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:

Conditioning Regimens

Comparing efficacy of reduced-toxicity allogeneic hematopoietic cell transplantation with conventional chemo-(immuno) therapy in patients with relapsed or refractory CLL: a Markov decision analysis

Bone Marrow Transplantation volume 47, pages 1164–1170 (2012)Cite this article

Subjects

Abstract

Despite therapeutic advances, relapsed/refractory CLL, particularly after fludarabine-based regimens, remains a major challenge for which optimal therapy is undefined. No randomized comparative data exist to suggest the superiority of reduced-toxicity allogeneic hematopoietic cell transplantation (RT-allo-HCT) over conventional chemo-(immuno) therapy (CCIT). By using estimates from a systematic review and by meta-analysis of available published evidence, we constructed a Markov decision model to examine these competing modalities. Cohort analysis demonstrated superior outcome for RT-allo-HCT, with a 10-month overall life expectancy (and 6-month quality-adjusted life expectancy (QALE)) advantage over CCIT. Although the model was sensitive to changes in base-case assumptions and transition probabilities, RT-allo-HCT provided superior overall life expectancy through a range of values supported by the meta-analysis. QALE was superior for RT-allo-HCT compared with CCIT. This conclusion was sensitive to change in the anticipated state utility associated with the post-allogeneic HCT state; however, RT-allo-HCT remained the optimal strategy for values supported by existing literature. This analysis provides a quantitative comparison of outcomes between RT-allo-HCT and CCIT for relapsed/refractory CLL in the absence of randomized comparative trials. Confirmation of these findings requires a prospective randomized trial, which compares the most effective RT-allo-HCT and CCIT regimens for relapsed/refractory CLL.

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
Figure 5

Similar content being viewed by others

References

  1. Jemal A, Siegel R, Xu J, Ward E . Cancer statistics. 2010 CA Cancer J Clin 60: 277–300.

    Article  PubMed  Google Scholar 

  2. Gribben JG . Stem cell transplantation in chronic lymphocytic leukemia. Biol Blood Marrow Transplant 2009; 15: 53–58.

    Article  PubMed  Google Scholar 

  3. Kharfan-Dabaja MA, Anasetti C, Santos ES . Hematopoietic cell transplantation for chronic lymphocytic leukemia: an evolving concept. Biol Blood Marrow Transplant 2007; 13: 373–385.

    Article  CAS  PubMed  Google Scholar 

  4. Doney KC, Chauncey T, Appelbaum FR . Allogeneic related donor hematopoietic stem cell transplantation for treatment of chronic lymphocytic leukemia. Bone Marrow Transplant 2002; 29: 817–823.

    Article  CAS  PubMed  Google Scholar 

  5. 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 

  6. 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 

  7. 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 

  8. Kolb HJ, Mittermuller J, Clemm C, Holler E, Ledderose G, Brehm G et al. Donor leukocyte transfusions for treatment of recurrent chronic myelogenous leukemia in marrow transplant patients. Blood 1990; 76: 2462–2465.

    CAS  PubMed  Google Scholar 

  9. Slavin S, Naparstek E, Nagler A, Ackerstein A, Kapelushnik J, Or R . Allogeneic cell therapy for relapsed leukemia after bone marrow transplantation with donor peripheral blood lymphocytes. Exp Hematol 1995; 23: 1553–1562.

    CAS  PubMed  Google Scholar 

  10. Bacigalupo A, Ballen K, Rizzo D, Giralt S, Lazarus H, Ho V et al. Defining the intensity of conditioning regimens: working definitions. Biol Blood Marrow Transplant 2009; 15: 1628–1633.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Weinstein M, Fineberg HV, Elstein AS, Frasier D, Neuhauser D, Neutra RR et al. Clinical Decision Analysis 1980. Philadelphia: PAWB Saunders.

    Google Scholar 

  12. Bosch F, Ferrer A, Lopez-Guillermo A, Giné 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.

    Article  CAS  PubMed  Google Scholar 

  13. Bowen DA, Call TG, Jenkins GD, Zent CS, Schwager SM, Van Dyke DL et al. Methylprednisolone-rituximab is an effective salvage therapy for patients with relapsed chronic lymphocytic leukemia including those with unfavorable cytogenetic features. Leuk Lymphoma 2007; 48: 2412–2417.

    Article  CAS  PubMed  Google Scholar 

  14. Byrd JC, Kipps TJ, Flinn IW, Castro J, Lin TS, Wierda W et al. Phase 1/2 study of lumiliximab combined with fludarabine, cyclophosphamide, and rituximab in patients with relapsed or refractory chronic lymphocytic leukemia. Blood 2010; 115: 489–495.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Castro JE, James DF, Sandoval-Sus JD, Jain S, Bole J, Rassenti L et al. Rituximab in combination with high-dose methylprednisolone for the treatment of chronic lymphocytic leukemia. Leukemia 2009; 23: 1779–1789.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Coiffier B, Lepretre S, Pedersen LM, Gadeberg O, Fredriksen H, van Oers MH et al. Safety and efficacy of ofatumumab, a fully human monoclonal anti-CD20 antibody, in patients with relapsed or refractory B-cell chronic lymphocytic leukemia: a phase 1–2 study. Blood 2008; 111: 1094–1100.

    Article  CAS  PubMed  Google Scholar 

  17. Cortelezzi A, Pasquini MC, Gardellini A, Gianelli U, Bossi A, Reda G et al. Low-dose subcutaneous alemtuzumab in refractory chronic lymphocytic leukaemia (CLL): results of a prospective, single-arm multicentre study. Leukemia 2009; 23: 2027–2033.

    Article  CAS  PubMed  Google Scholar 

  18. 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 

  19. Elter T, Borchmann P, Schulz H, Reiser M, Trelle S, Schnell R et al. Fludarabine in combination with alemtuzumab is effective and feasible in patients with relapsed or refractory B-cell chronic lymphocytic leukemia: results of a phase II trial. J Clin Oncol 2005; 23: 7024–7031.

    Article  CAS  PubMed  Google Scholar 

  20. Ferrajoli A, O'Brien SM, Cortes JE, Giles FJ, Thomas DA, Faderl S et al. Phase II study of alemtuzumab in chronic lymphoproliferative disorders. Cancer 2003; 98: 773–778.

    Article  CAS  PubMed  Google Scholar 

  21. Fiegl M, Falkner A, Hopfinger G, Brugger S, Zabernigg A, Bauer F et al. Routine clinical use of alemtuzumab in patients with heavily pretreated B-cell chronic lymphocytic leukemia: a nation-wide retrospective study in Austria. Cancer 2006; 107: 2408–2416.

    Article  CAS  PubMed  Google Scholar 

  22. Forconi F, Fabbri A, Lenoci M, Sozzi E, Gozzetti A, Tassi M et al. Low-dose oral fludarabine plus cyclophosphamide in elderly patients with untreated and relapsed or refractory chronic lymphocytic leukaemia. Hematol Oncol 2008; 26: 247–251.

    Article  CAS  PubMed  Google Scholar 

  23. Johnson SA, Catovsky D, Child JA, Newland AC, Milligan DW, Janmohamed R . Phase I/II evaluation of pentostatin (2'-deoxycoformycin) in a five day schedule for the treatment of relapsed/refractory B-cell chronic lymphocytic leukaemia. Invest New Drugs 1998; 16: 155–160.

    Article  CAS  PubMed  Google Scholar 

  24. Karlsson C, Lundin J, Kimby E, Kennedy B, Moreton P, Hillmen P et al. Phase II study of subcutaneous alemtuzumab without dose escalation in patients with advanced-stage, relapsed chronic lymphocytic leukaemia. Br J Haematol 2009; 144: 78–85.

    Article  CAS  PubMed  Google Scholar 

  25. Kath R, Blumenstengel K, Fricke HJ, Hoffken K . Bendamustine monotherapy in advanced and refractory chronic lymphocytic leukemia. J Cancer Res Clin Oncol 2001; 127: 48–54.

    Article  CAS  PubMed  Google Scholar 

  26. 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 

  27. Lamanna N, Kalaycio M, Maslak P, Jurcic JG, Heaney M, Brentjens R et al. Pentostatin, cyclophosphamide, and rituximab is an active, well-tolerated regimen for patients with previously treated chronic lymphocytic leukemia. J Clin Oncol 2006; 24: 1575–1581.

    Article  CAS  PubMed  Google Scholar 

  28. Lin TS, Flinn IW, Lucas MS, Porcu P, Sickler J, Moran ME et al. Filgrastim and alemtuzumab (Campath-1H) for refractory chronic lymphocytic leukemia. Leukemia 2005; 19: 1207–1210.

    Article  CAS  PubMed  Google Scholar 

  29. Lin TS, Ruppert AS, Johnson AJ, Fischer B, Heerema NA, Andritsos LA et al. Phase II study of flavopiridol in relapsed chronic lymphocytic leukemia demonstrating high response rates in genetically high-risk disease. J Clin Oncol 2009; 27: 6012–6018.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Mauro FR, Foa R, Meloni G, Gentile M, Giammartini E, Giannarelli D et al. Fludarabine, ara-C, novantrone and dexamethasone (FAND) in previously treated chronic lymphocytic leukemia patients. Haematologica 2002; 87: 926–933.

    CAS  PubMed  Google Scholar 

  31. O'Brien S, Moore JO, Boyd TE, Larratt LM, Skotnicki A, Koziner B et al. Randomized phase III trial of fludarabine plus cyclophosphamide with or without oblimersen sodium (Bcl-2 antisense) in patients with relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol 2007; 25: 1114–1120.

    Article  CAS  PubMed  Google Scholar 

  32. O'Brien S, Moore JO, Boyd TE, Larratt LM, Skotnicki AB, Koziner B et al. 5-year survival in patients with relapsed or refractory chronic lymphocytic leukemia in a randomized, phase III trial of fludarabine plus cyclophosphamide with or without oblimersen. J Clin Oncol 2009; 27: 5208–5212.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Osterborg A, Dyer MJ, Bunjes D, Pangalis GA, Bastion Y, Catovsky D et al. Phase II multicenter study of human CD52 antibody in previously treated chronic lymphocytic leukemia. European Study Group of CAMPATH-1H treatment in chronic lymphocytic leukemia. J Clin Oncol 1997; 15: 1567–1574.

    Article  CAS  PubMed  Google Scholar 

  34. Rai KR, Freter CE, Mercier RJ, Cooper MR, Mitchell BS, Stadtmauer EA et al. Alemtuzumab in previously treated chronic lymphocytic leukemia patients who also had received fludarabine. J Clin Oncol 2002; 20: 3891–3897.

    Article  CAS  PubMed  Google Scholar 

  35. Rao R, Shammo JM, Enschede SH, Porter C, Adler SS, Venugopal P et al. The combination of fludarabine, cyclophosphamide, and granulocyte-macrophage colony-stimulating factor in the treatment of patients with relapsed chronic lymphocytic leukemia and low-grade Non-Hodgkin's lymphoma. Clin Lymphoma 2005; 6: 26–30.

    Article  CAS  PubMed  Google Scholar 

  36. Robak T, Blasinka-Morawiec M, Krykowski E, Kasznicki M, Pluzanska A, Potemski P et al. Intermittent 2-hour intravenous infusions of 2-chlorodeoxyadenosine in the treatment of 110 patients with refractory or previously untreated B-cell chronic lymphocytic leukemia. Leuk Lymphoma 1996; 22: 509–514.

    Article  CAS  PubMed  Google Scholar 

  37. Robak T, Bonski JZ, Kasznicki M, Gora-Tybor J, Hellmann A, Konopka L et al. Re-treatment with cladribine-based regimens in relapsed patients with B-cell chronic lymphocytic leukemia. Efficacy and toxicity in comparison with previous treatment. Eur J Haematol 2002; 69: 27–36.

    Article  CAS  PubMed  Google Scholar 

  38. Robak T, Smolewski P, Cebula B, Grzybowska-Izydorczyk O, Blonski JZ . Rituximab plus cladribine with or without cyclophosphamide in patients with relapsed or refractory chronic lymphocytic leukemia. Eur J Haematol 2007; 79: 107–113.

    Article  CAS  PubMed  Google Scholar 

  39. Tallman MS, Hakimian D, Zanzig C, Hogan DK, Rademaker A, Rose E et al. Cladribine in the treatment of relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol 1995; 13: 983–988.

    Article  CAS  PubMed  Google Scholar 

  40. 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 

  41. Willis CR, Goodrich A, Park K, Waselenko JK, Lucas M, Reese A et al. A phase I/II study examining pentostatin, chlorambucil, and theophylline in patients with relapsed chronic lymphocytic leukemia and non-Hodgkin's lymphoma. Ann Hematol 2006; 85: 301–307.

    Article  CAS  PubMed  Google Scholar 

  42. Faderl S, Ferrajoli A, Wierda W, O'Brien S, Lerner S, Keating MJ . Alemtuzumab by continuous intravenous infusion followed by subcutaneous injection plus rituximab in the treatment of patients with chronic lymphocytic leukemia recurrence. Cancer 2010; 116: 2360–2365.

    CAS  PubMed  Google Scholar 

  43. Zent CS, LaPlant BR, Johnston PB, Call TG, Habermann TM, Micallef IN et al. The treatment of recurrent/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) with everolimus results in clinical responses and mobilization of CLL cells into the circulation. Cancer 2010; 116: 2201–2207.

    PubMed  Google Scholar 

  44. Chanan-Khan A, Miller KC, Lawrence D, Padmanabhan S, Miller A, Hernandez-Illatazurri F et al. Tumor flare reaction associated with lenalidomide treatment in patients with chronic lymphocytic leukemia predicts clinical response. Cancer 2011; 117: 2127–2135.

    Article  CAS  PubMed  Google Scholar 

  45. Ferrajoli A, Lee BN, Schlette EJ, O’Brien SM, Gao H, Wen S et al. Lenalidomide induces complete and partial remissions in patients with relapsed and refractory chronic lymphocytic leukemia. Blood 2008; 111: 5291–5297.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. 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 

  47. Caballero D, Garcia-Marco JA, Martino R, Mateos V, Ribera JM, Sarrá 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 

  48. Dreger P, Brand R, Hansz J, Milligan D, Corradini P, Finke J et al. Treatment-related mortality and graft-versus-leukemia activity after allogeneic stem cell transplantation for chronic lymphocytic leukemia using intensity-reduced conditioning. Leukemia 2003; 17: 841–848.

    Article  CAS  PubMed  Google Scholar 

  49. 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 

  50. 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.

    Article  CAS  PubMed  Google Scholar 

  51. 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 

  52. 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 

  53. Dreger P, Dohner H, Ritgen M, Böttcher 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 

  54. Khouri IF, Saliba RM, Admirand J, O’Brien S, Lee MS, Korbling M et al. Graft-versus-leukaemia effect after non-myeloablative haematopoietic transplantation can overcome the unfavourable expression of ZAP-70 in refractory chronic lymphocytic leukaemia. Br J Haematol 2007; 137: 355–363.

    Article  CAS  PubMed  Google Scholar 

  55. Lee SJ, Kuntz KM, Horowitz MM, McGlave PB, Goldman JM, Sobocinski KA et al. Unrelated donor bone marrow transplantation for chronic myelogenous leukemia: a decision analysis. Ann Intern Med 1997; 127: 1080–1088.

    Article  CAS  PubMed  Google Scholar 

  56. Cutler CS, Lee SJ, Greenberg P, Deeg JH, Perez WS, Anasetti C et al. A decision analysis of allogeneic bone marrow transplantation for the myelodysplastic syndromes: delayed transplantation for low-risk myelodysplasia is associated with improved outcome. Blood 2004; 104: 579–585.

    Article  CAS  PubMed  Google Scholar 

  57. Sung L, Buckstein R, Doyle JJ, Crump M, Detsky AS . Treatment options for patients with acute myeloid leukemia with a matched sibling donor: a decision analysis. Cancer 2003; 97: 592–600.

    Article  PubMed  Google Scholar 

  58. Dohner 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  CAS  PubMed  Google Scholar 

  59. Kharfan-Dabaja MA, Chavez JC, Khorfan KA, Pinilla-Ibarz J . Clinical and therapeutic implications of the mutational status of IgVH in patients with chronic lymphocytic leukemia. Cancer 2008; 113: 897–906.

    Article  PubMed  Google Scholar 

  60. 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.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Author notes

  1. M A Kharfan-Dabaja and J Pidala: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Internal Medicine, Division of Hematology-Oncology and Bone Marrow Transplantation, American University of Beirut, Beirut, Lebanon

    M A Kharfan-Dabaja

  2. Blood and Marrow Transplantation Department, Moffitt Cancer Center, Tampa, FL, USA

    J Pidala

  3. Oncologic Sciences Department, Moffitt Cancer Center/University of South Florida, Tampa, FL, USA

    J Pidala & B Djulbegovic

  4. Center for Evidence-Based Medicine, University of South Florida, Tampa, FL, USA

    A Kumar & B Djulbegovic

  5. Health Outcomes and Behavior Department, Moffitt Cancer Center, Tampa, FL, USA

    A Kumar & B Djulbegovic

  6. Nanakuri Sanatorium, Fujita Health University School of Medicine, Tsu, Japan

    T Terasawa

  7. Center for Clinical Evidence Synthesis, Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, Boston, MA, USA

    T Terasawa

  8. Clinical Research Center for Blood Diseases, National Hospital Organization Nagoya Medical Center, Nagoya, Japan

    T Terasawa

Authors
  1. M A Kharfan-Dabaja
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J Pidala
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A Kumar
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. T Terasawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. B Djulbegovic
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M A Kharfan-Dabaja.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on Bone Marrow Transplantation website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kharfan-Dabaja, M., Pidala, J., Kumar, A. et al. Comparing efficacy of reduced-toxicity allogeneic hematopoietic cell transplantation with conventional chemo-(immuno) therapy in patients with relapsed or refractory CLL: a Markov decision analysis. Bone Marrow Transplant 47, 1164–1170 (2012). https://doi.org/10.1038/bmt.2012.71

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/bmt.2012.71

Keywords

This article is cited by

Search

Advanced search

Quick links