Graft-versus-host disease after liver transplantation is associated with bone marrow failure, hemophagocytosis, and DNMT3A mutations

Laura F. Newell, Jennifer Dunlap, Ken Gatter, Grover C. Bagby, Richard D. Press, Rachel J. Cook, Luke Fletcher, Jessica T. Leonard, Kelli M. Leong, Joseph S. Bubalo, Ali Olyaei, Thomas G. Deloughery, Richard T. Maziarz, Erin Maynard, Susan L. Orloff, C. Kristian Enestvedt

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Graft-versus-host disease after liver transplantation (LT-GVHD) is rare, frequently fatal, and associated with bone marrow failure (BMF), cytopenias, and hyperferritinemia. Given hyperferritinemia and cytopenias are present in hemophagocytic lymphohistiocytosis (HLH), and somatic mutations in hematopoietic cells are associated with hyperinflammatory responses (clonal hematopoiesis of indeterminate potential, CHIP), we identified the frequency of hemophagocytosis and CHIP mutations in LT-GVHD. We reviewed bone marrow aspirates and biopsies, quantified blood/marrow chimerism, and performed next-generation sequencing (NGS) with a targeted panel of genes relevant to myeloid malignancies, CHIP, and BMF. In all, 12 marrows were reviewed from 9 LT-GVHD patients. In all, 10 aspirates were evaluable for hemophagocytosis; 7 had adequate DNA for NGS. NGS was also performed on marrow from an LT cohort (n = 6) without GVHD. Nine of 10 aspirates in LT-GVHD patients showed increased hemophagocytosis. Five (71%) of 7 with LT-GVHD had DNMT3A mutations; only 1 of 6 in the non-GVHD LT cohort demonstrated DNMT3A mutation (p =.04). Only 1 LT-GVHD patient survived. BMF with HLH features was associated with poor hematopoietic recovery, and DNMT3A mutations were over-represented, in LT-GVHD patients. Identification of HLH features may guide prognosis and therapeutics. Further studies are needed to clarify the origin and impact of CHIP mutations on the hyperinflammatory state.

Original languageEnglish (US)
Pages (from-to)3894-3906
Number of pages13
JournalAmerican Journal of Transplantation
Volume21
Issue number12
DOIs
StatePublished - Dec 2021

Keywords

  • clinical research/practice
  • graft-versus-host disease (GVHD)
  • hematology/oncology
  • immune regulation
  • immunosuppression/immune modulation
  • liver transplantation/hepatology
  • molecular biology: DNA
  • monitoring: immune
  • translational research/science

ASJC Scopus subject areas

  • Immunology and Allergy
  • Transplantation
  • Pharmacology (medical)

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