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Cited by 168Hematopoietic Stem Cell TransplantationAcute Myeloid Leukemia ResearchTransplantation: Methods and Outcomes

Donor Clonal Hematopoiesis and Recipient Outcomes After Transplantation

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Gibson, Christopher J., Kim, Haesook T., Zhao, Lin, Murdock, H. Moses, Hambley, Bryan, Ogata, Alana, Madero-Marroquin, Rafael, Wang, Shiyu +21 more·2022·Journal of Clinical Oncology
DOI 10.1200/jco.21.02286PMC PMC8718176

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Abstract

Background Clonal hematopoiesis (CH) can be transmitted from donor to recipient during allogeneic hematopoietic cell transplantation. Exclusion of candidate donors with CH is controversial since its impact on recipient outcomes and graft alloimmune function is uncertain. Methods We performed targeted error-corrected sequencing on samples from 1727 donors aged 40 or older and assessed the effect of donor CH on recipient clinical outcomes. We measured long-term engraftment of 102 donor clones and cytokine levels in 256 recipients at 3 and 12 months after transplant. Results CH was present in 22.5% of donors, with DNMT3A (14.6%) and TET2 (5.2% ) mutations being most common; 85% of donor clones showed engraftment in recipients after transplantation, including clones with variant allele fraction (VAF)<0.01. DNMT3A- CH with VAF≥0.01, but not smaller clones, was associated with improved recipient overall (HR 0.79, P=0.042) and progression-free survival (HR 0.72, P=0.003) after adjustment for significant clinical variables. In patients receiving calcineurin-based GVHD prophylaxis, donor DNMT3A- CH was associated with reduced relapse (sHR 0.59, P=0.014), increased chronic GVHD (sHR 1.36, P=0.042), and higher IL-12p70 levels in recipients. No recipient of sole DNMT3A or TET2 -CH developed donor cell leukemia (DCL). In 7 of 8 cases, DCL evolved from donor CH with rare TP53 or splicing factor mutations or from donors carrying germline DDX41 mutations. Conclusion Donor CH is associated with clinical outcomes in transplant recipients, with differential impact on alloimmune function and potential for leukemic transformation related to mutated gene and clonal abundance. DNMT3A -CH is associated with improved recipient survival due to reduced relapse risk and an augmented network of inflammatory cytokines in recipients. Risk of DCL is driven by pre-existing somatic MDS-associated mutations or germline predisposition in donors.

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  • Increased levels of inflammatory cytokines and chemokines are significantly associated with CH in human studies, even following stem cell transplantation with donor-derived CH in the hosts.

    “Increased levels of inflammatory cytokines and chemokines have been recognized as a significant association with CH in human studies, even following stem cell transplantation with donor-derived CH in the hosts [20,32,58].”

    From Clonal hematopoiesis and inflammation – the perpetual cycle (2023) · cites this paper as [58]

    The Results section reports significantly higher IL-12p70 in recipients of donor DNMT3A-CH at 12 months after transplantation (P = .002), supporting a post-transplant association. It does not establish increased levels of inflammatory cytokines and chemokines generally: the other reported cytokine findings are correlations with IL-12p70, not increases relative to other recipients, and no chemokine increase is reported. (LLM, conf=0.88)

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Research works printed but not linked: 47

  1. [1]Schlenk RF Döhner K Krauter J: Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N Engl J Med 358: 1909- 1918, 2008 18450602
  2. [4]Kollman C Spellman SR Zhang M-J: The effect of donor characteristics on survival after unrelated donor transplantation for hematologic malignancy. Blood 127: 260- 267, 2016 26527675 PMC4713163
  3. [5]Gragert L Eapen M Williams E: HLA match likelihoods for hematopoietic stem-cell grafts in the U.S. registry. N Engl J Med 371: 339- 348, 2014 25054717 PMC5965695
  4. [6]Pulsipher MA Logan BR Kiefer DM: Related peripheral blood stem cell donors experience more severe symptoms and less complete recovery at one year compared to unrelated donors. Haematologica 104: 844- 854, 2019 30381298 PMC6442962
  5. [7]McCurdy SR Zhang M-J St Martin A: Effect of donor characteristics on haploidentical transplantation with posttransplantation cyclophosphamide. Blood Adv 2: 299- 307, 2018 29440002 PMC5812334
  6. [9]Genovese G Kähler AK Handsaker RE: Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N Engl J Med 371: 2477- 2487, 2014 25426838 PMC4290021
  7. [10]Jaiswal S Natarajan P Silver AJ: Clonal hematopoiesis and risk of atherosclerotic cardiovascular disease. N Engl J Med 377: 111- 121, 2017 28636844 PMC6717509
  8. [12]Gibson CJ Kennedy JA Nikiforow S: Donor-engrafted CHIP is common among stem cell transplant recipients with unexplained cytopenias. Blood 130: 91- 94, 2017 28446434 PMC5501150
  9. [14]Wong WH Bhatt S Trinkaus K: Engraftment of rare, pathogenic donor hematopoietic mutations in unrelated hematopoietic stem cell transplantation. Sci Transl Med 12: eaax6249, 2020 31941826 PMC7521140
  10. [15]Boettcher S Wilk CM Singer J: Clonal hematopoiesis in donors and long-term survivors of related allogeneic hematopoietic stem cell transplantation. Blood 135: 1548- 1559, 2020 32181816
  11. [16]Oran B Champlin RE Wang F: Donor clonal hematopoiesis increases risk of acute graft versus host disease after matched sibling transplantation. Leukemia 10.1038/s41375-021-01312-3 [epub ahead of print on June 16, 2021] 34135465 · DOI
  12. [17]Newell LF Williams T Liu J: Engrafted donor-derived clonal hematopoiesis after allogenic hematopoietic cell transplantation is associated with chronic graft-versus-host disease requiring immunosuppressive therapy, but no adverse impact on overall survival or relapse. Transplant Cell Ther 27: 662.e1- 662.e9, 2021 33901720
  13. [18]DeZern AE Gondek LP: Stem cell donors should be screened for CHIP. Blood Adv 4: 784- 788, 2020 32097458 PMC7042978
  14. [19]Gibson CJ Lindsley RC: Stem cell donors should not be screened for clonal hematopoiesis. Blood Adv 4: 789- 792, 2020 32097457 PMC7042999
  15. [20]Seftel MD Kuxhausen M Burns L: Clonal hematopoiesis in related allogeneic transplant donors: Implications for screening and management. Biol Blood Marrow Transplant 26: e142- e144, 2020 32147534 PMC7440392
  16. [22]Armand P Gibson CJ Cutler C: A disease risk index for patients undergoing allogeneic stem cell transplantation. Blood 120: 905- 913, 2012 22709687 PMC3412351
  17. [24]Malcovati L Gallì A Travaglino E: Clinical significance of somatic mutation in unexplained blood cytopenia. Blood 129: 3371- 3378, 2017 28424163 PMC5542849
  18. [25]Eto M Mayumi H Tomita Y: Specific destruction of host-reactive mature T cells of donor origin prevents graft-versus-host disease in cyclophosphamide-induced tolerant mice. J Immunol 146: 1402- 1409, 1991 1671578
  19. [26]Wachsmuth LP Patterson MT Eckhaus MA: Post-transplantation cyclophosphamide prevents graft-versus-host disease by inducing alloreactive T cell dysfunction and suppression. J Clin Invest 129: 2357- 2373, 2019 30913039 PMC6546453
  20. [27]Jeong M Sun D Luo M: Large conserved domains of low DNA methylation maintained by Dnmt3a. Nat Genet 46: 17- 23, 2014 24270360 PMC3920905
  21. [28]Ley TJ Ding L Walter MJ: DNMT3A mutations in acute myeloid leukemia. N Engl J Med 363: 2424- 2433, 2010 21067377 PMC3201818
  22. [29]Walter MJ Ding L Shen D: Recurrent DNMT3A mutations in patients with myelodysplastic syndromes. Leukemia 25: 1153- 1158, 2011 21415852 PMC3202965
  23. [30]Patel JP Gönen M Figueroa ME: Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N Engl J Med 366: 1079- 1089, 2012 22417203 PMC3545649
  24. [32]Miles LA Bowman RL Merlinsky TR: Single-cell mutation analysis of clonal evolution in myeloid malignancies. Nature 587: 477- 482, 2020 33116311 PMC7677169
  25. [33]Young AL Tong RS Birmann BM: Clonal hematopoiesis and risk of acute myeloid leukemia. Haematologica 104: 2410- 2417, 2019 31004019 PMC6959179
  26. [34]Kim SJ Zhao H Hardikar S: A DNMT3A mutation common in AML exhibits dominant-negative effects in murine ES cells. Blood 122: 4086- 4089, 2013 24167195 PMC3952368
  27. [35]Buscarlet M Provost S Feroz Zada Y: Lineage restriction analyses in CHIP indicate myeloid bias for TET2 and multipotent stem cell origin for DNMT3A. Blood 132: 277- 288, 2018 29764839
  28. [36]Nisticò A Young NS: Gamma-interferon gene expression in the bone marrow of patients with aplastic anemia. Ann Intern Med 120: 463- 469, 1994 8311369
  29. [37]Baldridge MT King KY Boles NC: Quiescent haematopoietic stem cells are activated by IFN-gamma in response to chronic infection. Nature 465: 793- 797, 2010 20535209 PMC2935898
  30. [38]Young K Eudy E Bell R: Decline in IGF1 in the bone marrow microenvironment initiates hematopoietic stem cell aging. Cell Stem Cell 28: 1473- 1482.e7, 2021 33848471 PMC8349778
  31. [39]Gondek LP Zheng G Ghiaur G: Donor cell leukemia arising from clonal hematopoiesis after bone marrow transplantation. Leukemia 30: 1916- 1920, 2016 26975880 PMC5014666
  32. [40]Kobayashi S Kobayashi A Osawa Y: Donor cell leukemia arising from preleukemic clones with a novel germline DDX41 mutation after allogenic hematopoietic stem cell transplantation. Leukemia 31: 1020- 1022, 2017 28194039
  33. [41]Nevejan L Nollet F Devos H: Malignant progression of donor-engrafted clonal hematopoiesis in sibling recipients after stem cell transplantation. Blood Adv 4: 5631- 5634, 2020 33186460 PMC7686891
  34. [43]Polprasert C Schulze I Sekeres MA: Inherited and somatic defects in DDX41 in myeloid neoplasms. Cancer Cell 27: 658- 670, 2015 25920683 PMC8713504
  35. [44]Macatonia SE Hosken NA Litton M: Dendritic cells produce IL-12 and direct the development of Th1 cells from naive CD4+ T cells. J Immunol 154: 5071- 5079, 1995 7730613
  36. [45]Christopher MJ Petti AA Rettig MP: Immune escape of relapsed AML cells after allogeneic transplantation. N Engl J Med 379: 2330- 2341, 2018 30380364 PMC6322675
  37. [46]Murphy EE Terres G Macatonia SE: B7 and interleukin 12 cooperate for proliferation and interferon gamma production by mouse T helper clones that are unresponsive to B7 costimulation. J Exp Med 180: 223- 231, 1994 7516409 PMC2191551
  38. [47]Reddy V Winer AG Eksioglu E: Interleukin 12 is associated with reduced relapse without increased incidence of graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 11: 1014- 1021, 2005 16338624
  39. [48]Darlak KA Wang Y Li J-M: Enrichment of IL-12-producing plasmacytoid dendritic cells in donor bone marrow grafts enhances graft-versus-leukemia activity in allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 19: 1331- 1339, 2013 23810844
  40. [49]Kernan NA Collins NH Juliano L: Clonable T lymphocytes in T cell-depleted bone marrow transplants correlate with development of graft-v-host disease. Blood 68: 770- 773, 1986 3527302
  41. [50]Ghoneim HE Fan Y Moustaki A: De novo epigenetic programs inhibit PD-1 blockade-mediated T cell rejuvenation. Cell 170: 142- 157.e19, 2017 28648661 PMC5568784
  42. [51]Youngblood B Hale JS Kissick HT: Effector CD8 T cells dedifferentiate into long-lived memory cells. Nature 552: 404- 409, 2017 29236683 PMC5965677
  43. [52]Kanakry CG O’Donnell PV Furlong T: Multi-institutional study of post-transplantation cyclophosphamide as single-agent graft-versus-host disease prophylaxis after allogeneic bone marrow transplantation using myeloablative busulfan and fludarabine conditioning. J Clin Oncol 32: 3497- 3505, 2014 25267759 PMC4209101
  44. [53]Kasamon YL Bolanos-Meade J Prince GT: Outcomes of nonmyeloablative HLA-haploidentical blood or marrow transplantation with high-dose post-transplantation cyclophosphamide in older adults. J Clin Oncol 33: 3152- 3161, 2015 26261255 PMC4582145
  45. [54]Herold S Kuhn M Bonin MV: Donor cell leukemia: Evidence for multiple preleukemic clones and parallel long term clonal evolution in donor and recipient. Leukemia 31: 1637- 1640, 2017 28348390
  46. [55]Rojek K Nickels E Neistadt B: Identifying inherited and acquired genetic factors involved in poor stem cell mobilization and donor-derived malignancy. Biol Blood Marrow Transplant 22: 2100- 2103, 2016 27497531 PMC5592729
  47. [56]DeZern AE Franklin C Tsai H-L: Relationship of donor age and relationship to outcomes of haploidentical transplantation with posttransplant cyclophosphamide. Blood Adv 5: 1360- 1368, 2021 33661299 PMC7948266

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Authors
Gibson, C. J., Kim, H. T., Zhao, L., Murdock, H. M., Hambley, B., Ogata, A., Madero-Marroquin, R., Wang, S., Green, L., Fleharty, M., Dougan, T., Cheng, C.-A., Blumenstiel, B., Cibulskis, C., Tsuji, J., Duran, M., Gocke, C. D., Antin, J. H., Nikiforow, S., DeZern, A. E., Chen, Y.-B., Ho, V. T., Jones, R. J., Lennon, N. J., Walt, D. R., Ritz, J., Soiffer, R. J., Gondek, L. P., & Lindsley, R. C.
Affiliations
  • Dana-Farber Cancer Institute (US)
  • Johns Hopkins University (US)
  • Brigham and Women's Hospital (US)
  • Broad Institute (US)
  • University of Washington (US)
  • Massachusetts General Hospital (US)
Corresponding author
Lindsley, R. Coleman
ORCID
Venue
Journal of Clinical Oncology
Publisher
American Society of Clinical Oncology (ASCO)
Published
2022-01-10
Volume
40
Issue
2
Pages
189-201
ISSN
  • 0732-183X (ISSN-L)
  • 1527-7755
DOI
10.1200/jco.21.02286
PMC
PMC8718176
OpenAlex
W3212829453
Cited by
168
References
7
Citations by year
2026: 23 · 2025: 27 · 2024: 42 · 2023: 42 · 2022: 34
FWCI
19.28
Type
journal article
Language
en
Open access
Licence
cc-by-nc-nd
Locations
  • Journal of Clinical Oncology (publishedVersion, cc-by-nc-nd)
  • medRxiv (acceptedVersion)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Funders
  • Damon Runyon Cancer Research Foundation
  • National Institutes of Health
  • National Heart, Lung, and Blood Institute (K08HL136894, R01HL156144)
  • National Cancer Institute (K08CA263555, K08CA204734, P50CA206963, P01CA229092, P01CA066996)
  • National Institute of Diabetes and Digestive and Kidney Diseases (RC2DK122533)
Topics
  • Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
  • Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
  • Health Sciences › Medicine › Surgery › Transplantation: Methods and Outcomes
Keywords
clonal hematopoiesis, allogeneic hematopoietic stem cell transplantation, DNMT3A mutation, TET2 mutation, donor cell leukemia, graft-versus-host disease, chronic graft-versus-host disease, relapse, interleukin-12p70, inflammatory cytokines, donor engraftment, somatic mutations, variant allele frequency, TP53 mutation, splicing factor mutations
MeSH terms
Progression-Free Survival, Clonal Hematopoiesis, DNA Methyltransferase 3A, Adolescent, Adult, Aged, Alleles, Child, Child, Preschool, Chronic Disease, DNA-Binding Proteins, Female, Graft vs Host Disease, Humans, Infant, Leukemia, Male, Middle Aged, Mutation, Recurrence, Time Factors, Transplantation, Homologous, Survival Rate, Cytokines, Hematopoietic Stem Cell Transplantation, Hematologic Neoplasms, Dioxygenases, Young Adult, Unrelated Donors, Calcineurin Inhibitors

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