TY - JOUR
T1 - Graft-versus-host disease after liver transplantation is associated with bone marrow failure, hemophagocytosis, and DNMT3A mutations
AU - Newell, Laura F.
AU - Dunlap, Jennifer
AU - Gatter, Ken
AU - Bagby, Grover C.
AU - Press, Richard D.
AU - Cook, Rachel J.
AU - Fletcher, Luke
AU - Leonard, Jessica T.
AU - Leong, Kelli M.
AU - Bubalo, Joseph S.
AU - Olyaei, Ali
AU - Deloughery, Thomas G.
AU - Maziarz, Richard T.
AU - Maynard, Erin
AU - Orloff, Susan L.
AU - Enestvedt, C. Kristian
N1 - Publisher Copyright:
© 2021 The American Society of Transplantation and the American Society of Transplant Surgeons
PY - 2021/12
Y1 - 2021/12
N2 - 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.
AB - 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.
KW - clinical research/practice
KW - graft-versus-host disease (GVHD)
KW - hematology/oncology
KW - immune regulation
KW - immunosuppression/immune modulation
KW - liver transplantation/hepatology
KW - molecular biology: DNA
KW - monitoring: immune
KW - translational research/science
UR - http://www.scopus.com/inward/record.url?scp=85110470349&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85110470349&partnerID=8YFLogxK
U2 - 10.1111/ajt.16635
DO - 10.1111/ajt.16635
M3 - Article
C2 - 33961341
AN - SCOPUS:85110470349
SN - 1600-6135
VL - 21
SP - 3894
EP - 3906
JO - American Journal of Transplantation
JF - American Journal of Transplantation
IS - 12
ER -