Clonal Hematopoiesis and Inflammation Predict Hematologic Toxicity and Secondary Myeloid Malignancies after B-Cell Maturation Antigen-Directed Chimeric Antigen Receptor T-cell Therapy.

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.