Role of Donor Clonal Hematopoiesis in Allogeneic Hematopoietic Stem-Cell Transplantation

TY - JOUR

T1 - Role of Donor Clonal Hematopoiesis in Allogeneic Hematopoietic Stem-Cell Transplantation

AU - Frick, Mareike

AU - Chan, Willy

AU - Arends, Christopher Maximilian

AU - Hablesreiter, Raphael

AU - Halik, Adriane

AU - Heuser, Michael

AU - Michonneau, David

AU - Blau, Olga

AU - Hoyer, Kaja

AU - Christen, Friederike

AU - Galan-Sousa, Joel

AU - Noerenberg, Daniel

AU - Wais, Verena

AU - Stadler, Michael

AU - Yoshida, Kenichi

AU - Schetelig, Johannes

AU - Schuler, Esther

AU - Thol, Felicitas

AU - Clappier, Emmanuelle

AU - Christopeit, Maximilian

AU - Ayuk, Francis

AU - Bornhäuser, Martin

AU - Blau, Igor Wolfgang

AU - Ogawa, Seishi

AU - Zemojtel, Tomasz

AU - Gerbitz, Armin

AU - Wagner, Eva M

AU - Spriewald, Bernd M

AU - Schrezenmeier, Hubert

AU - Kuchenbauer, Florian

AU - Kobbe, Guido

AU - Wiesneth, Markus

AU - Koldehoff, Michael

AU - Socié, Gérard

AU - Kroeger, Nicolaus

AU - Bullinger, Lars

AU - Thiede, Christian

AU - Damm, Frederik

PY - 2019/2/10

Y1 - 2019/2/10

N2 - PURPOSE: Clonal hematopoiesis of indeterminate potential (CHIP) occurs in the blood of approximately 20% of older persons. CHIP is linked to an increased risk of hematologic malignancies and of all-cause mortality; thus, the eligibility of stem-cell donors with CHIP is questionable. We comprehensively investigated how donor CHIP affects outcome of allogeneic hematopoietic stem-cell transplantation (HSCT).METHODS: We collected blood samples from 500 healthy, related HSCT donors (age ≥ 55 years) at the time of stem-cell donation for targeted sequencing with a 66-gene panel. The effect of donor CHIP was assessed on recipient outcomes, including graft-versus-host disease (GVHD), cumulative incidence of relapse/progression (CIR/P), and overall survival (OS).RESULTS: A total of 92 clonal mutations with a median variant allele frequency of 5.9% were identified in 80 (16.0%) of 500 donors. CHIP prevalence was higher in donors related to patients with myeloid compared with lymphoid malignancies (19.2% v 6.3%; P ≤ .001). In recipients allografted with donor CHIP, we found a high cumulative incidence of chronic GVHD (cGVHD; hazard ratio [HR], 1.73; 95% CI, 1.21 to 2.49; P = .003) and lower CIR/P (univariate: HR, 0.62; 95% CI, 0.40 to 0.97; P = .027; multivariate: HR, 0.63; 95% CI, 0.41 to 0.98; P = .042) but no effect on nonrelapse mortality. Serial quantification of 25 mutations showed engraftment of 24 of 25 clones and disproportionate expansion in half of them. Donor-cell leukemia was observed in two recipients. OS was not affected by donor CHIP status (HR, 0.88; 95% CI, 0.65 to 1.321; P = .434).CONCLUSION: Allogeneic HSCT from donors with CHIP seems safe and results in similar survival in the setting of older, related donors. Future studies in younger and unrelated donors are warranted to extend these results. Confirmatory studies and mechanistic experiments are warranted to challenge the hypothesis that donor CHIP might foster cGVHD development and reduce relapse/progression risk.

AB - PURPOSE: Clonal hematopoiesis of indeterminate potential (CHIP) occurs in the blood of approximately 20% of older persons. CHIP is linked to an increased risk of hematologic malignancies and of all-cause mortality; thus, the eligibility of stem-cell donors with CHIP is questionable. We comprehensively investigated how donor CHIP affects outcome of allogeneic hematopoietic stem-cell transplantation (HSCT).METHODS: We collected blood samples from 500 healthy, related HSCT donors (age ≥ 55 years) at the time of stem-cell donation for targeted sequencing with a 66-gene panel. The effect of donor CHIP was assessed on recipient outcomes, including graft-versus-host disease (GVHD), cumulative incidence of relapse/progression (CIR/P), and overall survival (OS).RESULTS: A total of 92 clonal mutations with a median variant allele frequency of 5.9% were identified in 80 (16.0%) of 500 donors. CHIP prevalence was higher in donors related to patients with myeloid compared with lymphoid malignancies (19.2% v 6.3%; P ≤ .001). In recipients allografted with donor CHIP, we found a high cumulative incidence of chronic GVHD (cGVHD; hazard ratio [HR], 1.73; 95% CI, 1.21 to 2.49; P = .003) and lower CIR/P (univariate: HR, 0.62; 95% CI, 0.40 to 0.97; P = .027; multivariate: HR, 0.63; 95% CI, 0.41 to 0.98; P = .042) but no effect on nonrelapse mortality. Serial quantification of 25 mutations showed engraftment of 24 of 25 clones and disproportionate expansion in half of them. Donor-cell leukemia was observed in two recipients. OS was not affected by donor CHIP status (HR, 0.88; 95% CI, 0.65 to 1.321; P = .434).CONCLUSION: Allogeneic HSCT from donors with CHIP seems safe and results in similar survival in the setting of older, related donors. Future studies in younger and unrelated donors are warranted to extend these results. Confirmatory studies and mechanistic experiments are warranted to challenge the hypothesis that donor CHIP might foster cGVHD development and reduce relapse/progression risk.

KW - Age Factors

KW - Aged

KW - Female

KW - Gene Frequency

KW - Graft vs Host Disease/genetics

KW - Hematologic Neoplasms/genetics

KW - Hematopoiesis/genetics

KW - Hematopoietic Stem Cell Transplantation/adverse effects

KW - Hematopoietic Stem Cells/cytology

KW - Humans

KW - Male

KW - Middle Aged

KW - Mutation

KW - Retrospective Studies

KW - Transplantation, Homologous

KW - Treatment Outcome

KW - Unrelated Donors

U2 - 10.1200/JCO.2018.79.2184

DO - 10.1200/JCO.2018.79.2184

M3 - SCORING: Journal article

C2 - 30403573

VL - 37

SP - 375

EP - 385

JO - J CLIN ONCOL

JF - J CLIN ONCOL

SN - 0732-183X

IS - 5

ER -