Rejeski Kai, Sanz Jaime, Fei Teng, Nair Monica S, Hashmi Hamza, Avigdor Abraham, Beyar-Katz Ofrat, Bücklein Veit L, Curran Kevin J, Einarsdottir Sigrun, Esensten Jonathan H, Glaubach Netta, Golan-Accav Noa, Gomez-Llobell Marina, Halamis Iris, Itzhaki Orit, Locke Frederick L, Mailankody Sham, Marcus Ronit, Maus Marcela V, Palomba M Lia, Park Jae H, Pasquini Marcelo, Raj Sandeep, Rajeeve Sridevi, Salles Gilles, Scordo Michael, Shah Gunjan L, Shimoni Avichai, Subklewe Marion, Tix Tobias, Usmani Saad Z, Valid Ori, Valtis Yannis K, Zuckerman Tsila, Shah Nirali N, Perales Miguel-Angel, Shouval Roni
Adult Bone Marrow Transplant Service, Division of Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY.
Cellular Therapy Service, Division of Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY.
Blood. 2025 Aug 14;146(7):834-846. doi: 10.1182/blood.2025028833.
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.
免疫效应细胞相关血液毒性（ICAHT）最近被引入作为嵌合抗原受体（CAR）T细胞（CAR-T）疗法的一种独特毒性类别。尽管有人提出了一种仅基于中性粒细胞计数的分级系统（以下称为N-ICAHT），但血小板减少症的患病率和预后影响仍未明确界定。在这项多中心观察性研究中，我们系统地检查了744例接受商业化CD19 CAR-T治疗B细胞非霍奇金淋巴瘤（B-NHL）患者的血小板减少模式。我们基于血小板减少症的深度、持续时间和发生时间，开发了一种称为T-ICAHT的分级系统，其阈值与N-ICAHT密切相关。在核心NHL数据集中，43%的患者出现任何级别的早期T-ICAHT（第0至30天），其中23%出现严重（≥3级）表现。42%的患者出现晚期T-ICAHT（第31至100天）（≥3级，13%）。尽管T-ICAHT和N-ICAHT分级显示出一定相关性，但也存在相当大的不一致性。多变量分析显示，桥接治疗、较差的体能状态和较高的血液毒性评分与严重早期T-ICAHT风险增加相关。T-ICAHT分级较高的患者显示血小板和红细胞输血负担增加，出血事件更多。T-ICAHT分级与总生存期（OS）呈负相关，标志性的2年估计值范围为67%（0级）至48%（1-2级）和35%（≥3级）。在多变量Cox回归分析中，证实了T-ICAHT对OS的独立预后能力。最后，我们在另外599例儿科和成人患者（NHL、多发性骨髓瘤和B细胞急性淋巴细胞白血病）的3个外部队列中验证了T-ICAHT的临床和预后效用，证实了其广泛适用性。这些发现支持将T-ICAHT纳入ICAHT框架，以规范CAR-T接受者的血小板减少分级。
