Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Effects of donor-engrafted clonal hematopoiesis in allogeneic and autologous stem cell transplantation: a systematic review and meta-analysis

Bone Marrow Transplantation (2024)Cite this article

Subjects

Abstract

Donor stem cell health may be critically important to the success of hematopoietic stem cell transplantation (HSCT). Herein, we performed this systematic review and meta-analysis including meta-regression to assess the impact of donor-engrafted clonal hematopoiesis (CH) in allogeneic HSCT (allo-HSCT) and impact of pre-transplant CH in autologous HSCT (auto-HSCT). We applied random-effects models to analyze 5 allo-HSCT studies with 3192 donor-recipient pairs and 9 auto-HSCT studies with 2854 patients. We found that donor-engrafted CH after allo-HSCT decreased the risk of disease relapse [Hazard Ratio (HR) = 0.79, 95% Confidence Interval (CI): (0.67, 0.93)], but did not affect overall survival (OS) [HR = 0.91, 95% CI: (0.75, 1.11)], progression-free survival (PFS) [HR = 0.94, 95% CI: (0.63, 1.41)], or non-relapse mortality [HR = 1.06, 95% CI: (0.81, 1.39)]. In contrast, pre-transplant CH in auto-HSCT recipients resulted in inferior OS [HR = 1.30, 95% CI: (1.16, 1.46)], inferior PFS [HR = 1.35, 95% CI: (1.18, 1.54)], and higher risk for therapy-related myeloid neoplasm [HR = 4.85, 95% CI: (2.39, 9.82)] when compared to auto-HSCT recipients without CH. This study sheds light onto the debate about prospective “CHIP screening” for stem cell donors and addresses the impact of CH as a transmissible phenomenon.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Flow diagrams for systematic review and meta-analysis.
Fig. 2: Forest and funnel plots for allo-HSCT.
Fig. 3: Forest and funnel plots for auto-HSCT.
Fig. 4: Overview of advantages and disadvantages of screening for CH in donors prior to HSCT.

Similar content being viewed by others

Data availability

All data generated or analyzed during this study are included in this published article and its supplementary information files.

References

  1. 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 

  2. Weeks LD, Niroula A, Neuberg D, Wong W, Lindsley RC, Luskin M, et al. Prediction of risk for myeloid malignancy in clonal hematopoiesis. NEJM Evid. 2023;2, https://doi.org/10.1056/evidoa2200310.

  3. Jaiswal S. Clonal hematopoiesis and nonhematologic disorders. Blood. 2020;136:1606–14.

    PubMed  PubMed Central  Google Scholar 

  4. Jaiswal S, Ebert BL. Clonal hematopoiesis in human aging and disease. Science. 2019;366:eaan4673.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Agrawal M, Niroula A, Cunin P, McConkey M, Shkolnik V, Kim PG, et al. TET2-mutant clonal hematopoiesis and risk of gout. Blood. 2022;140:1094–103.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Yu Z, Fidler TP, Ruan Y, Vlasschaert C, Nakao T, Uddin MM, et al. Genetic modification of inflammation- and clonal hematopoiesis-associated cardiovascular risk. J Clin Invest. 2023;133:e168597.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Ortmann CA, Dorsheimer L, Abou-El-Ardat K, Hoffrichter J, Assmus B, Bonig H, et al. Functional Dominance of CHIP-Mutated Hematopoietic Stem Cells in Patients Undergoing Autologous Transplantation. Cell Rep. 2019;27:2022–8.e3.

    Article  CAS  PubMed  Google Scholar 

  8. Wong WH, Bhatt S, Trinkaus K, Pusic I, Elliott K, Mahajan N, et al. Engraftment of rare, pathogenic donor hematopoietic mutations in unrelated hematopoietic stem cell transplantation. Sci Transl Med. 2020;12:eaax6249.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Rojek K, Nickels E, Neistadt B, Marquez R, Wickrema A, Artz A, et al. Identifying inherited and acquired genetic factors involved in poor stem cell mobilization and donor-derived malignancy. Biol Blood Marrow Transpl. 2016;22:2100–3.

    Article  CAS  Google Scholar 

  10. Hertenstein B, Hambach L, Bacigalupo A, Schmitz N, McCann S, Slavin S, et al. Development of leukemia in donor cells after allogeneic stem cell transplantation-a survey of the European Group for Blood and Marrow Transplantation (EBMT). Haematologica. 2005;90:969–75.

    PubMed  Google Scholar 

  11. Newell LF, Williams T, Liu J, Yu Y, Chen Y, Booth GC, et al. 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. Transpl Cell Ther. 2021;27:662.e1–662.e9.

    Article  CAS  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. Oran B, Champlin RE, Wang F, Tanaka T, Saliba RM, Al-Atrash G, et al. Donor clonal hematopoiesis increases risk of acute graft versus host disease after matched sibling transplantation. Leukemia. 2022;36:257–62.

    Article  CAS  PubMed  Google Scholar 

  14. Gibson CJ, Kim HT, Zhao L, Murdock HM, Hambley B, Ogata A, et al. Donor Clonal Hematopoiesis and Recipient Outcomes After Transplantation. J Clin Oncol. 2022;40:189–201.

    Article  CAS  PubMed  Google Scholar 

  15. Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. Int J Surg. 2021;88:105906.

    Article  PubMed  Google Scholar 

  16. Arber DA, Orazi A, Hasserjian RP, Borowitz MJ, Calvo KR, Kvasnicka HM, et al. International Consensus Classification of Myeloid Neoplasms and Acute Leukemias: integrating morphologic, clinical, and genomic data. Blood. 2022;140:1200–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Kelley GA, Kelley KS. Statistical models for meta-analysis: a brief tutorial. World J Methodol. 2012;2:27.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Rosenthal JA. Qualitative Descriptors of Strength of Association and Effect Size. J Soc Serv Res. 1996;21:37–59.

    Article  Google Scholar 

  19. Kim KH, Kim T, Novitzky-Basso I, Lee H, Yoo Y, Ahn JS, et al. Clonal hematopoiesis in the donor does not adversely affect long-term outcomes following allogeneic hematopoietic stem cell transplantation: result from a 13-year follow-up. Haematologica. 2023;108:1817–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Williams T, Wang Y, Liu J, Newell L, Cook R, Press R, et al. Donor-Derived Clonal Hematopoiesis After Allogeneic Hematapoietic Stem Cell Transplant: Impact on Hematology Recovery and Evaluation of Clonal Expansion. Mod Pathol. 2020;33:1405–6.

    Google Scholar 

  21. Gibson CJ, Lindsley RC, Tchekmedyian V, Mar BG, Shi J, Jaiswal S, et al. Clonal Hematopoiesis Associated With Adverse Outcomes After Autologous Stem-Cell Transplantation for Lymphoma. J Clin Oncol. 2017;35:1598–605.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Lackraj T, Ben Barouch S, Medeiros JJF, Pedersen S, Danesh A, Bakhtiari M, et al. Clinical significance of clonal hematopoiesis in the setting of autologous stem cell transplantation for lymphoma. Am J Hematol. 2022;97:1538–47.

    Article  CAS  PubMed  Google Scholar 

  23. Husby S, Favero F, Nielsen C, Sørensen BS, Bæch J, Grell K, et al. Clinical impact of clonal hematopoiesis in patients with lymphoma undergoing ASCT: a national population-based cohort study. Leukemia. 2020;34:3256–68.

    Article  CAS  PubMed  Google Scholar 

  24. Hazenberg CLE, de Graaf AO, Mulder R, Bungener LB, van Bergen MGJM, Mulder AB, et al. Clonal hematopoiesis in patients with stem cell mobilization failure: a nested case-control study. Blood Adv. 2023;7:1269–78.

    Article  CAS  PubMed  Google Scholar 

  25. Mouhieddine TH, Sperling AS, Redd R, Park J, Leventhal M, Gibson CJ, et al. Clonal hematopoiesis is associated with adverse outcomes in multiple myeloma patients undergoing transplant. Nat Commun. 2020;11:2996.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Malek E, Martin P, Caimi PF, Tomlinson BK, Caldwell M, Ravi G, et al. Presence of Chip-Mutated Autologous Hematopoietic Cells in Mobilized Peripheral Blood Products Is Associated with Shorter Progression-Free Survival after Autologous Transplants for Multiple Myeloma. Blood. 2019;134:515.

    Article  Google Scholar 

  27. Wudhikarn K, Padrnos L, Lasho T, LaPlant B, Kumar S, Dispenzieri A, et al. Clinical correlates and prognostic impact of clonal hematopoiesis in multiple myeloma patients receiving post-autologous stem cell transplantation lenalidomide maintenance therapy. Am J Hematol. 2021;96:E157–E162.

    Article  CAS  PubMed  Google Scholar 

  28. Stelmach P, Richter S, Sauer S, Fabre MA, Gu M, Rohde C, et al. Clonal hematopoiesis with DNMT3A and PPM1D mutations impairs regeneration in autologous stem cell transplant recipients. Haematologica. 2023;108:3308–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Eskelund CW, Husby S, Favero F, Klausen TW, Rodriguez-Gonzalez FG, Kolstad A, et al. Clonal hematopoiesis evolves from pretreatment clones and stabilizes after end of chemotherapy in patients with MCL. Blood. 2020;135:2000–4.

    Article  PubMed  Google Scholar 

  30. Gibson CJ, Lindsley RC. Stem cell donors should not be screened for clonal hematopoiesis. Blood Adv. 2020;4:789–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. DeZern AE, Gondek LP. Stem cell donors should be screened for CHIP. Blood Adv. 2020;4:784–8.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Jaiswal S, Natarajan P, Silver AJ, Gibson CJ, Bick AG, Shvartz E, et al. Clonal Hematopoiesis and Risk of Atherosclerotic Cardiovascular Disease. N Engl J Med. 2017;377:111–21.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Bouzid H, Belk JA, Jan M, Qi Y, Sarnowski C, Wirth S, et al. Clonal hematopoiesis is associated with protection from Alzheimer’s disease. Nat Med. 2023;29:1662–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Weeks LD, Ebert BL. Causes and Consequences of Clonal Hematopoiesis. Blood. 2023;142:2235–46.

    Article  CAS  PubMed  Google Scholar 

  35. Khoury JD, Solary E, Abla O, Akkari Y, Alaggio R, Apperley JF, et al. The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms. Leukemia. 2022;36:1703–19.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Weinstock JS, Gopakumar J, Burugula BB, Uddin MM, Jahn N, Belk JA, et al. Aberrant activation of TCL1A promotes stem cell expansion in clonal haematopoiesis. Nature. 2023;616:755–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Mitchell E, Spencer Chapman M, Williams N, Dawson KJ, Mende N, Calderbank EF, et al. Clonal dynamics of haematopoiesis across the human lifespan. Nature. 2022;606:343–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Patel SA, Dalela D, Fan AC, Lloyd MR, Zhang TY. Niche-directed therapy in acute myeloid leukemia: optimization of stem cell competition for niche occupancy. Leuk Lymphoma. 2022;63:10–18.

    Article  CAS  PubMed  Google Scholar 

  39. Bernard E, Tuechler H, Greenberg PL, Hasserjian RP, Arango Ossa JE, Nannya Y, et al. Molecular International Prognostic Scoring System for Myelodysplastic Syndromes. NEJM Evid. 2022;1:355–68.

    Article  Google Scholar 

  40. Bernard E, Nannya Y, Hasserjian RP, Devlin SM, Tuechler H, Medina-Martinez JS, et al. Implications of TP53 allelic state for genome stability, clinical presentation and outcomes in myelodysplastic syndromes. Nat Med. 2020;26:1549–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Patel SA, Lloyd MR, Cerny J, Shi Q, Simin K, Ediriwickrema A, et al. Clinico-genomic profiling and clonal dynamic modeling of TP53-aberrant myelodysplastic syndrome and acute myeloid leukemia. Leuk Lymphoma. 2021;62:3348–60.

    Article  CAS  PubMed  Google Scholar 

  42. Patel SA, Cerny J, Gerber WK, Ramanathan M, Ediriwickrema A, Tanenbaum B, et al. Prognostic heterogeneity and clonal dynamics within distinct subgroups of myelodysplastic syndrome and acute myeloid leukemia with TP53 disruptions. EJHaem. 2023;4:1059–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Patel SA, Gerber WK, Zheng R, Khanna S, Hutchinson L, Abel GA, et al. Natural history of clonal haematopoiesis seen in real-world haematology settings. Br J Haematol. 2024;204:1844–55.

    Article  CAS  PubMed  Google Scholar 

  44. Patel SA, Gerber WK, Zheng R, Khanna S, Hutchinson L, Cerny J, et al. Sole DNMT3A/TET2/ASXL1 Mutations Define a Distinct Clinical Trajectory for Patients with Clonal Hematopoiesis. Blood. 2023;142:4068.

    Article  Google Scholar 

Download references

Funding

SAP received research funding in 2022-23 from the UMass Center for Clinical and Translational Science (CCTS) Pilot Project Program grant (NIH / NCATS Grant UL1TR001453). SAP received travel support in 2024 from AAMDSIF. LDW is supported by the Edward P Evans Foundation for MDS, American Society of Hematology/Robert Wood Johnson Foundation AMFDP and Breakthrough Cancer Foundation. JT received the 2022 ASH Physician-Scientist Career Development Award. TYZ receives research funding from NIH/NCI grant 5K08CA248940-04. CY received research funding in 2022-23 from the NIH/NIDCR Grant R01DE029963 and the NIH/NIMH Grant P50MH129701. These are unrelated to the present work, and the funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Author information

Authors and Affiliations

  1. Dept. of Medicine – Division of Hematology/Oncology, UMass Memorial Medical Center, UMass Chan Medical School, Worcester, MA, USA

    Yiyu Xie, Vera Kazakova, Jonathan M. Gerber & Shyam A. Patel

  2. Center for Early Detection and Interception of Blood Cancers, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA

    Lachelle D. Weeks

  3. Center for Clinical and Translational Science, UMass Chan Medical School, Worcester, MA, USA

    Jonathan M. Gerber & Shyam A. Patel

  4. Dept. of Medicine – Division of Hematology, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA

    Jesse Tai & Tian Y. Zhang

  5. Dept. of Medicine – Division of Blood & Marrow Transplantation & Cellular Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA

    Robert Lowsky

  6. National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China

    Xiaojin Wu

  7. Measurement, Outcome, and Design Section, Division of Biostatistics and Health Service Research, Department of Population and Quantitative Health Sciences, T.H. Chan School of Medicine, UMass Chan Medical School, Worcester, MA, USA

    Chengwu Yang

  8. Department of Obstetrics & Gynecology, T.H. Chan School of Medicine, UMass Chan Medical School, Worcester, MA, USA

    Chengwu Yang

Authors
  1. Yiyu Xie
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Vera Kazakova
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lachelle D. Weeks
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jonathan M. Gerber
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jesse Tai
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Tian Y. Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Robert Lowsky
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Xiaojin Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Chengwu Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Shyam A. Patel
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

YX and SAP conceived the manuscript. YX, VK, and SAP wrote the manuscript. YX and XW developed the search criteria. XW, LDW, JMG, JT, TYZ, CY, and RL gave critical insight into analysis and critically revised the manuscript. Under CY’s supervision, YX performed and analyzed meta-analyses and meta-regression. YX, CY, and SAP gave final approval.

Corresponding authors

Correspondence to Chengwu Yang or Shyam A. Patel.

Ethics declarations

Competing interests

SAP served on the Myelodysplastic Syndrome advisory board and the Acute Myeloid Leukemia advisory board for Bristol Myers Squibb and served on the Multiple Myeloma advisory board for Pfizer. LDW reports consulting fees from AbbVie, Vertex and Sobi all unrelated to the present work. JMG served on an MDS Advisory Board for Novartis and holds US Patent No. 9012215, US Patent No. 10222376, and US Patent No. 11209435. Other authors have no conflicts of interest.

Ethics approval and consent to participate

All methods were performed in accordance with the relevant guidelines and regulations. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were strictly followed. Informed consent is not applicable as this was a meta-analysis. There are no patient identifiable images in this manuscript.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Xie, Y., Kazakova, V., Weeks, L.D. et al. Effects of donor-engrafted clonal hematopoiesis in allogeneic and autologous stem cell transplantation: a systematic review and meta-analysis. Bone Marrow Transplant (2024). https://doi.org/10.1038/s41409-024-02403-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41409-024-02403-2

Search

Advanced search

Quick links