Work

Impact of Clonal Hematopoiesis of Indeterminate Potential (CHIP) on Treatment Outcomes in Multiple Myeloma Patients Undergoing CAR-T Cell Therapy.

Year: 2025

Type: article

Abstract: Introduction Clonal hematopoiesis of indeterminate potential (CHIP) includes hematologic malignancy-associated somatic mutations that drive clonal expansion and are seen in patients without myeloid or lymphoid neoplasms. In multiple myeloma (MM), the implications of CHIP on chimeric antigen receptor (CAR)-T cell outcomes and toxicities are not well-defined. Objectives This study aims to explore associations between CHIP and clinical outcomes in patients with MM undergoing CAR-T cell therapy. Methods We performed a retrospective, single center study at UCLA medical center of adults with multiple myeloma who received commercial CAR-T cell therapy, had available NGS data from bone marrow within 1 year of CAR-T cell infusion, and had no prior history of myelodysplastic syndrome or acute myeloid leukemia. Results Of the 51 patients identified, 17 (33%) patients had CHIP mutations (defined as a somatic mutation with variant allele frequency of 2-40% and excluding mutations in TP53, KRAS, BRAF, and EZH2). The average age was comparable between groups at 62 years old without CHIP and 66 years old with CHIP. The median lines of prior therapy were 5.35 without CHIP and 4.76 with CHIP, with similar rates of prior autologous stem cell transplant between groups (70.6% no CHIP, 76.5% with CHIP). The overall response rate in patients undergoing CAR-T cell therapy did not differ by the presence of CHIP mutations (94% with CHIP vs. 91% in no CHIP; p=0.99). The presence of a CHIP mutation was also not associated with progression-free survival (PFS) (HR 0.54; 95% CI: 0.15-1.96; p=0.35) or overall survival (OS) (HR 0.41; 95% CI; 0.05-3.71; p=0.43). Patients with CHIP mutations were more likely to develop cytokine release syndrome (CRS) than those without CHIP mutations (100% vs. 65%; p=0.004), and CHIP was associated with a higher grade of CRS (p=0.04). The incidence of immune effector cell-associated neurotoxicity (ICANS) was 41% in patients with CHIP vs. 21% in patients without CHIP (p=0.18), and again was associated with a higher grade, though not statistically significant (p=0.19). Despite there being no significant differences in absolute neutrophil count between patients without CHIP and with CHIP on days 28 (1.59 vs. 1.29, p=0.42), 90 (2.03 vs. 0.88, p=0.82), and 120 (1.41 vs. 3.44, p=0.55), there was a notable increase in use of G-CSF between days 90 and 120 for patients with CHIP mutations, though not statistically significant (27% vs. 4%; p=0.07). Conclusion Although CHIP conferred a higher risk of inflammatory response seen with increased frequency and grade of CRS, the presence of CHIP did not negatively influence the response rate, survival, or progression free survival in MM patients after CAR-T cell therapy.

Source: Transplantation and Cellular Therapy

DOI: 10.1016/j.jtct.2025.01.359