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.

Indications for allogeneic stem cell transplantation in chronic lymphocytic leukemia: the EBMT transplant consensus

Abstract

The aim of this project was to identify situations where allogeneic stem cell transplantation (allo-SCT) might be considered as a preferred treatment option for patients with B-cell chronic lymphocytic leukemia (CLL). Based on a MEDLINE search and additional sources, a consented proposal was drafted, refined and approved upon final discussion by an international expert panel. Key elements of the consensus are (1) allo-SCT is a procedure with evidence-based efficacy in poor-risk CLL; (2) although definition of ‘poor-risk CLL’ requires further investigation, allo-SCT is a reasonable treatment option for younger patients with (i) non-response or early relapse (within 12 months) after purine analogues, (ii) relapse within 24 months after having achieved a response with purine-analogue-based combination therapy or autologous transplantation, and (iii) patients with p53 abnormalities requiring treatment; and (3) optimum transplant strategies may vary according to distinct clinical situations and should be defined in prospective trials. This is the first attempt to define standard indications for allo-SCT in CLL. Nevertheless, whenever possible, allo-SCT should be performed within disease-specific prospective clinical protocols in order to continuously refine transplant indications according to new developments in risk assessment and treatment of CLL.

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

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

References

  1. 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.

    CAS  Article  PubMed  Google Scholar 

  2. Khouri IF, Keating MJ, Saliba RM, Champlin RE . Long-term follow-up of patients with CLL treated with allogeneic hematopoietic transplantation. Cytotherapy 2002; 4: 217–221.

    CAS  Article  PubMed  Google Scholar 

  3. Michallet M, Archimbaud E, Rowlings PA, Bandini G, Horowitz MM, Bortin MM et al. HLA-identical sibling bone marrow transplants for chronic lymphocytic leukemia. Ann Intern Med 1996; 124: 311–315.

    CAS  Article  PubMed  Google Scholar 

  4. Schetelig J, Thiede C, Bornhauser M, Schwerdtfeger R, Kiehl M, Beyer J et al. Evidence of a graft-versus-leukemia effect in chronic lymphocytic leukemia after reduced-intensity conditioning and allogeneic stem-cell transplantation: the Cooperative German Transplant Study Group. J Clin Oncol 2003; 21: 2747–2753.

    CAS  Article  PubMed  Google Scholar 

  5. Sorror ML, Maris MB, Sandmaier BM, Storer B, Jain-Stuart M, Al-Ali H et al. Hematopoietic cell transplantation after nonmyeloablative conditioning for advanced chronic lymphocytic leukemia. J Clin Oncol 2005; 23: 3819–3829.

    Article  PubMed  Google Scholar 

  6. 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. Clin Cancer Res 2005; 11: 7757–7763.

    CAS  Article  PubMed  Google Scholar 

  7. Mattsson J, Uzunel M, Remberger M, Ljungman P, Kimby E, Ringden O et al. Minimal residual disease is common after allogeneic stem cell transplantation in patients with B cell chronic lymphocytic leukemia and may be controlled by graft-versus-host disease. Leukemia 2000; 14: 247–254.

    CAS  Article  PubMed  Google Scholar 

  8. Esteve J, Villamor N, Colomer D, Montserrat E . Different clinical value of minimal residual disease after autologous and allogeneic stem cell transplantation for chronic lymphocytic leukemia. Blood 2002; 99: 1873–1874.

    Article  PubMed  Google Scholar 

  9. 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.

    CAS  Article  PubMed  Google Scholar 

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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  11. Rondon G, Giralt S, Huh Y, Khouri I, Andersson B, Andreeff M et al. Graft-versus-leukemia effect after allogeneic bone marrow transplantation for chronic lymphocytic leukemia. Bone Marrow Transplant 1996; 18: 669–672.

    CAS  PubMed  Google Scholar 

  12. Dreger P, Ritgen M, Böttcher S, Schmitz N, Kneba M . The prognostic impact of minimal residual disease assessment after stem cell transplantation for chronic lymphocytic leukemia: is achievement of molecular remission worthwile? Leukemia 2005; 19: 1135–1138.

    CAS  Article  PubMed  Google Scholar 

  13. Moreno C, Villamor N, Esteve J, Colomer D, Bosch F, Campo E et al. Clinical significance of minimal residual disease, as assessed by different techniques, after stem cell transplantation for chronic lymphocytic leukemia. Blood 2006; 107: 4563–4569.

    CAS  Article  PubMed  Google Scholar 

  14. Byrd JC, Stilgenbauer S, Flinn IW . Chronic lymphocytic leukemia. Hematology (Am Soc Hematol Educ Program) 2004, 163–183.

  15. Gribben JG . Salvage therapy for CLL and the role of stem cell transplantation. Hematology (Am Soc Hematol Educ Program) 2005, 292–298.

  16. Montserrat E, Moreno C, Esteve J, Urbano-Ispizua A, Gine E, Bosch F . How I treat refractory CLL. Blood 2006; 107: 1276–1283.

    CAS  Article  PubMed  Google Scholar 

  17. Ritgen M, Stilgenbauer S, von Neuhoff N, Humpe A, Brüggemann M, Pott C et al. Graft-versus-leukemia activity may overcome therapeutic resistance of chronic lymphocytic leukemia with unmutated immunoglobulin variable heavy chain gene status: implications of minimal residual disease measurement with quantitative PCR. Blood 2004; 104: 2600–2602.

    CAS  Article  PubMed  Google Scholar 

  18. Keating MJ, O'Brien S, Kontoyiannis D, Plunkett W, Koller C, Beran M et al. Results of first salvage therapy for patients refractory to a fludarabine regimen in chronic lymphocytic leukemia. Leuk Lymphoma 2002; 43: 1755–1762.

    CAS  Article  PubMed  Google Scholar 

  19. Perkins JG, Flynn JM, Howard RS, Byrd JC . Frequency and type of serious infections in fludarabine-refractory B-cell chronic lymphocytic leukemia and small lymphocytic lymphoma: implications for clinical trials in this patient population. Cancer 2002; 94: 2033–2039.

    Article  PubMed  Google Scholar 

  20. 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.

    CAS  Article  PubMed  Google Scholar 

  21. O'Brien SM, Kantarjian HM, Cortes J, Beran M, Koller CA, Giles FJ et al. Results of the fludarabine and cyclophosphamide combination regimen in chronic lymphocytic leukemia. J Clin Oncol 2001; 19: 1414–1420.

    CAS  Article  PubMed  Google Scholar 

  22. 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.

    CAS  Article  PubMed  Google Scholar 

  23. Lozanski G, Heerema NA, Flinn IW, Smith L, Harbison J, Webb J et al. Alemtuzumab is an effective therapy for chronic lymphocytic leukemia with p53 mutations and deletions. Blood 2004; 103: 3278–3281.

    CAS  Article  PubMed  Google Scholar 

  24. Mauro FR, Foa R, Giannarelli D, Cordone I, Crescenzi S, Pescarmona E et al. Clinical characteristics and outcome of young chronic lymphocytic leukemia patients: a single institution study of 204 cases. Blood 1999; 94: 448–454.

    CAS  PubMed  Google Scholar 

  25. Keating MJ, O'Brien S, Lerner S, Koller C, Beran M, Robertson LE et al. Long-term follow-up of patients with chronic lymphocytic leukemia (CLL) receiving fludarabine regimens as initial therapy. Blood 1998; 92: 1165–1171.

    CAS  PubMed  Google Scholar 

  26. Bosch F, Ferrer A, Lopez-Guillermo A, Gine E, Bellosillo B, Villamor N et al. Fludarabine, cyclophosphamide and mitoxantrone in the treatment of resistant or relapsed chronic lymphocytic leukaemia. Br J Haematol 2002; 119: 976–984.

    CAS  Article  PubMed  Google Scholar 

  27. 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.

    CAS  Article  PubMed  Google Scholar 

  28. Döhner H, Fischer K, Bentz M, Hansen K, Benner A, Cabot G et al. p53 gene deletion predicts for poor survival and non-response to therapy with purine analogs in chronic B-cell leukemias. Blood 1995; 85: 1580–1587.

    PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  30. Byrd JC, Gribben JG, Peterson BL, Grever MR, Lozanski G, Lucas DM et al. Select high-risk genetic features predict earlier progression following chemoimmunotherapy with fludarabine and rituximab in chronic lymphocytic leukemia: justification for risk-adapted therapy. J Clin Oncol 2006; 24: 437–443.

    CAS  Article  PubMed  Google Scholar 

  31. Kröber A, Bloehdorn J, Hafner S, Buhler A, Seiler T, Kienle D et al. Additional genetic high-risk features such as 11q deletion, 17p deletion, and V3-21 usage characterize discordance of ZAP-70 and. J Clin Oncol 2006; 24: 969–975.

    Article  PubMed  Google Scholar 

  32. Damle RN, Wasil T, Fais F, Ghiotto F, Valetto A, Allen SL et al. Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia. Blood 1999; 94: 1840–1847.

    CAS  PubMed  Google Scholar 

  33. Hamblin TJ, Davis Z, Gardiner A, Oscier DG, Stevenson FK . Unmutated Ig VH genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood 1999; 94: 1848–1854.

    CAS  PubMed  Google Scholar 

  34. Crespo M, Bosch F, Villamor N, Bellosillo B, Colomer D, Rozman M et al. ZAP-70 expression as a surrogate for immunoglobulin-variable-region mutations in chronic lymphocytic leukemia. N Engl J Med 2003; 348: 1764–1775.

    CAS  Article  PubMed  Google Scholar 

  35. Wiestner A, Rosenwald A, Barry TS, Wright G, Davis RE, Henrickson SE et al. ZAP-70 expression identifies a chronic lymphocytic leukemia subtype with unmutated immunoglobulin genes, inferior clinical outcome, and distinct gene expression profile. Blood 2003; 101: 4944–4951.

    CAS  Article  PubMed  Google Scholar 

  36. Hamblin M, Orchard JA, Gardiner A, Oscier DG, Davis Z, Stevenson FK . Immunoglobulin V genes and CD38 expression in CLL. Blood 2000; 95: 2455–2457.

    CAS  PubMed  Google Scholar 

  37. Durig J, Nuckel H, Huttmann A, Kruse E, Holter T, Halfmeyer K et al. Expression of ribosomal and translation-associated genes is correlated with a favorable clinical course in chronic lymphocytic leukemia. Blood 2003; 101: 2748–2755.

    CAS  Article  PubMed  Google Scholar 

  38. Deaglio S, Vaisitti T, Aydin S, Ferrero E, Malavasi F . In-tandem insight from basic science combined with clinical research: CD38 as both marker and key component of the pathogenetic network underlying chronic lymphocytic leukemia. Blood 2006; 108: 1135–1144.

    CAS  Article  PubMed  Google Scholar 

  39. Binet JL, Caligaris-Cappio F, Catovsky D, Cheson B, Davis T, Dighiero G et al. Perspectives on the use of new diagnostic tools in the treatment of chronic lymphocytic leukemia. Blood 2006; 107: 1276–1283.

    Article  Google Scholar 

  40. Pavletic SZ, Khouri IF, Haagenson M, King RJ, Bierman PJ, Bishop MR et al. Unrelated donor marrow transplantation for B-cell chronic lymphocytic leukemia after using myeloablative conditioning: results from the center for international blood and marrow transplant research. J Clin Oncol 2005; 23: 5788–5794.

    Article  PubMed  Google Scholar 

  41. Tsimberidou AM, O'Brien S, Khouri I, Giles FJ, Kantarjian HM, Champlin R et al. Clinical outcomes and prognostic factors in patients with Richter's syndrome treated with chemotherapy or chemoimmunotherapy with or without stem-cell transplantation. J Clin Oncol 2006; 24: 2343–2351.

    CAS  Article  PubMed  Google Scholar 

  42. Dearden CE, Matutes E, Cazin B, Tjonnfjord GE, Parreira A, Nomdedeu B et al. High remission rate in T-cell prolymphocytic leukemia with CAMPATH-1H. Blood 2001; 98: 1721–1726.

    CAS  Article  PubMed  Google Scholar 

  43. 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 

Download references

Acknowledgements

This proposal has been adopted for the German CLL Study Group (GCLLSG; Chairman: Professor Dr M Hallek, Cologne) by the GCLLSG general assembly on November 4, 2005. PD, PC, EK, MM, DM, JS, WW, DN and EM participated in designing the project; all authors reviewed and interpreted available data; PD and EM wrote the paper; and all authors checked the final version of the manuscript. This work was presented in preliminary version in abstract form at the XI International Workshop on CLL, New York, September 2005.

Author information

Authors and Affiliations

Authors

Consortia

Corresponding author

Correspondence to P Dreger.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Dreger, P., Corradini, P., Kimby, E. et al. Indications for allogeneic stem cell transplantation in chronic lymphocytic leukemia: the EBMT transplant consensus. Leukemia 21, 12–17 (2007). https://doi.org/10.1038/sj.leu.2404441

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.leu.2404441

Keywords

  • CLL
  • salvage treatment
  • allogeneic stem cell transplantation
  • practice guidelines

This article is cited by

Search

Quick links