T-ICAHT: Grading and Prognostic Impact of Thrombocytopenia After CAR T-cell Therapy

ABSTRACT: Immune effector cell-associated hematotoxicity (ICAHT) was recently introduced as a distinct toxicity category of chimeric antigen receptor (CAR) T-cell (CAR-T) therapy. Although a grading system based solely on neutrophil counts was proposed (hereafter termed N-ICAHT), the prevalence and prognostic impact of thrombocytopenia remain poorly defined. In this multicenter observational study, we systematically examined patterns of thrombocytopenia in 744 patients treated with commercial CD19 CAR-T for B-cell non-Hodgkin lymphoma (B-NHL). We developed a grading system termed T-ICAHT, with thresholds that closely aligned with N-ICAHT, based on depth, duration, and timing of thrombocytopenia. In the core NHL data set, 43% of patients developed any-grade early T-ICAHT (days 0-30), with 23% developing severe (grade ≥3) manifestations. Late T-ICAHT (days 31-100) was observed in 42% (grade ≥3, 13%). Although T-ICAHT and N-ICAHT gradings showed some correlation, considerable discordance was noted. On multivariate analysis, bridging therapy, poor performance status, and high HEMATOTOX scores were associated with increased risk of severe early T-ICAHT. Patients with higher T-ICAHT grades showed increased platelet and red blood cell transfusion burden and more bleeding events. T-ICAHT grades were inversely associated with overall survival (OS), with landmarked 2-year estimates ranging from 67% (grade 0) to 48% (grade 1-2) and 35% (grade ≥3). In multivariable Cox regression analysis, the independent prognostic capacity of T-ICAHT for OS was confirmed. Finally, we validated T-ICAHT's clinical and prognostic utility in 3 external cohorts spanning an additional 599 pediatric and adult patients (NHL, multiple myeloma, and B-cell acute lymphoblastic leukemia), confirming its broad applicability. These findings support integrating T-ICAHT into the ICAHT framework to standardize thrombocytopenia grading in CAR-T recipients.