Clinical Practice Recommendations for Hematopoietic Cell Transplantation and Cellular Therapies in Follicular Lymphoma: A Collaborative Effort on behalf of The American Society of Transplantation and Cellular Therapy and the European Society of Blood and Marrow Transplantation.

Follicular lymphoma (FL) is the most common indolent B-cell non-Hodgkin lymphoma (NHL), accounting for nearly one-third of all NHL. The therapeutic landscape for patients with FL has significantly expanded over the past decade, but the disease continues to be considered incurable. Hematopoietic cell transplantation (HCT) is potentially curative in some cases. Recently, the emergence of chimeric antigen receptor T-cell therapy (CAR-T) for patients with relapsed/refractory (R/R) FL has yielded impressive response rates and long-term remissions, but definitive statement on the curative potential of CAR-T is currently not possible due to limited patient numbers and relatively short follow up. A consensus on the contemporary role, optimal timing, and sequencing of HCT (autologous or allogeneic) and cellular therapies in FL is needed. As a result, the American Society of Transplantation and Cellular Therapy (ASTCT) Committee on Practice Guidelines endorsed this effort to formulate consensus recommendations to address this unmet need. The RAND-modified Delphi method was used to generate 15 consensus statements/recommendations. Of note, the use of bispecific antibodies in R/R FL was not in the scope of this project. Key statements/recommendations are as follows: 1) Autologous HCT is recommended as an option for consolidation therapy in patients with progression of untransformed disease within 24 months of front line chemoimmunotherapy and upon achieving a complete (CR) or partial response (PR) to salvage second line therapies; 2) CAR-T is considered as a treatment option for patients who did not achieve CR or PR after second or subsequent lines of therapies; 3) Allogeneic HCT is considered as consolidative treatment in relapsed FL patients with chemosensitive disease who have received 3 or more lines of systemic therapy and are the following clinical scenarios: post CAR-T failure; lack of access to CAR-T or have therapy related myeloid neoplasm. These clinical practice recommendations will help guide clinicians managing patients with FL.

Matching-adjusted indirect comparisons of axicabtagene ciloleucel to mosunetuzumab for the treatment of relapsed/refractory follicular lymphoma.

BACKGROUND: Axicabtagene ciloleucel (axi-cel) was the first chimeric antigen receptor (CAR) T-cell therapy approved for relapsed/refractory (R/R) follicular lymphoma (FL) patients, while mosunetuzumab was the first bispecific monoclonal antibody approved in this population. In the absence of head-to-head evidence, this study sought to conduct a matching-adjusted indirect comparison (MAIC) to estimate the comparative efficacy and safety of these treatments in 3rd line or higher (3L+) FL. METHODS: The evidence base consisted of individual patient data (IPD) of all enrolled patients, regardless of infusion status, from the single-arm axi-cel trial, ZUMA-5 (NCT03105336), and aggregate data from the mosunetuzumab FL trial (NCT02500407) from publications identified through a systematic review. Efficacy outcomes were progression-free survival (PFS), duration of response (DoR), objective response rate (ORR), complete response rate (CRR). Analyses used independent central review for both trials, where possible. Safety outcomes were cytokine release syndrome (CRS), neurological events (NE), and treatment-related adverse events (TRAEs). Unanchored MAICs were conducted to align ZUMA-5 to the patient characteristics of the mosunetuzumab trial. For each outcome, prognostic factors were identified a priori through quantitative analysis and clinical experts. For time-to-event outcomes, hazard ratios (HRs) were estimated using Cox regression using IPD from ZUMA-5 and pseudo-IPD extracted from Kaplan-Meier plots for mosunetuzumab. RESULTS: Patient characteristics were well-aligned between trials leading to large effective-sample sizes after matching, ranging from 93.4 to 115.5, for ZUMA-5 (n=127). In comparisons to mosunetuzumab (n=90), axi-cel was associated with improved PFS (HR: 0.39; 95% confidence interval [CI]: 0.24-0.62) and DoR (HR: 0.45; 95% CI: 0.27-0.76). Similarly, axi-cel led to higher ORR (OR: 3.87; 95% CI: 1.53-9.76) and CRR (OR: 2.80; 95% CI: 1.50-5.26). Although axi-cel was associated with a higher rate of all-grade CRS (OR: 5.54; 95% CI: 2.63-8.94) and NEs (OR: 3.54; 95% CI: 1.28-9.83), differences in grade ≥3 CRS and TRAEs were not statistically significant. CONCLUSIONS: Findings from this study show improved efficacy and more durable response for the treatment of 3L+ R/R FL with axi-cel relative to mosunetuzumab, with increased odds of all-grade CRS and NE, but not G3+ CRS and TRAEs.

Cost-effectiveness of treating relapsed or refractory 3L+ follicular lymphoma with axicabtagene ciloleucel vs mosunetuzumab in the United States.

Introduction: Novel therapies for 3L+ relapsed/refractory (r/r) follicular lymphoma (FL) have been approved recently by the US Food and Drug Administration including anti-CD19 CAR-T therapies such as axicabtagene ciloleucel (axi-cel) and CD20 × CD3 T-cell-engaging bispecific monoclonal antibodies such as mosunetuzumab (mosun). The objective of this study was to assess the cost-effectiveness of axi-cel compared to mosun in 3L+ r/r FL patients from a US third-party payer perspective. Methods: A three-state (progression-free, progressed disease, and death) partitioned-survival model was used to compare two treatments over a lifetime horizon in a hypothetical cohort of US adults (age ≥18) receiving 3L+ treatment for r/r FL. ZUMA-5 and GO29781 trial data were used to inform progression-free survival (PFS) and overall survival (OS). Mosun survival was modeled via hazard ratios (HRs) applied to axi-cel survival curves. The PFS HR value was estimated via a matching-adjusted indirect comparison (MAIC) based on mosun pseudo-individual patient data and adjusted axi-cel data to account for trial populations differences. One-way sensitivity analysis (OWSA) and probabilistic sensitivity analyses (PSA) were conducted. Scenario analyses included: 1) the mosun HRs were applied to the weighted (adjusted) ZUMA-5 24-month data to most exactly reflect the MAIC, 2) mosun HR values were applied to axi-cel 48-month follow-up data, and 3) recent axi-cel health state utility values in diffuse large B-cell lymphoma patients. Results: The analysis estimated increases of 1.82 LY and 1.89 QALY for axi-cel compared to mosun. PFS for axi-cel patients was 6.42 LY vs. 1.60 LY for mosun. Increase of $257,113 in the progression-free state was driven by one-time axi-cel treatment costs. Total incremental costs for axi-cel were $204,377, resulting in an ICER of $108,307/QALY gained. The OWSA led to ICERs ranging from $240,255 to $75,624, with all but two parameters falling below $150,000/QALY. In the PSA, axi-cel had an 64% probability of being cost-effective across 5,000 iterations using a $150,000 willingness-to-pay threshold. Scenarios one and two resulted in ICERs of $105,353 and $102,695, respectively. Discussion: This study finds that axi-cel is cost-effective compared to mosun at the commonly cited $150,000/QALY US willingness-to-pay threshold, with robust results across a range of sensitivity analyses accounting for parameter uncertainty.

ACT To Sustain: Adoptive Cell Therapy To Sustain Access to Non-Commercialized Genetically Modified Cell Therapies.

Genetically modified cell therapies (GMCT), particularly immune effector cells (IEC) such as chimeric receptor antigen (CAR) T cells, have shown promise in curing cancer and rare diseases after a single treatment course. Following close behind CAR T approvals are GMCT based on hematopoietic stem cells, such as products developed for hemoglobinopathies and other disorders. Academically sponsored GMCT products, often developed in academic centers without industry involvement, face challenges in sustaining access after completion of early phase studies when there is no commercial partner invested in completing registration trials for marketing applications. The American Society for Transplantation and Cellular Therapy (ASTCT) formed a task force named ACT To Sustain (Adoptive Cell Therapy to Sustain) to address the "valley of death" of academic GMCT products. This paper presents the task force's findings and considerations regarding financial sustainability of academically sponsored GMCT products in the absence of commercial development. We outline case scenarios illustrating barriers to maintaining access to promising GMCT developed by academic centers. The paper also delves into the current state of GMCT development, commercialization, and reimbursement, citing examples of abandoned products, cost estimates associated with GMCT manufacturing and real-world use of cost recovery. We propose potential solutions to address the financial, regulatory, and logistical challenges associated with sustaining access to academically sponsored GMCT products and to ensure that products with promising results do not languish in a "valley of death" due to financial or implementational barriers. The suggestions include aligning US Food and Drug Administration (FDA) designations with benefit coverage, allowing for cost recovery of certain products as a covered benefit, and engaging with regulators and policy makers to discuss alternative pathways for academic centers to provide access. We stress the importance of sustainable access to GMCT and call for collaborative efforts to develop regulatory pathways that support access to academically sponsored GMCT products.

Axicabtagene ciloleucel vs standard of care in second-line large B-cell lymphoma: outcomes by metabolic tumor volume.

ABSTRACT: Metabolic tumor volume (MTV) assessed using 2-deoxy-2-[18F]fluoro-d-glucose positron emission tomography, a measure of tumor burden, is a promising prognostic indicator in large B-cell lymphoma (LBCL). This exploratory analysis evaluated relationships between baseline MTV (categorized as low [median or less] vs high [greater than median]) and clinical outcomes in the phase 3 ZUMA-7 study (NCT03391466). Patients with LBCL relapsed within 12 months of or refractory to first-line chemoimmunotherapy were randomized 1:1 to axicabtagene ciloleucel (axi-cel; autologous anti-CD19 chimeric antigen receptor T-cell therapy) or standard care (2-3 cycles of chemoimmunotherapy followed by high-dose chemotherapy with autologous stem cell transplantation in patients who had a response). All P values are descriptive. Within high- and low-MTV subgroups, event-free survival (EFS) and progression-free survival (PFS) were superior with axi-cel vs standard care. EFS in patients with high MTV (vs low MTV) was numerically shorter with axi-cel and was significantly shorter with standard care. PFS was shorter in patients with high MTV vs low MTV in both the axi-cel and standard-care arms, and median MTV was lower in patients in ongoing response at data cutoff vs others. Median MTV was higher in patients treated with axi-cel who experienced grade ≥3 neurologic events or cytokine release syndrome (CRS) than in patients with grade 1/2 or no neurologic events or CRS, respectively. Baseline MTV less than or equal to median was associated with better clinical outcomes in patients receiving axi-cel or standard care for second-line LBCL. The trial was registered at www.clinicaltrials.gov as #NCT03391466.

Network meta-analysis of CAR T-Cell therapy for the treatment of 3L+ R/R LBCL after using published comparative studies.

INTRODUCTION: Studies have compared chimeric antigen receptor (CAR) T-cell therapies and salvage chemotherapy in relapsed/refractory large B-cell lymphoma (LBCL) patients, but further evidence of their relative effectiveness is warranted. METHODS: Our systematic review identified studies comparing efficacy and safety outcomes of axicabtagene ciloleucel (axi-cel), lisocabtagene maraleucel (liso-cel) and tisagenlecleucel (tisa-cel) trials to salvage chemotherapy cohorts in LBCL patients with ≥2 prior lines of treatment; and an extended evidence network included indirect comparisons comparing CAR T-cell therapies. We conducted network meta-analyzes using Bayesian hierarchical modeling. RESULTS: Three studies comparing ZUMA-1 (axi-cel), TRANSCEND (liso-cel) and JULIET (tisa-cel) trials to salvage chemotherapy within the SCHOLAR-1 cohort were identified. Axi-cel (odds ratio [OR]:5.63; 95% credible interval [CrI]:2.66-12.42) and liso-cel (OR:4.26; 95%CrI:2.33-7.93) showed a significant increased overall response rate compared to tisa-cel, but not to one-another. Axi-cel demonstrated significant improvements in overall survival relative to liso-cel (hazard ratio [HR]:0.54; 95%CrI:0.37-0.79) and tisa-cel (HR:0.47; 95%CrI:0.26-0.88). Higher rates of grade ≥3 neurological events were observed with axi-cel than with tisa-cel and liso-cel. CONCLUSIONS: We highlight important differences in clinical outcomes between CAR T-cell therapies. Axi-cel demonstrated improved overall survival compared to tisa-cel and liso-cel, and both axi-cel and liso-cel showed higher response rates compared to tisa-cel.

Cost-Effectiveness of Axicabtagene Ciloleucel for Adult Patients With Relapsed or Refractory Follicular Lymphoma in the United States.

OBJECTIVES: The results of a recent single-arm trial (ZUMA-5) of axicabtagene ciloleucel (axi-cel) for relapsed/refractory (r/r) follicular lymphoma (FL) demonstrated high rates of durable response and tolerable toxicity among treated patients. To quantify the value of axi-cel compared with standard of care (SOC) to manage r/r FL patients who have had at least 2 prior lines of systemic therapy (3L+), a cost-effectiveness model was developed from a US third-party payer perspective. METHODS: A 3-state partitioned-survival cost-effectiveness model was developed with a lifetime horizon. Patient-level analyses of the 36-month ZUMA-5 (axi-cel) and SCHOLAR-5 (SOC) studies were used to extrapolate progression-free and overall survivals. After 5 years of survival, an estimated 40% of the modeled population was assumed to experience long-term remission based on literature. Results include the incremental cost-effectiveness ratio (ICER) measured as incremental cost per quality-adjusted life year (QALY) gained. One-way sensitivity analysis, probabilistic sensitivity analysis, and scenario analyses were performed. All outcomes were discounted 3% per year. RESULTS: Axi-cel led to an increase of 4.28 life-years, 3.64 QALYs, and a total cost increase of $321 192 relative to SOC, resulting in an ICER of $88 300 per QALY. Across all parameters varied in the one-way sensitivity analysis, the ICER varied between $133 030 and $67 277. In the probabilistic sensitivity analysis, axi-cel had a 99% probability of being cost-effective across 5000 iterations using a $150 000 willingness-to-pay threshold. CONCLUSIONS: Given the robustness of the model results and sensitivity analyses, axi-cel is expected to be a cost-effective treatment in 3L+ r/r FL.

Outcomes of subsequent antilymphoma therapies after second-line axicabtagene ciloleucel or standard of care in ZUMA-7.

ABSTRACT: The optimal management of patients with relapsed/refractory large B-cell lymphoma (LBCL) after disease progression or lack of response to second-line (2L) therapy remains unclear. Here, we report outcomes among patients who received subsequent antilymphoma therapy per investigator discretion separately by their randomized 2L arm in ZUMA-7, namely axicabtagene ciloleucel (axi-cel) vs standard of care (SOC). Progression-free survival (PFS) and overall survival (OS) were calculated from 3L therapy initiation. In the SOC arm, 127 of 179 randomized patients (71%) received 3L therapy. Median PFS among those who received 3L cellular immunotherapy (n = 68) vs those who did not (n = 59) was 6.3 vs 1.9 months, respectively; median OS was 16.3 vs 9.5 months, respectively. In the axi-cel arm, 84 of 180 randomized patients (47%) received 3L therapy. Median PFS among those who received 3L chemotherapy (n = 60) vs cellular immunotherapy (n = 8) was 1.7 vs 3.5 months, respectively; median OS was 8.1 months vs not reached, respectively. Of the 60 patients who received 3L chemotherapy, 10 underwent stem cell transplantation (SCT) after salvage chemotherapy. Median PFS was 11.5 vs 1.6 months, and median OS was 17.5 vs 7.2 months for those who did vs did not reach SCT, respectively. Eight patients received 3L cellular immunotherapy after 2L axi-cel. Of these, 6 patients received subsequent SCT in any line; all 6 were alive at data cutoff. These findings help inform subsequent treatment choices after 2L therapy failure for relapsed/refractory LBCL. The trial was registered at www.clinicaltrials.gov as #NCT03391466.

Cost-effectiveness of axicabtagene ciloleucel versus tisagenlecleucel for the treatment of 3L + relapsed/refractory large B-cell lymphoma in the United States: incorporating longer survival results.

AIMS: To provide an update on the cost-effectiveness of the chimeric antigen receptor (CAR) T-cell therapies axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) for the treatment of relapsed/refractory (r/r) large B-cell lymphoma (LBCL) among patients who have previously received ≥2 lines of systemic therapy using more mature clinical trial data cuts (60 months for axi-cel overall survival [OS] and 45 months for tisa-cel OS and progression-free survival [PFS]). METHODS: A partitioned survival model consisting of three health states (pre-progression, post-progression and death) was used to estimate quality-adjusted life years (QALYs) and costs associated with axi-cel and tisa-cel over a lifetime horizon. PFS and OS inputs for axi-cel and tisa-cel were based on a previously published matching-adjusted indirect treatment comparison (MAIC). Long-term OS and PFS were extrapolated using parametric survival mixture cure models (PS-MCMs). Costs of CAR-T cell therapy drug acquisition and administration, conditioning chemotherapy, apheresis, CAR T-specific monitoring, stem cell transplant, hospitalization, adverse events, routine care, and terminal care were sourced from US cost databases. Health state utilities were derived from previous publications. Model inputs were varied using a range of sensitivity and scenario analyses. RESULTS: Compared with tisa-cel, axi-cel resulted in 2.51 additional QALYs and $50,185 additional costs (an incremental cost-effectiveness ratio [ICER] of $19,994 per QALY gained). In probabilistic sensitivity analysis (PSA), the ICER for axi-cel versus tisa-cel was ≤$50,000/QALY in 99.4% of simulations and ≤$33,500 in 99% of simulations. Axi-cel remained cost-effective versus tisa-cel (assuming a willingness-to-pay threshold of $150,000 per QALY) across a range of scenarios. CONCLUSIONS: With longer-term survival data, axi-cel continues to represent a cost-effective option versus tisa-cel for treatment of r/r LBCL among patients who have previously received ≥2 lines of systemic therapy, from a US payer perspective.

Long-term outcomes of patients with large B-cell lymphoma treated with axicabtagene ciloleucel and prophylactic corticosteroids.

ZUMA-1 safety management cohort 6 investigated the impact of prophylactic corticosteroids and earlier corticosteroids and/or tocilizumab on the incidence and severity of cytokine release syndrome (CRS) and neurologic events (NEs) following axicabtagene ciloleucel (axi-cel) in patients with relapsed/refractory large B-cell lymphoma (R/R LBCL). Prior analyses of cohort 6 with limited follow-up demonstrated no Grade ≥3 CRS, a low rate of NEs, and high response rates, without negatively impacting axi-cel pharmacokinetics. Herein, long-term outcomes of cohort 6 (N = 40) are reported (median follow-up, 26.9 months). Since the 1-year analysis (Oluwole, et al. Blood. 2022;138[suppl 1]:2832), no new CRS was reported. Two new NEs occurred in two patients (Grade 2 dementia unrelated to axi-cel; Grade 5 axi-cel-related leukoencephalopathy). Six new infections and eight deaths (five progressive disease; one leukoencephalopathy; two COVID-19) occurred. Objective and complete response rates remained at 95% and 80%, respectively. Median duration of response and progression-free survival were reached at 25.9 and 26.8 months, respectively. Median overall survival has not yet been reached. Eighteen patients (45%) remained in ongoing response at data cutoff. With ≥2 years of follow-up, prophylactic corticosteroids and earlier corticosteroids and/or tocilizumab continued to demonstrate CRS improvement without compromising efficacy outcomes, which remained high and durable.

Three-year follow-up analysis of axicabtagene ciloleucel in relapsed/refractory indolent non-Hodgkin lymphoma (ZUMA-5).

ABSTRACT: Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for relapsed/refractory (R/R) follicular lymphoma (FL). Approval was supported by the phase 2, multicenter, single-arm ZUMA-5 study of axi-cel for patients with R/R indolent non-Hodgkin lymphoma (iNHL; N = 104), including FL and marginal zone lymphoma (MZL). In the primary analysis (median follow-up, 17.5 months), the overall response rate (ORR) was 92% (complete response rate, 74%). Here, we report long-term outcomes from ZUMA-5. Eligible patients with R/R iNHL after ≥2 lines of therapy underwent leukapheresis, followed by lymphodepleting chemotherapy and axi-cel infusion (2 × 106 CAR T cells per kg). The primary end point was ORR, assessed in this analysis by investigators in all enrolled patients (intent-to-treat). After median follow-up of 41.7 months in FL (n = 127) and 31.8 months in MZL (n = 31), ORR was comparable with that of the primary analysis (FL, 94%; MZL, 77%). Median progression-free survival was 40.2 months in FL and not reached in MZL. Medians of overall survival were not reached in either disease type. Grade ≥3 adverse events of interest that occurred after the prior analyses were largely in recently treated patients. Clinical and pharmacokinetic outcomes correlated negatively with recent exposure to bendamustine and high metabolic tumor volume. After 3 years of follow-up in ZUMA-5, axi-cel demonstrated continued durable responses, with very few relapses beyond 2 years, and manageable safety in patients with R/R iNHL. The ZUMA-5 study was registered at www.clinicaltrials.gov as #NCT03105336.

Chimeric Antigen Receptor T Cell Therapy for Myeloma: Where Are We Now and What Is Needed to Move Chimeric Antigen Receptor T Cells Forward to Earlier Lines of Therapy? Expert Panel Opinion from the American Society for Transplantation and Cellular Therapy.

Since 2021, 2 B cell maturation antigen (BCMA)-directed chimeric antigen receptor T cell (CAR-T) therapies-idecabtagene vicleucel (ide-cel), and ciltacabtagene autoleucel (cilta-cel)-have been approved by the US Food and Drug Administration (FDA) for treating relapsed or refractory multiple myeloma (RRMM) after 4 or more prior lines of therapy, including an immunomodulatory drug, a proteasome inhibitor, and an anti-CD38 antibody. The 2 products have shown unprecedented activity in RRMM, but relapses remain common, and access to and safety of CAR-T therapy in patients with rapidly progressing advanced disease are not ideal. Sequencing CAR-T therapy with other options, including the 2 recently approved BCMA-directed T cell-engaging bispecific antibodies teclistamab and elranatamab, has become increasingly challenging owing to data showing inferior outcomes from CAR-T therapy after prior BCMA-directed therapy. This has led to the consideration of CAR-T therapy earlier in the course of disease for myeloma, when T cells are potentially healthier and the myeloma is less aggressive. To address the question of earlier use of CAR-T therapy, several trials are either ongoing or planned, and results have recently been reported for 2 randomized trials of CAR-T therapy showing improved progression-free survival compared to standard of care therapy in second-line (CARTITUDE-4) or third-line therapy (KarMMA-3). With the anticipation of the FDA possibly expanding approval of CAR-T to earlier lines of myeloma therapy, the American Society for Transplantation and Cellular Therapy convened a group of experts to provide a comprehensive review of the studies that led to the approval of CAR-T therapy in late-line therapy for myeloma, discuss the recently reported and ongoing studies designed to move CAR-T therapy to earlier lines of therapy, and share insights and considerations for sequencing therapy and optimization of patient selection for BCMA-directed therapies in current practice.

Chimeric Antigen Receptor T-Cell Therapy in the Outpatient Setting: An Expert Panel Opinion from the American Society for Transplantation and Cellular Therapy.

The first series of chimeric antigen receptor T (CAR-T) cell therapy products were approved in 2017 to 2019 and have shown remarkable efficacy in both clinical trials and the real-world setting, but at the cost of prolonged patient hospitalization. As the toxicity management protocols were refined, the concept of cellular therapy administered in the outpatient setting gained steam, and single institutions began to perform certain aspects of CAR-T monitoring in the outpatient setting for select patients. However, there are many considerations for a successful outpatient program. In anticipation of increasing use of CAR-T-cell therapy in the outpatient setting as a mechanism to overcome frequent hospital bed shortages and high cost of inpatient care, the American Society for Transplantation and Cellular Therapy convened a group of experts in hematology, oncology, and cellular therapy to provide a comprehensive review of the existing publications on outpatient CAR-T cell therapy, discuss selected ongoing clinical trials of outpatient CAR-T, and describe strategies to optimize safety without compromising efficacy for patients treated and monitored in the outpatient setting.

An updated cost-effectiveness analysis of axicabtagene ciloleucel in second-line large B-cell lymphoma patients in the United States.

AIMS: This economic evaluation of axicabtagene ciloleucel (axi-cel) versus previous standard of care (SOC; salvage chemotherapy followed by high-dose therapy with autologous stem cell rescue) in the second line (2L) large B-cell lymphoma population is an update of previous economic models that contained immature survival data. METHODS: This analysis is based on primary overall survival (OS) ZUMA-7 clinical trial data (median follow-up of 47.2 months), from a United States (US) payer perspective, with a model time horizon of 50 years. Mixture cure models were used to extrapolate updated survival data; subsequent treatment data and costs were updated. Patients who remained in the event-free survival state by 5 years were assumed to have achieved long-term remission and not require subsequent treatment. RESULTS: Substantial survival and quality of life benefits were observed despite 57% of patients in the SOC arm receiving subsequent cellular therapy: median model-projected (ZUMA-7 trial Kaplan-Meier estimated) OS was 78 months (median not reached) for axi-cel versus 25 months (31 months) for SOC, resulting in incremental quality-adjusted life year (QALY) difference of 1.63 in favor of axi-cel. Incrementally higher subsequent treatment costs were observed in the SOC arm due to substantial crossover to cellular therapies, thus, when considering the generally accepted willingness to pay threshold of $150,000 per QALY in the US, axi-cel was cost-effective with an incremental cost-effectiveness ratio of $98,040 per QALY. CONCLUSIONS: Results remained consistent across a wide range of sensitivity and scenario analysis, including a crossover adjusted analysis, suggesting that the mature OS data has significantly reduced the uncertainty of axi-cel's cost-effectiveness in the 2L setting in the US. Deferring treatment with CAR T therapies after attempting a path to transplant may result in excess mortality, lower quality of life and would be an inefficient use of resources relative to 2L axi-cel.

Impact of prior therapies and subsequent transplantation on outcomes in adult patients with relapsed or refractory B-cell acute lymphoblastic leukemia treated with brexucabtagene autoleucel in ZUMA-3.

BACKGROUND: Brexucabtagene autoleucel (brexu-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved in the USA for adults with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) and in the European Union for patients ≥26 years with R/R B-ALL. After 2 years of follow-up in ZUMA-3, the overall complete remission (CR) rate (CR+CR with incomplete hematological recovery (CRi)) was 73%, and the median overall survival (OS) was 25.4 months in 78 Phase 1 and 2 patients with R/R B-ALL who received the pivotal dose of brexu-cel. Outcomes by prior therapies and subsequent allogeneic stem cell transplantation (alloSCT) are reported. METHODS: Eligible adults had R/R B-ALL and received one infusion of brexu-cel (1×106 CAR T cells/kg) following conditioning chemotherapy. The primary endpoint was the CR/CRi rate per central review. Post hoc subgroup analyses were exploratory with descriptive statistics provided. RESULTS: Phase 1 and 2 patients (N=78) were included with median follow-up of 29.7 months (range, 20.7-58.3). High CR/CRi rates were observed across all prior therapy subgroups examined: 1 prior line of therapy (87%, n=15) and ≥2 prior lines (70%, n=63); prior blinatumomab (63%, n=38) and no prior blinatumomab (83%, n=40); prior inotuzumab (59%, n=17) and no prior inotuzumab (77%, n=61); and prior alloSCT (76%, n=29) and no prior alloSCT (71%, n=49). The frequency of Grade ≥3 cytokine release syndrome, neurological events, and treatment-related Grade 5 adverse events were largely similar among prior therapy subgroups.Median duration of remission (DOR) in responders with (n=14) and without (n=43) subsequent alloSCT was 44.2 (95% CI, 8.1 to not estimable (NE)) and 18.6 months (95% CI, 9.4 to NE); median OS was 47.0 months (95% CI, 10.2 to NE) and not reached (95% CI, 23.2 to NE), respectively. Median DOR and OS were not reached in responders without prior or subsequent alloSCT (n=22). CONCLUSIONS: In ZUMA-3, adults with R/R B-ALL benefited from brexu-cel, regardless of prior therapies and subsequent alloSCT status, though survival appeared better in patients without certain prior therapies and in earlier lines of therapy. Additional studies are needed to determine the impact prior therapies and subsequent alloSCT have on outcomes of patients who receive brexu-cel.

Identifying an optimal fludarabine exposure for improved outcomes after axi-cel therapy for aggressive B-cell non-Hodgkin lymphoma.

Fludarabine is one of the most common agents given for lymphodepletion before CD19 chimeric antigen receptor T cells, but its optimal therapeutic intensity is unknown. Using data from a multicenter consortium, we estimated fludarabine exposure (area under the curve [AUC]) using a population pharmacokinetic (PK) model in 199 adult patients with aggressive B-cell non-Hodgkin lymphomas who received commercial axicabtagene ciloleucel (Axi-cel). We evaluated the association of estimated fludarabine AUC with key outcomes, aiming to find an AUC that optimized efficacy and tolerability. We identified low (<18 mg × hour/L [mgh/L]), optimal (18-20 mgh/L), and high (>20 mgh/L) AUC groups for analyses; the 6-month cumulative incidences of relapse/progression of disease (relapse/POD) by AUC groups were 54% (45%-62%), 28% (15%-44%), and 30% (14%-47%), respectively; and the 1-year progression-free survival (PFS) rates were 39% (31%-48%), 66% (52%-84%), and 46% (30%-70%) and the overall survival (OS) rates were 58% (50%-67%), 77% (64%-92%), and 66% (50%-87%), respectively. In multivariable analyses compared with low AUC, an optimal AUC was associated with the highest PFS (hazard ratio [HR], 0.52; 0.3-0.91; P = .02) and lowest risk of relapse/POD (HR, 0.46; 0.25-0.84; P = .01) without an increased risk of any-grade cytokine release syndrome (HR, 1.1; 0.7-1.6; P = .8) or and immune effector cell-associated neurotoxicity syndrome (ICANS) (HR, 1.36; 0.83-2.3; P = .2). A high AUC was associated with the greatest risk of any-grade ICANS (HR, 1.9; 1.1-3.2; P = .02). Although the main cause of death in all groups was relapse/POD, nonrelapse-related deaths, including 3 deaths from ICANS, were more frequent in the high AUC group. These findings suggest that PK-directed fludarabine dosing to achieve an optimal AUC may result in improved outcomes for patients receiving axi-cel.

Survival with Axicabtagene Ciloleucel in Large B-Cell Lymphoma.

BACKGROUND: In an analysis of the primary outcome of this phase 3 trial, patients with early relapsed or refractory large B-cell lymphoma who received axicabtagene ciloleucel (axi-cel), an autologous anti-CD19 chimeric antigen receptor T-cell therapy, as second-line treatment had significantly longer event-free survival than those who received standard care. Data were needed on longer-term outcomes. METHODS: In this trial, we randomly assigned patients with early relapsed or refractory large B-cell lymphoma in a 1:1 ratio to receive either axi-cel or standard care (two to three cycles of chemoimmunotherapy followed by high-dose chemotherapy with autologous stem-cell transplantation in patients who had a response). The primary outcome was event-free survival, and key secondary outcomes were response and overall survival. Here, we report the results of the prespecified overall survival analysis at 5 years after the first patient underwent randomization. RESULTS: A total of 359 patients underwent randomization to receive axi-cel (180 patients) or standard care (179 patients). At a median follow-up of 47.2 months, death had been reported in 82 patients in the axi-cel group and in 95 patients in the standard-care group. The median overall survival was not reached in the axi-cel group and was 31.1 months in the standard-care group; the estimated 4-year overall survival was 54.6% and 46.0%, respectively (hazard ratio for death, 0.73; 95% confidence interval [CI], 0.54 to 0.98; P = 0.03 by stratified two-sided log-rank test). This increased survival with axi-cel was observed in the intention-to-treat population, which included 74% of patients with primary refractory disease and other high-risk features. The median investigator-assessed progression-free survival was 14.7 months in the axi-cel group and 3.7 months in the standard-care group, with estimated 4-year percentages of 41.8% and 24.4%, respectively (hazard ratio, 0.51; 95% CI, 0.38 to 0.67). No new treatment-related deaths had occurred since the primary analysis of event-free survival. CONCLUSIONS: At a median follow-up of 47.2 months, axi-cel as second-line treatment for patients with early relapsed or refractory large B-cell lymphoma resulted in significantly longer overall survival than standard care. (Funded by Kite; ZUMA-7 ClinicalTrials.gov number, NCT03391466.).

Patient Characteristics and Outcomes of Outpatient Tisagenlecleucel Recipients for B Cell Non-Hodgkin Lymphoma.

Tisagenlecleucel (tisa-cel) is an approved CD19-directed chimeric antigen receptor T cell (CAR-T) therapy for relapsed/refractory B cell malignancies. Given potentially life-threatening toxicities, including cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, inpatient tisa-cel infusion and toxicity monitoring are often considered; however, the toxicity profile of tisa-cel may be conducive to outpatient administration. Here we review the characteristics and outcomes of tisa-cel recipients treated in the outpatient setting. Patients age ≥18 years with B cell non-Hodgkin lymphoma who received tisa-cel between June 25, 2018, and January 22, 2021, at 9 US academic medical centers were included in a retrospective analysis. Six of the 9 representative centers (75%) had an outpatient program in place. A total of 157 patients were evaluable, including 93 (57%) in the outpatient treatment group and 64 (43%) in the inpatient treatment group. Baseline characteristics, toxicity and efficacy, and resource utilization were summarized. The most common lymphodepletion (LD) regimen was bendamustine in the outpatient group (65%) and fludarabine/cyclophosphamide (91%) in the inpatient group. The outpatient group had more patients with a Charlson Comorbidity Index of 0 (51% versus 15%; P < .001), fewer patients with an elevated lactate dehydrogenase (LDH) level above the normal range at the time of LD (32% versus 57%, P = .003) compared to the inpatient group, and a lower Endothelial Activation and Stress Index score (.57 versus 1.4; P < .001). Any-grade CRS and ICANS were lower in the outpatient group (29% versus 56% [P < .001] and 10% versus 16% [P = .051], respectively). Forty-two outpatient tisa-cel recipients (45%) required an unplanned admission, with a median length of stay of 5 days (range, 1 to 27 days), compared to 13 days (range, 4 to 38 days) in the inpatient group. The median number of tocilizumab doses administered was similar in the 2 groups as were the rate of intensive care unit (ICU) transfer (5% versus 8%; P = .5) and median length of ICU stay (6 days versus 5 days; P = .7). There were no toxicity-related deaths in the 30 days post-CAR-T infusion in either group. Progression-free survival and overall survival were similar in the 2 groups. With careful patient selection, outpatient tisa-cel administration is feasible and associated with similar efficacy outcomes as inpatient treatment. Outpatient toxicity monitoring and management may help optimize healthcare resource utilization.

Safety and Efficacy of Axicabtagene Ciloleucel versus Standard of Care in Patients 65 Years of Age or Older with Relapsed/Refractory Large B-Cell Lymphoma.

PURPOSE: Older patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL) may be considered ineligible for curative-intent therapy including high-dose chemotherapy with autologous stem-cell transplantation (HDT-ASCT). Here, we report outcomes of a preplanned subgroup analysis of patients ≥65 years in ZUMA-7. PATIENTS AND METHODS: Patients with LBCL refractory to or relapsed ≤12 months after first-line chemoimmunotherapy were randomized 1:1 to axicabtagene ciloleucel [axi-cel; autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy] or standard of care (SOC; 2-3 cycles of chemoimmunotherapy followed by HDT-ASCT). The primary endpoint was event-free survival (EFS). Secondary endpoints included safety and patient-reported outcomes (PROs). RESULTS: Fifty-one and 58 patients aged ≥65 years were randomized to axi-cel and SOC, respectively. Median EFS was greater with axi-cel versus SOC (21.5 vs. 2.5 months; median follow-up: 24.3 months; HR, 0.276; descriptive P < 0.0001). Objective response rate was higher with axi-cel versus SOC (88% vs. 52%; OR, 8.81; descriptive P < 0.0001; complete response rate: 75% vs. 33%). Grade ≥3 adverse events occurred in 94% of axi-cel and 82% of SOC patients. No grade 5 cytokine release syndrome or neurologic events occurred. In the quality-of-life analysis, the mean change in PRO scores from baseline at days 100 and 150 favored axi-cel for EORTC QLQ-C30 Global Health, Physical Functioning, and EQ-5D-5L visual analog scale (descriptive P < 0.05). CAR T-cell expansion and baseline serum inflammatory profile were comparable in patients ≥65 and <65 years. CONCLUSIONS: Axi-cel is an effective second-line curative-intent therapy with a manageable safety profile and improved PROs for patients ≥65 years with R/R LBCL.