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

J Clin Oncol. 2017 May 10;35(14):1598-1605. doi: 10.1200/JCO.2016.71.6712. Epub 2017 Jan 9.

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.

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Clone Cells
  • DNA (Cytosine-5-)-Methyltransferases / genetics
  • DNA Mutational Analysis
  • DNA-Binding Proteins / genetics
  • Exome
  • Female
  • Hematopoiesis
  • Hematopoietic Stem Cell Transplantation / adverse effects*
  • Hodgkin Disease / therapy*
  • Humans
  • Leukemia, Myeloid, Acute / etiology*
  • Leukemia, Myeloid, Acute / genetics
  • Lymphoma, Non-Hodgkin / therapy*
  • Male
  • Middle Aged
  • Myelodysplastic Syndromes / etiology*
  • Myelodysplastic Syndromes / genetics
  • Neoplasms, Second Primary / etiology*
  • Neoplasms, Second Primary / genetics
  • Protein Phosphatase 2C / genetics
  • Proto-Oncogene Proteins / genetics
  • Repressor Proteins / genetics
  • Survival Rate
  • Transplantation, Autologous / adverse effects
  • Tumor Suppressor Protein p53 / genetics

Substances

  • ASXL1 protein, human
  • DNA-Binding Proteins
  • Proto-Oncogene Proteins
  • Repressor Proteins
  • TET2 protein, human
  • Tumor Suppressor Protein p53
  • DNA (Cytosine-5-)-Methyltransferases
  • DNA methyltransferase 3A
  • PPM1D protein, human
  • Protein Phosphatase 2C