Current Hematologic Malignancy Reports

, Volume 7, Issue 2, pp 144–152 | Cite as

The Role of Allogeneic Hematopoietic Stem Cell Transplantation in the Therapy of Patients with Acute Lymphoblastic Leukemia

Acute Lymphocytic Leukemia (F Ravandi, Section Editor)

Abstract

Allogeneic hematopoietic stem cell transplantation (alloHSCT) is an effective post-remission therapy in patients with acute lymphoblastic leukemia (ALL), but is associated with significant toxicity, so the optimal timing and use of this modality remains an issue of debate. Increased advances in reduced-intensity transplant preparative regimens and alternative donors has increased the accessibility of allogeneic transplantation. A risk adapted paradigm, using minimal residual disease analysis, may help in the selection of patients at highest risk for relapse, who may benefit most from alloHSCT. In this review, we summarize the indications for allogeneic transplantation within the risk-oriented paradigm, and also explore the latest literature on reduced intensity transplant regimens, as well as alternative donor transplantation for patients with ALL.

Keywords

Acute lymphoblastic leukemia Allogeneic hematopoietic stem cell transplantation Minimal residual disease Haplo-identical stem cell transplantation Cord blood transplantation Reduced intensity transplant regimen Philadelphia chromosome positive ALL 

Notes

Disclosure

No potential conflicts of interest relevant to this article were reported.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Pui CH, Evans WE. Treatment of acute lymphoblastic leukemia. N Engl J Med. 2006;354(2):166–78.PubMedCrossRefGoogle Scholar
  2. 2.
    Thomas X, et al. Outcome of treatment in adults with acute lymphoblastic leukemia: analysis of the LALA-94 trial. J Clin Oncol. 2004;22(20):4075–86.PubMedCrossRefGoogle Scholar
  3. 3.
    Kantarjian H, et al. Long-term follow-up results of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (Hyper-CVAD), a dose-intensive regimen, in adult acute lymphocytic leukemia. Cancer. 2004;101(12):2788–801.PubMedCrossRefGoogle Scholar
  4. 4.
    Gokbuget N, et al. Treatment of adult ALL according to protocols of the German Multicenter Study Group for Adult ALL (GMALL). Hematol Oncol Clin North Am. 2000;14(6):1307–25. ix.PubMedCrossRefGoogle Scholar
  5. 5.
    Rowe JM, et al. Induction therapy for adults with acute lymphoblastic leukemia: results of more than 1500 patients from the international ALL trial: MRC UKALL XII/ECOG E2993. Blood. 2005;106(12):3760–7.PubMedCrossRefGoogle Scholar
  6. 6.
    Baker KS, et al. Late effects in survivors of acute leukemia treated with hematopoietic cell transplantation: a report from the Bone Marrow Transplant Survivor Study. Leukemia. 2010;24(12):2039–47.PubMedCrossRefGoogle Scholar
  7. 7.
    Pui CH, Evans WE. Acute lymphoblastic leukemia. N Engl J Med. 1998;339(9):605–15.PubMedCrossRefGoogle Scholar
  8. 8.
    Marks DI, et al. T-cell acute lymphoblastic leukemia in adults: clinical features, immunophenotype, cytogenetics, and outcome from the large randomized prospective trial (UKALL XII/ECOG 2993). Blood. 2009;114(25):5136–45.PubMedCrossRefGoogle Scholar
  9. 9.
    Czuczman MS, et al. Value of immunophenotype in intensively treated adult acute lymphoblastic leukemia: cancer and leukemia Group B study 8364. Blood. 1999;93(11):3931–9.PubMedGoogle Scholar
  10. 10.
    Gokbuget N, Hoelzer D. Treatment of adult acute lymphoblastic leukemia. Hematol Am Soc Hematol Educ Program. 2006:133–41.Google Scholar
  11. 11.
    Moorman AV, et al. Karyotype is an independent prognostic factor in adult acute lymphoblastic leukemia (ALL): analysis of cytogenetic data from patients treated on the Medical Research Council (MRC) UKALLXII/Eastern Cooperative Oncology Group (ECOG) 2993 trial. Blood. 2007;109(8):3189–97.PubMedCrossRefGoogle Scholar
  12. 12.
    Bruggemann M, et al. Clinical significance of minimal residual disease quantification in adult patients with standard-risk acute lymphoblastic leukemia. Blood. 2006;107(3):1116–23.PubMedCrossRefGoogle Scholar
  13. 13.
    Patel B, et al. Minimal residual disease is a significant predictor of treatment failure in non T-lineage adult acute lymphoblastic leukaemia: final results of the international trial UKALL XII/ECOG2993. Br J Haematol. 2009;148(1):80–9.PubMedCrossRefGoogle Scholar
  14. 14.
    Gokbuget N. Improved outcome in high risk and very high risk ALL by risk adapted SCT and in standard risk ALL by intensive chemotherapy in 713 adult ALL patients treated according to the prospective GMALL study 07/2003. American Society of Hematology Annual meeting 2009. Oral session, Abstract 12.Google Scholar
  15. 15.
    Ribera JM. Treatment of High-Risk (HR) Philadelphia chromosome-negative (Ph-) adult Acute Lymphoblastic Leukemia (ALL) according to baseline risk factors and Minimal Residual Disease (MRD). Results of the PETHEMA ALL-AR-03 trial including the use of Propensity Score (PS) method to reduce assignment bias. In American Society of Hematology 2009. 2009.Google Scholar
  16. 16.
    •• Goldstone AH, et al. In adults with standard-risk acute lymphoblastic leukemia, the greatest benefit is achieved from a matched sibling allogeneic transplantation in first complete remission, and an autologous transplantation is less effective than conventional consolidation/maintenance chemotherapy in all patients: final results of the International ALL Trial (MRC UKALL XII/ECOG E2993). Blood. 2008;111(4):1827–33. Largest prospective study on efficacy of alloHSCT as consolidation therapy in patients with ALL, and largest study which showed that standard-risk patients benefit most from transplant. PubMedCrossRefGoogle Scholar
  17. 17.
    Hunault M, et al. Better outcome of adult acute lymphoblastic leukemia after early genoidentical allogeneic bone marrow transplantation (BMT) than after late high-dose therapy and autologous BMT: a GOELAMS trial. Blood. 2004;104(10):3028–37.PubMedCrossRefGoogle Scholar
  18. 18.
    Labar B, et al. Allogeneic stem cell transplantation in acute lymphoblastic leukemia and non-Hodgkin’s lymphoma for patients <or=50 years old in first complete remission: results of the EORTC ALL-3 trial. Haematologica. 2004;89(7):809–17.PubMedGoogle Scholar
  19. 19.
    Ribera JM, et al. Comparison of intensive chemotherapy, allogeneic or autologous stem cell transplantation as post-remission treatment for adult patients with high-risk acute lymphoblastic leukemia. Results of the PETHEMA ALL-93 trial. Haematologica. 2005;90(10):1346–56.PubMedGoogle Scholar
  20. 20.
    Sebban C, et al. Allogeneic bone marrow transplantation in adult acute lymphoblastic leukemia in first complete remission: a comparative study. French group of therapy of adult acute lymphoblastic leukemia. J Clin Oncol. 1994;12(12):2580–7.PubMedGoogle Scholar
  21. 21.
    Takeuchi J, et al. Induction therapy by frequent administration of doxorubicin with four other drugs, followed by intensive consolidation and maintenance therapy for adult acute lymphoblastic leukemia: the JALSG-ALL93 study. Leukemia. 2002;16(7):1259–66.PubMedCrossRefGoogle Scholar
  22. 22.
    Paulson K, Szwajcer D, Seftel MD. The role of allogeneic stem cell transplantation for adult acute lymphoblastic leukemia. Transfus Apher Sci. 2011;44(2):197–203.PubMedCrossRefGoogle Scholar
  23. 23.
    Cornelissen JJ, et al. Myeloablative allogeneic versus autologous stem cell transplantation in adult patients with acute lymphoblastic leukemia in first remission: a prospective sibling donor versus no-donor comparison. Blood. 2009;113(6):1375–82.PubMedCrossRefGoogle Scholar
  24. 24.
    Yanada M, et al. Allogeneic hematopoietic stem cell transplantation as part of postremission therapy improves survival for adult patients with high-risk acute lymphoblastic leukemia: a metaanalysis. Cancer. 2006;106(12):2657–63.PubMedCrossRefGoogle Scholar
  25. 25.
    Ram R, et al. Management of adult patients with acute lymphoblastic leukemia in first complete remission: systematic review and meta-analysis. Cancer. 116(14):3447–57.Google Scholar
  26. 26.
    •• Pidala J, et al. Allogeneic hematopoietic cell transplantation for adult acute lymphoblastic leukemia (ALL) in first complete remission. Cochrane Database Syst Rev. 2011;10:CD008818. This was the largest meta-analysis which included 14 trials consisting of 3157 patients and which showed that patients >15 years old, in donor-group had superior overall survival, disease-free survival, and reduced relapse rates but increased risks of non-relapse mortality as compared to the no-donor group. PubMedGoogle Scholar
  27. 27.
    Bassan R, Lerede T, Barbui T. Strategies for the treatment of recurrent acute lymphoblastic leukemia in adults. Haematologica. 1996;81(1):20–36.PubMedGoogle Scholar
  28. 28.
    Garcia-Manero G, Thomas DA. Salvage therapy for refractory or relapsed acute lymphocytic leukemia. Hematol Oncol Clin North Am. 2001;15(1):163–205.PubMedCrossRefGoogle Scholar
  29. 29.
    Oriol A, et al. Outcome after relapse of acute lymphoblastic leukemia in adult patients included in four consecutive risk-adapted trials by the PETHEMA Study Group. Haematologica. 95(4):589–96.Google Scholar
  30. 30.
    Tavernier E, et al. Outcome of treatment after first relapse in adults with acute lymphoblastic leukemia initially treated by the LALA-94 trial. Leukemia. 2007;21(9):1907–14.PubMedCrossRefGoogle Scholar
  31. 31.
    Martino R, et al. Allogeneic or autologous stem cell transplantation following salvage chemotherapy for adults with refractory or relapsed acute lymphoblastic leukemia. Bone Marrow Transplant. 1998;21(10):1023–7.PubMedCrossRefGoogle Scholar
  32. 32.
    Thomas DA, et al. Primary refractory and relapsed adult acute lymphoblastic leukemia: characteristics, treatment results, and prognosis with salvage therapy. Cancer. 1999;86(7):1216–30.PubMedCrossRefGoogle Scholar
  33. 33.
    Terwey TH, et al. Allogeneic SCT in refractory or relapsed adult ALL is effective without prior reinduction chemotherapy. Bone Marrow Transplant. 2008;42(12):791–8.PubMedCrossRefGoogle Scholar
  34. 34.
    Cornelissen JJ, et al. Unrelated marrow transplantation for adult patients with poor-risk acute lymphoblastic leukemia: strong graft-versus-leukemia effect and risk factors determining outcome. Blood. 2001;97(6):1572–7.PubMedCrossRefGoogle Scholar
  35. 35.
    Doney K, et al. Predictive factors for outcome of allogeneic hematopoietic cell transplantation for adult acute lymphoblastic leukemia. Biol Blood Marrow Transplant. 2003;9(7):472–81.PubMedCrossRefGoogle Scholar
  36. 36.
    • Marks DI, et al. The outcome of full-intensity and reduced-intensity conditioning matched sibling or unrelated donor transplantation in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia in first and second complete remission. Blood. 2010;116(3):366–74. Large registry data from the CIBMTR, looking at differences between RIC and myeloablative SCT for treatment of Philadelphia-negative ALL. Although findings suggest conditioning intensity did not affect transplantation-related mortality or relapse risks, this may have been affected by selection bias associated with a retrospective review. PubMedCrossRefGoogle Scholar
  37. 37.
    Clavert A, et al. Reduced-intensity conditioning allogeneic stem cell transplant for relapsed or transformed aggressive B-cell non-Hodgkin lymphoma. Leuk Lymphoma. 2010;51(8):1502–8.PubMedCrossRefGoogle Scholar
  38. 38.
    Arnold R, et al. Nonmyeloablative stem cell transplantation in adults with high-risk ALL may be effective in early but not in advanced disease. Leukemia. 2002;16(12):2423–8.PubMedCrossRefGoogle Scholar
  39. 39.
    Stein AS, et al. Reduced-intensity conditioning followed by peripheral blood stem cell transplantation for adult patients with high-risk acute lymphoblastic leukemia. Biol Blood Marrow Transplant. 2009;15(11):1407–14.PubMedCrossRefGoogle Scholar
  40. 40.
    Cho BS, et al. Reduced-intensity conditioning allogeneic stem cell transplantation is a potential therapeutic approach for adults with high-risk acute lymphoblastic leukemia in remission: results of a prospective phase 2 study. Leukemia. 2009;23(10):1763–70.PubMedCrossRefGoogle Scholar
  41. 41.
    Ram R, et al. Non-myeloablative conditioning with allogeneic hematopoietic cell transplantation for the treatment of high-risk acute lymphoblastic leukemia. Haematologica. 2011;96(8):1113–20.PubMedCrossRefGoogle Scholar
  42. 42.
    Santarone S, et al. Fludarabine and pharmacokinetic-targeted busulfan before allografting for adults with acute lymphoid leukemia. Biol Blood Marrow Transplant. 2011;17(10):1505–11.PubMedCrossRefGoogle Scholar
  43. 43.
    Russell JA, et al. Allogeneic transplantation for adult acute leukemia in first and second remission with a novel regimen incorporating daily intravenous busulfan, fludarabine, 400 CGY total-body irradiation, and thymoglobulin. Biol Blood Marrow Transplant. 2007;13(7):814–21.PubMedCrossRefGoogle Scholar
  44. 44.
    Bachanova V, et al. Prolonged survival in adults with acute lymphoblastic leukemia after reduced-intensity conditioning with cord blood or sibling donor transplantation. Blood. 2009;113(13):2902–5.PubMedCrossRefGoogle Scholar
  45. 45.
    Kiehl MG, et al. Outcome of allogeneic hematopoietic stem-cell transplantation in adult patients with acute lymphoblastic leukemia: no difference in related compared with unrelated transplant in first complete remission. J Clin Oncol. 2004;22(14):2816–25.PubMedCrossRefGoogle Scholar
  46. 46.
    • Ringden O, 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(13):3110–8. Large registry data from CIBMTR showing similar relapse rates/NRM and LFS after alloHCT from MUD compared to MSD in ALL patients. PubMedCrossRefGoogle Scholar
  47. 47.
    Lee S, et al. Allogeneic stem cell transplantation in first complete remission enhances graft-versus-leukemia effect in adults with acute lymphoblastic leukemia: antileukemic activity of chronic graft-versus-host disease. Biol Blood Marrow Transplant. 2007;13(9):1083–94.PubMedCrossRefGoogle Scholar
  48. 48.
    Dahlke J, et al. Comparable results in patients with acute lymphoblastic leukemia after related and unrelated stem cell transplantation. Bone Marrow Transplant. 2006;37(2):155–63.PubMedCrossRefGoogle Scholar
  49. 49.
    Laughlin MJ, et al. Outcomes after transplantation of cord blood or bone marrow from unrelated donors in adults with leukemia. N Engl J Med. 2004;351(22):2265–75.PubMedCrossRefGoogle Scholar
  50. 50.
    Rocha V, et al. Transplants of umbilical-cord blood or bone marrow from unrelated donors in adults with acute leukemia. N Engl J Med. 2004;351(22):2276–85.PubMedCrossRefGoogle Scholar
  51. 51.
    •• Eapen M, et al. Effect of graft source on unrelated donor haemopoietic stem-cell transplantation in adults with acute leukaemia: a retrospective analysis. Lancet Oncol. 11(7):653–60. One of the largest registry data demonstrating that leukemia-free survival after unrelated cord blood transplantation is comparable to that after 8/8 and 7/8 allele matched transplant, hence supporting the use of unrelated cord blood for patients with acute leukemia when there is no HLA matched unrelated adult donor available. Google Scholar
  52. 52.
    Tomblyn MB, et al. Myeloablative hematopoietic cell transplantation for acute lymphoblastic leukemia: analysis of graft sources and long-term outcome. J Clin Oncol. 2009;27(22):3634–41.PubMedCrossRefGoogle Scholar
  53. 53.
    Ciceri F, et al. A survey of fully haploidentical hematopoietic stem cell transplantation in adults with high-risk acute leukemia: a risk factor analysis of outcomes for patients in remission at transplantation. Blood. 2008;112(9):3574–81.PubMedCrossRefGoogle Scholar
  54. 54.
    Luznik L, et al. HLA-haploidentical bone marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and high-dose, posttransplantation cyclophosphamide. Biol Blood Marrow Transplant: J Am Soc Blood Marrow Transplant. 2008;14(6):641–50.CrossRefGoogle Scholar
  55. 55.
    Luznik L, et al. High-dose cyclophosphamide as single-agent, short-course prophylaxis of graft-versus-host disease. Blood. 115(16):3224–30.Google Scholar
  56. 56.
    Giebel S, et al. Status of minimal residual disease determines outcome of autologous hematopoietic SCT in adult ALL. Bone Marrow Transplant. 2010;45(6):1095–101.PubMedCrossRefGoogle Scholar
  57. 57.
    Wetzler M, et al. Prospective karyotype analysis in adult acute lymphoblastic leukemia: the cancer and leukemia Group B experience. Blood. 1999;93(11):3983–93.PubMedGoogle Scholar
  58. 58.
    Laport GG, et al. Long-term remission of Philadelphia chromosome-positive acute lymphoblastic leukemia after allogeneic hematopoietic cell transplantation from matched sibling donors: a 20-year experience with the fractionated total body irradiation-etoposide regimen. Blood. 2008;112(3):903–9.PubMedCrossRefGoogle Scholar
  59. 59.
    Snyder DS, et al. Long-term follow-up of 23 patients with Philadelphia chromosome-positive acute lymphoblastic leukemia treated with allogeneic bone marrow transplant in first complete remission. Leukemia. 1999;13(12):2053–8.PubMedCrossRefGoogle Scholar
  60. 60.
    Fielding AK, et al. Prospective outcome data on 267 unselected adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia confirms superiority of allogeneic transplantation over chemotherapy in the pre-imatinib era: results from the International ALL Trial MRC UKALLXII/ECOG2993. Blood. 2009;113(19):4489–96.PubMedCrossRefGoogle Scholar
  61. 61.
    Thomas DA, et al. Treatment of Philadelphia chromosome-positive acute lymphocytic leukemia with hyper-CVAD and imatinib mesylate. Blood. 2004;103(12):4396–407.PubMedCrossRefGoogle Scholar
  62. 62.
    Tanguy-Schmidt A, et al. Long-term results of the Imatinib GRAAPH-2003 study in newly-diagnosed patients with de novo Philadelphia chromosome-positive acute lymphoblastic leukemia. ASH Annu Meet Abstr. 2009;114(22):3080.Google Scholar
  63. 63.
    Fielding AK, et al. Imatinib significantly enhances long-term outcomes in Philadelphia positive acute lymphoblastic leukaemia; Final results of the UKALLXII/ECOG2993 trial. ASH Annu Meet Abstr. 2010;116(21):169.Google Scholar
  64. 64.
    de Labarthe A, et al. Imatinib combined with induction or consolidation chemotherapy in patients with de novo Philadelphia chromosome-positive acute lymphoblastic leukemia: results of the GRAAPH-2003 study. Blood. 2007;109(4):1408–13.PubMedCrossRefGoogle Scholar
  65. 65.
    Yanada M, et al. High complete remission rate and promising outcome by combination of Imatinib and chemotherapy for newly diagnosed BCR-ABL–Positive acute lymphoblastic leukemia: a phase II study by the Japan adult leukemia study group. J Clin Oncol. 2006;24(3):460–6.PubMedCrossRefGoogle Scholar
  66. 66.
    Pfeifer H, et al. Long-term outcome of 335 adult patients receiving different schedules of Imatinib and chemotherapy as front-line treatment for Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL). ASH Annu Meet Abstr. 116(21):173-.Google Scholar
  67. 67.
    Ravandi F, et al. First report of phase 2 study of dasatinib with hyper-CVAD for the frontline treatment of patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia. Blood. 2010;116(12):2070–7.PubMedCrossRefGoogle Scholar
  68. 68.
    Foa R, et al. Dasatinib as first-line treatment for adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood. 2011;118(25):6521–8.PubMedCrossRefGoogle Scholar
  69. 69.
    Wassmann B, et al. Early molecular response to posttransplantation imatinib determines outcome in MRD+ Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL). Blood. 2005;106(2):458–63.PubMedCrossRefGoogle Scholar
  70. 70.
    Kebriaei P, et al. Long-term follow-up of allogeneic hematopoietic stem cell transplantation for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia: impact of tyrosine kinase inhibitors on treatment outcomes. Biol Blood Marrow Transplant. 2011 Epub.Google Scholar
  71. 71.
    Wassmann B. Up-front versus minimal residual disease triggered imatinib after stem cell transplantation for Philadelphia chromosome-positive acute lymphoblastic leukaemia: interim results of a randomized phase III GMALL study. Bone Marrow Transplant. 2009;43:S48.Google Scholar
  72. 72.
    Ribera JM, et al. Concurrent intensive chemotherapy and imatinib before and after stem cell transplantation in newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia. Final results of the CSTIBES02 trial. Haematologica. 95(1):87–95.Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Department of Stem Cell Transplantation and Cellular TherapyMD Anderson Cancer CenterHoustonUSA
  2. 2.Department of Stem Cell TransplantThe University of Texas, MD Anderson Cancer CenterHoustonUSA

Personalised recommendations