Clonal Hematopoiesis Associated With Adverse Outcomes After Autologous Stem-Cell Transplantation for Lymphoma

Abstract

Purpose Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related condition characterized by somatic mutations in the blood of otherwise healthy adults. We hypothesized that in patients undergoing autologous stem-cell transplantation (ASCT) for lymphoma, CHIP at the time of ASCT would be associated with an increased risk of myelodysplastic syndrome and acute myeloid leukemia, collectively termed therapy-related myeloid neoplasm (TMN), and other adverse outcomes. Methods We performed whole-exome sequencing on pre- and post-ASCT samples from 12 patients who developed TMN after autologous transplantation for Hodgkin lymphoma or non-Hodgkin lymphoma and targeted sequencing on cryopreserved aliquots of autologous stem-cell products from 401 patients who underwent ASCT for non-Hodgkin lymphoma between 2003 and 2010. We assessed the effect of CHIP at the time of ASCT on subsequent outcomes, including TMN, cause-specific mortality, and overall survival. Results For six of 12 patients in the exome sequencing cohort, mutations found in the TMN specimen were also detectable in the pre-ASCT specimen. In the targeted sequencing cohort, 120 patients (29.9%) had CHIP at the time of ASCT, which was associated with an increased rate of TMN (10-year cumulative incidence, 14.1% v 4.3% for those with and without CHIP, respectively; P = .002). Patients with CHIP had significantly inferior overall survival compared with those without CHIP (10-year overall survival, 30.4% v 60.9%, respectively; P < .001), including increased risk of death from TMN and cardiovascular disease. Conclusion In patients undergoing ASCT for lymphoma, CHIP at the time of transplantation is associated with inferior survival and increased risk of TMN.

Fig 1.

Characteristics of clonal hematopoiesis of indeterminate potential (CHIP) in targeted sequencing cohort. (A) Number of total mutations in each gene in the cohort. The number of mutations for each gene is listed above that gene’s respective bar; genes without a number above their bar were mutated only once each. (B) Prevalence of CHIP per each age decade of patients in the cohort.

Fig 2.

Outcomes of patients with clonal hematopoiesis of indeterminate potential (CHIP). (A) Cumulative incidence of therapy-related myeloid neoplasm (TMN) in patients with CHIP versus patients without CHIP, with death as an absorbing competing risk and patients censored at the date of any subsequent allogeneic transplantation. (B) Overall survival among patients with CHIP versus those without CHIP. (C) Event-free survival among patients with CHIP versus those without CHIP; death, lymphoma relapse, and TMN were considered events. (D) Cumulative incidence of relapse in patients with CHIP versus patients without CHIP (solid lines), with death in the absence of relapse (dashed lines) as the competing risk. (E) Variables that remained significantly associated with overall survival in a Cox proportional hazards model stratified by type of lymphoma. All P values are for log-rank tests.

Fig 3.

Outcomes of patients with PPM1D mutations. (A) Overall survival among patients with PPM1D mutations (n = 48) compared with patients with other mutations (n = 72) and those with no mutation (n = 281). (B) Cumulative incidence of relapse (solid lines) and death without relapse (dashed lines) for the same three groups. The cumulative incidence of relapse was not significantly different between the three groups (10-year cumulative incidence of relapse, 56% for PPM1D mutations, 48.6% for other mutations, and 45.9% for no clonal hematopoiesis of indeterminate potential [CHIP]; P = .48).