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Stem Cell Transplantation

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

Leukemia volume 36, pages 257–262 (2022)Cite this article

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A Correction to this article was published on 07 December 2021

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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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References

  1. Flowers ME, Inamoto Y, Carpenter PA, Lee SJ, Kiem HP, Petersdorf EW, et al. Comparative analysis of risk factors for acute graft-versus-host disease and for chronic graft-versus-host disease according to National Institutes of Health consensus criteria. Blood. 2011;117:3214–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Kollman C, Howe CWS, Anasetti C, Antin JH, Davies SM, Filipovich AH, et al. Donor characteristics as risk factors in recipients after transplantation of bone marrow from unrelated donors: the effect of donor age. Blood. 2001;98:2043–51.

    Article  CAS  PubMed  Google Scholar 

  3. Miller RA. The aging immune system: primer and prospectus. Science. 1996;273:70–4.

    Article  CAS  PubMed  Google Scholar 

  4. Xie M, Lu C, Wang J, McLellan MD, Johnson KJ, Wendl MC, et al. Age-related mutations associated with clonal hematopoietic expansion and malignancies. Nat Med. 2014;20:1472–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Jaiswal S, Fontanillas P, Flannick J, Manning A, Grauman PV, Mar BG, et al. Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med. 2014;371:2488–98.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Genovese G, Kahler AK, Handsaker RE, Lindberg J, Rose SA, Bakhoum SF, et al. Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N Engl J Med. 2014;371:2477–87.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Steensma DP, Bejar R, Jaiswal S, Lindsley RC, Sekeres MA, Hasserjian RP, et al. Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes. Blood. 2015;126:9–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Savola P, Lundgren S, Keranen MAI, Almusa H, Ellonen P, Leirisalo-Repo M, et al. Clonal hematopoiesis in patients with rheumatoid arthritis. Blood Cancer J. 2018;8:69.

  9. Mas-Peiro S, Hoffmann J, Fichtlscherer S, Dorsheimer L, Rieger MA, Dimmeler S, et al. Clonal haematopoiesis in patients with degenerative aortic valve stenosis undergoing transcatheter aortic valve implantation. Eur Heart J. 2020;41:933–9.

    Article  CAS  PubMed  Google Scholar 

  10. Jaiswal S, Natarajan P, Silver AJ, Gibson CJ, Bick AG, Shvartz E, et al. Clonal hematopoiesis and risk of atherosclerotic cardiovascular disease. New Engl J Med. 2017;377:111–21.

    Article  PubMed  Google Scholar 

  11. Fuster JJ, MacLauchlan S, Zuriaga MA, Polackal MN, Ostriker AC, Chakraborty R, et al. Clonal hematopoiesis associated with TET2 deficiency accelerates atherosclerosis development in mice. Science. 2017;355:842–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Frick M, Chan W, Arends CM, Hablesreiter R, Halik A, Heuser M, et al. Role of donor clonal hematopoiesis in allogeneic hematopoietic stem-cell transplantation. J Clin Oncol. 2019;37:375–85.

    Article  CAS  PubMed  Google Scholar 

  13. Morita K, Kantarjian HM, Wang F, Yan Y, Bueso-Ramos C, Sasaki K, et al. Clearance of somatic mutations at remission and the risk of relapse in acute myeloid leukemia. J Clin Oncol. 2018;36:1788–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. McLaren JE, Michael DR, Ashlin TG, Ramji DP. Cytokines, macrophage lipid metabolism and foam cells: implications for cardiovascular disease therapy. Prog Lipid Res. 2011;50:331–47.

    Article  CAS  PubMed  Google Scholar 

  15. Li X, Zhang Q, Ding Y, Liu Y, Zhao D, Zhao K, et al. Methyltransferase Dnmt3a upregulates HDAC9 to deacetylate the kinase TBK1 for activation of antiviral innate immunity. Nat Immunol. 2016;17:806–15.

    Article  CAS  PubMed  Google Scholar 

  16. Leoni C, Montagner S, Rinaldi A, Bertoni F, Polletti S, Balestrieri C, et al. Dnmt3a restrains mast cell inflammatory responses. Proc Natl Acad Sci USA. 2017;114:E1490–E9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Holtan SG, Pasquini M, Weisdorf DJ. Acute graft-versus-host disease: a bench-to-bedside update. Blood. 2014;124:363–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Jankovic D, Ganesan J, Bscheider M, Stickel N, Weber FC, Guarda G, et al. The Nlrp3 inflammasome regulates acute graft-versus-host disease. J Exp Med. 2013;210:1899–910.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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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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Authors and Affiliations

  1. Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA

    Betül Oran, Richard E. Champlin, Rima M. Saliba, Gheath Al-Atrash, Elizabeth J. Shpall, Amin M. Alousi, Rohtesh S. Mehta & Uday Popat

  2. Department of Genomics Medicine, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA

    Feng Wang, Tomoyuki Tanaka, Andy Futreal & Koichi Takahashi

  3. Department of Leukemia, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA

    Guillermo Garcia-Manero, Hagop Kantarjian & Koichi Takahashi

  4. Department of Laboratory Medicine, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA

    Kai Cao

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  1. Betül Oran
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Correspondence to Betül Oran or Koichi Takahashi.

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COMPETING INTERESTS

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 36, 257–262 (2022). https://doi.org/10.1038/s41375-021-01312-3

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