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J Clin Oncol. 2019 Feb 10;37(5):375-385. doi: 10.1200/JCO.2018.79.2184. Epub 2018 Nov 7.

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

Author information

1
1 Charité - University Medical Center Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany.
2
2 Berlin Institute of Health, Berlin, Germany.
3
3 Hannover Medical School, Hannover, Germany.
4
4 David Michonneau and Gérard Socié, INSERM U1160, Institut Universitaire d'Hematologie, Paris/University Paris Diderot, Paris, France.
5
5 University Hospital Ulm, Ulm, Germany.
6
6 Kyoto University, Kyoto, Japan.
7
7 Carl Gustav Carus University Hospital Dresden, Dresden, Germany.
8
8 Heinrich Heine University, Düsseldorf, Germany.
9
9 Saint Louis Hospital/University Paris Diderot, Paris, France.
10
10 University Hospital Eppendorf, Hamburg, Germany.
11
11 Berlin Institute of Health (BIH) Core Genomics Facility, Charité, University Medical Center, Berlin, Germany.
12
12 UCT Johannes Gutenberg University Mainz, Mainz, Germany.
13
13 University Hospital Erlangen, Friedrich Alexander University Erlangen Nürnberg (FAU), Erlangen, Germany.
14
14 German Red Cross Blood Transfusion Service Baden-Württemberg-Hessen and Institute of Transfusion Medicine, Ulm, Germany.
15
15 West German Cancer Centre, University Hospital of Essen, University of Duisburg-Essen, Duisburg, Germany.
16
16 German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany.

Abstract

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.

PMID:
30403573
DOI:
10.1200/JCO.2018.79.2184
[Indexed for MEDLINE]

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