Clonal Hematopoiesis Is Associated with Increased Risk of Severe Neurotoxicity in Axicabtagene Ciloleucel Therapy of Large B-Cell Lymphoma

Abstract

To explore the role of clonal hematopoiesis (CH) in chimeric antigen receptor (CAR) T-cell therapy outcomes, we performed targeted deep sequencing on buffy coats collected during the 21 days before lymphodepleting chemotherapy from 114 large B-cell lymphoma patients treated with anti-CD19 CAR T cells. We detected CH in 42 (36.8%) pretreatment samples, most frequently in PPM1D (19/114) and TP53 (13/114) genes. Grade ≥3 immune effector cell-associated neurotoxicity syndrome (ICANS) incidence was higher in CH-positive patients than CH-negative patients (45.2% vs. 25.0%, P = 0.038). Higher toxicities with CH were primarily associated with DNMT3A, TET2, and ASXL1 genes (DTA mutations). Grade ≥3 ICANS (58.9% vs. 25%, P = 0.02) and ≥3 cytokine release syndrome (17.7% vs. 4.2%, P = 0.08) incidences were higher in DTA-positive than in CH-negative patients. The estimated 24-month cumulative incidence of therapy-related myeloid neoplasms after CAR T-cell therapy was higher in CH-positive than CH-negative patients [19% (95% CI, 5.5-38.7) vs. 4.2% (95% CI, 0.3-18.4), P = 0.028].

Significance: Our study reveals that CH mutations, especially those associated with inflammation (DNMT3A, TET2, and ASXL1), are associated with severe-grade neurotoxicities in lymphoma patients receiving anti-CD19 CAR T-cell therapy. Further studies to investigate the mechanisms and interventions to improve toxicities in the context of CH are warranted. See related content by Uslu and June, p. 382. This article is highlighted in the In This Issue feature, p. 369.

Figure 1.

Oncoplot of CH mutations at baseline in LBCL patients treated with anti-CD19 CAR T-cell therapy and their association with response and toxicity outcomes. Abbreviations: CR, complete response; CRS, cytokine release syndrome; ICANS, immune cell-associated neurotoxicity syndrome; n/a, not evaluable; t-MNs, treatment-related myeloid neoplasms; PR, partial response; PD/SD, progressive disease/stable disease.

Figure 2.

Associations between clinical outcomes and CH status in LBCL patients treated with anti-CD19 CAR T-cell therapy. A, Bar graph showing best response rates in CH versus no-CH patients. B, Kaplan–Meier curve of PFS in patients with CH and no CH. C, Bar graph showing the incidence of grade 3/4 severe CRS and grade 3/4 severe ICANS in the CH and no-CH patients. D, Cumulative incidence of therapy-related myeloid neoplasms in patients with CH compared to without CH. *, P = 0.038. Abbreviations: CR, complete response; CRS, cytokine release syndrome; ICANS, immune cell-associated neurotoxicity syndrome; ORR, overall response rates; t-MNs, treatment-related myeloid neoplasms; PR, partial response; PD, progressive disease; SD, stable disease.