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Purpose: Axicabtagene ciloleucel (axi-cel) is an autologous CD19 chimeric antigen receptor (CAR) T-cell therapy that is approved for the treatment of relapsed or refractory large B-cell lymphoma. Little is known about the long-term survivorship after CAR T-cell therapy., Methods: We previously reported the results of 298 patients who were leukapheresed with the intent to receive standard-of-care axi-cel (n = 275 infused) after two or more previous lines of therapy at a median follow-up of 12.9 months. Here, we report extended follow-up of this cohort to a median of 58 months, with a focus on late survivorship events., Results: Among axi-cel-infused patients, progression-free survival at 5 years was 29% and overall survival (OS) at 5 years was 40%. The 5-year lymphoma-specific survival was 53% with infrequent late relapses. However, the 5-year nonrelapse mortality (NRM) was 16.2%, with over half of NRM events occurring beyond 2 years. Patients who were 60 years and older had a lower risk of relapse ( P = .02), but a higher risk of NRM compared with patients younger than 60 years (NRM odds ratio, 4.5 [95% CI, 2.1 to 10.8]; P < .001). Late NRM was mainly due to infections and subsequent malignant neoplasms (SMNs). In total, SMNs occurred in 24 patients (9%), including therapy-related myeloid neoplasms (n = 15), solid tumors (n = 7), and unrelated lymphoid malignancies (n = 2)., Conclusion: In the standard-of-care setting, axi-cel exhibits outcomes consistent with those reported in clinical trials, with sustained, durable responses observed at the 5-year time point. However, late infections and the development of SMN are key survivorship issues that reduce long-term survival after CAR T-cell therapy, particularly in the elderly.

Introduction: Chimeric antigen receptor T-cell (CAR T) therapies have transformed diffuse large B-cell lymphoma (DLBCL) treatment. It is important to better understand their use in Medicare Fee-for-Service (FFS) patients, who often differ from commercially insured populations in important ways., Methods: We analyzed Medicare FFS claims data, focusing on the utilization patterns across three CAR T products-lisocabtagene maraleucel (liso-cel), tisagenlecleucel (tisa-cel), and axicabtagene autoleucel (axi-cel)-which are indicated for the treatment of DLBCL. Our investigation covered the period from 2021 through 2022. This analysis spanned a 180-day period prior to CAR T procedure and extended to a 90-day post-CAR T. Utilization of healthcare services, healthcare spending, and comorbidities were assessed in the pre- and post-periods. Clinical trial and PPS-exempt center claims were removed from the analysis. Statistical comparisons between inpatient and outpatient cohorts were made using Wilcoxon's rank-sum tests for continuous variables and Chi-square tests or Fisher's exact tests for categorical variables., Results: Among the total 391 CAR T claims assessed, most of the CAR T therapies were administered in the inpatient setting (79%) compared to outpatient (21%). CAR T therapy in the inpatient setting received an average Medicare cost of US$498,723 ($276,138-$1,066,524), while the average Medicare cost for outpatient CAR T claims was $414,393 ($276,980-$849,878). There was a higher 3-month average post-period cost for those hospitals utilizing CAR T in the outpatient setting than the inpatient setting ($15,794 vs. $10,244). Despite the higher post-period cost, when looking at the CAR T procedure and pre- and post-periods as a single episode, beneficiaries receiving outpatient CAR T had less cost for the total episode of care ($587,908 vs. $529,188). Follow-up inpatient claims were also assessed post-CAR T procedure for 30 days. The rate of post-CAR T inpatient re-admission was significantly lower for beneficiaries receiving the index CAR T in the inpatient setting (21%) compared to outpatient CAR T (59%). Days between index CAR T discharge and IP admission were also significantly shorter for OP CAR T compared to IP CAR T (8.0 vs. 14.1 days, p < 0.0001). Additionally, IP CAR T had a longer ALOS on the admission claim (6.9 vs. 6.2 days)., Conclusion: CAR T therapy for the treatment of LBCL has become more common within the Medicare population, primarily in the inpatient setting. This study helps understand providers' cost and associated patient care around CAR T administration. The data show that the average cost received by hospitals encompasses the expenses related to both the CAR T drug and the medical services delivered to patients., (© 2024. The Author(s).)

Abstract: Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for relapsed/refractory (R/R) large B-cell lymphoma (LBCL). Despite extensive data supporting its use, outcomes stratified by race and ethnicity groups are limited. Here, we report clinical outcomes with axi-cel in patients with R/R LBCL by race and ethnicity in both real-world and clinical trial settings. In the real-world setting, 1290 patients who received axi-cel between 2017 and 2020 were identified from the Center for International Blood and Marrow Transplant Research database; 106 and 169 patients were included from the ZUMA-1 and ZUMA-7 trials, respectively. Overall survival was consistent across race/ethnicity groups. However, non-Hispanic (NH) Black patients had lower overall response rate (OR, 0.37; 95% CI, 0.22-0.63) and lower complete response rate (OR, 0.57; 95% CI, 0.33-0.97) than NH White patients. NH Black patients also had a shorter progression-free survival vs NH White (HR, 1.41; 95% CI, 1.04-1.90) and NH Asian patients (HR, 1.67; 95% CI, 1.08-2.59). NH Asian patients had a longer duration of response than NH White (HR, 0.56; 95% CI, 0.33-0.94) and Hispanic patients (HR, 0.54; 95% CI, 0.30-0.97). There was no difference in cytokine release syndrome by race/ethnicity; however, higher rates of any-grade immune effector cell-associated neurotoxicity syndrome were observed in NH White patients than in other patients. These results provide important context when treating patients with R/R LBCL with CAR T-cell therapy across different racial and ethnic groups. ZUMA-1 and ZUMA-7 (ClinicalTrials.gov identifiers: #NCT02348216 and #NCT03391466, respectively) are registered on ClinicalTrials.gov., (© 2024 American Society of Hematology. Published by Elsevier Inc. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: The prognosis of patients with early relapsed or refractory large B-cell lymphoma after the receipt of first-line chemoimmunotherapy is poor., Methods: In this international, phase 3 trial, we randomly assigned, in a 1:1 ratio, patients with large B-cell lymphoma that was refractory to or had relapsed no more than 12 months after first-line chemoimmunotherapy to receive axicabtagene ciloleucel (axi-cel, an autologous anti-CD19 chimeric antigen receptor T-cell therapy) or standard care (two or three cycles of investigator-selected, protocol-defined chemoimmunotherapy, followed by high-dose chemotherapy with autologous stem-cell transplantation in patients with a response to the chemoimmunotherapy). The primary end point was event-free survival according to blinded central review. Key secondary end points were response and overall survival. Safety was also assessed., Results: A total of 180 patients were randomly assigned to receive axi-cel and 179 to receive standard care. The primary end-point analysis of event-free survival showed that axi-cel therapy was superior to standard care. At a median follow-up of 24.9 months, the median event-free survival was 8.3 months in the axi-cel group and 2.0 months in the standard-care group, and the 24-month event-free survival was 41% and 16%, respectively (hazard ratio for event or death, 0.40; 95% confidence interval, 0.31 to 0.51; P<0.001). A response occurred in 83% of the patients in the axi-cel group and in 50% of those in the standard-care group (with a complete response in 65% and 32%, respectively). In an interim analysis, the estimated overall survival at 2 years was 61% in the axi-cel group and 52% in the standard-care group. Adverse events of grade 3 or higher occurred in 91% of the patients who received axi-cel and in 83% of those who received standard care. Among patients who received axi-cel, grade 3 or higher cytokine release syndrome occurred in 6% and grade 3 or higher neurologic events in 21%. No deaths related to cytokine release syndrome or neurologic events occurred., Conclusions: Axi-cel therapy led to significant improvements, as compared with standard care, in event-free survival and response, with the expected level of high-grade toxic effects. (Funded by Kite; ZUMA-7 ClinicalTrials.gov number, NCT03391466.)., (Copyright © 2021 Massachusetts Medical Society.)

Background: Despite treatment with novel therapies and allogeneic stem-cell transplant (allo-SCT) consolidation, outcomes in adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia remain poor, underlining the need for more effective therapies., Methods: We report the pivotal phase 2 results of ZUMA-3, an international, multicentre, single-arm, open-label study evaluating the efficacy and safety of the autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy KTE-X19 in adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia. Patients were enrolled at 25 sites in the USA, Canada, and Europe. Eligible patients were aged 18 years or older, with Eastern Cooperative Oncology Group performance status of 0-1, and morphological disease in the bone marrow (>5% blasts). After leukapheresis and conditioning chemotherapy, patients received a single KTE-X19 infusion (1 × 10 6 CAR T cells per kg bodyweight). The primary endpoint was the rate of overall complete remission or complete remission with incomplete haematological recovery by central assessment. Duration of remission and relapse-free survival, overall survival, minimal residual disease (MRD) negativity rate, and allo-SCT rate were assessed as secondary endpoints. Efficacy and safety analyses were done in the treated population (all patients who received a dose of KTE-X19). This study is registered with ClinicalTrials.gov, NCT02614066., Findings: Between Oct 1, 2018, and Oct 9, 2019, 71 patients were enrolled and underwent leukapheresis. KTE-X19 was successfully manufactured for 65 (92%) patients and administered to 55 (77%). The median age of treated patients was 40 years (IQR 28-52). At the median follow-up of 16·4 months (13·8-19·6), 39 patients (71%; 95% CI 57-82, p<0·0001) had complete remission or complete remission with incomplete haematological recovery, with 31 (56%) patients reaching complete remission. Median duration of remission was 12·8 months (95% CI 8·7-not estimable), median relapse-free survival was 11·6 months (2·7-15·5), and median overall survival was 18·2 months (15·9-not estimable). Among responders, the median overall survival was not reached, and 38 (97%) patients had MRD negativity. Ten (18%) patients received allo-SCT consolidation after KTE-X19 infusion. The most common adverse events of grade 3 or higher were anaemia (27 [49%] patients) and pyrexia (20 [36%] patients). 14 (25%) patients had infections of grade 3 or higher. Two grade 5 KTE-X19-related events occurred (brain herniation and septic shock). Cytokine release syndrome of grade 3 or higher occurred in 13 (24%) patients and neurological events of grade 3 or higher occurred in 14 (25%) patients., Interpretation: KTE-X19 showed a high rate of complete remission or complete remission with incomplete haematological recovery in adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia, with the median overall survival not reached in responding patients, and a manageable safety profile. These findings indicate that KTE-X19 has the potential to confer long-term clinical benefit to these patients., Funding: Kite, a Gilead Company., Competing Interests: Declaration of interests BDS reports honoraria from Kite, a Gilead Company, and BeiGene; a consultancy or advisory role for BeiGene, Pepromene Bio, Kite, a Gilead Company, Celgene, Bristol Myers Squibb (BMS), Juno, Novartis, Pfizer, Amgen, Precision Biosciences, Adaptive Biotechnologies, and Jazz Pharmaceuticals; research funding from Kite, a Gilead Company, Jazz Pharmaceuticals, Incyte, Chotiner Pediatric Research Foundation, Lymphoma Research Foundation, and the National Institutes of Health; travel support from Kite, a Gilead Company; a leadership or fiduciary role for the National Cancer Center Network, the International Working Group for Acute Leukemia and CAR T, and the Society of Hematologic Oncology; and payment for expert testimony from Bayer. AG reports consultancy or advisory role for Amgen, Kite, a Gilead Company, Atara, Wugen, and Celgene; and research funding from Amgen and Kite, a Gilead Company. OOO reports a consultancy or advisory role for Kite, a Gilead Company, Pfizer, and Janssen; and research funding from Kite, a Gilead Company. ACL reports honoraria from Amgen; a consultancy or advisory role for Amgen, Pfizer, BMS, and Incyte; and research funding from Autolus, Amphivena, Astellas, Jazz Pharmaceuticals, Kadmon, Kite, a Gilead Company, and Pharmacyclics. NB reports honoraria from Servier and Jazz Pharmaceuticals; a consultancy or advisory role for Amgen, Pfizer, Gilead Sciences, Novartis, Jazz Pharmaceuticals, and Servier; and travel support from Amgen. RDC reports employment with Seagen; stock or other ownership in Seagen; honoraria from Pfizer; a consultancy or advisory role for Kite, a Gilead Company, Pfizer, Amgen, and Pepromene Bio; research funding from Pfizer, Merck, Amgen, Kite, a Gilead Company, and Vanda; and travel support from Pfizer. MRBi reports honoraria from Kite, a Gilead Company; a consultancy or advisory role for Kite, a Gilead Company; and speakers' bureau participation for Kite, a Gilead Company. MST reports consultancy or advisory role for Gilead Sciences, Roche, and Regeneron; and research funding from Amgen, Kite, a Gilead Company, Roche, MacroGenics, and Regeneron. DT reports a consultancy or advisory role for Takeda and Kite, a Gilead Company; speakers' bureau participation for Takeda and Kite, a Gilead Company; and research funding from BMS. KMO reports a consultancy or advisory role for Beam Therapeutics. MLA reports a consultancy or advisory role for Gilead Sciences, Kite, a Gilead Company, and Syndax Pharmaceuticals. YL reports a consultancy or advisory role for Kite, a Gilead Company, Celgene, Juno, Bluebird Bio, Janssen, Legend, Gamida Cell, Novartis, Iovance, Takeda, Fosun Kite, and Sorrento; and research funding from Kite, a Gilead Company, Celgene, Bluebird Bio, Janssen, Legend, Merck, Takeda, and Boston Scientific. GJS reports honoraria from Kite, a Gilead Company. JHP reports honoraria from Clinical Care Options and Aptitude Health; a consultancy or advisory role for Kite, a Gilead Company, Novartis, AstraZeneca, Amgen, Autolus, Allogene, Artiva, Baxalta, Curocell, GlaxoSmithKline, Incyte, Innate Pharma, Intellia, Kura Oncology, Minerva, Pfizer, Takeda, Umoja, Affyimmune, and Bright Pharmaceutical Services. MA reports consultancy or advisory role for Celgene; speakers' bureau participation for BMS and Kite, a Gilead Company; and research funding from the National Institutes of Health and California Institute for Regenerative Medicine. MCM reports honoraria from Gilead Sciences, Janssen-Cilag, BMS, Roche, and Celgene; a consultancy or advisory role for Janssen-Cilag, Takeda, and Alnylam; travel support from Celgene; and a leadership or fiduciary role for diagnostic guidelines for plasma cell dyscrasias and treatment guidelines for amyloid light-chain amyloidosis in the Netherlands. DJD reports honoraria from AbbVie, Amgen, Agios, Autolus, Blueprint Medicines, Forty Seven, GlycoMimetics, Incyte, Jazz Pharmaceuticals, Novartis, Pfizer, Servier, and Takeda; a consultancy or advisory role for Daiichi-Sankya, FibroGen, and Mount Sinai Hospital; research funding from AbbVie, GlycoMimetics, Novartis, and Blueprint Medicines; and travel support from GlycoMimetics. PS reports research funding from Kite, a Gilead Company. DJ reports research funding from Pfizer and Jazz Pharmaceuticals. CF and JMR report employment with Kite, a Gilead Company; and stock or other ownership in Gilead Sciences. JD reports employment with Kite, a Gilead Company; and stock or other ownership in Kite, a Gilead Company. TS reports employment with Kite, a Gilead Company; stock or other ownership in Kite, a Gilead Company; research funding from Kite, a Gilead Company; and travel support from Kite, a Gilead Company. FM reports employment with Kite, a Gilead Company; stock or other ownership in Gilead Sciences; and travel support from Kite, a Gilead Company. RV reports employment with Kite, a Gilead Company. BKM reports employment with Kite, a Gilead Company; and stock or other ownership in Kite, a Gilead Company, GlaxoSmithKline, Immatics, Novartis, BMS, and Roche. RH reports consultancy or advisory role for Kite, a Gilead Company; research funding from Kite, a Gilead Company; and travel support from Kite, a Gilead Company. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

ZUMA-3 is a phase 1/2 study evaluating KTE-X19, an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, in adult relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL). We report the phase 1 results. After fludarabine-cyclophosphamide lymphodepletion, patients received a single infusion of KTE-X19 at 2 × 106, 1 × 106, or 0.5 × 106 cells per kg. The rate of dose-limiting toxicities (DLTs) within 28 days after KTE-X19 infusion was the primary end point. KTE-X19 was manufactured for 54 enrolled patients and administered to 45 (median age, 46 years; range, 18-77 years). No DLTs occurred in the DLT-evaluable cohort. Grade ≥3 cytokine release syndrome (CRS) and neurologic events (NEs) occurred in 31% and 38% of patients, respectively. To optimize the risk-benefit ratio, revised adverse event (AE) management for CRS and NEs (earlier steroid use for NEs and tocilizumab only for CRS) was evaluated at 1 × 106 cells per kg KTE-X19. In the 9 patients treated under revised AE management, 33% had grade 3 CRS and 11% had grade 3 NEs, with no grade 4 or 5 NEs. The overall complete remission rate correlated with CAR T-cell expansion and was 83% in patients treated with 1 × 106 cells per kg and 69% in all patients. Minimal residual disease was undetectable in all responding patients. At a median follow-up of 22.1 months (range, 7.1-36.1 months), the median duration of remission was 17.6 months (95% confidence interval [CI], 5.8-17.6 months) in patients treated with 1 × 106 cells per kg and 14.5 months (95% CI, 5.8-18.1 months) in all patients. KTE-X19 treatment provided a high response rate and tolerable safety in adults with R/R B-ALL. Phase 2 is ongoing at 1 × 106 cells per kg with revised AE management. This trial is registered at www.clinicaltrials.gov as #NCT02614066., (© 2021 by The American Society of Hematology.)

ZUMA-1 demonstrated a high rate of durable response and a manageable safety profile with axicabtagene ciloleucel (axi-cel), an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, in patients with refractory large B-cell lymphoma. As previously reported, prespecified clinical covariates for secondary end point analysis were not clearly predictive of efficacy; these included Eastern Cooperative Oncology Group performance status (0 vs 1), age, disease subtype, disease stage, and International Prognostic Index score. We interrogated covariates included in the statistical analysis plan and an extensive panel of biomarkers according to an expanded translational biomarker plan. Univariable and multivariable analyses indicated that rapid CAR T-cell expansion commensurate with pretreatment tumor burden (influenced by product T-cell fitness), the number of CD8 and CCR7+CD45RA+ T cells infused, and host systemic inflammation, were the most significant determining factors for durable response. Key parameters differentially associated with clinical efficacy and toxicities, with both theoretical and practical implications for optimizing CAR T-cell therapy. This trial was registered at www.clinicaltrials.gov as #NCT02348216., (© 2020 by The American Society of Hematology.)

On August 30, 2017 the US Food and Drug Administration approved tisagenlecleucel (Kymriah; Novartis, Basel, Switzerland), a synthetic bioimmune product of anti-CD19 chimeric antigen receptor T cells (CAR-T), for the treatment of children and young adults with relapsed/refractory B cell acute lymphoblastic leukemia (B-ALL). With this new era of personalized cancer immunotherapy, multiple challenges are present, ranging from implementation of a CAR-T program to safe delivery of the drug, long-term toxicity monitoring, and disease assessments. To address these issues experts representing the American Society for Blood and Marrow Transplant, the European Society for Blood and Marrow Transplantation, the International Society of Cell and Gene Therapy, and the Foundation for the Accreditation of Cellular Therapy formed a global CAR-T task force to identify and address key questions pertinent for hematologists and transplant physicians regarding the clinical use of anti CD19 CAR-T therapy in patients with B-ALL. This article presents an initial roadmap for navigating common clinical practice scenarios that will become more prevalent now that the first commercially available CAR-T product for B-ALL has been approved., (Copyright © 2018 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

T cell malignancies represent a group of hematologic cancers with high rates of relapse and mortality in patients for whom no effective targeted therapies exist. The shared expression of target antigens between chimeric antigen receptor (CAR) T cells and malignant T cells has limited the development of CAR-T because of unintended CAR-T fratricide and an inability to harvest sufficient autologous T cells. Here, we describe a fratricide-resistant "off-the-shelf" CAR-T (or UCART7) that targets CD7+ T cell malignancies and, through CRISPR/Cas9 gene editing, lacks both CD7 and T cell receptor alpha chain (TRAC) expression. UCART7 demonstrates efficacy against human T cell acute lymphoblastic leukemia (T-ALL) cell lines and primary T-ALL in vitro and in vivo without the induction of xenogeneic GvHD. Fratricide-resistant, allo-tolerant "off-the-shelf" CAR-T represents a strategy for treatment of relapsed and refractory T-ALL and non-Hodgkin's T cell lymphoma without a requirement for autologous T cells.

Non-Hodgkin Lymphoma (NHL) is the most common hematologic malignancy. More than 20,000 people in United States, more than 37,000 people in Europe and more than 199,000 people worldwide die of NHL every year. Recent advances in immunotherapeutic approaches for cancer have resulted in development of new classes of very effective immunotherapeutic approaches including chimeric antigen receptor T (CAR-T) cell therapy that are designed to bypass cancer immune evasion. Here, we review recent advances in CAR-T cell therapy for NHL. US food and drug administration (FDA) recently approved axicabtagene ciloleucel (Yescarta) a CD19 CAR T cell therapy for treatment of relapsed refractory diffuse large B cell lymphoma (DLBCL), high grade lymphoma, and primary mediastinal B cell lymphoma (PMBCL). Approval of Yescarta and rapid development of other CAR T cell therapies at various stages of development are opening up the door for a new wave of CAR T cell therapies that will dramatically change the way we treat NHL and hopefully other malignancies in the near future., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

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 2×10 6 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 .).