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:

Extramedullary relapses of acute leukemias after allogeneic hematopoietic stem cell transplantation: clinical features, cumulative incidence, and risk factors

Abstract

The aim of this study was to evaluate extramedullary (EM) relapses and its features in an allogeneic hematopoietic stem cell transplantation (alloHSCT) cohort, which consisted of patients with acute leukemia and advanced-phase chronic myeloid leukemia. One hundred and twenty-eight alloHSCT patients transplanted between the years 2001 and 2014 were analyzed. EM relapses observed in acute lymphoblastic leukemia (ALL) were more frequent than that of in acute myeloid leukemia (AML) and CML, although calculation of cumulative risk incidence, BM relapse, EM relapse, and non-relapse mortality were considered as competing risks of each other. At the 60th month, estimated CBMR and CEMR incidences were, respectively, 14.3 (5.1)% and 25.9 (6.6)% in ALL, 25.8 (5.9)% and 15.5 (4.8)% in AML, and 61.5 (16.5)% and 17.9 (13.4)% in CML. Among multiple parameters, the only type of conditioning regimen (p:0.046), EM involvement at diagnosis (p:0.009), and the presence of GVHD were found to be associated with EM relapse risk independently (p:0.045). Chronic GVHD and TBI-based regimens significantly decreased the EM relapse risk, whereas it was higher with Mel/Flu and its variants. In conclusion, EM relapse is not uncommon after alloHSCT. GVHD and TBI-based regimens may prevent this complication.

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

Access options

Buy this article

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

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Ge L, Ye F, Mao X, Chen J, Sun A, Zhu X, et al. Extramedullary relapse of acute leukemia after allogeneic hematopoietic stem cell transplantation: different characteristics between acute myelogenous leukemia and acute lymphoblastic leukemia. Biol Blood Marrow Transplant. 2014;20:1040–7. https://doi.org/10.1016/j.bbmt.2014.03.030. e-pub ahead of print 2014/04/08

    Article  PubMed  Google Scholar 

  2. Huang Q, Reddi D, Chu P, Snyder DS, Weisenburger DD. Clinical and pathologic analysis of extramedullary tumors after hematopoietic stem cell transplantation. Hum Pathol. 2014;45:2404–10. https://doi.org/10.1016/j.humpath.2014.07.022. e-pub ahead of print 2014/10/09

    Article  PubMed  Google Scholar 

  3. Shimizu H, Saitoh T, Hatsumi N, Takada S, Handa H, Jimbo T, et al. Prevalence of extramedullary relapses is higher after allogeneic stem cell transplantation than after chemotherapy in adult patients with acute myeloid leukemia. Leuk Res. 2013;37:1477–81. https://doi.org/10.1016/j.leukres.2013.08.017. e-pub ahead of print 2013/09/24

    Article  CAS  PubMed  Google Scholar 

  4. Dohner H, Estey EH, Amadori S, Appelbaum FR, Buchner T, Burnett AK, et al. Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood. 2010;115:453–74. https://doi.org/10.1182/blood-2009-07-235358. e-pub ahead of print 2009/11/03

    Article  CAS  PubMed  Google Scholar 

  5. Ruiz-Arguelles GJ, Gomez-Almaguer D, Vela-Ojeda J, Morales-Toquero A, Gomez-Rangel JD, Garcia-Ruiz-Esparza MA, et al. Extramedullary leukemic relapses following hematopoietic stem cell transplantation with nonmyeloablative conditioning. Int J Hematol. 2005;82:262–5. https://doi.org/10.1532/ijh97.04195. e-pub ahead of print 2005/10/07

    Article  PubMed  Google Scholar 

  6. Au WY, Kwong YL, Lie AK, Ma SK, Liang R. Extra-medullary relapse of leukemia following allogeneic bone marrow transplantation. Hematol Oncol. 1999;17:45–52. e-pub ahead of print 1999/10/16

    Article  CAS  Google Scholar 

  7. Larson RA, Dodge RK, Burns CP, Lee EJ, Stone RM, Schulman P, et al. A five-drug remission induction regimen with intensive consolidation for adults with acute lymphoblastic leukemia: cancer and leukemia group B study 8811. Blood. 1995;85:2025–37. e-pub ahead of print 1995/04/15

    CAS  PubMed  Google Scholar 

  8. Moricke A, Reiter A, Zimmermann M, Gadner H, Stanulla M, Dordelmann M, et al. Risk-adjusted therapy of acute lymphoblastic leukemia can decrease treatment burden and improve survival: treatment results of 2169 unselected pediatric and adolescent patients enrolled in the trial ALL-BFM 95. Blood. 2008;111:4477–89. https://doi.org/10.1182/blood-2007-09-112920. e-pub ahead of print 2008/02/21

    Article  CAS  PubMed  Google Scholar 

  9. Greenwood MJ, Seftel MD, Richardson C, Barbaric D, Barnett MJ, Bruyere H, et al. Leukocyte count as a predictor of death during remission induction in acute myeloid leukemia. Leuk & Lymphoma. 2006;47:1245–52. https://doi.org/10.1080/10428190600572673. e-pub ahead of print 2006/08/23

    Article  CAS  Google Scholar 

  10. Gokbuget N, Hoelzer D. Treatment of adult acute lymphoblastic leukemia. Semin Hematol. 2009;46:64–75. https://doi.org/10.1053/j.seminhematol.2008.09.003. e-pub ahead of print 2008/12/23

    Article  PubMed  Google Scholar 

  11. Baccarani M, Saglio G, Goldman J, Hochhaus A, Simonsson B, Appelbaum F, et al. Evolving concepts in the management of chronic myeloid leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood. 2006;108:1809–20. https://doi.org/10.1182/blood-2006-02-005686. e-pub ahead of print 2006/05/20

    Article  CAS  PubMed  Google Scholar 

  12. Gray RJ. A Class of K-Sample Tests for Comparing the Cumulative Incidence of a Competing Risk. Annal Stat, 1988; 16: 1141-1154.

    Article  Google Scholar 

  13. Scrucca L, Santucci A, Aversa F. Competing risk analysis using R: an easy guide for clinicians. Bone Marrow Transplant. 2007;40:381–7. https://doi.org/10.1038/sj.bmt.1705727. e-pub ahead of print 2007/06/15

    Article  CAS  PubMed  Google Scholar 

  14. Team RC R: A language and environment for statistical computing. Vienna, Austria: R Foundation for Statistical Computing. pp. ISBN 3–900051–900007–900050, The R project for statistical computing website. Available: http://www.R-project.org/. Accessed 30 December 2013 (2012).

  15. Shi JM, Meng XJ, Luo Y, Tan YM, Zhu XL, Zheng GF, et al. Clinical characteristics and outcome of isolated extramedullary relapse in acute leukemia after allogeneic stem cell transplantation: a single-center analysis. Leuk Res. 2013;37:372–7. https://doi.org/10.1016/j.leukres.2012.12.002. e-pub ahead of print 2013/01/26

    Article  PubMed  Google Scholar 

  16. Harris AC, Kitko CL, Couriel DR, Braun TM, Choi SW, Magenau J, et al. Extramedullary relapse of acute myeloid leukemia following allogeneic hematopoietic stem cell transplantation: incidence, risk factors and outcomes. Haematologica. 2013;98:179–84. https://doi.org/10.3324/haematol.2012.073189. e-pub ahead of print 2012/10/16

    Article  PubMed  PubMed Central  Google Scholar 

  17. Lee KH, Lee JH, Choi SJ, Lee JH, Kim S, Seol M, et al. Bone marrow vs extramedullary relapse of acute leukemia after allogeneic hematopoietic cell transplantation: risk factors and clinical course. Bone Marrow Transplant. 2003;32:835–42. https://doi.org/10.1038/sj.bmt.1704223. e-pub ahead of print 2003/10/02

    Article  CAS  PubMed  Google Scholar 

  18. Kogut N, Tsai NC, Thomas SH, Palmer J, Paris T, Murata-Collins J, et al. Extramedullary relapse following reduced intensity allogeneic hematopoietic cell transplant for adult acute myelogenous leukemia. Leuk Lymphoma. 2013;54:665–8. https://doi.org/10.3109/10428194.2012.720375. e-pub ahead of print 2012/08/22

    Article  PubMed  Google Scholar 

  19. Kim JH, Stein A, Tsai N, Schultheiss TE, Palmer J, Liu A, et al. Extramedullary relapse following total marrow and lymphoid irradiation in patients undergoing allogeneic hematopoietic cell transplantation. Int J Radiat Oncol Biol Phys. 2014;89:75–81. https://doi.org/10.1016/j.ijrobp.2014.01.036. e-pub ahead of print 2014/04/15

    Article  PubMed  Google Scholar 

  20. Goyal SD, Zhang MJ, Wang HL, Akpek G, Copelan EA, Freytes C, et al. Allogeneic hematopoietic cell transplant for AML: no impact of pre-transplant extramedullary disease on outcome. Bone Marrow Transplant. 2015;50:1057–62. https://doi.org/10.1038/bmt.2015.82. e-pub ahead of print 2015/04/29

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Bourlon C, Lipton JH, Deotare U, Gupta V, Kim DD, Kuruvilla J, et al. Extramedullary disease at diagnosis of AML does not influence outcome of patients undergoing allogeneic hematopoietic cell transplant in CR1. Eur J Haematol. 2017;99:234–9. https://doi.org/10.1111/ejh.12909. e-pub ahead of print 2017/05/31

    Article  CAS  PubMed  Google Scholar 

  22. Oshima K, Kanda Y, Yamashita T, Takahashi S, Mori T, Nakaseko C, et al. Central nervous system relapse of leukemia after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2008;14:1100–7. https://doi.org/10.1016/j.bbmt.2008.07.002. e-pub ahead of print 2008/09/23

    Article  PubMed  Google Scholar 

  23. Solh M, DeFor TE, Weisdorf DJ, Kaufman DS. Extramedullary relapse of acute myelogenous leukemia after allogeneic hematopoietic stem cell transplantation: better prognosis than systemic relapse. Biol Blood Marrow Transplant. 2012;18:106–12. https://doi.org/10.1016/j.bbmt.2011.05.023. e-pub ahead of print 2011/06/28

    Article  PubMed  Google Scholar 

  24. Yoshihara S, Ando T, Ogawa H. Extramedullary relapse of acute myeloid leukemia after allogeneic hematopoietic stem cell transplantation: an easily overlooked but significant pattern of relapse. Biol Blood Marrow Transplant. 2012;18:1800–7. https://doi.org/10.1016/j.bbmt.2012.05.010. e-pub ahead of print 2012/05/29

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Gursel Gunes.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gunes, G., Goker, H., Demiroglu, H. et al. Extramedullary relapses of acute leukemias after allogeneic hematopoietic stem cell transplantation: clinical features, cumulative incidence, and risk factors. Bone Marrow Transplant 54, 595–600 (2019). https://doi.org/10.1038/s41409-018-0303-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41409-018-0303-5

This article is cited by

Search

Quick links