Advertisement

Current Hematologic Malignancy Reports

, Volume 8, Issue 2, pp 132–140 | Cite as

Strategies to Reduce Relapse after Allogeneic Hematopoietic Cell Transplantation in Acute Myeloid Leukemia

  • Raya Mawad
  • Jack M. Lionberger
  • John M. PagelEmail author
Acute Leukemias (E Feldman, Section Editor)

Abstract

The incidence of acute myeloid leukemia (AML) is expected to increase in conjunction with our ageing population. Although it is proving to be a heterogeneous disease process, the only treatment with proven survival benefit for poor risk AML remains allogeneic hematopoietic cell transplant. Although this is presumed to be a curative strategy, many patients relapse after transplant, prompting us to examine various ways that we can improve outcomes. These efforts involve every step of AML diagnostics and therapy, including the intricate processes of conditioning, graft manipulation and immunomodulation. The hope is that improvement in these steps will ultimately improve survival and decrease relapse rates for AML patients after transplant.

Keywords

Acute myeloid leukemia Allogeneic hematopoietic cell transplant Relapse Strategies 

Notes

Conflict of Interest

The authors declare no competing financial interests.

References

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

  1. 1.
    Porter DL, Alyea EP, Antin JH, et al. NCI First International Workshop on the Biology, Prevention, and Treatment of Relapse After Allogeneic Hematopoietic Stem Cell Transplantation: report from the committee on treatment of relapse after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2010;16:1467–503.PubMedCrossRefGoogle Scholar
  2. 2.
    •• Alyea EP, DeAngelo DJ, Moldrem J, et al. NCI First International Workshop on The Biology, Prevention and Treatment of Relapse after Allogeneic Hematopoietic Cell Transplantation: report from the committee on prevention of relapse following allogeneic cell transplantation for hematologic malignancies. Biol Blood Marrow Transplant. 2010;16:1037–69. This workshop review annotates various strategies used to decrease relapse of myeloid diseases after allogeneic hematopoeitic transplant.PubMedCrossRefGoogle Scholar
  3. 3.
    Kim DH, Sohn SK, Kim JG, et al. Parameters for predicting allogeneic PBSCT outcome of acute myeloid leukemia: cytogenetics at presentation versus disease status at transplantation. Ann Hematol. 2005;84:25–32.PubMedCrossRefGoogle Scholar
  4. 4.
    Byrd JC, Mrózek K, Dodge RK, et al. Pretreatment cytogenetic abnormalities are predictive of induction success, cumulative incidence of relapse, and overall survival in adult patients with de novo acute myeloid leukemia: results from Cancer and Leukemia Group B (CALGB 8461). Blood. 2002;100:4325–36.PubMedCrossRefGoogle Scholar
  5. 5.
    Ferrant A, Labopin M, Frassoni F, et al. Karyotype in acute myeloblastic leukemia: prognostic significance for bone marrow transplantation in first remission: a European Group for Blood and Marrow Transplantation study. Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT). Blood. 1997;90:2931–8.PubMedGoogle Scholar
  6. 6.
    Tallman MS, Dewald GW, Gandham S, et al. Impact of cytogenetics on outcome of matched unrelated donor hematopoietic stem cell transplantation for acute myeloid leukemia in first or second complete remission. Blood. 2007;110:409–17.PubMedCrossRefGoogle Scholar
  7. 7.
    Paschka P, Marcucci G, Ruppert AS, et al. Adverse prognostic significance of KIT mutations in adult acute myeloid leukemia with inv(16) and t(8;21): a Cancer and Leukemia Group B Study. J Clin Oncol. 2006;24:3904–11.PubMedCrossRefGoogle Scholar
  8. 8.
    Metzelder S, Wang Y, Wollmer E, et al. Compassionate use of sorafenib in FLT3-ITD-positive acute myeloid leukemia: sustained regression before and after allogeneic stem cell transplantation. Blood. 2009;113:6567–71.PubMedCrossRefGoogle Scholar
  9. 9.
    Cortes JE ea. Abstract #2576: A phase II open-label, AC220 monotherapy efficacy study in patients with refractory/relapsed Flt3-Itd positive acute myeloid leukemia : Updated interim results. American Society of Hematology. San Diego, CA: Oral Poster and Abstract; 2011.Google Scholar
  10. 10.
    Burton E ea. Abstract#3632: The novel inhibitor PLX3397 effectively inhibits FLT3-mutant AML. American Society of Hematology. San Diego, CA: Oral Poster and Abstract; 2011.Google Scholar
  11. 11.
    Al-Mawali A, Gillis D, Hissaria P, Lewis I. Incidence, sensitivity, and specificity of leukemia-associated phenotypes in acute myeloid leukemia using specific five-color multiparameter flow cytometry. Am J Clin Pathol. 2008;129:934–45.PubMedCrossRefGoogle Scholar
  12. 12.
    • Walter RB, Gooley TA, Wood BL, et al. Impact of pretransplantation minimal residual disease, as detected by multiparametric flow cytometry, on outcome of myeloablative hematopoietic cell transplantation for acute myeloid leukemia. J Clin Oncol. 2011;29:1190–7. This data supports the concept that MRD is a significant predictor of post-transplant survival for patients with AML.PubMedCrossRefGoogle Scholar
  13. 13.
    • Chen Y, Cortes J, Estrov Z, et al. Persistence of cytogenetic abnormalities at complete remission after induction in patients with acute myeloid leukemia: prognostic significance and the potential role of allogeneic stem-cell transplantation. J Clin Oncol. 2011;29:2507–13. Examines the prognostic role of persistent cytogenetic abnormalities despite morphologic CR, and its prognostic effect.PubMedCrossRefGoogle Scholar
  14. 14.
    Löwenberg B, Ossenkoppele GJ, van Putten W, et al. High-dose daunorubicin in older patients with acute myeloid leukemia. N Engl J Med. 2009;361:1235–48.PubMedCrossRefGoogle Scholar
  15. 15.
    Fernandez HF, Sun Z, Yao X, et al. Anthracycline dose intensification in acute myeloid leukemia. N Engl J Med. 2009;361:1249–59.PubMedCrossRefGoogle Scholar
  16. 16.
    Scandura JM, Roboz GJ, Moh M, et al. Phase 1 study of epigenetic priming with decitabine prior to standard induction chemotherapy for patients with AML. Blood. 2011;118:1472–80.PubMedCrossRefGoogle Scholar
  17. 17.
    Faderl S, Ravandi F, Huang X, et al. A randomized study of clofarabine versus clofarabine plus low-dose cytarabine as front-line therapy for patients aged 60 years and older with acute myeloid leukemia and high-risk myelodysplastic syndrome. Blood. 2008;112:1638–45.PubMedCrossRefGoogle Scholar
  18. 18.
    Faderl S, Ravandi F, Huang X, et al. Clofarabine plus low-dose cytarabine followed by clofarabine plus low-dose cytarabine alternating with decitabine in acute myeloid leukemia frontline therapy for older patients. Cancer 2012.Google Scholar
  19. 19.
    Clift RA, Buckner CD, Appelbaum FR, et al. Allogeneic marrow transplantation in patients with acute myeloid leukemia in first remission: a randomized trial of two irradiation regimens. Blood. 1990;76:1867–71.PubMedGoogle Scholar
  20. 20.
    • Magenau J, Tobai H, Pawarode A, et al. Clofarabine and busulfan conditioning facilitates engraftment and provides significant antitumor activity in nonremission hematologic malignancies. Blood. 2011;118:4258–64. Provides some encouraging data for the use of Clofarabine for transplant conditioning of myeloid malignancies.PubMedCrossRefGoogle Scholar
  21. 21.
    Andersson BS, Valdez BC, de Lima M, et al. Clofarabine ± fludarabine with once daily i.v. busulfan as pretransplant conditioning therapy for advanced myeloid leukemia and MDS. Biol Blood Marrow Transplant. 2011;17:893–900.PubMedCrossRefGoogle Scholar
  22. 22.
    Pagel JM, Appelbaum FR, Eary JF, et al. 131I-anti-CD45 antibody plus busulfan and cyclophosphamide before allogeneic hematopoietic cell transplantation for treatment of acute myeloid leukemia in first remission. Blood. 2006;107:2184–91.PubMedCrossRefGoogle Scholar
  23. 23.
    • Pagel JM, Gooley TA, Rajendran J, et al. Allogeneic hematopoietic cell transplantation after conditioning with 131I-anti-CD45 antibody plus fludarabine and low-dose total body irradiation for elderly patients with advanced acute myeloid leukemia or high-risk myelodysplastic syndrome. Blood. 2009;114:5444–53. Provides encouraging data regarding the potential use of targeted radioimmunotherapy in conditioning regimens for myeloid malignancies.PubMedCrossRefGoogle Scholar
  24. 24.
    Sorror ML, Sandmaier BM, Storer BE, et al. Long-term outcomes among older patients following nonmyeloablative conditioning and allogeneic hematopoietic cell transplantation for advanced hematologic malignancies. JAMA. 2011;306:1874–83.PubMedCrossRefGoogle Scholar
  25. 25.
    Hegenbart U, Niederwieser D, Sandmaier BM, et al. Treatment for acute myelogenous leukemia by low-dose, total-body, irradiation-based conditioning and hematopoietic cell transplantation from related and unrelated donors. J Clin Oncol. 2006;24:444–53.PubMedCrossRefGoogle Scholar
  26. 26.
    Alatrash G, de Lima M, Hamerschlak N, et al. Myeloablative reduced-toxicity i.v. busulfan-fludarabine and allogeneic hematopoietic stem cell transplant for patients with acute myeloid leukemia or myelodysplastic syndrome in the sixth through eighth decades of life. Biol Blood Marrow Transplant. 2011;17:1490–6.PubMedCrossRefGoogle Scholar
  27. 27.
    Popat U, de Lima MJ, Saliba RM, et al. Long-term outcome of reduced-intensity allogeneic hematopoietic SCT in patients with AML in CR. Bone Marrow Transplant 2011.Google Scholar
  28. 28.
    Jakubowski AA, Small TN, Young JW, et al. T cell depleted stem-cell transplantation for adults with hematologic malignancies: sustained engraftment of HLA-matched related donor grafts without the use of antithymocyte globulin. Blood. 2007;110:4552–9.PubMedCrossRefGoogle Scholar
  29. 29.
    Jakubowski AA, Small TN, Kernan NA, et al. T cell-depleted unrelated donor stem cell transplantation provides favorable disease-free survival for adults with hematologic malignancies. Biol Blood Marrow Transplant. 2011;17:1335–42.PubMedCrossRefGoogle Scholar
  30. 30.
    Devine SM, Carter S, Soiffer RJ, et al. Low risk of chronic graft-versus-host disease and relapse associated with T cell-depleted peripheral blood stem cell transplantation for acute myelogenous leukemia in first remission: results of the blood and marrow transplant clinical trials network protocol 0303. Biol Blood Marrow Transplant. 2011;17:1343–51.PubMedCrossRefGoogle Scholar
  31. 31.
    André-Schmutz I, Le Deist F, Hacein-Bey-Abina S, et al. Immune reconstitution without graft-versus-host disease after haemopoietic stem-cell transplantation: a phase 1/2 study. Lancet. 2002;360:130–7.PubMedCrossRefGoogle Scholar
  32. 32.
    Solomon SR, Mielke S, Savani BN, et al. Selective depletion of alloreactive donor lymphocytes: a novel method to reduce the severity of graft-versus-host disease in older patients undergoing matched sibling donor stem cell transplantation. Blood. 2005;106:1123–9.PubMedCrossRefGoogle Scholar
  33. 33.
    Luznik L, O'Donnell PV, Symons HJ, et al. HLA-haploidentical bone marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and high-dose, posttransplantation cyclophosphamide. Biol Blood Marrow Transplant. 2008;14:641–50.PubMedCrossRefGoogle Scholar
  34. 34.
    Baron F, Maris MB, Sandmaier BM, et al. Graft-versus-tumor effects after allogeneic hematopoietic cell transplantation with nonmyeloablative conditioning. J Clin Oncol. 2005;23:1993–2003.PubMedCrossRefGoogle Scholar
  35. 35.
    Wagner JE, Thompson JS, Carter SL, Kernan NA, Trial UDMT. 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;366:733–41.PubMedCrossRefGoogle Scholar
  36. 36.
    Collins RH, Shpilberg O, Drobyski WR, et al. Donor leukocyte infusions in 140 patients with relapsed malignancy after allogeneic bone marrow transplantation. J Clin Oncol. 1997;15:433–44.PubMedGoogle Scholar
  37. 37.
    Kolb HJ, Schattenberg A, Goldman JM, et al. Graft-versus-leukemia effect of donor lymphocyte transfusions in marrow grafted patients. Blood. 1995;86:2041–50.PubMedGoogle Scholar
  38. 38.
    Linn YC, Goh YT, Tan HC. Relapse of leukemia and lymphoma after marrow transplant: a review of cases with extramedullary relapse. Leuk Lymphoma. 2000;38:137–46.PubMedGoogle Scholar
  39. 39.
    Schmid C, Labopin M, Nagler A, et al. Donor lymphocyte infusion in the treatment of first hematological relapse after allogeneic stem-cell transplantation in adults with acute myeloid leukemia: a retrospective risk factors analysis and comparison with other strategies by the EBMT Acute Leukemia Working Party. J Clin Oncol. 2007;25:4938–45.PubMedCrossRefGoogle Scholar
  40. 40.
    Levine JE, Braun T, Penza SL, et al. Prospective trial of chemotherapy and donor leukocyte infusions for relapse of advanced myeloid malignancies after allogeneic stem-cell transplantation. J Clin Oncol. 2002;20:405–12.PubMedCrossRefGoogle Scholar
  41. 41.
    Porter DL, Levine BL, Bunin N, et al. A phase 1 trial of donor lymphocyte infusions expanded and activated ex vivo via CD3/CD28 costimulation. Blood. 2006;107:1325–31.PubMedCrossRefGoogle Scholar
  42. 42.
    Schmid C, Schleuning M, Ledderose G, Tischer J, Kolb HJ. Sequential regimen of chemotherapy, reduced-intensity conditioning for allogeneic stem-cell transplantation, and prophylactic donor lymphocyte transfusion in high-risk acute myeloid leukemia and myelodysplastic syndrome. J Clin Oncol. 2005;23:5675–87.PubMedCrossRefGoogle Scholar
  43. 43.
    Kobbe G, Fenk R, Neumann F, et al. Transplantation of allogeneic CD34 + -selected cells followed by early T-cell add-backs: favorable results in acute and chronic myeloid leukemia. Cytotherapy. 2004;6:533–42.PubMedCrossRefGoogle Scholar
  44. 44.
    Sharma M, Ravandi F, Bayraktar UD, et al. Treatment of FLT3-ITD-positive acute myeloid leukemia relapsing after allogeneic stem cell transplantation with sorafenib. Biol Blood Marrow Transplant. 2011;17:1874–7.PubMedCrossRefGoogle Scholar
  45. 45.
    Pinto A, Maio M, Attadia V, Zappacosta S, Cimino R. Modulation of HLA-DR antigens expression in human myeloid leukaemia cells by cytarabine and 5-aza-2'-deoxycytidine. Lancet. 1984;2:867–8.PubMedCrossRefGoogle Scholar
  46. 46.
    Coral S, Sigalotti L, Gasparollo A, et al. Prolonged upregulation of the expression of HLA class I antigens and costimulatory molecules on melanoma cells treated with 5-aza-2'-deoxycytidine (5-AZA-CdR). J Immunother. 1999;22:16–24.PubMedCrossRefGoogle Scholar
  47. 47.
    Choi J, Ritchey J, Prior JL, et al. In vivo administration of hypomethylating agents mitigate graft-versus-host disease without sacrificing graft-versus-leukemia. Blood. 2010;116:129–39.PubMedCrossRefGoogle Scholar
  48. 48.
    Bolaños-Meade J, Smith BD, Gore SD, et al. 5-azacytidine as salvage treatment in relapsed myeloid tumors after allogeneic bone marrow transplantation. Biol Blood Marrow Transplant. 2011;17:754–8.PubMedCrossRefGoogle Scholar
  49. 49.
    de Lima M, Giralt S, Thall PF, et al. Maintenance therapy with low-dose azacitidine after allogeneic hematopoietic stem cell transplantation for recurrent acute myelogenous leukemia or myelodysplastic syndrome: a dose and schedule finding study. Cancer. 2010;116:5420–31.PubMedCrossRefGoogle Scholar
  50. 50.
    Garcia-Manero G, Yang H, Bueso-Ramos C, et al. Phase 1 study of the histone deacetylase inhibitor vorinostat (suberoylanilide hydroxamic acid [SAHA]) in patients with advanced leukemias and myelodysplastic syndromes. Blood. 2008;111:1060–6.PubMedCrossRefGoogle Scholar
  51. 51.
    Dermime S, Mavroudis D, Jiang YZ, Hensel N, Molldrem J, Barrett AJ. Immune escape from a graft-versus-leukemia effect may play a role in the relapse of myeloid leukemias following allogeneic bone marrow transplantation. Bone Marrow Transplant. 1997;19:989–99.PubMedCrossRefGoogle Scholar
  52. 52.
    Tsuboi A, Oka Y, Ogawa H, et al. Constitutive expression of the Wilms' tumor gene WT1 inhibits the differentiation of myeloid progenitor cells but promotes their proliferation in response to granulocyte-colony stimulating factor (G-CSF). Leuk Res. 1999;23:499–505.PubMedCrossRefGoogle Scholar
  53. 53.
    Hewitt SM, Hamada S, McDonnell TJ, Rauscher FJ, Saunders GF. Regulation of the proto-oncogenes bcl-2 and c-myc by the Wilms' tumor suppressor gene WT1. Cancer Res. 1995;55:5386–9.PubMedGoogle Scholar
  54. 54.
    Mailänder V, Scheibenbogen C, Thiel E, Letsch A, Blau IW, Keilholz U. Complete remission in a patient with recurrent acute myeloid leukemia induced by vaccination with WT1 peptide in the absence of hematological or renal toxicity. Leukemia. 2004;18:165–6.PubMedCrossRefGoogle Scholar
  55. 55.
    Keilholz U, Letsch A, Busse A, et al. A clinical and immunologic phase 2 trial of Wilms tumor gene product 1 (WT1) peptide vaccination in patients with AML and MDS. Blood. 2009;113:6541–8.PubMedCrossRefGoogle Scholar
  56. 56.
    Rezvani K, Yong AS, Mielke S, et al. Repeated PR1 and WT1 peptide vaccination in Montanide-adjuvant fails to induce sustained high-avidity, epitope-specific CD8+ T cells in myeloid malignancies. Haematologica. 2011;96:432–40.PubMedCrossRefGoogle Scholar
  57. 57.
    de Bueger M, Bakker A, Van Rood JJ, Van der Woude F, Goulmy E. Tissue distribution of human minor histocompatibility antigens. Ubiquitous versus restricted tissue distribution indicates heterogeneity among human cytotoxic T lymphocyte-defined non-MHC antigens. J Immunol. 1992;149:1788–94.PubMedGoogle Scholar
  58. 58.
    Li N, Matte-Martone C, Zheng H, et al. Memory T cells from minor histocompatibility antigen-vaccinated and virus-immune donors improve GVL and immune reconstitution. Blood. 2011;118:5965–76.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Raya Mawad
    • 1
    • 2
  • Jack M. Lionberger
    • 3
  • John M. Pagel
    • 1
    • 2
    Email author
  1. 1.Clinical Research DivisionFred Hutchinson Cancer Research CenterSeattleUSA
  2. 2.Department of Medicine, Division of Medical OncologyUniversity of WashingtonSeattleUSA
  3. 3.Department of Medicine, Hematology/Oncology DivisionSt. Louis UniversitySt. LouisUSA

Personalised recommendations