Best Practice & Research Clinical Haematology
Volume 23, Issue 1 , Pages 109-119 , March 2010

Stem cell transplantation in chronic lymphocytic leukaemia – steering a safe course over shifting sands

  • Simon Hallam, MB BChir MA MRCP
  • ,
  • John G. Gribben, MD DSc FRCP FRCPath FMed Sci (Professor)

      Affiliations

    • Corresponding Author InformationCorresponding author. Tel./Fax: +44 0 20 7882 6126.

References 

  1. Johnson S, Smith AG, Loffler H, et al. Multicentre prospective randomised trial of fludarabine versus cyclophosphamide, doxorubicin, and prednisone (CAP) for treatment of advanced-stage chronic lymphocytic leukaemia. The French Cooperative Group on CLL. Lancet. 1996 May 25;1432–14383479013
  2. Rai KR, Peterson BL, Appelbaum FR, et al. Fludarabine compared with chlorambucil as primary therapy for chronic lymphocytic leukemia. N Engl J Med. 2000 Dec 14;343(24):1750–1757
  3. Leporrier M, Chevret S, Cazin B, et al. Randomized comparison of fludarabine, CAP, and ChOP in 938 previously untreated stage B and C chronic lymphocytic leukemia patients. Blood. 2001 Oct 15;98(8):2319–2325
  4. Eichhorst BF, Busch R, Hopfinger G, et al. Fludarabine plus cyclophosphamide versus fludarabine alone in first-line therapy of younger patients with chronic lymphocytic leukemia. Blood. 2006 Feb 1;107(3):885–891
  5. Grever MR, Lucas DM, Dewald GW, et al. Comprehensive assessment of genetic and molecular features predicting outcome in patients with chronic lymphocytic leukemia: results from the US Intergroup Phase III Trial E2997. J Clin Oncol. 2007 Mar 1;25(7):799–804
  6. Catovsky D, Richards S, Matutes E, et al. Assessment of fludarabine plus cyclophosphamide for patients with chronic lymphocytic leukaemia (the LRF CLL4 Trial): a randomised controlled trial. Lancet. 2007 Jul 21;370(9583):230–239
  7. Byrd JC, Rai K, Peterson BL, 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 Jan 1;105(1):49–53
  8. Keating MJ, O'Brien S, Albitar M, et al. Early results of a chemoimmunotherapy regimen of fludarabine, cyclophosphamide, and rituximab as initial therapy for chronic lymphocytic leukemia. J Clin Oncol. 2005 Jun 20;23(18):4079–4088
  9. Dohner H, Fischer K, Bentz M, et al. p53 gene deletion predicts for poor survival and non-response to therapy with purine analogs in chronic B-cell leukemias. Blood. 1995 Mar 15;85(6):1580–1589
  10. Keating MJ, O'Brien S, Kontoyiannis D, et al. Results of first salvage therapy for patients refractory to a fludarabine regimen in chronic lymphocytic leukemia. Leuk Lymphoma. 2002 Sep;43(9):1755–1762
  11. Keating MJ, Flinn I, Jain V, et al. Therapeutic role of alemtuzumab (Campath-1H) in patients who have failed fludarabine: results of a large international study. Blood. 2002 May 15;99(10):3554–3561
  12. Stilgenbauer S, Dohner H. Campath-1H-induced complete remission of chronic lymphocytic leukemia despite p53 gene mutation and resistance to chemotherapy. N Engl J Med. 2002 Aug 8;347(6):452–453
  13. Lozanski G, Heerema NA, Flinn IW, et al. Alemtuzumab is an effective therapy for chronic lymphocytic leukemia with p53 mutations and deletions. Blood. 2004 May 1;103(9):3278–3281
  14. Kennedy B, Rawstron A, Carter C, et al. Campath-1H and fludarabine in combination are highly active in refractory chronic lymphocytic leukemia. Blood. 2002 Mar 15;99(6):2245–2247
  15. Elter T, Borchmann P, Schulz H, 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 Oct 1;23(28):7024–7031
  16. Wendtner CM, Ritgen M, Schweighofer CD, et al. Consolidation with alemtuzumab in patients with chronic lymphocytic leukemia (CLL) in first remission–experience on safety and efficacy within a randomized multicenter phase III trial of the German CLL Study Group (GCLLSG). Leukemia. 2004 Jun;18(6):1093–1101
  17. Montillo M, Tedeschi A, Rossi V, et al. Successful CD34+ cell mobilization by intermediate-dose Ara-C in chronic lymphocytic leukemia patients treated with sequential fludarabine and Campath-1H. Leukemia. 2004 Jan;18(1):57–62
  18. Dreger P, Stilgenbauer S, Benner A, 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 Apr 1;103(7):2850–2858
  19. Rabinowe SN, Soiffer RJ, Gribben JG, et al. Autologous and allogeneic bone marrow transplantation for poor prognosis patients with B-cell chronic lymphocytic leukemia. Blood. 1993 Aug 15;82(4):1366–1376
  20. Khouri IF, Keating MJ, Vriesendorp HM, et al. Autologous and allogeneic bone marrow transplantation for chronic lymphocytic leukemia: preliminary results. J Clin Oncol. 1994 Apr;12(4):748–758
  21. Itala M, Pelliniemi TT, Rajamaki A, et al. Autologous blood cell transplantation in B-CLL: response to chemotherapy prior to mobilization predicts the stem cell yield. Bone Marrow Transplant. 1997 Apr;19(7):647–651
  22. Dreger P, von Neuhoff N, Kuse R, et al. Early stem cell transplantation for chronic lymphocytic leukaemia: a chance for cure?. Br J Cancer. 1998 Jun;77(12):2291–2297
  23. Pavletic ZS, Bierman PJ, Vose JM, et al. High incidence of relapse after autologous stem-cell transplantation for B-cell chronic lymphocytic leukemia or small lymphocytic lymphoma. Ann Oncol. 1998 Sep;9(9):1023–1026
  24. Milligan DW, Fernandes S, Dasgupta R, et al. Results of the MRC pilot study show autografting for younger patients with chronic lymphocytic leukemia is safe and achieves a high percentage of molecular responses. Blood. 2005 Jan 1;105(1):397–404
  25. Gribben JG, Zahrieh D, Stephans K, et al. Autologous and allogeneic stem cell transplantations for poor-risk chronic lymphocytic leukemia. Blood. 2005 Dec 15;106(13):4389–4396
  26. Jantunen E, Itala M, Siitonen T, et al. Autologous stem cell transplantation in patients with chronic lymphocytic leukaemia: the Finnish experience. Bone Marrow Transplant. 2006 Jun;37(12):1093–1098
  27. Ritgen M, Lange A, Stilgenbauer S, et al. Unmutated immunoglobulin variable heavy-chain gene status remains an adverse prognostic factor after autologous stem cell transplantation for chronic lymphocytic leukemia. Blood. 2003 Mar 1;101(5):2049–2053
  28. Ritgen M, Stilgenbauer S, von Neuhoff N, 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 Oct 15;104(8):2600–2602
  29. Moreno C, Villamor N, Colomer D, 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 May 20;23(15):3433–3438
  30. Sala R, Mauro FR, Bellucci R, et al. Evaluation of marrow and blood haemopoietic progenitors in chronic lymphocytic leukaemia before and after chemotherapy. Eur J Haematol. 1998 Jul;61(1):14–20
  31. Michallet M, Thiebaut A, Dreger P, et al. Peripheral blood stem cell (PBSC) mobilization and transplantation after fludarabine therapy in chronic lymphocytic leukaemia (CLL): a report of the European Blood and Marrow Transplantation (EBMT) CLL subcommittee on behalf of the EBMT Chronic Leukaemias Working Party (CLWP). Br J Haematol. 2000 Mar;108(3):595–601
  32. Dreger P, Montserrat E. Autologous and allogeneic stem cell transplantation for chronic lymphocytic leukemia. Leukemia. 2002 Jun;16(6):985–992
  33. Rawstron AC, Kennedy B, Evans PA, et al. Quantitation of minimal disease levels in chronic lymphocytic leukemia using a sensitive flow cytometric assay improves the prediction of outcome and can be used to optimize therapy. Blood. 2001 Jul 1;98(1):29–35
  34. Provan D, Bartlett-Pandite L, Zwicky C, et al. Eradication of polymerase chain reaction-detectable chronic lymphocytic leukemia cells is associated with improved outcome after bone marrow transplantation. Blood. 1996 Sep 15;88(6):2228–2235
  35. Schey S, Ahsan G, Jones R. Dose intensification and molecular responses in patients with chronic lymphocytic leukaemia: a phase II single centre study. Bone Marrow Transplant. 1999 Nov;24(9):989–993
  36. Schultze JL, Donovan JW, Gribben JG. Minimal residual disease detection after myeloablative chemotherapy in chronic lymphatic leukemia. J Mol Med. 1999 Feb;77(2):259–265
  37. Zenz T, Ritgen M, Dreger P, et al. Autologous graft-versus-host disease-like syndrome after an alemtuzumab-containing conditioning regimen and autologous stem cell transplantation for chronic lymphocytic leukemia. Blood. 2006 Sep 15;108(6):2127–2130
  38. Marin GH, Porto A, Prates V, et al. Graft versus host disease in autologous stem cell transplantation. J Exp Clin Cancer Res. 1999 Jun;18(2):201–208
  39. Montillo M, Tedeschi A, Miqueleiz S, et al. Alemtuzumab as consolidation after a response to fludarabine is effective in purging residual disease in patients with chronic lymphocytic leukemia. J Clin Oncol. 2006 May 20;24(15):2337–2342
  40. Sutton L, Maloum K, Gonzalez H, et al. Autologous hematopoietic stem cell transplantation as salvage treatment for advanced B cell chronic lymphocytic leukemia. Leukemia. 1998 Nov;12(11):1699–1707
  41. Michallet M, Corront B, Hollard D, et al. Allogeneic bone marrow transplantation in chronic lymphocytic leukemia: report from the European Cooperative Group for bone marrow transplantation (8 cases). Nouv Rev Fr Hematol. 1988;30(5–6):467–470
  42. Michallet M, Archimbaud E, Bandini 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 Feb 1;124(3):311–315
  43. Khouri I, Champlin R. Allogenic bone marrow transplantation in chronic lymphocytic leukemia. Ann Intern Med. 1996 Nov 1;125(9):780
  44. Pavletic ZS, Arrowsmith ER, Bierman PJ, et al. Outcome of allogeneic stem cell transplantation for B cell chronic lymphocytic leukemia. Bone Marrow Transplant. 2000 Apr;25(7):717–722
  45. Doney KC, Chauncey T, Appelbaum FR. Allogeneic related donor hematopoietic stem cell transplantation for treatment of chronic lymphocytic leukemia. Bone Marrow Transplant. 2002 May;29(10):817–823
  46. Toze CL, Galal A, Barnett MJ, 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 Nov;36(9):825–830
  47. Rondon G, Giralt S, Huh Y, et al. Graft-versus-leukemia effect after allogeneic bone marrow transplantation for chronic lymphocytic leukemia. Bone Marrow Transplant. 1996 Sep;18(3):669–672
  48. deMagalhaes-Silverman M, Donnenberg A, Hammert L, et al. Induction of graft-versus-leukemia effect in a patient with chronic lymphocytic leukemia. Bone Marrow Transplant. 1997 Jul;20(2):175–177
  49. Pavletic SZ, Khouri IF, Haagenson M, 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 Aug 20;23(24):5788–5794
  50. Khouri IF, Przepiorka D, van Besien K, et al. Allogeneic blood or marrow transplantation for chronic lymphocytic leukaemia: timing of transplantation and potential effect of fludarabine on acute graft-versus-host disease. Br J Haematol. 1997;97(2):466–473
  51. Esteve J, Villamor N, Colomer D, et al. Stem cell transplantation for chronic lymphocytic leukemia: different outcome after autologous and allogeneic transplantation and correlation with minimal residual disease status. Leukemia. 2001 Mar;15(3):445–451
  52. Schetelig J, Thiede C, Bornhauser M, et al. Reduced non-relapse mortality after reduced intensity conditioning in advanced chronic lymphocytic leukemia. Ann Hematol. 2002;81(Suppl. 2):S47–S48
  53. Schetelig J, Thiede C, Bornhauser M, 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 Jul 15;21(14):2747–2753
  54. Khouri IF, Keating M, Korbling M, et al. Transplant-lite: induction of graft-versus-malignancy using fludarabine-based nonablative chemotherapy and allogeneic blood progenitor-cell transplantation as treatment for lymphoid malignancies. J Clin Oncol. 1998 Aug;16(8):2817–2824
  55. Khouri IF, Saliba RM, Giralt SA, et al. Nonablative allogeneic hematopoietic transplantation as adoptive immunotherapy for indolent lymphoma: low incidence of toxicity, acute graft-versus-host disease, and treatment-related mortality. Blood. 2001 Dec 15;98(13):3595–3599
  56. Dreger P, Brand R, Hansz 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 May;17(5):841–848
  57. Sorror ML, Maris MB, Sandmaier BM, et al. Hematopoietic cell transplantation after nonmyeloablative conditioning for advanced chronic lymphocytic leukemia. J Clin Oncol. 2005 Jun 1;23(16):3819–3829
  58. Brown JR, Kim HT, Li S, et al. Predictors of improved progression-free survival after nonmyeloablative allogeneic stem cell transplantation for advanced chronic lymphocytic leukemia. Biol Blood Marrow Transplant. 2006 Oct;12(10):1056–1064
  59. Dreger P, Brand R, Milligan D, et al. Reduced-intensity conditioning lowers treatment-related mortality of allogeneic stem cell transplantation for chronic lymphocytic leukemia: a population-matched analysis. Leukemia. 2005 Jun;19(6):1029–1033
  60. Sorror ML, Storer BE, Sandmaier BM, 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 Oct 20;26(30):4912–4920
  61. Hertzberg M, Grigg A, Gottlieb D, et al. Reduced-intensity allogeneic haemopoietic stem cell transplantation induces durable responses in patients with chronic B-lymphoproliferative disorders. Bone Marrow Transplant. 2006 May;37(10):923–928
  62. Caballero D, Garcia-Marco JA, Martino R, 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 Nov 1;11(21):7757–7763
  63. Kottaridis PD, Milligan DW, Chopra R, et al. In vivo CAMPATH-1H prevents graft-versus-host disease following nonmyeloablative stem cell transplantation. Blood. 2000 Oct 1;96(7):2419–2425
  64. Morris E, Thomson K, Craddock C, et al. Outcomes after alemtuzumab-containing reduced-intensity allogeneic transplantation regimen for relapsed and refractory non-Hodgkin lymphoma. Blood. 2004 Dec 15;104(13):3865–3871
  65. Delgado J, Thomson K, Russell N, 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 Feb 15;107(4):1724–1730
  66. Wagner JE, Thompson JS, Carter SL, et al. Effect of graft-versus-host disease prophylaxis on 3-year disease-free survival in recipients of unrelated donor bone marrow (T-cell Depletion Trial): a multi-centre, randomised phase II-III trial. Lancet. 2005 Aug 27–Sep 2;366(9487):733–741
  67. Delgado J, Pillai S, Benjamin R, et al. The effect of in vivo T cell depletion with alemtuzumab on reduced-intensity allogeneic hematopoietic cell transplantation for chronic lymphocytic leukemia. Biol Blood Marrow Transplant. 2008 Nov;14(11):1288–1297
  68. Perez-Simon JA, Kottaridis PD, Martino R, et al. Nonmyeloablative transplantation with or without alemtuzumab: comparison between 2 prospective studies in patients with lymphoproliferative disorders. Blood. 2002 Nov 1;100(9):3121–3127
  69. Khouri IF, Saliba RM, Admirand J, 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 May;137(4):355–363

PII: S1521-6926(09)00102-9

doi: 10.1016/j.beha.2009.12.001

Best Practice & Research Clinical Haematology
Volume 23, Issue 1 , Pages 109-119 , March 2010