The CAR‐HEMATOTOX score identifies patients at high risk for hematological toxicity, infectious complications, and poor treatment outcomes following brexucabtagene autoleucel for relapsed or refractory MCL

Abstract

CD19‐directed CAR T‐cell therapy with brexucabtagene autoleucel (brexu‐cel) has substantially improved treatment outcomes for patients with relapsed/refractory mantle cell lymphoma (r/r MCL). Prolonged cytopenias and infections represent common and clinically relevant side effects. In this multicenter observational study, we describe cytopenias and infections in 103 r/r MCL patients receiving brexu‐cel. Furthermore, we report associations between the baseline CAR‐HEMATOTOX (HT) score and toxicity events, non‐relapse mortality (NRM), and progression‐free/overall survival (PFS/OS). At lymphodepletion, 56 patients were HTlow (score 0–1) while 47 patients were HThigh (score ≥2). The HThigh cohort exhibited prolonged neutropenia (median 14 vs. 6 days, p < .001) and an increased rate of severe infections (30% vs. 5%, p = .001). Overall, 1‐year NRM was 10.4%, primarily attributed to infections, and differed by baseline HT score (high vs. low: 17% vs. 4.6%, p = .04). HThigh patients experienced inferior 90‐day complete response rate (68% vs. 93%, p = .002), PFS (median 9 months vs. not‐reached, p < .0001), and OS (median 26 months vs. not‐reached, p < .0001). Multivariable analyses showed that high HT scores were independently associated with severe hematotoxicity, infections, and poor PFS/OS. In conclusion, infections and hematotoxicity are common after brexu‐cel and contribute to NRM. The baseline HT score identified patients at increased risk of poor treatment outcomes.

Brexucabtagene autoleucel for relapsed or refractory mantle cell lymphoma in the United Kingdom: A real‐world intention‐to‐treat analysis

“…The HEMATOTOX (HT) score has been shown to delineate those at higher risk of NRM, severe infections, and haematotoxicity post-brexu-cel. 17 In our analysis, risk factors for NRM included older age, male sex, LDH > ULN, and severe or life-threatening infection with 1 month of infusion. The excess of late NRM events (>90 days, 58%) is of concern, F I G U R E 6 (A, B) Progression-free survival outcome (A) and overall survival outcome (B) for all patients harvested with/without manufacturing failure.…”

“… 14 , 15 , 16 Disease‐specific features associated with an inferior PFS include high simplified MIPI score, 15 , 16 Ki‐67 ≥ 50%, complex karyotype, TP53 aberration, and blastoid/pleomorphic variant. 16 However, rates of non‐relapse mortality (NRM) are significantly higher in the real‐world relative to ZUMA‐2 (3%), ranging from 9% to 15%, 15 , 16 , 17 with a signal for late fatal infectious events. Identification of those most likely to benefit and an understanding of late toxicities are key to appropriate patient selection and tailored care post‐infusion.…”

Applying the EHA/EBMT grading for ICAHT after CAR-T: comparative incidence and association with infections and mortality

“…The grading system for early ICAHT ( Table 1 ) was applied to a real-world cohort of 549 patients treated with BCMA- or CD19-directed CAR T-cells for relapsed/refractory B-cell malignancies (112 MM, 334 LBCL, and 103 MCL) across 12 international CAR-T centers ( supplementary Methods ). 18 , 19 , 25 A uniform data collection form with an embedded data dictionary was provided to all participating centers by the coordinating center (LMU Munich), along with an example of guidelines for data collection. All sites returned data to the coordinating center.…”

“… 15 , 27 Infections were studied until day +90 after CAR-T infusion and were graded on a 5-grade scale as mild, moderate, severe, life-threatening, or fatal. 15 , 17 , 18 , 19 , 28 Severe infections (grade 3 or higher) were defined as requiring intravenous anti-infective therapy and/or hospitalization. Infectious events were either characterized based on microbiologic or histopathologic data or as a clinical syndrome of infection (eg, pneumonia, cellulitis, cystitis) based on retrospective chart review.…”

“…Notably, a high frequency of hematotoxicity has been observed across CAR products and disease entities, irrespective of target antigen (eg, CD19, CD22, BCMA) and costimulatory domain (eg, 4-1BB, CD28z). 8 , 11 , 18 , 19 , 20 , 21 Current grading systems, such as the Common Terminology Criteria for Adverse Events (CTCAE) describe cytopenias predominantly in quantitative terms by assigning severity grades according to cytopenia depth. However, the cumulative risk of secondary complications such as infections primarily increases with the respective duration of observed cytopenia.…”