Dataset Information

Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma.

ABSTRACT: BACKGROUND:In a phase 1 trial, axicabtagene ciloleucel (axi-cel), an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, showed efficacy in patients with refractory large B-cell lymphoma after the failure of conventional therapy. METHODS:In this multicenter, phase 2 trial, we enrolled 111 patients with diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, or transformed follicular lymphoma who had refractory disease despite undergoing recommended prior therapy. Patients received a target dose of 2×106 anti-CD19 CAR T cells per kilogram of body weight after receiving a conditioning regimen of low-dose cyclophosphamide and fludarabine. The primary end point was the rate of objective response (calculated as the combined rates of complete response and partial response). Secondary end points included overall survival, safety, and biomarker assessments. RESULTS:Among the 111 patients who were enrolled, axi-cel was successfully manufactured for 110 (99%) and administered to 101 (91%). The objective response rate was 82%, and the complete response rate was 54%.With a median follow-up of 15.4 months, 42% of the patients continued to have a response, with 40% continuing to have a complete response. The overall rate of survival at 18 months was 52%. The most common adverse events of grade 3 or higher during treatment were neutropenia (in 78% of the patients), anemia (in 43%), and thrombocytopenia (in 38%). Grade 3 or higher cytokine release syndrome and neurologic events occurred in 13% and 28% of the patients, respectively. Three of the patients died during treatment. Higher CAR T-cell levels in blood were associated with response. CONCLUSIONS:In this multicenter study, patients with refractory large B-cell lymphoma who received CAR T-cell therapy with axi-cel had high levels of durable response, with a safety profile that included myelosuppression, the cytokine release syndrome, and neurologic events. (Funded by Kite Pharma and the Leukemia and Lymphoma Society Therapy Acceleration Program; ZUMA-1 ClinicalTrials.gov number, NCT02348216 .).

SUBMITTER: Neelapu SS

PROVIDER: S-EPMC5882485 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma.

Neelapu Sattva S SS Locke Frederick L FL Bartlett Nancy L NL Lekakis Lazaros J LJ Miklos David B DB Jacobson Caron A CA Braunschweig Ira I Oluwole Olalekan O OO Siddiqi Tanya T Lin Yi Y Timmerman John M JM Stiff Patrick J PJ Friedberg Jonathan W JW Flinn Ian W IW Goy Andre A Hill Brian T BT Smith Mitchell R MR Deol Abhinav A Farooq Umar U McSweeney Peter P Munoz Javier J Avivi Irit I Castro Januario E JE Westin Jason R JR Chavez Julio C JC Ghobadi Armin A Komanduri Krishna V KV Levy Ronald R Jacobsen Eric D ED Witzig Thomas E TE Reagan Patrick P Bot Adrian A Rossi John J Navale Lynn L Jiang Yizhou Y Aycock Jeff J Elias Meg M Chang David D Wiezorek Jeff J Go William Y WY

The New England journal of medicine 20171210 26

<h4>Background</h4>In a phase 1 trial, axicabtagene ciloleucel (axi-cel), an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, showed efficacy in patients with refractory large B-cell lymphoma after the failure of conventional therapy.<h4>Methods</h4>In this multicenter, phase 2 trial, we enrolled 111 patients with diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, or transformed follicular lymphoma who had refractory disease despite undergoing recommended pri ...[more]

PMID: 29226797

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Project description:PurposeAxicabtagene ciloleucel (axi-cel) is a CD19-directed chimeric antigen receptor (CAR) T-cell therapy for relapsed or refractory diffuse large B-cell lymphoma. Bridging therapy may be required for lymphoma control during the manufacturing interval between collection of autologous T cells and final CAR T product administration. The optimal bridging therapy is not known and patients are often chemorefractory. We present a case series of patients receiving radiation as a bridge to axi-cel.Methods and materialsBetween December 2017 and October 2018, 12 patients were intended to receive bridging radiation before axi-cel. The group was characterized by highly aggressive disease including 6 of 12 with "double hit" lymphoma and 6 of 12 with disease ≥10 cm in diameter. All patients received 2 to 4 Gy/fraction to a median dose of 20 Gy (range, 6-36.5 Gy). Half of patients received either 30 Gy in 10 fractions or 20 Gy in 5 fractions. Seven patients received concurrent chemotherapy. Eleven patients underwent axi-cel infusion and one did not. Median follow-up was 3.3 months (range, 1.1-12.0 months).ResultsNo significant toxicities were identified during bridging radiation, and no patient experienced in-field progression of disease before axi-cel infusion. One patient experienced abdominal pain, which resolved after dose reduction. Two patients had out-of-field progression of disease during the bridging period. After axi-cel infusion, 3 of 11 patients (27%) experienced severe cytokine release syndrome or neurotoxicity. At 30 days, the objective response rate was 81.8% (11 of 12 evaluable; 1 stable disease, 1 out-of-field progression), with complete response in 27% (3 of 11). At last follow-up, the best objective response rate was 81.8%, with a complete response attained in 45% (5 of 11). Lymphocyte counts decreased slightly in 10 of 12 patients during radiation (median, 0.25 k/uL).ConclusionsRadiation (with or without concurrent chemotherapy) can be safely administered as a bridge to axi-cel in high-risk lymphoma. Caution should be taken if irradiation is started before apheresis, and lymphocyte counts should be monitored closely throughout. Future investigation is warranted to optimize the use of bridging radiation before CAR T therapy.

Project description:The ZUMA-7 (Efficacy of Axicabtagene Ciloleucel Compared to Standard of Care Therapy in Subjects With Relapsed/Refractory Diffuse Large B Cell Lymphoma) study showed that axicabtagene ciloleucel (axi-cel) improved event-free survival (EFS) compared with standard of care (SOC) salvage chemoimmunotherapy followed by autologous stem cell transplant in primary refractory/early relapsed diffuse large B-cell lymphoma (DLBCL); this led to its recent US Food and Drug Administration approval in this setting. We modeled a hypothetical cohort of US adults (mean age, 65 years) with primary refractory/early relapsed DLBCL by developing a Markov model (lifetime horizon) to model the cost-effectiveness of second-line axi-cel compared with SOC using a range of plausible long-term outcomes. EFS and OS were estimated from ZUMA-7. Outcome measures were reported in incremental cost-effectiveness ratios, with a willingness-to-pay (WTP) threshold of $150 000 per quality-adjusted life-year (QALY). Assuming a 5-year EFS of 35% with second-line axi-cel and 10% with SOC, axi-cel was cost-effective at a WTP of $150 000 per QALY ($93 547 per QALY). axi-cel was no longer cost-effective if its 5-year EFS was ≤26.4% or if it cost more than $972 061 at a WTP of $150 000. Second-line axi-cel was the cost-effective strategy in 73% of the 10 000 Monte Carlo iterations at a WTP of $150 000. If the absolute benefit in EFS is maintained over time, second-line axi-cel for aggressive relapsed/refractory DLBCL is cost-effective compared with SOC at a WTP of $150 000 per QALY. However, its cost-effectiveness is highly dependent on long-term outcomes. Routine use of second-line chimeric antigen receptor T-cell therapy would add significantly to health care expenditures in the United States (more than $1 billion each year), even when used in a high-risk subpopulation. Further reductions in the cost of chimeric antigen receptor T-cell therapy are needed to be affordable in many regions of the world.

Project description:ImportanceChimeric antigen receptor (CAR) T cell therapies are approved as a third-line or later therapy for several hematological malignant neoplasms. Recently, randomized clinical trials have investigated their efficacy as a second-line treatment in high-risk relapsed or refractory diffuse large B-cell lymphoma (DLBCL) compared with salvage chemotherapy followed by hematopoietic stem cell transplantation (HSCT).ObjectiveTo evaluate the cost-effectiveness of axicabtagene ciloleucel and tisagenlecleucel vs standard care (SC) as second-line or later therapy for relapsed or refractory DLBCL, from both US health care sector and societal perspectives at a cost-effectiveness threshold of $150 000 per quality-adjusted life-year (QALY).Design, setting, and participantsThis economic evaluation assessed cost-effectiveness using a partitioned survival model with 2021 US dollars and QALYs over a lifetime horizon. Model inputs were derived from 2 randomized clinical trials (ZUMA-7 and BELINDA) and published literature. In the trials, patients who did not respond to SC received CAR T cells (treatment switching or crossover), either outside the protocol (ZUMA-7) or as part of the protocol (BELINDA). A separate scenario analysis compared second-line axicabtagene ciloleucel with SC alone without treatment crossover to CAR T cell therapy. Data analysis was performed from December 18, 2021, to September 13, 2022.ExposuresCAR T cell therapy (axicabtagene ciloleucel and tisagenlecleucel) compared with salvage chemotherapy followed by HSCT.Main outcomes and measuresCosts and QALYs were used to derive incremental cost-effectiveness ratios (ICERs) for the health care sector and societal perspectives. Cost and QALYs were discounted at 3.0% annually. Univariate and multivariate probabilistic sensitivity analysis using 10 000 Monte Carlo simulations were applied to test model uncertainty on the ICER.ResultsSecond-line axicabtagene ciloleucel was associated with an ICER of $99 101 per QALY from the health care sector perspective and an ICER of $97 977 per QALY from the societal perspective, while second-line tisagenlecleucel was dominated by SC (incremental costs of $37 803 from the health care sector and $39 480 from the societal perspective with decremental QALY of -0.02). Third-line or later tisagenlecleucel was associated with an ICER of $126 593 per QALY from the health care sector perspective and an ICER of $128 012 per QALY from the societal perspective. Based on the scenario analysis of no treatment switching, second-line axicabtagene ciloleucel yielded an ICER of $216 790 per QALY from the health care sector perspective and an ICER of $218 907 per QALY from the societal perspective, compared with SC. When accounting for patients achieving prolonged progression-free survival who would not incur progression-related costs, in this scenario ICER changed to $125 962 per QALY from the health care sector perspective and $122 931 per QALY from the societal perspective. These results were most sensitive to increased list prices of CAR T cell therapy and QALY losses associated with axicabtagene ciloleucel and tisagenlecleucel.Conclusions and relevanceThese findings suggest that second-line axicabtagene ciloleucel and third-line or later tisagenlecleucel were cost-effective in treating patients with relapsed or refractory DLBCL at the cost-effectiveness threshold of $150 000 per QALY. However, uncertainty remains regarding the best candidates who would experience value gains from receiving CAR T cell therapy.

Dataset Information

Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma.

Publications

Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma.

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