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 CAR-T therapy. While a grading system based solely on neutrophil counts was proposed (hereafter termed N-ICAHT), the prevalence and prognostic impact of thrombocytopenia remains 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 dataset, 43% of patients developed any-grade early T-ICAHT (day 0-30), with 23% developing severe (G3+) manifestations. Late T-ICAHT (day 31-100) was observed in 42% (G3+: 13%). While 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 (p<0.001) and more bleeding events (p=0.01). T-ICAHT grades were inversely associated with overall survival (OS), with landmarked 2-year estimates ranging from 67% (G0), to 48% (G1-2) and 35% (G3+). 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, MM, B-ALL), confirming its broad applicability. These findings support integrating T-ICAHT into the ICAHT framework to standardize thrombocytopenia grading in CAR-T recipients.
Article Details
Authors (38)
Kai Rejeski
Memorial Sloan Kettering Cancer Center, New York, New York, United States
Jaime Sanz
2Hospital Universitari i Politècnic La Fe, Valencia Departament de Medicina Universitat de Valencia, CIBERONC, Instituto Carlos III, Madrid, Spain, Hematology Department, Valencia, Spain
Teng Fei
College of Life and Health Sciences, Northeastern University
Monica S Nair
Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health (NIH), Bethesda, Maryland, United States
Hamza Hashmi
Memorial Sloan Kettering Cancer Center, New York
Abraham Avigdor
3Division of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel HaShomer, Ramat Gan, Israel
Ofrat Beyar-Katz
5Department of Hematology and Bone Marrow Transplantation, Rambam Health Care Campus, Haifa, Israel
Veit L. Bücklein
7Department of Medicine III, Hematology/Oncology, LMU University Hospital, LMU Munich, Munich, Germany
Kevin J. Curran
Sigrun Einarsdottir
1Adult Bone Marrow Transplantation Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
Jonathan H Esensten
Memorial Sloan Kettering Cancer Center, United States
Netta Glaubach
Rambam Health Care Campus, Haifa, Israel
Noa Golan-Accav
Chaim Sheba Medical Center, Tel-Hashomer, affiliated with Faculty of MedicineTel Aviv University, Ramat Gan, Israel
Marina Gomez-Llobell
1Adult Bone Marrow Transplantation Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
Iris Halamis
Rambam Healthcare Campus, Haifa, Israel
Orit Itzhaki
1Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel
Frederick L. Locke
Sham Mailankody
Cellular Therapy Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York
Ronit Marcus
3Division of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel HaShomer, Ramat Gan, Israel
Marcela V. Maus
M. Lia Palomba
5Memorial Sloan Kettering Cancer Center, New York, NY
Jae H Park
Memorial Sloan-Kettering Cancer Center, New York, New York, United States
Marcelo C. Pasquini
18Center for International Blood and Marrow Transplant Research, Medical College of Wisconsin, Milwaukee, WI
Sandeep S Raj
MSKCC, New York, New York, United States
Sridevi Rajeeve
1Memorial Sloan Kettering Cancer Center, Myeloma Service, Department of Medicine, New York, United States
Gilles A. Salles
Memorial Sloan Kettering Cancer Center, New York, New York, United States
Michael Scordo
Cellular Therapy Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York
Gunjan L Shah
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, United States
Avichai Shimoni
3Division of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel HaShomer, Ramat Gan, Israel
Marion Subklewe
Ludwig Maximilian University Hospital, Munich, Germany
Tobias Tix
7Department of Medicine III, Hematology/Oncology, LMU University Hospital, LMU Munich, Munich, Germany
Saad Z Usmani
Memorial Sloan Kettering Cancer Center, New York, New York, United States
Ori Ben Valid
3Division of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel HaShomer, Ramat Gan, Israel
Yannis K. Valtis
22Cell Therapy Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
Tsila Zuckerman
1Rambam Health Care Campus, Department of Hematology and Bone Marrow Transplantation, Haifa, Israel
Nirali N Shah
Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health (NIH), Bethesda, Maryland, United States
Miguel-Angel Perales
1Adult Bone Marrow Transplant Service, Memorial Sloan Kettering Cancer Center, New York, NY
Roni Shouval
1Adult Bone Marrow Transplantation Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY