PURPOSE: Brexucabtagene autoleucel (brexu-cel) is an autologous CD19-directed chimeric antigen receptor (CAR) T-cell therapy approved for relapsed/refractory mantle cell lymphoma (MCL). This therapy was approved on the basis of the single-arm phase II ZUMA-2 trial, which showed best overall and complete response rates of 91% and 68%, respectively. We report clinical outcomes with brexu-cel in the standard-of-care setting for the approved indication. PATIENTS AND METHODS: Patients who underwent leukapheresis between August 1, 2020 and December 31, 2021, at 16 US institutions, with an intent to manufacture commercial brexu-cel for relapsed/refractory MCL, were included. Patient data were collected for analyses of responses, outcomes, and toxicities as per standard guidelines. RESULTS: Of 189 patients who underwent leukapheresis, 168 (89%) received brexu-cel infusion. Of leukapheresed patients, 79% would not have met ZUMA-2 eligibility criteria. Best overall and complete response rates were 90% and 82%, respectively. At a median follow-up of 14.3 months after infusion, the estimates for 6- and 12-month progression-free survival (PFS) were 69% (95% CI, 61 to 75) and 59% (95% CI, 51 to 66), respectively. The nonrelapse mortality was 9.1% at 1 year, primarily because of infections. Grade 3 or higher cytokine release syndrome and neurotoxicity occurred in 8% and 32%, respectively. In univariable analysis, high-risk simplified MCL international prognostic index, high Ki-67, TP53 aberration, complex karyotype, and blastoid/pleomorphic variant were associated with shorter PFS after brexu-cel infusion. Patients with recent bendamustine exposure (within 24 months before leukapheresis) had shorter PFS and overall survival after leukapheresis in intention-to-treat univariable analysis. CONCLUSION: In the standard-of-care setting, the efficacy and toxicity of brexu-cel were consistent with those reported in the ZUMA-2 trial. Tumor-intrinsic features of MCL, and possibly recent bendamustine exposure, may be associated with inferior efficacy outcomes.

T-cell redirecting therapy (TCRT), specifically chimeric antigen receptor T-cell therapy (CAR T-cells) and bispecific T-cell engagers (TCEs) represent a remarkable advance in the treatment of multiple myeloma (MM). There are several products available around the world and several more in development targeting primarily B-cell maturation antigen (BCMA) and G protein–coupled receptor class C group 5 member D (GRPC5D). The relatively rapid availability of multiple immunotherapies brings the necessity to understand how a certain agent may affect the safety and efficacy of a subsequent immunotherapy so MM physicians and patients can aim at optimal sequential use of these therapies. The International Myeloma Working Group conveyed panel of experts to review patient and disease-related factors affecting efficacy and safety of immunotherapy, summarize existing information on sequencing therapy and provide a series of core recommendations.

We report 14 cases of immune effector cell (IEC)-associated enterocolitis following chimeric antigen receptor T-cell (CAR-T) therapy in multiple myeloma, with a 1.2% incidence overall (0.2% for idecabtagene vicleucel and 2.2% for ciltacabtagene autoleucel). Patients developed acute-onset symptoms (typically non-bloody Grade 3+ diarrhea) with negative infectious workup beginning a median of 92.5 days (range: 22–210 days) after CAR-T therapy and a median of 85 days after cytokine release syndrome resolution. Gut biopsies uniformly demonstrated inflammation, including intra-epithelial lymphocytosis and villous blunting. In one case where CAR-specific immunofluorescence stains were available, CAR T-cell presence was confirmed within the lamina propria. Systemic corticosteroids were initiated in 10 patients (71%) a median of 25.5 days following symptom onset, with symptom improvement in 40%. Subsequent infliximab or vedolizumab led to improvement in 50% and 33% of corticosteroid-refractory patients, respectively. Five patients (36%) have died from bowel perforation or treatment-emergent sepsis. In conclusion, IEC-associated enterocolitis is a distinct but rare complication of CAR-T therapy typically beginning 1–3 months after infusion. Thorough diagnostic workup is essential, including evaluation for potential T-cell malignancies. The early use of infliximab or vedolizumab may potentially hasten symptom resolution and lower reliance on high-dose corticosteroids during the post-CAR-T period.

Hematologic malignancy outcomes have remarkably improved in the past decade with further advancement expected in future years. However, the detrimental effects of financial toxicity (FT) on patients with hematologic malignancies, because of both diagnoses and subsequent treatments, have not been studied comprehensively. We performed a systematic review of all studies reporting FT as a primary or secondary outcome among adult or pediatric patients with hematological malignancies. A total of 55 studies met the inclusion criteria for analysis. Across studies, 20–50% of patients reported some form of FT, including loss of work productivity, food and transportation costs, and depletion of savings. Younger age, lower-income level, unemployment, and rural residence were the most commonly identified risk factors for FT. Two studies looked at survival outcomes, with one reporting improvement in survival with a decrease in financial toxicity. However, significant heterogeneity in FT definitions was found between countries and payor systems. Only half of the studies (51%, n = 28) used validated survey instruments such as the COST assessment. The present systematic review identified that FT is common in patients with hematological malignancies and may be associated with poorer outcomes. However, studies of FT generally use non-standardized methods with cross-sectional analyses rather than longitudinal, prospective assessments. Further work is needed to standardize FT reporting and investigate measures to alleviate FT among patients with hematologic malignancies.

Preemptive administration of tocilizumab (toci) to manage cytokine release syndrome (CRS) after chimeric antigen receptor T cell (CAR-T) therapy may reduce rates of serious CRS but conversely may worsen neurotoxicity or risk of infections. Optimal toci administration strategies for patients with relapsed/refractory multiple myeloma (RRMM) receiving B cell maturation antigen (BCMA)-directed CAR-T therapies have not been evaluated. The objective of this study was to identify whether shorter time-to-toci intervals (hours between first fever attributed to CRS and first dose of toci) have any impact on therapy-related toxicities or clinical outcomes among patients with RRMM receiving BCMA-directed CAR-T therapies. We retrospectively analyzed our institution's experience with 4 BCMA-directed CAR-T therapies (idecabtagene vicleucel, bb21217, ciltacabtagene autoleucel, and orvacabtagene autoceucel) for RRMM over a 3-year period ending in June 2020. We divided patients based on the administration of toci and median time-to-toci interval into early-toci (time-to-toci ≤50th percentile), late-toci (time-to-toci >50th percentile), and no-toci (no toci received) groups. We compared the early-toci and late-toci groups with regard to patient characteristics, weight-based CAR-T toxicities, selected toxicities (CRS, neurotoxicity, macrophage activation syndrome, or infections), and clinical outcomes. Of 50 analyzed patients with a median follow-up of 15.3 months, 76% (n = 38) received ≥1 dose of toci (range, 1 to 3) and were classified into early-toci (time-to-toci ≤12 hours) or late-toci (time-to-toci >12 hours) groups. The 2 groups (n = 19 each) had similar CRS grade distributions, hours to CRS onset, CRS-related biomarkers, and incidences of neurotoxicity or severe infections; however, weight-adjusted CAR-T cell doses were higher in the early-toci group (median 5.99 versus 3.80 × 106 cells/kg, P < 0.01). Peak CRS grades (range, 0 to 2) using American Society for Transplantation and Cellular Therapy consensus criteria, neurotoxicity rates, and rates of severe infections were similar between groups; however, the median CRS duration was 18.6 hours for the early-toci group versus 84.7 hours for the late-toci group. The median progression-free survival was 35.7 months in the early-toci group and 13.2 months in the late-toci group. While limited by small sample size and known confounders such as CAR-T cell dose, our analysis suggests that preemptive toci strategies for CRS management with BCMA-directed CAR-T therapy-specifically, toci administration within 12 hours of the first fever attributed to CRS-do not appear to increase rates of therapy-related toxicities or compromise efficacy. However, total CRS duration may be shorter with early-toci workflows. Prospective validation of our findings may lead to improved safety and cost-effectiveness profiles for CAR-T therapy in RRMM.