Clonal Hematopoiesis and Therapy-Related Myeloid Neoplasms After Autologous Transplant for Hodgkin Lymphoma.

Abstract

Therapy-related myeloid neoplasm (t-MN) is a life-threatening complication of autologous peripheral blood stem cell transplantation (aPBSCT) for Hodgkin lymphoma (HL). Although previous studies have reported an association between clonal hematopoiesis (CH) in the infused PBSC product and subsequent post-aPBSCT risk of t-MN in patients with non-HL, information about patients with HL treated with aPBSCT is not available. We constructed a retrospective cohort of 321 patients with HL transplanted at a median age of 34 years (range, 18-71). Targeted DNA sequencing of PBSC products performed for CH-associated or myeloid malignancy-associated genes identified pathogenic mutations in these patients. CH was identified in the PBSC product of 46 patients (14.3%) with most prominent representation of <i>DNMT3A</i> (n = 25), <i>PPM1D</i> (n = 7), <i>TET2</i> (n = 7), and <i>TP53</i> (n = 5) mutations. Presence of CH in the PBSC product was an independent predictor of t-MN (adjusted hazard ratio [aHR], 4.50 [95% CI, 1.54 to 13.19]). Notably all patients with <i>TP53</i> mutations in the PBSC product developed t-MN, whereas none of the patients with <i>DNMT3A</i> mutations alone (without co-occurring <i>TP53</i> or <i>PPM1D</i> mutations) did. Presence of <i>TP53</i> and/or <i>PPM1D</i> mutations was associated with a 7.29-fold higher hazard of t-MN when compared with individuals carrying no CH mutations (95% CI, 1.72 to 30.94). The presence of <i>TP53</i> and/or <i>PPM1D</i> mutations was also associated with a 4.17-fold higher hazard of nonrelapse mortality (95% CI, 1.25 to 13.87). There was no association between CH and relapse-related mortality. The presence of <i>TP53</i> and/or <i>PPM1D</i> mutations in the PBSC product increases the risk of post-aPBSCT t-MN and nonrelapse mortality among patients with HL and may support alternative therapeutic strategies.