TY - JOUR
T1 - Molecular disparity of HLA-DPB1 is associated with the development of subsequent solid cancer after allogeneic hematopoietic stem cell transplantation
AU - Zou, Jun
AU - Kongtim, Piyanuch
AU - Oran, Betül
AU - Srour, Samer A.
AU - Greenbaum, Uri
AU - Carmazzi, Yudith
AU - Rondon, Gabriela
AU - Ciurea, Stefan O.
AU - Ma, Qing
AU - Shpall, Elizabeth J.
AU - Champlin, Richard E.
AU - Cao, Kai
N1 - Funding Information:
The authors thank Kevin Harrell and Dr. Jar-How Lee from Thermo Fisher Scientific for their help in the eplet analysis for this manuscript. We thank Erica Goodoff, senior scientific editor in the Research Medical Library at The University of Texas MD Anderson Cancer Center, for editing this article.
Publisher Copyright:
© 2023 American Cancer Society.
PY - 2023/4/15
Y1 - 2023/4/15
N2 - Background: An increased incidence of subsequent solid cancers (SSCs) has been reported in long-term survivors of allogeneic hematopoietic stem cell transplantation (allo-HSCT), and SSC is associated with inferior mortality and morbidity. Previous studies showed that the incidence of SSC is significantly higher in those who underwent allo-HSCT from HLA-mismatched donors, suggesting that persistent alloimmunity may predispose patients to SSCs. It was recently reported that, in a cohort of patients who received allo-HSCT from an unrelated donor matched at HLA-A, -B, -C, -DRB1/3/4/5, and -DQB1 loci, HLA-DPB1 alloimmunity determined by high mismatched eplets (MEs) and Predicted Indirectly Recognizable HLA Epitopes (PIRCHE) score (PS), was associated with relapse protection and increased risk of acute graft-versus-host disease (GVHD). Methods: In the present study, the impact of HLA-DPB1 alloimmunity assessed by molecular mismatch algorithms on the development of SSCs in a cohort of 1514 patients who underwent allo-HSCT for hematologic malignancies was further investigated. ME load at the HLA-DPB1 locus was measured using the HLAMatchmaker module incorporated in HLA Fusion software, and the PS for mismatched HLA-DPB1 was calculated using the HSCT module from the PIRCHE online matching service. Results: In multivariable analysis after adjusting for baseline risk factors, higher ME, PS-I, and PS-II in the GVH direction, but not in the HVG direction, were associated with an increased risk of SSCs (ME: subdistribution hazard ratio [SHR] 1.58, p =.01; PS-I: SHR 1.59, p =.009; PS-II: SHR 1.71, p =.003). In contrast, nonpermissive HLA-DPB1 mismatches defined by the conventional T-cell epitope algorithm were not predictive of the risk of SSCs. Moreover, posttransplant cyclophosphamide-based GVHD prophylaxis was associated with a reduced risk of subsequent solid cancer (SHR 0.34, p =.021). Conclusions: These results indicate for the first time that increased GVH alloreactivity could contribute to the development of SSCs in allo-HSCT survivors.
AB - Background: An increased incidence of subsequent solid cancers (SSCs) has been reported in long-term survivors of allogeneic hematopoietic stem cell transplantation (allo-HSCT), and SSC is associated with inferior mortality and morbidity. Previous studies showed that the incidence of SSC is significantly higher in those who underwent allo-HSCT from HLA-mismatched donors, suggesting that persistent alloimmunity may predispose patients to SSCs. It was recently reported that, in a cohort of patients who received allo-HSCT from an unrelated donor matched at HLA-A, -B, -C, -DRB1/3/4/5, and -DQB1 loci, HLA-DPB1 alloimmunity determined by high mismatched eplets (MEs) and Predicted Indirectly Recognizable HLA Epitopes (PIRCHE) score (PS), was associated with relapse protection and increased risk of acute graft-versus-host disease (GVHD). Methods: In the present study, the impact of HLA-DPB1 alloimmunity assessed by molecular mismatch algorithms on the development of SSCs in a cohort of 1514 patients who underwent allo-HSCT for hematologic malignancies was further investigated. ME load at the HLA-DPB1 locus was measured using the HLAMatchmaker module incorporated in HLA Fusion software, and the PS for mismatched HLA-DPB1 was calculated using the HSCT module from the PIRCHE online matching service. Results: In multivariable analysis after adjusting for baseline risk factors, higher ME, PS-I, and PS-II in the GVH direction, but not in the HVG direction, were associated with an increased risk of SSCs (ME: subdistribution hazard ratio [SHR] 1.58, p =.01; PS-I: SHR 1.59, p =.009; PS-II: SHR 1.71, p =.003). In contrast, nonpermissive HLA-DPB1 mismatches defined by the conventional T-cell epitope algorithm were not predictive of the risk of SSCs. Moreover, posttransplant cyclophosphamide-based GVHD prophylaxis was associated with a reduced risk of subsequent solid cancer (SHR 0.34, p =.021). Conclusions: These results indicate for the first time that increased GVH alloreactivity could contribute to the development of SSCs in allo-HSCT survivors.
KW - allo-HSCT
KW - HLA-DPB1 mismatch
KW - molecular mismatch
KW - posttransplant cyclophosphamide
KW - subsequent solid cancers
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U2 - 10.1002/cncr.34671
DO - 10.1002/cncr.34671
M3 - Article
C2 - 36738229
AN - SCOPUS:85147528237
SN - 0008-543X
VL - 129
SP - 1205
EP - 1216
JO - Cancer
JF - Cancer
IS - 8
ER -