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.

  • Original Article
  • Published:

Chronic Leukemia

Clinical and biological predictors of outcome following relapse of CML post-allo-SCT

Bone Marrow Transplantation volume 50, pages 189–196 (2015)Cite this article

Subjects

Abstract

Although there are now fewer allo-SCTs performed for CML, leukemic relapse post transplant remains a persistent problem. To better define clinical and biological parameters determining postrelapse outcome, we studied 59 patients with CML relapsing after HLA-identical sibling allo-SCT between 1993 and 2008. Eighteen (30.5%) were transplanted in advanced phase and 41 (69.5%) in chronic phase. With a median follow-up from relapse of 7.9 years, 5-year post relapse survival (PRS) was 62%. Multivariate analysis found disease status at transplant, time to diagnosis of relapse from transplant and pretransplant tyrosine kinase inhibitor (TKI) use as significant factors associated with PRS. Analysis of BCR-ABL transcript expression in the hematopoietic progenitor compartment was performed in 36 patients (22 relapsed, 8 non-relapsed and 6 TKI alone controls). Patients with BCR-ABL expression in their early hematopoietic stem cell compartment (Lineage−CD34+CD38−CD90+) had worse survival irrespective of the disease status. We conclude that disease status remains the strongest clinical prognostic factor for PRS in CML following allo-SCT. The persistence of BCR-ABL expression in the progenitor cell compartment in some patients after SCT emphasizes the need to target CML-leukemia stem cells.

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

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  1. Barrett AJ, van Rhee F. . Graft-versus-leukaemia. Baillieres Clin Haematol 1997; 10: 337–355.

    Article  CAS  PubMed  Google Scholar 

  2. Ringden O, Pavletic SZ, Anasetti C, Barrett AJ, Wang T, Wang D et al. The graft-versus-leukemia effect using matched unrelated donors is not superior to HLA-identical siblings for hematopoietic stem cell transplantation. Blood 2009; 113: 3110–3118.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Clift RA, Buckner CD, Thomas ED, Doney K, Fefer A, Neiman PE et al. Treatment of chronic granulocytic leukaemia in chronic phase by allogeneic marrow transplantation. Lancet 1982; 2: 621–623.

    Article  CAS  PubMed  Google Scholar 

  4. Goldman JM, Apperley JF, Jones L, Marcus R, Goolden AW, Batchelor R et al. Bone marrow transplantation for patients with chronic myeloid leukemia. N Engl J Med 1986; 314: 202–207.

    Article  CAS  PubMed  Google Scholar 

  5. Speck B, Bortin MM, Champlin R, Goldman JM, Herzig RH, McGlave PB et al. Allogeneic bone-marrow transplantation for chronic myelogenous leukaemia. Lancet 1984; 1: 665–668.

    Article  CAS  PubMed  Google Scholar 

  6. Olavarria E, Ottmann OG, Deininger M, Clark RE, Bandini G, Byrne J et al. Response to imatinib in patients who relapse after allogeneic stem cell transplantation for chronic myeloid leukemia. Leukemia 2003; 17: 1707–1712.

    Article  CAS  PubMed  Google Scholar 

  7. Kantarjian HM, O'Brien S, Cortes JE, Giralt SA, Rios MB, Shan J et al. Imatinib mesylate therapy for relapse after allogeneic stem cell transplantation for chronic myelogenous leukemia. Blood 2002; 100: 1590–1595.

    CAS  PubMed  Google Scholar 

  8. Ullmann AJ, Hess G, Kolbe K, Friedrich-Freksa A, Meyer RG, Gschaidmeier H et al. Current results on the use of imatinib mesylate in patients with relapsed Philadelphia chromosome positive leukemia after allogeneic or syngeneic hematopoietic stem cell transplantation. Keio J Med 2003; 52: 182–188.

    Article  PubMed  Google Scholar 

  9. Kim YJ, Kim DW, Lee S, Kim YL, Hwang JY, Park YH et al. Cytogenetic clonal evolution alone in CML relapse post-transplantation does not adversely affect response to imatinib mesylate treatment. Bone Marrow Transplant 2004; 33: 237–242.

    Article  CAS  PubMed  Google Scholar 

  10. DeAngelo DJ, Hochberg EP, Alyea EP, Longtine J, Lee S, Galinsky I et al. Extended follow-up of patients treated with imatinib mesylate (gleevec) for chronic myelogenous leukemia relapse after allogeneic transplantation: durable cytogenetic remission and conversion to complete donor chimerism without graft-versus-host disease. Clin Cancer Res 2004; 10: 5065–5071.

    Article  CAS  PubMed  Google Scholar 

  11. Goldman JM, Melo JV. . Chronic myeloid leukemia—advances in biology and new approaches to treatment. N Engl J Med 2003; 349: 1451–1464.

    Article  CAS  PubMed  Google Scholar 

  12. 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: 1809–1820.

    Article  CAS  PubMed  Google Scholar 

  13. Jabbour E, Cortes J, Kantarjian HM, Giralt S, Jones D, Jones R et al. Allogeneic stem cell transplantation for patients with chronic myeloid leukemia and acute lymphocytic leukemia after Bcr-Abl kinase mutation-related imatinib failure. Blood 2006; 108: 1421–1423.

    Article  CAS  PubMed  Google Scholar 

  14. Pavlu J, Szydlo RM, Goldman JM, Apperley JF. . Three decades of transplantation for chronic myeloid leukemia: what have we learned? Blood 2011; 117: 755–763.

    Article  CAS  PubMed  Google Scholar 

  15. Silver RT. . The blast phase of chronic myeloid leukaemia. Best Pract Res Clin Haematol 2009; 22: 387–394.

    Article  PubMed  Google Scholar 

  16. van Rhee F, Lin F, Cullis JO, Spencer A, Cross NC, Chase A et al. Relapse of chronic myeloid leukemia after allogeneic bone marrow transplant: the case for giving donor leukocyte transfusions before the onset of hematologic relapse. Blood 1994; 83: 3377–3383.

    CAS  PubMed  Google Scholar 

  17. Goldman JM, Majhail NS, Klein JP, Wang Z, Sobocinski KA, Arora M et al. Relapse and late mortality in 5-year survivors of myeloablative allogeneic hematopoietic cell transplantation for chronic myeloid leukemia in first chronic phase. J Clin Oncol 2010; 28: 1888–1895.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Yong AS, Goldman JM. . Relapse of chronic myeloid leukaemia 14 years after allogeneic bone marrow transplantation. Bone Marrow Transplant 1999; 23: 827–828.

    Article  CAS  PubMed  Google Scholar 

  19. Savani BN, Montero A, Kurlander R, Childs R, Hensel N, Barrett AJ. . Imatinib synergizes with donor lymphocyte infusions to achieve rapid molecular remission of CML relapsing after allogeneic stem cell transplantation. Bone Marrow Transplant 2005; 36: 1009–1015.

    Article  CAS  PubMed  Google Scholar 

  20. Goldman JM. . The significance of BCR-ABL transcripts after allogeneic stem cell transplantation for chronic myeloid leukemia. Biol Blood Marrow Transplant 2013; 19: 679–680.

    Article  CAS  PubMed  Google Scholar 

  21. Jamieson CH, Ailles LE, Dylla SJ, Muijtjens M, Jones C, Zehnder JL et al. Granulocyte-macrophage progenitors as candidate leukemic stem cells in blast-crisis CML. N Engl J Med 2004; 351: 657–667.

    Article  CAS  PubMed  Google Scholar 

  22. Solomon SR, Nakamura R, Read EJ, Leitman SF, Carter C, Childs R et al. Cyclosporine is required to prevent severe acute GVHD following T-cell-depleted peripheral blood stem cell transplantation. Bone Marrow Transplant 2003; 31: 783–788.

    Article  CAS  PubMed  Google Scholar 

  23. Agarwal R, Doren S, Hicks B, Dunbar CE. . Long-term culture of chronic myelogenous leukemia marrow cells on stem cell factor-deficient stroma favors benign progenitors. Blood 1995; 85: 1306–1312.

    CAS  PubMed  Google Scholar 

  24. Mensink E, van de Locht A, Schattenberg A, Linders E, Schaap N, Geurts van Kessel A et al. Quantitation of minimal residual disease in Philadelphia chromosome positive chronic myeloid leukaemia patients using real-time quantitative RT-PCR. Br J Haematol 1998; 102: 768–774.

    Article  CAS  PubMed  Google Scholar 

  25. Savani BN, Rezvani K, Mielke S, Montero A, Kurlander R, Carter CS et al. Factors associated with early molecular remission after T cell-depleted allogeneic stem cell transplantation for chronic myelogenous leukemia. Blood 2006; 107: 1688–1695.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Khoury HJ, Kukreja M, Goldman JM, Wang T, Halter J, Arora M et al. Prognostic factors for outcomes in allogeneic transplantation for CML in the imatinib era: a CIBMTR analysis. Bone Marrow Transplant 2012; 47: 810–816.

    Article  CAS  PubMed  Google Scholar 

  27. Ito S, Pophali P, Co W, Koklanaris EK, Superata J, Fahle GA et al. CMV reactivation is associated with a lower incidence of relapse after allo-SCT for CML. Bone Marrow Transplant 2013; 48: 1313–1316.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Yong AS, Szydlo RM, Goldman JM, Apperley JF, Melo JV. . Molecular profiling of CD34+ cells identifies low expression of CD7, along with high expression of proteinase 3 or elastase, as predictors of longer survival in patients with CML. Blood 2006; 107: 205–212.

    Article  CAS  PubMed  Google Scholar 

  29. Yong AS, Keyvanfar K, Eniafe R, Savani BN, Rezvani K, Sloand EM et al. Hematopoietic stem cells and progenitors of chronic myeloid leukemia express leukemia-associated antigens: implications for the graft-versus-leukemia effect and peptide vaccine-based immunotherapy. Leukemia 2008; 22: 1721–1727.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Beillard E, Pallisgaard N, van der Velden VH, Bi W, Dee R, van der Schoot E et al. Evaluation of candidate control genes for diagnosis and residual disease detection in leukemic patients using 'real-time' quantitative reverse-transcriptase polymerase chain reaction (RQ-PCR)—a Europe against cancer program. Leukemia 2003; 17: 2474–2486.

    Article  CAS  PubMed  Google Scholar 

  31. Gabert J, Beillard E, van der Velden VH, Bi W, Grimwade D, Pallisgaard N et al. Standardization and quality control studies of 'real-time' quantitative reverse transcriptase polymerase chain reaction of fusion gene transcripts for residual disease detection in leukemia—a Europe Against Cancer program. Leukemia 2003; 17: 2318–2357.

    Article  CAS  PubMed  Google Scholar 

  32. Kaeda J, O'Shea D, Szydlo RM, Olavarria E, Dazzi F, Marin D et al. Serial measurement of BCR-ABL transcripts in the peripheral blood after allogeneic stem cell transplantation for chronic myeloid leukemia: an attempt to define patients who may not require further therapy. Blood 2006; 107: 4171–4176.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Sobrinho-Simoes M, Wilczek V, Score J, Cross NC, Apperley JF, Melo JV. . In search of the original leukemic clone in chronic myeloid leukemia patients in complete molecular remission after stem cell transplantation or imatinib. Blood 2010; 116: 1329–1335.

    Article  CAS  PubMed  Google Scholar 

  34. Barrett AJ. . Understanding and harnessing the graft-versus-leukaemia effect. Br J Haematol 2008; 142: 877–888.

    Article  CAS  PubMed  Google Scholar 

  35. Boehm A, Walcherberger B, Sperr WR, Wohrer S, Dieckmann K, Rosenmayr A et al. Improved outcome in patients with chronic myelogenous leukemia after allogeneic hematopoietic stem cell transplantation over the past 25 years: a single-center experience. Biol Blood Marrow Transplant 2011; 17: 133–140.

    Article  PubMed  Google Scholar 

  36. Eisterer W, Jiang X, Christ O, Glimm H, Lee KH, Pang E et al. Different subsets of primary chronic myeloid leukemia stem cells engraft immunodeficient mice and produce a model of the human disease. Leukemia 2005; 19: 435–441.

    Article  CAS  PubMed  Google Scholar 

  37. Corbin AS, Agarwal A, Loriaux M, Cortes J, Deininger MW, Druker BJ. . Human chronic myeloid leukemia stem cells are insensitive to imatinib despite inhibition of BCR-ABL activity. J Clin Invest 2011; 121: 396–409.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This paper is dedicated to the memory of John Michael Goldman who inspired us with his insightful observations on the definition and nature of cure of CML. We thank N Hensel, S Miner, M Franco Colon and F Chinian (Hematology Branch, NHLBI, NIH, USA) for their technical support. We also thank all patients who participated in this study. This research was supported by the Intramural Research Program of the National Institutes of Health at the National Heart, Lung, and Blood Institute.

Author Contributions

Study concept and design: NAJ, SI, AJB and ASY; in vitro experiment and data collection: KK and ASY; analysis and interpretation of data: NAJ, SI, RK, MB, PM, AJB and ASY; drafting of the manuscript: NAJ, SI, RK, MB, CH, PM, AJB and ASY; statistical analysis: NAJ, SI and XT; subject enrollment and clinical data collection: MB, KL, BNS, VM, KR, RQL, AS, EK, JS, AJB and ASY; obtaining BM samples from controls: VM; and obtainment of funding and study supervision: AJB.

Author information

Author notes

  1. B N Savani

    Present address: VanderbiltUniversity VAMC Transplant Program, Nashville, TN, USA.,

  2. K Rezvani

    Present address: Division of Cancer Medicine, Department of Stem Cell Transplantation, The Universityof Texas MD Anderson Cancer Center, Houston, TX, USA.,

  3. R Q Le

    Present address: Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Rockville, MD, USA.,

  4. A Shenoy

    Present address: Hematology/Oncology, Washington Cancer Institute, Medstar Washington Hospital Center, 110 Irving Street NW C2151, Washington, DC, USA.,

  5. A S M Yong

    Present address: Department of Haematology, SA Pathology, and Department of Medicine, University of Adelaide, Adelaide, SA, Australia.,

  6. N A Jain and S Ito: These authors contributed equally to this work.

Authors and Affiliations

  1. Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA

    N A Jain, S Ito, M Battiwalla, K Lu, B N Savani, K Rezvani, R Q Le, A Shenoy, C S Hourigan, K Keyvanfar, E Koklanaris, J Superata, P Muranski, A J Barrett & A S M Yong

  2. Office of Biostatistics Research, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA

    X Tian

  3. Department of Laboratory Medicine, Clinical Research Center, National Institutes of Health, Bethesda, MD, USA

    R Kurlander

  4. Hematology/Oncology, Washington Cancer Institute, Medstar Washington Hospital Center, Washington, DC, USA

    V Malkovska

Authors
  1. N A Jain
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S Ito
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. X Tian
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. R Kurlander
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M Battiwalla
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. K Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. B N Savani
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. V Malkovska
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. K Rezvani
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. R Q Le
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. A Shenoy
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. C S Hourigan
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. K Keyvanfar
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. E Koklanaris
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. J Superata
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. P Muranski
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. A J Barrett
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. A S M Yong
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to S Ito.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on Bone Marrow Transplantation website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jain, N., Ito, S., Tian, X. et al. Clinical and biological predictors of outcome following relapse of CML post-allo-SCT. Bone Marrow Transplant 50, 189–196 (2015). https://doi.org/10.1038/bmt.2014.249

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/bmt.2014.249

This article is cited by

Search

Advanced search

Quick links