Clonal hematopoiesis and cytopenias following CAR19 therapy

CD19-directed chimeric antigen receptor T cell therapy (CAR19) improves survival in relapsed/refractory large B cell lymphoma compared with immunochemotherapy with intent for autologous hematopoietic cell transplantation (autoHCT). However, major toxicities include prolonged cytopenias, infection and secondary hematologic malignancies. Here, to investigate these complications, we studied patients with lymphoma receiving CAR19 and compared clinical outcomes to propensity-matched autoHCT-treated controls. CAR19-treated patients exhibited impaired immune reconstitution and increased infection. Bone marrow analysis showed that prolonged post-CAR cytopenias are associated with clonal cytopenias of undetermined significance and interferon-mediated inflammation. Clonal hematopoiesis (CH) commonly expanded following CAR19 infusion and was associated with impaired immune reconstitution and treatment-related myeloid malignancy (tMN). Post-CAR tMN was molecularly and clinically comparable to post-autoHCT tMN. Single-cell DNA analysis revealed mostly independent CH clones, while CAR integration into CH-mutant T cells occurred frequently and may drive expansion and persistence. Together, these findings implicate CH expansion and marrow inflammation in key CAR19-associated toxicities.