Clinical Implications and Dynamics of Clonal Hematopoiesis in Anti-CD19 CAR T-cell Treated Patients

Abstract

Recent evidence revealed important interactions between clonal hematopoiesis (CH) and cellular therapies established for the treatment of hematologic malignancies. The impact of CH on safety, efficacy, and outcome of chimeric antigen receptor (CAR) T-cell therapy is currently under investigation. We analyzed 110 patients with relapsed/refractory B-cell non-Hodgkin lymphoma (n = 105) or acute lymphoblastic leukemia (ALL) (n = 5), treated with Axicabtagene-Ciloleucel (39%), Tisagenlecleucel (51%), or Brexucabtagene autoleucel (10%). Using error-corrected targeted sequencing, a high CH prevalence of 56.4% (variant allele frequency [VAF] ≥1%) at the time of CAR T-cell infusion was detected. The most frequently mutated gene was PPM1D followed by DNMT3A, TET2, ASXL1, and TP53. Variant allele frequencies were significantly lower in B and T cells compared with monocytes and granulocytes. CH did not increase the risk of CAR T-related toxicities. The incidences of cytokine release syndrome and immune effector-cell-associated neurotoxicity syndrome were similar between CHpos and CHneg patients, regardless of clone size, age, or CAR T product. Prolonged cytopenias were not associated with CH. Best overall response rates (ORRs) were numerically but not significantly higher in CHpos patients (ORR 76.7% versus 62.2%; P = 0.13). Furthermore, CH status did not predict progression-free survival or overall survival. Lastly, sequential analysis showed a modest VAF increase of 1.3% and acquisition of novel mutations within 100 days postinfusion. CH was frequent in large B-cell lymphoma/ALL patients receiving CAR T-cells but did not affect toxicity nor treatment response or outcome.

T-Cell Malignant Neoplasms After Chimeric Antigen Receptor T-Cell Therapy

“…The high frequency of myeloid neoplasms should be interpreted in the context of the substantial treatment burden in patients receiving CAR-T therapy, including exposure to prior tumorigenic therapies. Additionally, CAR-T therapy might facilitate progression of preexisting clonal hematopoiesis to overt myeloid neoplasia . Extended survival also allows more time for SPMN development.…”

Non-relapse mortality after CAR T-cell therapy: A systematic review and meta-analysis of 7,788 lymphoma and myeloma patients

“…94 Supporting this hypothesis, a recent study found a high prevalence of clonal hematopoiesis of 50-60% at time of CAR-T infusion. 95,96 Nonetheless, considering the growing body of evidence elucidating the role of in ammatory stressors for clonal expansion, 97,98 the impact of CAR-T induced in ammatory stress on the development of secondary myeloid malignancies warrants future systematic study.…”

Answering the “Doctor, can CAR-T therapy cause cancer?” question in clinic

“…16 However, >95% of CARTITUDE-1 participants had received prior lenalidomide, a drug known to predispose patients to myeloid malignancies through its effects on hematopoietic progenitor cells. 17 , 18 In general, clonal hematopoiesis of indeterminate potential is present in 20% to 60% of patients at baseline before receiving CAR T. 19 , 20 , 21 …”