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Stem Cell Transplantation

Donor clonal hematopoiesis increases risk of acute graft versus host disease after matched sibling transplantation

Abstract

Clonal hematopoiesis (CH) is associated with older age and an increased risk of myeloid malignancies and cardiovascular complications. We analyzed donor DNA samples in patients with AML/MDS who underwent first allogeneic stem cell transplant (SCT) to investigate the association between donor CH and transplant outcomes. We performed targeted deep sequencing of 300 genes on donor blood samples and identified CH with the minimum variant allele frequency of 2%. Among 363 donors, 65 (18%) had CH. The most frequently mutated genes were DNMT3A (31 of 65; 48%), TET2 (16 of 65; 25%), PPM1D (5 of 65, 8%), and ASXL1 (7 of 65; 11%). Transplant outcomes: time to neutrophil and platelet recovery, relapse incidence, transplant-related mortality and progression-free survival, were comparable by donor CH. However, risk of grade II–IV and III–IV acute graft versus host disease (aGvHD) at 6 months after transplant was higher with donor CH vs. without donor CH (hazard ratio (HR) = 2.4, 95% Confidence Interval (CI) = 1.6–3.6, p < 0.001 and HR = 3.8, 95% CI = 1.6–8.9, p = 0.003). In this homogenous population of AML/MDS patients, donor CH was associated with increased risk of grade II–IV and III–IV aGvHD. Further studies to investigate the mechanisms of increased aGvHD and therapeutic interventions to improve aGvHD in the context of donor CH are warranted.

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Fig. 1: Of the 421 AML and MDS patients who had first allogeneic stem cell transplantation using an older donor aged ≥55 years between 2000 and 2018, 363 had donor DNA samples available for CH analyses.
Fig. 2: The distribution of mutations consistent with donor CH.
Fig. 3: Acute GvHD incidences by donor CH and donor age.
Fig. 4: PFS, relapse incidence and TRM by donor CH.

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Acknowledgements

This study was supported in part by the Cancer Prevention and Research Institute of Texas (grant R120501 to AF), the Welch Foundation (grant G-0040 to AF), the University of Texas System STARS Award (grant PS100149 to AF), Physician Scientist Program at MD Anderson (to KT), Andrew Sabin Family Foundation Award (to KT), Lyda Hill Foundation (to AF), the Charif Souki Cancer Research Fund (to HK), the MD Anderson Cancer Center Leukemia SPORE grant (NIH P50 CA100632) (to HK and KT), the MD Anderson Cancer Center Support Grant (NIH/NCI P30 CA016672), and generous philanthropic contributions to MD Anderson’s Moon Shot Program (to AF, KT, GG-M, and HK).

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Correspondence to Betül Oran or Koichi Takahash.

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BO has received research funding from ASTEX Pharmaceuticals and AROG Pharmaceuticals. KT has been on the advisory boards of Symbio Pharmaceuticals, Novartis, Celgene, and GSK. All other authors declare no competing interests.

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Oran, B., Champlin, R.E., Wang, F. et al. Donor clonal hematopoiesis increases risk of acute graft versus host disease after matched sibling transplantation. Leukemia (2021). https://doi.org/10.1038/s41375-021-01312-3

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