 months and 8 months after UCART19 infusion. One of these patients was CD19-, and 1 was CD19+, but both were MRD-positive by PCR prior to receiving their transplant.
A third patient died 2.5 months after allo-HSCT from transplant-related complications, including thrombotic microangiopathy, BK hemorrhagic cystitis, and nephritis.
The remaining 3 patients are still alive at 1.5 months, 10 months, and 11 months after UCART19 infusion. Two are still MRD-negative, and 1 is MRD-positive. The MRD-positive patient has not undergone allo-HSCT.
*Data in the abstract were updated in the presentation.
ICER assesses value of CAR T-cell therapies
The Institute for Clinical and Economic Review (ICER) has made policy recommendations intended to ensure affordability and access to chimeric antigen receptor (CAR) T-cell therapies.
ICER released a Final Evidence Report on tisagenlecleucel (Kymriah, Novartis) and axicabtagene ciloleucel (Yescarta, Kite Pharma/Gilead), 2 CAR T-cell therapies approved in the US to treat B-cell acute lymphoblastic leukemia (B-ALL) and non-Hodgkin lymphoma (NHL), respectively.
The report says the pricing of these therapies aligns with patient benefit, but changes will be needed in future pricing, payment, and delivery mechanisms to ensure patient access without threatening health system affordability.
“Given the currently available evidence, these therapies appear to be effective options for those with B-ALL or NHL, though uncertainty in the evidence raised questions around the long-term value for money,” said Dan Ollendorf, PhD, ICER’s chief scientific officer.
Net health benefit
ICER’s report says tisagenlecleucel provides a net health benefit for children with B-ALL, and both tisagenlecleucel and axicabtagene ciloleucel provide a net health benefit for adults with certain types of NHL. (Novartis is seeking approval for tisagenlecleucel in NHL).
The evidence suggests there is at least a small net health benefit of the CAR T-cell therapies compared to other therapies. The benefit may be substantial, but uncertainties remain.
The data show complete remission (CR), disease-free survival (DFS), and overall survival (OS) rates are superior for NHL patients who receive axicabtagene ciloleucel, compared to patients who receive standard chemoimmunotherapy regimens.
Similarly, B-ALL patients treated with tisagenlecleucel have superior CR, DFS, and OS rates to patients treated with standard therapies. CR and OS rates are also superior in NHL patients treated with tisagenlecleucel, but DFS has not been reported in this population.
The report says there is insufficient evidence to distinguish between the 2 CAR T-cell therapies for the treatment of NHL.
Toxicity and uncertainty
The report highlights the fact that cytokine release syndrome, neurological symptoms, and B-cell aplasia have been observed in patients who receive CAR T-cell therapies. However, these sometimes severe adverse events are generally “manageable.”
In addition to toxicity, the report highlights sources of uncertainty. These include the fact that studies of tisagenlecleucel and axicabtagene ciloleucel are small, single-arm trials with short follow-up; comparisons with historical controls may be misleading; and improvements in the CAR T-cell manufacturing process may change outcomes.
Cost-effectiveness
The report states that the cost-effectiveness of each therapy fell below or within commonly cited thresholds of $50,000 to $150,000 per quality-adjusted life-year (QALY) over a lifetime.
For its analyses, ICER used the wholesale acquisition cost (WAC) plus an assumed hospital mark-up. The analyses were also based on the assumption that survival benefits observed in clinical trials would continue after the trials ended.
For tisagenlecleucel in pediatric B-ALL, the WAC is $475,000. The long-term cost-effectiveness compared to clofarabine is $45,871 per QALY gained.
For axicabtagene ciloleucel in adults with NHL, the WAC is $373,000. The long-term cost-effectiveness compared to salvage chemotherapy is $136,078 per QALY gained. The effectiveness assumptions for chemotherapy were based on an average of salvage chemotherapy regimens from the SCHOLAR-1 trial, and the cost assumptions were based on the cost of the R-DHAP (rituximab, dexamethasone, cytarabine, and cisplatin) regimen.
The report says tisagenlecleucel’s price would remain in alignment with value even if price premiums of 102% to 194% were applied.
Meanwhile, axicabtagene ciloleucel’s price could be increased by up to 11% and remain in alignment with the upper threshold ($150,000 per QALY gained) but would need to be discounted by 28% to align with the lower threshold ($100,000 per QALY gained).
Tisagenlecleucel, as a treatment for B-ALL, is not expected to cross the $915 million threshold for annual budget impact.
However, the short-term costs of axicabtagene ciloleucel for relapsed/refractory NHL could exceed the threshold. Only 38% of the estimated 5900 eligible patients could receive axicabtagene ciloleucel in a year before crossing the threshold.
Because of these findings, ICER issued an “Affordability and Access Alert” for axicabtagene ciloleucel.
This alert is intended to signal when the added costs associated with a new treatment may be difficult for the healthcare system to absorb over the short-term without displacing other needed services or contributing to unsustainable growth in healthcare insurance costs.
“Based on current evidence, both therapies appear to be priced in alignment with their clinical value, but there are potential short-term affordability concerns—for axicabtagene ciloleucel under its current indication and for both treatments should they receive future approvals for broader patient populations,” Dr Ollendorf said.
Panel voting results
ICER’s report was reviewed at a public meeting of the California Technology Assessment Forum on March 2.
Most of the panel said tisagenlecleucel provides intermediate long-term value for money when treating B-ALL. However, the significant uncertainty surrounding the long-term risks and benefits of the therapy precluded a high-value vote.
After deliberating on the value of axicabtagene ciloleucel to treat NHL, the panel’s votes were split between low-value and intermediate-value, driven by similar concerns about long-term uncertainty.
Policy recommendations
Following the voting session, ICER convened a policy roundtable of experts, including physicians, patient advocates, manufacturer representatives, and payer representatives.
Based on the roundtable discussion, ICER developed recommendations for enhanced stakeholder communication, innovative payment models, generation of additional evidence, settings of care, and patient education.
“With many other potentially transformative therapies in the pipeline, stakeholders must collaborate now to develop payment and delivery systems that can ensure timely patient access, manage short-term affordability for expensive one-time treatments, and continue to reward the innovation that brings these new treatments to market,” Dr Ollendorf said.
Some of ICER’s recommendations include:
- When launching novel therapies approved with limited clinical evidence, such as CAR T-cell therapies, manufacturers and payers should consider using a lower launch price that could be increased if substantial clinical benefits are confirmed or using a higher initial price tied to a requirement for refunds or rebates if real-world evidence fails to confirm high expectations.
- Outcomes-based pricing arrangements must be linked to “meaningful clinical outcomes assessed with sufficient follow up.”
- Hospital mark-up for CAR T-cell therapies “should reflect the expected additional cost for care delivered in the hospital, rather than a percentage of the drug cost to avoid perverse incentives in choosing the treatment location.”
- Initially, CAR T-cell therapies should be delivered in “manufacturer-accredited centers to ensure the quality and appropriateness of care.” Later, “centers of excellence accredited by specialty societies” can administer these therapies, as long as providers have “sufficient expertise” to manage serious side effects.
- Centers should ensure that patients understand what to expect from CAR T-cell therapy, including long-term consequences.
- Because additional evidence on CAR T-cell therapies is needed, all patients who receive these therapies should enter into a registry with planned long-term follow-up.
- Studies should determine the optimal timing of CAR T-cell therapy in the sequence of treatments for B-ALL and NHL.
Additional recommendations and more details are available in ICER’s report.
About ICER
ICER is an independent, non-profit research institute that produces reports analyzing evidence on the effectiveness and value of drugs and other medical services.
ICER’s reports include evidence-based calculations of prices for new drugs that reflect the degree of improvement expected in long-term patient outcomes, while also highlighting price levels that might contribute to unaffordable short-term cost growth for the overall healthcare system.
ICER’s reports incorporate input from stakeholders and are the subject of public hearings through 3 core programs: the California Technology Assessment Forum, the Midwest Comparative Effectiveness Public Advisory Council, and the New England Comparative Effectiveness Public Advisory Council.
These independent panels review ICER’s reports at public meetings to deliberate on the evidence and develop recommendations for how patients, clinicians, insurers, and policymakers can improve the quality and value of healthcare.
The Institute for Clinical and Economic Review (ICER) has made policy recommendations intended to ensure affordability and access to chimeric antigen receptor (CAR) T-cell therapies.
ICER released a Final Evidence Report on tisagenlecleucel (Kymriah, Novartis) and axicabtagene ciloleucel (Yescarta, Kite Pharma/Gilead), 2 CAR T-cell therapies approved in the US to treat B-cell acute lymphoblastic leukemia (B-ALL) and non-Hodgkin lymphoma (NHL), respectively.
The report says the pricing of these therapies aligns with patient benefit, but changes will be needed in future pricing, payment, and delivery mechanisms to ensure patient access without threatening health system affordability.
“Given the currently available evidence, these therapies appear to be effective options for those with B-ALL or NHL, though uncertainty in the evidence raised questions around the long-term value for money,” said Dan Ollendorf, PhD, ICER’s chief scientific officer.
Net health benefit
ICER’s report says tisagenlecleucel provides a net health benefit for children with B-ALL, and both tisagenlecleucel and axicabtagene ciloleucel provide a net health benefit for adults with certain types of NHL. (Novartis is seeking approval for tisagenlecleucel in NHL).
The evidence suggests there is at least a small net health benefit of the CAR T-cell therapies compared to other therapies. The benefit may be substantial, but uncertainties remain.
The data show complete remission (CR), disease-free survival (DFS), and overall survival (OS) rates are superior for NHL patients who receive axicabtagene ciloleucel, compared to patients who receive standard chemoimmunotherapy regimens.
Similarly, B-ALL patients treated with tisagenlecleucel have superior CR, DFS, and OS rates to patients treated with standard therapies. CR and OS rates are also superior in NHL patients treated with tisagenlecleucel, but DFS has not been reported in this population.
The report says there is insufficient evidence to distinguish between the 2 CAR T-cell therapies for the treatment of NHL.
Toxicity and uncertainty
The report highlights the fact that cytokine release syndrome, neurological symptoms, and B-cell aplasia have been observed in patients who receive CAR T-cell therapies. However, these sometimes severe adverse events are generally “manageable.”
In addition to toxicity, the report highlights sources of uncertainty. These include the fact that studies of tisagenlecleucel and axicabtagene ciloleucel are small, single-arm trials with short follow-up; comparisons with historical controls may be misleading; and improvements in the CAR T-cell manufacturing process may change outcomes.
Cost-effectiveness
The report states that the cost-effectiveness of each therapy fell below or within commonly cited thresholds of $50,000 to $150,000 per quality-adjusted life-year (QALY) over a lifetime.
For its analyses, ICER used the wholesale acquisition cost (WAC) plus an assumed hospital mark-up. The analyses were also based on the assumption that survival benefits observed in clinical trials would continue after the trials ended.
For tisagenlecleucel in pediatric B-ALL, the WAC is $475,000. The long-term cost-effectiveness compared to clofarabine is $45,871 per QALY gained.
For axicabtagene ciloleucel in adults with NHL, the WAC is $373,000. The long-term cost-effectiveness compared to salvage chemotherapy is $136,078 per QALY gained. The effectiveness assumptions for chemotherapy were based on an average of salvage chemotherapy regimens from the SCHOLAR-1 trial, and the cost assumptions were based on the cost of the R-DHAP (rituximab, dexamethasone, cytarabine, and cisplatin) regimen.
The report says tisagenlecleucel’s price would remain in alignment with value even if price premiums of 102% to 194% were applied.
Meanwhile, axicabtagene ciloleucel’s price could be increased by up to 11% and remain in alignment with the upper threshold ($150,000 per QALY gained) but would need to be discounted by 28% to align with the lower threshold ($100,000 per QALY gained).
Tisagenlecleucel, as a treatment for B-ALL, is not expected to cross the $915 million threshold for annual budget impact.
However, the short-term costs of axicabtagene ciloleucel for relapsed/refractory NHL could exceed the threshold. Only 38% of the estimated 5900 eligible patients could receive axicabtagene ciloleucel in a year before crossing the threshold.
Because of these findings, ICER issued an “Affordability and Access Alert” for axicabtagene ciloleucel.
This alert is intended to signal when the added costs associated with a new treatment may be difficult for the healthcare system to absorb over the short-term without displacing other needed services or contributing to unsustainable growth in healthcare insurance costs.
“Based on current evidence, both therapies appear to be priced in alignment with their clinical value, but there are potential short-term affordability concerns—for axicabtagene ciloleucel under its current indication and for both treatments should they receive future approvals for broader patient populations,” Dr Ollendorf said.
Panel voting results
ICER’s report was reviewed at a public meeting of the California Technology Assessment Forum on March 2.
Most of the panel said tisagenlecleucel provides intermediate long-term value for money when treating B-ALL. However, the significant uncertainty surrounding the long-term risks and benefits of the therapy precluded a high-value vote.
After deliberating on the value of axicabtagene ciloleucel to treat NHL, the panel’s votes were split between low-value and intermediate-value, driven by similar concerns about long-term uncertainty.
Policy recommendations
Following the voting session, ICER convened a policy roundtable of experts, including physicians, patient advocates, manufacturer representatives, and payer representatives.
Based on the roundtable discussion, ICER developed recommendations for enhanced stakeholder communication, innovative payment models, generation of additional evidence, settings of care, and patient education.
“With many other potentially transformative therapies in the pipeline, stakeholders must collaborate now to develop payment and delivery systems that can ensure timely patient access, manage short-term affordability for expensive one-time treatments, and continue to reward the innovation that brings these new treatments to market,” Dr Ollendorf said.
Some of ICER’s recommendations include:
- When launching novel therapies approved with limited clinical evidence, such as CAR T-cell therapies, manufacturers and payers should consider using a lower launch price that could be increased if substantial clinical benefits are confirmed or using a higher initial price tied to a requirement for refunds or rebates if real-world evidence fails to confirm high expectations.
- Outcomes-based pricing arrangements must be linked to “meaningful clinical outcomes assessed with sufficient follow up.”
- Hospital mark-up for CAR T-cell therapies “should reflect the expected additional cost for care delivered in the hospital, rather than a percentage of the drug cost to avoid perverse incentives in choosing the treatment location.”
- Initially, CAR T-cell therapies should be delivered in “manufacturer-accredited centers to ensure the quality and appropriateness of care.” Later, “centers of excellence accredited by specialty societies” can administer these therapies, as long as providers have “sufficient expertise” to manage serious side effects.
- Centers should ensure that patients understand what to expect from CAR T-cell therapy, including long-term consequences.
- Because additional evidence on CAR T-cell therapies is needed, all patients who receive these therapies should enter into a registry with planned long-term follow-up.
- Studies should determine the optimal timing of CAR T-cell therapy in the sequence of treatments for B-ALL and NHL.
Additional recommendations and more details are available in ICER’s report.
About ICER
ICER is an independent, non-profit research institute that produces reports analyzing evidence on the effectiveness and value of drugs and other medical services.
ICER’s reports include evidence-based calculations of prices for new drugs that reflect the degree of improvement expected in long-term patient outcomes, while also highlighting price levels that might contribute to unaffordable short-term cost growth for the overall healthcare system.
ICER’s reports incorporate input from stakeholders and are the subject of public hearings through 3 core programs: the California Technology Assessment Forum, the Midwest Comparative Effectiveness Public Advisory Council, and the New England Comparative Effectiveness Public Advisory Council.
These independent panels review ICER’s reports at public meetings to deliberate on the evidence and develop recommendations for how patients, clinicians, insurers, and policymakers can improve the quality and value of healthcare.
The Institute for Clinical and Economic Review (ICER) has made policy recommendations intended to ensure affordability and access to chimeric antigen receptor (CAR) T-cell therapies.
ICER released a Final Evidence Report on tisagenlecleucel (Kymriah, Novartis) and axicabtagene ciloleucel (Yescarta, Kite Pharma/Gilead), 2 CAR T-cell therapies approved in the US to treat B-cell acute lymphoblastic leukemia (B-ALL) and non-Hodgkin lymphoma (NHL), respectively.
The report says the pricing of these therapies aligns with patient benefit, but changes will be needed in future pricing, payment, and delivery mechanisms to ensure patient access without threatening health system affordability.
“Given the currently available evidence, these therapies appear to be effective options for those with B-ALL or NHL, though uncertainty in the evidence raised questions around the long-term value for money,” said Dan Ollendorf, PhD, ICER’s chief scientific officer.
Net health benefit
ICER’s report says tisagenlecleucel provides a net health benefit for children with B-ALL, and both tisagenlecleucel and axicabtagene ciloleucel provide a net health benefit for adults with certain types of NHL. (Novartis is seeking approval for tisagenlecleucel in NHL).
The evidence suggests there is at least a small net health benefit of the CAR T-cell therapies compared to other therapies. The benefit may be substantial, but uncertainties remain.
The data show complete remission (CR), disease-free survival (DFS), and overall survival (OS) rates are superior for NHL patients who receive axicabtagene ciloleucel, compared to patients who receive standard chemoimmunotherapy regimens.
Similarly, B-ALL patients treated with tisagenlecleucel have superior CR, DFS, and OS rates to patients treated with standard therapies. CR and OS rates are also superior in NHL patients treated with tisagenlecleucel, but DFS has not been reported in this population.
The report says there is insufficient evidence to distinguish between the 2 CAR T-cell therapies for the treatment of NHL.
Toxicity and uncertainty
The report highlights the fact that cytokine release syndrome, neurological symptoms, and B-cell aplasia have been observed in patients who receive CAR T-cell therapies. However, these sometimes severe adverse events are generally “manageable.”
In addition to toxicity, the report highlights sources of uncertainty. These include the fact that studies of tisagenlecleucel and axicabtagene ciloleucel are small, single-arm trials with short follow-up; comparisons with historical controls may be misleading; and improvements in the CAR T-cell manufacturing process may change outcomes.
Cost-effectiveness
The report states that the cost-effectiveness of each therapy fell below or within commonly cited thresholds of $50,000 to $150,000 per quality-adjusted life-year (QALY) over a lifetime.
For its analyses, ICER used the wholesale acquisition cost (WAC) plus an assumed hospital mark-up. The analyses were also based on the assumption that survival benefits observed in clinical trials would continue after the trials ended.
For tisagenlecleucel in pediatric B-ALL, the WAC is $475,000. The long-term cost-effectiveness compared to clofarabine is $45,871 per QALY gained.
For axicabtagene ciloleucel in adults with NHL, the WAC is $373,000. The long-term cost-effectiveness compared to salvage chemotherapy is $136,078 per QALY gained. The effectiveness assumptions for chemotherapy were based on an average of salvage chemotherapy regimens from the SCHOLAR-1 trial, and the cost assumptions were based on the cost of the R-DHAP (rituximab, dexamethasone, cytarabine, and cisplatin) regimen.
The report says tisagenlecleucel’s price would remain in alignment with value even if price premiums of 102% to 194% were applied.
Meanwhile, axicabtagene ciloleucel’s price could be increased by up to 11% and remain in alignment with the upper threshold ($150,000 per QALY gained) but would need to be discounted by 28% to align with the lower threshold ($100,000 per QALY gained).
Tisagenlecleucel, as a treatment for B-ALL, is not expected to cross the $915 million threshold for annual budget impact.
However, the short-term costs of axicabtagene ciloleucel for relapsed/refractory NHL could exceed the threshold. Only 38% of the estimated 5900 eligible patients could receive axicabtagene ciloleucel in a year before crossing the threshold.
Because of these findings, ICER issued an “Affordability and Access Alert” for axicabtagene ciloleucel.
This alert is intended to signal when the added costs associated with a new treatment may be difficult for the healthcare system to absorb over the short-term without displacing other needed services or contributing to unsustainable growth in healthcare insurance costs.
“Based on current evidence, both therapies appear to be priced in alignment with their clinical value, but there are potential short-term affordability concerns—for axicabtagene ciloleucel under its current indication and for both treatments should they receive future approvals for broader patient populations,” Dr Ollendorf said.
Panel voting results
ICER’s report was reviewed at a public meeting of the California Technology Assessment Forum on March 2.
Most of the panel said tisagenlecleucel provides intermediate long-term value for money when treating B-ALL. However, the significant uncertainty surrounding the long-term risks and benefits of the therapy precluded a high-value vote.
After deliberating on the value of axicabtagene ciloleucel to treat NHL, the panel’s votes were split between low-value and intermediate-value, driven by similar concerns about long-term uncertainty.
Policy recommendations
Following the voting session, ICER convened a policy roundtable of experts, including physicians, patient advocates, manufacturer representatives, and payer representatives.
Based on the roundtable discussion, ICER developed recommendations for enhanced stakeholder communication, innovative payment models, generation of additional evidence, settings of care, and patient education.
“With many other potentially transformative therapies in the pipeline, stakeholders must collaborate now to develop payment and delivery systems that can ensure timely patient access, manage short-term affordability for expensive one-time treatments, and continue to reward the innovation that brings these new treatments to market,” Dr Ollendorf said.
Some of ICER’s recommendations include:
- When launching novel therapies approved with limited clinical evidence, such as CAR T-cell therapies, manufacturers and payers should consider using a lower launch price that could be increased if substantial clinical benefits are confirmed or using a higher initial price tied to a requirement for refunds or rebates if real-world evidence fails to confirm high expectations.
- Outcomes-based pricing arrangements must be linked to “meaningful clinical outcomes assessed with sufficient follow up.”
- Hospital mark-up for CAR T-cell therapies “should reflect the expected additional cost for care delivered in the hospital, rather than a percentage of the drug cost to avoid perverse incentives in choosing the treatment location.”
- Initially, CAR T-cell therapies should be delivered in “manufacturer-accredited centers to ensure the quality and appropriateness of care.” Later, “centers of excellence accredited by specialty societies” can administer these therapies, as long as providers have “sufficient expertise” to manage serious side effects.
- Centers should ensure that patients understand what to expect from CAR T-cell therapy, including long-term consequences.
- Because additional evidence on CAR T-cell therapies is needed, all patients who receive these therapies should enter into a registry with planned long-term follow-up.
- Studies should determine the optimal timing of CAR T-cell therapy in the sequence of treatments for B-ALL and NHL.
Additional recommendations and more details are available in ICER’s report.
About ICER
ICER is an independent, non-profit research institute that produces reports analyzing evidence on the effectiveness and value of drugs and other medical services.
ICER’s reports include evidence-based calculations of prices for new drugs that reflect the degree of improvement expected in long-term patient outcomes, while also highlighting price levels that might contribute to unaffordable short-term cost growth for the overall healthcare system.
ICER’s reports incorporate input from stakeholders and are the subject of public hearings through 3 core programs: the California Technology Assessment Forum, the Midwest Comparative Effectiveness Public Advisory Council, and the New England Comparative Effectiveness Public Advisory Council.
These independent panels review ICER’s reports at public meetings to deliberate on the evidence and develop recommendations for how patients, clinicians, insurers, and policymakers can improve the quality and value of healthcare.