Clinical cancer research : an official journal of the American Association for Cancer Research · 2025
Clonal Hematopoiesis and Inflammation Predict Hematologic Toxicity and Secondary Myeloid Malignancies after B-Cell Maturation Antigen-Directed Chimeric Antigen Receptor T-cell Therapy.
СтатьяНазвание и аннотация: Перевод в очереди
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Avigan Zachary M, Catlett Jerrel, Bodnar Saoirse, Pan Darren, Aleman Adolfo, Sheng Tianxiang, Moshier Erin, Rossi Adriana C, Richard Shambavi, Kaur Gurbakhash, Richter Joshua, Sanchez Larysa J, Rodriguez Cesar, Cho Hearn Jay, Hussein Shafinaz, Salib Christian, Silverman Lewis R, Jagannath Sundar, Parekh Samir, Thibaud Santiago
Аннотация
PURPOSE: Chimeric antigen receptor T cells (CAR-T) have demonstrated remarkable efficacy in multiple myeloma, but prolonged hematologic toxicity remains a common adverse event, and secondary myeloid malignancies are a significant safety concern.
EXPERIMENTAL DESIGN: We evaluated 213 patients with myeloma treated with B-cell maturation antigen-directed CAR-T at our center to characterize clinical, inflammatory, and myeloid clonal features associated with hematologic toxicity.
RESULTS: Patients with persistent grade ≥3 neutropenia or thrombocytopenia at day 100 (19%) had shorter progression-free survival (P = 0.0003) and overall survival (P < 0.0001), and among those with continued remissions, 64% developed prolonged high-grade cytopenias beyond 1 year. Whereas baseline inflammation is a risk factor for hematologic toxicity, underlying clonal hematopoiesis (CH) modulated this risk, and the combination of CH and elevated ferritin was highly predictive of delayed recovery (adjusted HR, 0.38, P = 0.006). Serum cytokine analysis in patients with delayed myeloid recovery showed a signature of persistent inflammation and endothelial dysfunction. Finally, 9% developed secondary myeloid diseases, including 5% with high-grade myelodysplastic syndrome (MDS) requiring therapy, a median of 14.5 months after CAR-T. MDS was associated with clonal expansion of underlying TP53-mutated CH from a median variant allele frequency of 3.4% before CAR-T to 44.0%. Whereas patients with baseline TP53-mutated CH exhibited clonal evolution and a high incidence of MDS (67%), other CH mutations did not show similar expansion after CAR-T (P > 0.99).
CONCLUSIONS: This study underscores the impact of hematologic toxicity and CH on B-cell maturation antigen CAR-T outcomes and suggests a potential role of CAR-T in influencing TP53 clonal dynamics and myeloid disease development.
EXPERIMENTAL DESIGN: We evaluated 213 patients with myeloma treated with B-cell maturation antigen-directed CAR-T at our center to characterize clinical, inflammatory, and myeloid clonal features associated with hematologic toxicity.
RESULTS: Patients with persistent grade ≥3 neutropenia or thrombocytopenia at day 100 (19%) had shorter progression-free survival (P = 0.0003) and overall survival (P < 0.0001), and among those with continued remissions, 64% developed prolonged high-grade cytopenias beyond 1 year. Whereas baseline inflammation is a risk factor for hematologic toxicity, underlying clonal hematopoiesis (CH) modulated this risk, and the combination of CH and elevated ferritin was highly predictive of delayed recovery (adjusted HR, 0.38, P = 0.006). Serum cytokine analysis in patients with delayed myeloid recovery showed a signature of persistent inflammation and endothelial dysfunction. Finally, 9% developed secondary myeloid diseases, including 5% with high-grade myelodysplastic syndrome (MDS) requiring therapy, a median of 14.5 months after CAR-T. MDS was associated with clonal expansion of underlying TP53-mutated CH from a median variant allele frequency of 3.4% before CAR-T to 44.0%. Whereas patients with baseline TP53-mutated CH exhibited clonal evolution and a high incidence of MDS (67%), other CH mutations did not show similar expansion after CAR-T (P > 0.99).
CONCLUSIONS: This study underscores the impact of hematologic toxicity and CH on B-cell maturation antigen CAR-T outcomes and suggests a potential role of CAR-T in influencing TP53 clonal dynamics and myeloid disease development.