Plasma-derived proteomic biomarkers in human leukocyte antigen-haploidentical or human leukocyte antigen-matched bone marrow transplantation using post-transplantation cyclophosphamide

Haematologica. 2017 May;102(5):932-940. doi: 10.3324/haematol.2016.152322. Epub 2017 Jan 25.


Recent studies have suggested that plasma-derived proteins may be potential biomarkers relevant for graft-versus-host disease and/or non-relapse mortality occurring after allogeneic blood or marrow transplantation. However, none of these putative biomarkers have been assessed in patients treated either with human leukocyte antigen-haploidentical blood or marrow transplantation or with post-transplantation cyclophosphamide, which has been repeatedly associated with low rates of severe acute graft-versus-host disease, chronic graft-versus-host disease, and non-relapse mortality. We explored whether seven of these plasma-derived proteins, as measured by enzyme-linked immunosorbent assays, were predictive of clinical outcomes in post-transplantation cyclophosphamide-treated patients using plasma samples collected at serial predetermined timepoints from patients treated on prospective clinical studies of human leukocyte antigen-haploidentical (n=58; Identifier: 00796562) or human leukocyte antigen-matched-related or -unrelated (n=100; Identifiers: 00134017 and 00809276) T-cell-replete bone marrow transplantation. Day 30 levels of interleukin-2 receptor α, tumor necrosis factor receptor 1, serum STimulation-2 (IL1RL1 gene product), and regenerating islet-derived 3-α all had high areas under the curve of 0.74-0.97 for predicting non-relapse mortality occurrence by 3 months post-transplant in both the human leukocyte antigen-matched and human leukocyte antigen-haploidentical cohorts. In both cohorts, all four of these proteins were also predictive of subsequent non-relapse mortality occurring by 6, 9, or 12 months post-transplant and were significantly associated with non-relapse mortality in univariable analyses. Furthermore, day 30 elevations of interleukin-2 receptor α were associated with grade II-IV and III-IV acute graft-versus-host disease occurring after day 30 in both cohorts. These data confirm that plasma-derived proteins previously assessed in other transplantation platforms appear to retain prognostic and predictive utility in patients treated with post-transplantation cyclophosphamide.

Publication types

  • Multicenter Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Antineoplastic Agents, Alkylating / therapeutic use
  • Biomarkers / blood*
  • Bone Marrow Transplantation / methods*
  • Cyclophosphamide / therapeutic use*
  • Female
  • Graft vs Host Disease / diagnosis
  • Graft vs Host Disease / prevention & control
  • HLA Antigens / analysis*
  • Hematologic Neoplasms / mortality
  • Hematologic Neoplasms / therapy*
  • Histocompatibility Testing
  • Humans
  • Interleukin-1 Receptor-Like 1 Protein / blood
  • Interleukin-2 Receptor alpha Subunit / blood
  • Male
  • Middle Aged
  • Pancreatitis-Associated Proteins / blood
  • Prospective Studies
  • Proteomics
  • Receptors, Tumor Necrosis Factor, Type I / blood
  • Survival Rate
  • Time Factors
  • Transplantation Conditioning
  • Transplantation, Homologous


  • Antineoplastic Agents, Alkylating
  • Biomarkers
  • HLA Antigens
  • IL1RL1 protein, human
  • Interleukin-1 Receptor-Like 1 Protein
  • Interleukin-2 Receptor alpha Subunit
  • Pancreatitis-Associated Proteins
  • REG3A protein, human
  • Receptors, Tumor Necrosis Factor, Type I
  • Cyclophosphamide