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 Lymphocytic Leukemia

Long-term follow-up of reduced-intensity allogeneic stem cell transplantation for chronic lymphocytic leukemia: prognostic model to predict outcome

Leukemia volume 27, pages 362–369 (2013)Cite this article

Subjects

Abstract

Chronic lymphocytic leukemia (CLL) remains incurable with chemoimmunotherapy, and allogeneic hematopoietic stem cell transplantation (HSCT) offers the potential for cure. We assessed the outcomes of 108 CLL patients undergoing first allogeneic HSCTs, 76 with reduced-intensity (RIC) and 32 with myeloablative conditioning (MAC) between 1998 and 2009 at Dana-Farber Cancer Institute. With median follow-up of 5.9 years in surviving patients, the 5-year overall survival (OS) for the entire cohort is 63% for RIC regimens and 49% for MAC regimens (P=0.18). The risk of death declined significantly starting in 2004, and we found that 5-year OS for HSCT between 2004 and 2009 was 83% for RIC regimens compared with 47% for MAC regimens (P=0.003). For RIC transplantation, we developed a prognostic model based on predictors of progression-free survival (PFS), specifically remission status, lactate dehydrogenase, comorbidity score and lymphocyte count, and found 5-year PFS to be 83% for Score 0, 63% for Score 1, 24% for Score 2 and 6% for Score ⩾3 (P<0.0001). We conclude that RIC HSCT for CLL in the current era is associated with excellent long-term PFS and OS, and, as potentially curative therapy, should be considered early in the disease course of relapsed high-risk CLL patients.

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

Similar content being viewed by others

References

  1. Wierda W, O’Brien S, Wen S, Faderl S, Garcia-Manero G, Thomas D et al. Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab for relapsed and refractory chronic lymphocytic leukemia. J Clin Oncol 2005; 23: 4070–4078.

    Article  CAS  PubMed  Google Scholar 

  2. Keating MJ, O’Brien S, Albitar M, Lerner S, Plunkett W, Giles F et al. Early results of a chemoimmunotherapy regimen of fludarabine, cyclophosphamide, and rituximab as initial therapy for chronic lymphocytic leukemia. J Clin Oncol 2005; 23: 4079–4088.

    Article  CAS  PubMed  Google Scholar 

  3. Byrd JC, Rai K, Peterson BL, Appelbaum FR, Morrison VA, Kolitz JE et al. Addition of rituximab to fludarabine may prolong progression-free survival and overall survival in patients with previously untreated chronic lymphocytic leukemia: an updated retrospective comparative analysis of CALGB 9712 and CALGB 9011. Blood 2005; 105: 49–53.

    Article  CAS  PubMed  Google Scholar 

  4. Keating MJ, Flinn I, Jain V, Binet JL, Hillmen P, Byrd J et al. Therapeutic role of alemtuzumab (Campath-1H) in patients who have failed fludarabine: results of a large international study. Blood 2002; 99: 3554–3561.

    Article  CAS  PubMed  Google Scholar 

  5. Fischer K, Cramer P, Busch R, Stilgenbauer S, Bahlo J, Schweighofer CD et al. Bendamustine combined with rituximab in patients with relapsed and/or refractory chronic lymphocytic leukemia: a multicenter phase II trial of the German Chronic Lymphocytic Leukemia Study Group. J Clin Oncol 2011; 29: 3559–3566.

    Article  CAS  PubMed  Google Scholar 

  6. Badoux XC, Keating MJ, Wang X, O’Brien SM, Ferrajoli A, Faderl S et al. Fludarabine, cyclophosphamide, and rituximab chemoimmunotherapy is highly effective treatment for relapsed patients with CLL. Blood 2011; 117: 3016–3024.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Dreger P, Stilgenbauer S, Benner A, Ritgen M, Krober A, Kneba M et al. The prognostic impact of autologous stem cell transplantation in patients with chronic lymphocytic leukemia: a risk-matched analysis based on the VH gene mutational status. Blood 2004; 103: 2850–2858.

    Article  CAS  PubMed  Google Scholar 

  8. Gribben JG, Zahrieh D, Stephans K, Bartlett-Pandite L, Alyea EP, Fisher DC et al. Autologous and allogeneic stem cell transplantations for poor-risk chronic lymphocytic leukemia. Blood 2005; 106: 4389–4396.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Pavletic ZS, Bierman PJ, Vose JM, Bishop MR, Wu CD, Pierson JL et al. High incidence of relapse after autologous stem-cell transplantation for B-cell chronic lymphocytic leukemia or small lymphocytic lymphoma. Ann Oncol 1998; 9: 1023–1026.

    Article  CAS  PubMed  Google Scholar 

  10. Michallet M, Dreger P, Sutton L, Brand R, Richards S, van Os M et al. Autologous hematopoietic stem cell transplantation in chronic lymphocytic leukemia: results of European intergroup randomized trial comparing autografting versus observation. Blood 2011; 117: 1516–1521.

    Article  CAS  PubMed  Google Scholar 

  11. Sutton L, Chevret S, Tournilhac O, Divine M, Leblond V, Corront B et al. Autologous stem cell transplantation as a first-line treatment strategy for chronic lymphocytic leukemia: a multicenter, randomized, controlled trial from the SFGM-TC and GFLLC. Blood 2011; 117: 6109–6119.

    Article  CAS  PubMed  Google Scholar 

  12. Hallek M, Fischer K, Fingerle-Rowson G, Fink AM, Busch R, Mayer J et al. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet 2010; 376: 1164–1174.

    Article  CAS  PubMed  Google Scholar 

  13. Tam CS, O’Brien S, Wierda W, Kantarjian H, Wen S, Do KA et al. Long-term results of the fludarabine, cyclophosphamide, and rituximab regimen as initial therapy of chronic lymphocytic leukemia. Blood 2008; 112: 975–980.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Michallet M, Corront B, Hollard D, Gratwohl A, Milpied N, Dauriac C et al. Allogeneic bone marrow transplantation in chronic lymphocytic leukemia: 17 cases. Report from the EBMTG. Bone Marrow Transplant 1991; 7: 275–279.

    CAS  PubMed  Google Scholar 

  15. Khouri IF, Keating MJ, Vriesendorp HM, Reading CL, Przepiorka D, Huh YO et al. Autologous and allogeneic bone marrow transplantation for chronic lymphocytic leukemia: preliminary results. Clin Oncol 1994; 12: 748–758.

    Article  CAS  Google Scholar 

  16. Rabinowe SN, Soiffer RJ, Gribben JG, Daley H, Freedman AS, Daley J et al. Autologous and allogeneic bone marrow transplantation for poor prognosis patients with B-cell chronic lymphocytic leukemia. Blood 1993; 82: 1366–1376.

    CAS  PubMed  Google Scholar 

  17. Dreger P, Montserrat E . Autologous and allogeneic stem cell transplantation for chronic lymphocytic leukemia. Leukemia 2002; 16: 985–992.

    Article  CAS  PubMed  Google Scholar 

  18. Michallet M, Archimbaud E, Bandini G, Rowlings PA, Deeg HJ, Gahrton G et al. HLA-identical sibling bone marrow transplantation in younger patients with chronic lymphocytic leukemia. European Group for Blood and Marrow Transplantation and the International Bone Marrow Transplant Registry. Ann Intern Med 1996; 124: 311–315.

    Article  CAS  PubMed  Google Scholar 

  19. Moreno C, Villamor N, Colomer D, Esteve J, Martino R, Nomdedeu J et al. Allogeneic stem-cell transplantation may overcome the adverse prognosis of unmutated VH gene in patients with chronic lymphocytic leukemia. J Clin Oncol 2005; 23: 3433–3438.

    Article  PubMed  Google Scholar 

  20. Pavletic ZS, Arrowsmith ER, Bierman PJ, Goodman SA, Vose JM, Tarantolo SR et al. Outcome of allogeneic stem cell transplantation for B cell chronic lymphocytic leukemia. Bone Marrow Transplant 2000; 25: 717–722.

    Article  CAS  PubMed  Google Scholar 

  21. Toze CL, Galal A, Barnett MJ, Shepherd JD, Conneally EA, Hogge DE et al. Myeloablative allografting for chronic lymphocytic leukemia: evidence for a potent graft-versus-leukemia effect associated with graft-versus-host disease. Bone Marrow Transplant 2005; 36: 825–830.

    Article  CAS  PubMed  Google Scholar 

  22. Caballero D, Garcia-Marco JA, Martino R, Mateos V, Ribera JM, Sarra J et al. Allogeneic transplant with reduced intensity conditioning regimens may overcome the poor prognosis of B-cell chronic lymphocytic leukemia with unmutated immunoglobulin variable heavy-chain gene and chromosomal abnormalities (11q− and 17p−). Clin Cancer Res 2005; 11: 7757–7763.

    Article  CAS  PubMed  Google Scholar 

  23. Delgado J, Thomson K, Russell N, Ewing J, Stewart W, Cook G et al. Results of alemtuzumab-based reduced-intensity allogeneic transplantation for chronic lymphocytic leukemia: a British Society of Blood and Marrow Transplantation Study. Blood 2006; 107: 1724–1730.

    Article  CAS  PubMed  Google Scholar 

  24. Schetelig J, van Biezen A, Brand R, Caballero D, Martino R, Itala M et al. Allogeneic hematopoietic stem-cell transplantation for chronic lymphocytic leukemia with 17p deletion: a retrospective European Group for Blood and Marrow Transplantation analysis. J Clin Oncol 2008; 26: 5094–5100.

    Article  PubMed  Google Scholar 

  25. Sorror ML, Storer BE, Sandmaier BM, Maris M, Shizuru J, Maziarz R et al. Five-year follow-up of patients with advanced chronic lymphocytic leukemia treated with allogeneic hematopoietic cell transplantation after nonmyeloablative conditioning. J Clin Oncol 2008; 26: 4912–4920.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Dreger P, Dohner H, Ritgen M, Bottcher S, Busch R, Dietrich S et al. Allogeneic stem cell transplantation provides durable disease control in poor-risk chronic lymphocytic leukemia: long-term clinical and MRD results of the German CLL Study Group CLL3X trial. Blood 2010; 116: 2438–2447.

    Article  CAS  PubMed  Google Scholar 

  27. Khouri IF, Bassett R, Poindexter N, O’Brien S, Bueso-Ramos CE, Hsu Y et al. Nonmyeloablative allogeneic stem cell transplantation in relapsed/refractory chronic lymphocytic leukemia: long-term follow-up, prognostic factors, and effect of human leukocyte histocompatibility antigen subtype on outcome. Cancer 2011; 117: 4679–4688.

    Article  PubMed  Google Scholar 

  28. Brown JR, Kim HT, Li S, Stephans K, Fisher DC, Cutler C et al. Predictors of improved progression-free survival after nonmyeloablative allogeneic stem cell transplantation for advanced chronic lymphocytic leukemia. Biol Blood Marrow Transplant 2006; 12: 1056–1064.

    Article  PubMed  Google Scholar 

  29. Dreger P, Brand R, Milligan D, Corradini P, Finke J, Lambertenghi Deliliers G et al. Reduced-intensity conditioning lowers treatment-related mortality of allogeneic stem cell transplantation for chronic lymphocytic leukemia: a population-matched analysis. Leukemia 2005; 19: 1029–1033.

    Article  CAS  PubMed  Google Scholar 

  30. Sorror ML, Maris MB, Storb R, Baron F, Sandmaier BM, Maloney DG et al. Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk assessment before allogeneic HCT. Blood 2005; 106: 2912–2919.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Arora M, Nagaraj S, Witte J, DeFor TE, MacMillan M, Burns LJ et al. New classification of chronic GVHD: added clarity from the consensus diagnoses. Bone Marrow Transplant 2009; 43: 149–153.

    Article  CAS  PubMed  Google Scholar 

  32. Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J et al. 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant 1995; 15: 825–828.

    CAS  PubMed  Google Scholar 

  33. Dohner H, Stilgenbauer S, Benner A, Leupolt E, Krober A, Bullinger L et al. Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med 2000; 343: 1910–1916.

    Article  CAS  PubMed  Google Scholar 

  34. Cheson BD, Bennett JM, Grever M, Kay N, Keating MJ, O’Brien S et al. National Cancer Institute-sponsored Working Group guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis and treatment. Blood 1996; 87: 4990–4997.

    CAS  PubMed  Google Scholar 

  35. Jaglowski SM, Heerema NA, Elder P, Byrd JC, Devine S, Andritsos LA . Increasing genetic complexity predicts for inferior outcomes following reduced-intensity conditioning allogeneic transplant for chronic lymphocytic leukemia. Blood 2011; 118: 3090a.

    Google Scholar 

  36. Delgado J, Pillai S, Phillips N, Brunet S, Pratt G, Briones J et al. Does reduced-intensity allogeneic transplantation confer a survival advantage to patients with poor prognosis chronic lymphocytic leukaemia? A case–control retrospective analysis. Ann Oncol 2009; 20: 2007–2012.

    Article  CAS  PubMed  Google Scholar 

  37. Peres E, Braun T, Krijanovski O, Khaled Y, Levine JE, Yanik G et al. Reduced intensity versus full myeloablative stem cell transplant for advanced CLL. Bone Marrow Transplant 2009; 44: 579–583.

    Article  CAS  PubMed  Google Scholar 

  38. Armand P, Gannamaneni S, Kim HT, Cutler CS, Ho VT, Koreth J et al. Improved survival in lymphoma patients receiving sirolimus for graft-versus-host disease prophylaxis after allogeneic hematopoietic stem-cell transplantation with reduced-intensity conditioning. J Clin Oncol 2008; 26: 5767–5774.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We are indebted to the nurses, medical oncology fellows, house staff and social workers of the Dana-Farber Cancer Institute and Brigham and Women’s Hospital for their excellent care of these patients. We thank the staff of the Connell-O’Reilly Cell Manipulation Laboratory and the Blood Component Laboratory of the Dana-Farber Cancer Institute for processing stem cells for these patients, and the data management staff for their tireless work in maintaining the DFCI BMT clinical data repository, without which this project would not be possible. This work was supported by NIH Grants K23 CA115682-01 to JRB, PO1 HL070149, PO1 CA81538 to JGG, A129530 to RJS, P01 CA142106 to JHA, and by the Jock and Bunny Adams Research and Education Endowment and the Ted and Eileen Pasquarello Research Fund. JRB is a Scholar of the American Society of Hematology as well as a Scholar in Clinical Research of the Leukemia and Lymphoma Society.

Author contributions

JRB, HTK, JHA and EPA designed the research. JRB, HTK, PA, CC, DCF, VH, JK, JR, CW, JHA, RJS, JGG and EPA performed the research. PA, CC, DCF, VH, JK, JR, JHA, RJS, JGG and EPA enrolled patients. JRB and HTK analyzed the data. JRB and HTK wrote the paper with input from PA, JHA, RJS, JGG and EPA.

Author information

Author notes

  1. J R Brown and H T Kim: These authors contributed equally to this work.Presented in part at the Annual Meeting of ASH, December 2008.

Authors and Affiliations

  1. Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

    J R Brown, P Armand, C Cutler, D C Fisher, V Ho, J Koreth, J Ritz, C Wu, J H Antin, R J Soiffer, J G Gribben & E P Alyea

  2. Department of Medicine, Brigham and Women’s Hospital, Boston, MA, USA

    J R Brown, P Armand, C Cutler, D C Fisher, V Ho, J Koreth, J Ritz, C Wu, J H Antin, R J Soiffer, J G Gribben & E P Alyea

  3. Department of Medicine, Harvard Medical School, Boston, MA, USA

    J R Brown, P Armand, C Cutler, D C Fisher, V Ho, J Koreth, J Ritz, C Wu, J H Antin, R J Soiffer, J G Gribben & E P Alyea

  4. Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, USA

    H T Kim

Authors
  1. J R Brown
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. H T Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. P Armand
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. C Cutler
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. D C Fisher
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. V Ho
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. J Koreth
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. J Ritz
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. C Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. J H Antin
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. R J Soiffer
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. J G Gribben
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. E P Alyea
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J R Brown.

Ethics declarations

Competing interests

JR Brown has served as a consultant for Pharmacyclics and for Calistoga Pharmaceuticals.

Additional information

Supplementary Information accompanies the paper on the Leukemia website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Brown, J., Kim, H., Armand, P. et al. Long-term follow-up of reduced-intensity allogeneic stem cell transplantation for chronic lymphocytic leukemia: prognostic model to predict outcome. Leukemia 27, 362–369 (2013). https://doi.org/10.1038/leu.2012.228

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2012.228

Keywords

This article is cited by

Search

Advanced search

Quick links