High risk of adverse events after autologous stem-cell transplantation in lymphoma patients with dna repair pathway mutations: a nation-wide cohort study

Introduction: It is estimated that at least 30% of patients with lymphoma die within five years after autologous stem-cell transplantation (ASCT). A substantial fraction of patients succumb to therapy-related side effects. Identifying patients not suited for ASCT has so far been challenging, but clonal hematopoiesis (CHIP) mutations in peripheral blood and/or bone marrow has in single-center studies been proposed as markers of vulnerability. We performed a national population-based analysis of CHIP in lymphoma patients undergoing ASCT to investigate this. Methods: Patients in Denmark with a lymphoma diagnosis (both Non-Hodgkin and Hodgkin lymphoma) and a registered autologous stem cell sample harvested at Danish transplant centers between January 1, 2000 and July 1, 2012 were included. We performed targeted next generation sequencing (NGS) of autologous stem cell harvest material with a panel covering 21 of the most commonly mutated genes in clonal hematopoiesis. To allow accurate mutation calling unique molecular identifiers (UMI's) were employed and a median coverage of 5832X was obtained. We retrieved prospective clinical data from five independent nation-wide registries covering death, relapse, severe infections (sepsis and invasive fungal infection), secondary malignancies, days in hospital, use of transfusion products (red blood cell and platelets), and intensive care admission. Results: A total of 892 patients were identified; 565 patients fit inclusion criteria and were sequenced. The median follow-up was 9.1 years (IQR 7.0–10.3). Of these, 440 patients were intended for immediate ASCT, 121 patients had stem cells harvested as part of a ‘rainy day strategy’, and 4 patients had unknown infusion status. CHIP mutations were identified in 112 patients (25.5%) intended for immediate ASCT. These mutations were, in contrast to findings in single-center studies, not associated with a significant inferior overall survival after adjusting for age, sex, and line of therapy (hazard ratio [HR] 1.36, 95%CI 0.93–1.99, p = 0.11). However, patients with mutations in DNA repair pathway genes (PPM1D, TP53, BRCC3, and RAD21; 9.1% of patients in the cohort) had a significant independent inferior overall survival (adjusted HR 2.37, 95%CI 1.44–3.90, p<0.0001). In addition, patients with DNA repair pathway mutations had a significant higher incidence of admission to intensive care (p = 0.019; Figure 1), a significant higher incidence of therapy-related leukemia (p = 0.0018), and a non-significant higher incidence of severe infections (p = 0.061). We also found that these patients had a significantly increased number of days in hospital following ASCT (p = 0.0025). Keywords: autologous stem cell transplantation (ASCT); clonal hematopoiesis; non-Hodgkin lymphoma (NHL).