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:

Cancers after HLA-matched related bone marrow transplantation for aplastic anemia

Bone Marrow Transplantation volume 57, pages 83–88 (2022)Cite this article

Subjects

Abstract

We analyzed subsequent cancers in 329 patients with aplastic anemia given HLA-matched related marrow grafts. Median follow-up: 26 (range 1–47) years. Conditioning: cyclophosphamide ± antithymocyte globulin; graft-vs.-host disease (GVHD) prevention: methotrexate ± cyclosporine. The long follow-up and homogeneous treatment allowed definitive analyses of incidence, nature, time of onset, and potential causes of cancers. Fifty-three cancers occurred in 46 patients, 42 had solid tumors and 4 blood cancers. Of the 42, 22 had non-melanoma skin and 7 oropharyngeal cancers. The remainder had a spectrum of other cancers including two liver cancers from pre-transplant hepatitis C. The 26-year cumulative incidence (CI) of cancer was 11% and mortality 5%. Excluding non-melanoma skin cancers, the 26-year CI of cancer was 7%. Cancers were 2.03-fold more than expected from SEER data; that number was 1.89-fold after excluding liver cancers. Nearly all cancers developed between 14 and 34 years. Skin and oropharyngeal cancers showed significant association with chronic GVHD, whereby GVHD had resolved in most patients within 7 years of transplantation. Thus, tumors evolved after a lag time of 7–27 years. Other cancers showed no clear associations with chronic GVHD or drugs used for transplantation. Results reemphasize the importance of preventing chronic GVHD.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Fig. 1: Overall survival.
Fig. 2

Similar content being viewed by others

References

  1. Santos GW, Owens AH Jr. Allogeneic marrow transplants in cyclophosphamide treated mice. Transplant Proc. 1969;1:44–46.

    CAS  PubMed  Google Scholar 

  2. Storb R, Epstein RB, Rudolph RH, Thomas ED. Allogeneic canine bone marrow transplantation following cyclophosphamide. Transplantation. 1969;7:378–86.

    Article  CAS  Google Scholar 

  3. Storb R, Buckner CD, Dillingham LA, Thomas ED. Cyclophosphamide regimens in rhesus monkeys with and without marrow infusion. Cancer Res. 1970;30:2195–203.

    CAS  PubMed  Google Scholar 

  4. Thomas ED, Buckner CD, Storb R, Neiman PE, Fefer A, Clift RA, et al. Aplastic anaemia treated by marrow transplantation. Lancet. 1972;1:284–9.

    Article  CAS  Google Scholar 

  5. Storb R, Thomas ED, Buckner CD, Clift RA, Johnson FL, Fefer A, et al. Allogeneic marrow grafting for treatment of aplastic anemia. Blood. 1974;43:157–80.

    Article  CAS  Google Scholar 

  6. Storb R, Floersheim GL, Weiden PL, Graham TC, Kolb HJ, Lerner KG, et al. Effect of prior blood transfusions on marrow grafts: abrogation of sensitization by procarbazine and antithymocyte serum. J Immunol. 1974;112:1508–16.

    Article  CAS  PubMed  Google Scholar 

  7. Weiden PL, Storb R, Slichter S, Warren RP, Sale GE. Effect of six weekly transfusions on canine marrow grafts: tests for sensitization and abrogation of sensitization by procarbazine and antithymocyte serum. J Immunol. 1976;117:143–50. e-pub ahead of print 1976/07/01

    Article  CAS  PubMed  Google Scholar 

  8. Kotasek D, Shepherd KM, Sage RE, Dale BM, Norman JE, Charles P, et al. Factors affecting blood stem cell collections following high-dose cyclophosphamide mobilization in lymphoma, myeloma and solid tumors. Bone Marrow Transplant. 1992;9:11–7.

    CAS  PubMed  Google Scholar 

  9. Storb R, Etzioni R, Anasetti C, Appelbaum FR, Buckner CD, Bensinger W, et al. Cyclophosphamide combined with antithymocyte globulin in preparation for allogeneic marrow transplants in patients with aplastic anemia. Blood. 1994;84:941–9.

    Article  CAS  Google Scholar 

  10. Storb R, Deeg HJ, Farewell V, Doney K, Appelbaum F, Beatty P, et al. Marrow transplantation for severe aplastic anemia: methotrexate alone compared with a combination of methotrexate and cyclosporine for prevention of acute graft-versus-host disease. Blood. 1986;68:119–25.

    Article  CAS  Google Scholar 

  11. Storb R, Doney KC, Thomas ED, Appelbaum F, Buckner CD, Clift RA, et al. Marrow transplantation with or without donor buffy coat cells for 65 transfused aplastic anemia patients. Blood. 1982;59:236–46.

    Article  CAS  Google Scholar 

  12. Storb R, Deeg HJ, Whitehead J, Appelbaum F, Beatty P, Bensinger W, et al.Methotrexate and cyclosporine compared with cyclosporine alone for prophylaxis of acute graft versus host disease after marrow transplantation for leukemia.N Eng J Med.1986;314:729–35.

    Article  CAS  Google Scholar 

  13. Glucksberg H, Storb R, Fefer A, Buckner CD, Neiman PE, Clift RA, et al. Clinical manifestations of graft-versus-host disease in human recipients of marrow from HL-A-matched sibling donors. Transplantation. 1974;18:295–304.

    Article  CAS  Google Scholar 

  14. Doney KC, Weiden PL, Storb R, Thomas ED. Treatment of graft-versus-host disease in human allogeneic marrow graft recipients: a randomized trial comparing antithymocyte globulin and corticosteroids. Am J Hematol. 1981;11:1–8.

    Article  CAS  Google Scholar 

  15. Deeg HJ, Loughran TP Jr., Storb R, Kennedy MS, Sullivan KM, Doney K, et al. Treatment of human acute graft-versus-host disease with antithymocyte globulin and cyclosporine with or without methylprednisolone. Transplantation. 1985;40:162–6. https://doi.org/10.1097/00007890-198508000-00011

    Article  CAS  PubMed  Google Scholar 

  16. Kennedy MS, Deeg HJ, Storb R, Doney K, Sullivan KM, Witherspoon RP, et al. Treatment of acute graft-versus-host disease after allogeneic marrow transplantation: Randomized study comparing corticosteroids and cyclosporine. Am J Med. 1985;78:978–83.

    Article  CAS  Google Scholar 

  17. Deeg HJ, Doney K, Sullivan KM, Loughran TP, Appelbaum F, Kennedy M, et al. Antithymocyte globulin followed by cyclosporine for the treatment of acute GVHD in patients given HLA-identical or -nonidentical marrow grafts. Transplant Proc. 1986;18:791–3.

    Google Scholar 

  18. Sullivan KM, Deeg HJ, Sanders JE, Shulman HM, Witherspoon RP, Doney K, et al. Late complications after marrow transplantation. Semin Hematol. 1984;21:53–63.

    CAS  PubMed  Google Scholar 

  19. Filipovich AH, Weisdorf D, Pavletic S, Socie G, Wingard JR, Lee SJ, et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and Staging Working Group report. Biol Blood Marrow Transpl. 2005;11:945–56.

    Article  Google Scholar 

  20. Jagasia MH, Greinix HT, Arora M, Williams KM, Wolff D, Cowen EW, et al. National Institutes of Health Consensus Development Project on criteria for clinical trials in chronic Graft-versus-Host Disease: I. The 2014 Diagnosis and Staging Working Group Report. Biol Blood Marrow Transpl. 2015;21:389–401.

    Article  Google Scholar 

  21. Sullivan KM, Witherspoon RP, Storb R, Weiden P, Flournoy N, Dahlberg S, et al. Prednisone and azathioprine compared with prednisone and placebo for treatment of chronic graft-versus-host disease: prognostic influence of prolonged thrombocytopenia after allogeneic marrow transplantation. Blood. 1988;72:546–54.

    Article  CAS  Google Scholar 

  22. Sullivan KM, Witherspoon RP, Storb R, Deeg HJ, Dahlberg S, Sanders JE, et al. Alternating-day cyclosporine and prednisone for treatment of high-risk chronic graft-versus-host disease. Blood. 1988;72:555–61.

    Article  CAS  Google Scholar 

  23. Flowers ME, Martin PJ. How we treat chronic graft-versus-host disease. Blood. 2015;125:606–15.

    Article  CAS  Google Scholar 

  24. Deeg HJ, Socié G, Schoch G, Henry-Amar M, Witherspoon RP, Devergie A, et al. Malignancies after marrow transplantation for aplastic anemia and Fanconi anemia: a joint Seattle and Paris analysis of results in 700 patients. Blood. 1996;87:386–92.

    Article  CAS  Google Scholar 

  25. Gallo S, Woolfrey AE, Burroughs LM, Storer BE, Flowers ME, Hari P, et al. Marrow grafts from HLA-identical siblings for severe aplastic anemia: does limiting the number of transplanted marrow cells reduce the risk of chronic GVHD? Bone Marrow Transpl. 2016;51:1573–8. https://doi.org/10.1038/bmt.2016.198

    Article  CAS  Google Scholar 

  26. Socié G, Henry-Amar M, Bacigalupo A, Hows J, Tichelli A, Ljungman P. et al.Malignant tumors occurring after treatment of aplastic anemia.N Eng J Med. 1993;329:1152–7.

    Article  Google Scholar 

  27. ASCO Cancer.Net. Bladder Cancer: Risk Factors. In: American Society of Clinical Oncology (ASCO), 9999.

  28. Talar-Williams C, Hijazi YM, Walther MM, Linehan WM, Hallahan CW, Lubensky I, et al. Cyclophosphamide-induced cystitis and bladder cancer in patients with Wegener granulomatosis. Ann Intern Med. 1996;124:477–84. https://doi.org/10.7326/0003-4819-124-5-199603010-00003. e-pub ahead of print 1996/03/01

    Article  CAS  PubMed  Google Scholar 

  29. Xu Y, Wang H, Zhou S, Yu M, Wang X, Fu K, et al. Risk of second malignant neoplasms after cyclophosphamide-based chemotherapy with or without radiotherapy for non-Hodgkin lymphoma. Leuk Lymphoma. 2013;54:1396–404.

    Article  CAS  Google Scholar 

  30. Euvrard S, Kanitakis J, Claudy A. Skin cancers after organ transplantation (review). N Eng J Med. 2003;348:1681–91.

    Article  Google Scholar 

  31. Cockburn IT, Krupp P. The risk of neoplasms in patients treated with cyclosporine A. J Autoimmun. 1989;2:723–31. https://doi.org/10.1016/s0896-8411(89)80010-1. e-pub ahead of print 1989/10/01

    Article  CAS  PubMed  Google Scholar 

  32. Bewtra M, Lewis JD. Update on the risk of lymphoma following immunosuppressive therapy for inflammatory bowel disease. Expert Rev Clin Immunol. 2010;6:621–31. https://doi.org/10.1586/eci.10.36. e-pub ahead of print 2010/07/03

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. DePry JL, Vyas R, Lazarus HM, Caimi PF, Gerstenblith MR, Bordeaux JS. Cutaneous malignant neoplasms in hematopoietic cell transplant recipients: a systematic review. JAMA Dermatol. 2015;151:775–82. https://doi.org/10.1001/jamadermatol.2015.121. e-pub ahead of print 2015/04/23

    Article  PubMed  Google Scholar 

  34. Curtis RE, Metayer C, Rizzo JD, Socie G, Sobocinski KA, Flowers ME, et al. Impact of chronic GVHD therapy on the development of squamous-cell cancers after hematopoietic stem-cell transplantation: an international case-control study. Blood. 2005;105:3802–11. https://doi.org/10.1182/blood-2004-09-3411. e-pub ahead of print 2005/02/03

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Storb R, Anasetti C, Appelbaum F, Bensinger W, Buckner CD, Clift R, et al. Marrow transplantation for severe aplastic anemia and thalassemia major. Semin Hematol. 1991;28:235–9.

    CAS  PubMed  Google Scholar 

  36. Wiseman DH. Donor cell leukemia: a review (review). Biol Blood Marrow Transplant. 2011;17:771–89.

    Article  Google Scholar 

  37. Rossi DJ, Jamieson CH, Weissman IL. Stems cells and the pathways to aging and cancer (Review). Cell. 2008;132:681–96.

    Article  CAS  Google Scholar 

  38. Mayor PC, Eng KH, Singel KL, Abrams SI, Odunsi K, Moysich KB, et al. Cancer in primary immunodeficiency diseases: cancer incidence in the United States Immune Deficiency Network Registry. J allergy Clin Immunol. 2018;141:1028–35. https://doi.org/10.1016/j.jaci.2017.05.024. e-pub ahead of print 2017/06/14

    Article  PubMed  Google Scholar 

  39. Noel DR, Witherspoon RP, Storb R, Atkinson K, Doney K, Mickelson EM, et al. Does graft-versus-host disease influence the tempo of immunologic recovery after allogeneic human marrow transplantation? An observation on 56 long-term survivors. Blood. 1978;51:1087–105.

    Article  CAS  Google Scholar 

  40. Witherspoon RP, Storb R, Ochs HD, Flournoy N, Kopecky KJ, Sullivan KM, et al. Recovery of antibody production in human allogeneic marrow graft recipients: influence of time posttransplantation, the presence or absence of chronic graft-versus-host disease, and antithymocyte globulin treatment. Blood. 1981;58:360–8.

    Article  CAS  Google Scholar 

  41. Williams N, Lee J, Moore L, Baxter JE, Hewinson J, Dawson KJ, et al. Driver mutation acquisition in utero and childhood followed by lifelong clonal evolution underlie myeloproliferative neoplasms (Abstract). Blood. 2020;136:LBA-1-LBA-1. https://doi.org/10.1182/blood-2020-143813

  42. Aldoss I, Song JY, Curtin PT, Forman SJ. Multiple donor-derived leukemias in a recipient of allogeneic hematopoietic cell transplantation for myeloid malignancy. Blood Adv. 2020;4:4798–801. https://doi.org/10.1182/bloodadvances.2020002803. e-pub ahead of print 2020/10/07

    Article  PubMed  PubMed Central  Google Scholar 

  43. Shiozaki H, Yoshinaga K, Kondo T, Imai Y, Shiseki M, Mori N, et al. Donor cell-derived leukemia after cord blood transplantation and a review of the literature: differences between cord blood and BM as the transplant source. Bone Marrow Transpl. 2014;49:102–9. https://doi.org/10.1038/bmt.2013.127. e-pub ahead of print 2013/09/10

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Dr. Jason Coper for his assistance with data collection. We thank Dr. Barry Storer for his assistance with data analysis. We thank Gary Schoch for data management. We thank Drs. Cecilia Yeung and Min Fang for confirming pathology reports. We thank Helen Crawford for manuscript preparation. We thank the LTFU program for the database and most importantly, we thank your patients and their families for their participation in the clinical trials.

Funding

Research funding was provided by P01 HL122173 from NHLBI and P30 CA015704 from NCI, NIH.

Author information

Authors and Affiliations

  1. Division of Clinical Research, Fred Hutchinson Cancer Research Center, University of Washington, Seattle, WA, USA

    Phuong Vo, Lynn Onstad, Mary E. Flowers & Rainer Storb

  2. Department of Medicine, Fred Hutchinson Cancer Research Center, University of Washington, Seattle, WA, USA

    Phuong Vo, Mary E. Flowers & Rainer Storb

Authors
  1. Phuong Vo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lynn Onstad
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mary E. Flowers
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Rainer Storb
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

PV collected data and drafted the manuscript. LO analyzed data. RS drafted the manuscript. All authors critically revised the manuscript, and all authors reviewed and approved the final manuscript.

Corresponding author

Correspondence to Phuong Vo.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

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

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Vo, P., Onstad, L., Flowers, M.E. et al. Cancers after HLA-matched related bone marrow transplantation for aplastic anemia. Bone Marrow Transplant 57, 83–88 (2022). https://doi.org/10.1038/s41409-021-01498-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41409-021-01498-1

This article is cited by

Search

Advanced search

Quick links