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Treatment of relapsed or refractory acute myeloid leukemia

Author
Richard A Larson, MD
Section Editor
Bob Lowenberg, MD, PhD
Deputy Editor
Alan G Rosmarin, MD

INTRODUCTION

The first step in the successful treatment of a patient with acute myeloid leukemia (AML) is the attainment of a complete remission (CR), which is characterized by (table 1):

Normal values for absolute neutrophil count (>1000/microL) and platelet count (>100,000/microL), and independence from red cell transfusion.

A bone marrow biopsy that reveals no clusters or collections of blast cells. Extramedullary leukemia (eg, central nervous system or soft tissue involvement) must be absent.

A bone marrow aspiration revealing normal maturation of all cellular components (ie, erythroid, granulocytic, and megakaryocytic series). There is no requirement for bone marrow cellularity.

Less than 5 percent of blast cells present in the bone marrow, and none with a leukemic phenotype (eg, Auer rods). The persistence of dysplasia is worrisome as an indicator of residual AML, but has not been validated as a criterion for remission status.

                   

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Literature review current through: May 2017. | This topic last updated: Mar 31, 2017.
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References
Top
  1. Döhner H, Estey E, Grimwade D, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood 2017; 129:424.
  2. Rowe JM, Kim HT, Cassileth PA, et al. Adult patients with acute myeloid leukemia who achieve complete remission after 1 or 2 cycles of induction have a similar prognosis: a report on 1980 patients registered to 6 studies conducted by the Eastern Cooperative Oncology Group. Cancer 2010; 116:5012.
  3. Bachas C, Schuurhuis GJ, Hollink IH, et al. High-frequency type I/II mutational shifts between diagnosis and relapse are associated with outcome in pediatric AML: implications for personalized medicine. Blood 2010; 116:2752.
  4. Rowe JM, Tallman MS. How I treat acute myeloid leukemia. Blood 2010; 116:3147.
  5. Jabbour E, Daver N, Champlin R, et al. Allogeneic stem cell transplantation as initial salvage for patients with acute myeloid leukemia refractory to high-dose cytarabine-based induction chemotherapy. Am J Hematol 2014; 89:395.
  6. Duval M, Klein JP, He W, et al. Hematopoietic stem-cell transplantation for acute leukemia in relapse or primary induction failure. J Clin Oncol 2010; 28:3730.
  7. Roboz GJ, Rosenblat T, Arellano M, et al. International randomized phase III study of elacytarabine versus investigator choice in patients with relapsed/refractory acute myeloid leukemia. J Clin Oncol 2014; 32:1919.
  8. Herzig RH, Lazarus HM, Wolff SN, et al. High-dose cytosine arabinoside therapy with and without anthracycline antibiotics for remission reinduction of acute nonlymphoblastic leukemia. J Clin Oncol 1985; 3:992.
  9. Karanes C, Kopecky KJ, Head DR, et al. A phase III comparison of high dose ARA-C (HIDAC) versus HIDAC plus mitoxantrone in the treatment of first relapsed or refractory acute myeloid leukemia Southwest Oncology Group Study. Leuk Res 1999; 23:787.
  10. Breems DA, Van Putten WL, Huijgens PC, et al. Prognostic index for adult patients with acute myeloid leukemia in first relapse. J Clin Oncol 2005; 23:1969.
  11. Giles F, Verstovsek S, Garcia-Manero G, et al. Validation of the European Prognostic Index for younger adult patients with acute myeloid leukaemia in first relapse. Br J Haematol 2006; 134:58.
  12. Ho AD, Lipp T, Ehninger G, et al. Combination of mitoxantrone and etoposide in refractory acute myelogenous leukemia--an active and well-tolerated regimen. J Clin Oncol 1988; 6:213.
  13. Daenen S, Löwenberg B, Sonneveld P, et al. Efficacy of etoposide and mitoxantrone in patients with acute myelogenous leukemia refractory to standard induction therapy and intermediate-dose cytarabine with amsidine. Dutch Hematology-Oncology Working Group for Adults (HOVON). Leukemia 1994; 8:6.
  14. Rowe JM, Mazza JJ, Hines JD, et al. Mitoxantrone and etoposide in patients with relapsed and refractory acute nonlymphocytic leukemia. Haematol Blood Transfus 1990; 33:326.
  15. Amadori S, Arcese W, Isacchi G, et al. Mitoxantrone, etoposide, and intermediate-dose cytarabine: an effective and tolerable regimen for the treatment of refractory acute myeloid leukemia. J Clin Oncol 1991; 9:1210.
  16. Büchner T, Hiddemann W, Wörmann B, et al. Double induction strategy for acute myeloid leukemia: the effect of high-dose cytarabine with mitoxantrone instead of standard-dose cytarabine with daunorubicin and 6-thioguanine: a randomized trial by the German AML Cooperative Group. Blood 1999; 93:4116.
  17. Bergmann L, Heil G, Denzlinger C, et al. Triple combination of mitoxantrone, topotecan, araC (MTC) in relapsed or refractory AML (abstract). Proc ASCO 2002; 21:271a.
  18. Sternberg DW, Aird W, Neuberg D, et al. Treatment of patients with recurrent and primary refractory acute myelogenous leukemia using mitoxantrone and intermediate-dose cytarabine: a pharmacologically based regimen. Cancer 2000; 88:2037.
  19. Montillo M, Mirto S, Petti MC, et al. Fludarabine, cytarabine, and G-CSF (FLAG) for the treatment of poor risk acute myeloid leukemia. Am J Hematol 1998; 58:105.
  20. Jackson G, Taylor P, Smith GM, et al. A multicentre, open, non-comparative phase II study of a combination of fludarabine phosphate, cytarabine and granulocyte colony-stimulating factor in relapsed and refractory acute myeloid leukaemia and de novo refractory anaemia with excess of blasts in transformation. Br J Haematol 2001; 112:127.
  21. Martin MG, Welch JS, Augustin K, et al. Cladribine in the treatment of acute myeloid leukemia: a single-institution experience. Clin Lymphoma Myeloma 2009; 9:298.
  22. Wierzbowska A, Robak T, Pluta A, et al. Cladribine combined with high doses of arabinoside cytosine, mitoxantrone, and G-CSF (CLAG-M) is a highly effective salvage regimen in patients with refractory and relapsed acute myeloid leukemia of the poor risk: a final report of the Polish Adult Leukemia Group. Eur J Haematol 2008; 80:115.
  23. Brown RA, Herzig RH, Wolff SN, et al. High-dose etoposide and cyclophosphamide without bone marrow transplantation for resistant hematologic malignancy. Blood 1990; 76:473.
  24. Liu Yin JA, Wheatley K, Rees JK, et al. Comparison of 'sequential' versus 'standard' chemotherapy as re-induction treatment, with or without cyclosporine, in refractory/relapsed acute myeloid leukaemia (AML): results of the UK Medical Research Council AML-R trial. Br J Haematol 2001; 113:713.
  25. Cortes J, Estey E, O'Brien S, et al. High-dose liposomal daunorubicin and high-dose cytarabine combination in patients with refractory or relapsed acute myelogenous leukemia. Cancer 2001; 92:7.
  26. Fassas A, Buffels R, Anagnostopoulos A, et al. Safety and early efficacy assessment of liposomal daunorubicin (DaunoXome) in adults with refractory or relapsed acute myeloblastic leukaemia: a phase I-II study. Br J Haematol 2002; 116:308.
  27. Chevallier P, Delaunay J, Turlure P, et al. Long-term disease-free survival after gemtuzumab, intermediate-dose cytarabine, and mitoxantrone in patients with CD33(+) primary resistant or relapsed acute myeloid leukemia. J Clin Oncol 2008; 26:5192.
  28. Becker PS, Kantarjian HM, Appelbaum FR, et al. Clofarabine with high dose cytarabine and granulocyte colony-stimulating factor (G-CSF) priming for relapsed and refractory acute myeloid leukaemia. Br J Haematol 2011; 155:182.
  29. Scappini B, Gianfaldoni G, Caracciolo F, et al. Cytarabine and clofarabine after high-dose cytarabine in relapsed or refractory AML patients. Am J Hematol 2012; 87:1047.
  30. Othus M, Appelbaum FR, Petersdorf SH, et al. Fate of patients with newly diagnosed acute myeloid leukemia who fail primary induction therapy. Biol Blood Marrow Transplant 2015; 21:559.
  31. Chantry AD, Snowden JA, Craddock C, et al. Long-term outcomes of myeloablation and autologous transplantation of relapsed acute myeloid leukemia in second remission: a British Society of Blood and Marrow Transplantation registry study. Biol Blood Marrow Transplant 2006; 12:1310.
  32. McClune BL, Weisdorf DJ, Pedersen TL, et al. Effect of age on outcome of reduced-intensity hematopoietic cell transplantation for older patients with acute myeloid leukemia in first complete remission or with myelodysplastic syndrome. J Clin Oncol 2010; 28:1878.
  33. Gooley TA, Chien JW, Pergam SA, et al. Reduced mortality after allogeneic hematopoietic-cell transplantation. N Engl J Med 2010; 363:2091.
  34. Murata M, Nishida T, Haneda M, et al. A new preconditioning regimen with melphalan, busulphan and total body irradiation followed by low-dose immunosuppressant in allogeneic haemopoietic stem cell transplantation. Br J Haematol 1999; 105:799.
  35. Bacigalupo A, Vitale V, Corvò R, et al. The combined effect of total body irradiation (TBI) and cyclosporin A (CyA) on the risk of relapse in patients with acute myeloid leukaemia undergoing allogeneic bone marrow transplantation. Br J Haematol 2000; 108:99.
  36. Ringdén O, Labopin M, Ehninger G, et al. Reduced intensity conditioning compared with myeloablative conditioning using unrelated donor transplants in patients with acute myeloid leukemia. J Clin Oncol 2009; 27:4570.
  37. Taskesen E, Bullinger L, Corbacioglu A, et al. Prognostic impact, concurrent genetic mutations, and gene expression features of AML with CEBPA mutations in a cohort of 1182 cytogenetically normal AML patients: further evidence for CEBPA double mutant AML as a distinctive disease entity. Blood 2011; 117:2469.
  38. Grigg AP, Szer J, Beresford J, et al. Factors affecting the outcome of allogeneic bone marrow transplantation for adult patients with refractory or relapsed acute leukaemia. Br J Haematol 1999; 107:409.
  39. Wong R, Giralt SA, Martin T, et al. Reduced-intensity conditioning for unrelated donor hematopoietic stem cell transplantation as treatment for myeloid malignancies in patients older than 55 years. Blood 2003; 102:3052.
  40. de Lima M, Anagnostopoulos A, Munsell M, et al. Nonablative versus reduced-intensity conditioning regimens in the treatment of acute myeloid leukemia and high-risk myelodysplastic syndrome: dose is relevant for long-term disease control after allogeneic hematopoietic stem cell transplantation. Blood 2004; 104:865.
  41. Kobayashi K, Kami M, Murashige N, et al. Outcomes of patients with acute leukaemia who relapsed after reduced-intensity stem cell transplantation from HLA-identical or one antigen-mismatched related donors. Br J Haematol 2005; 129:795.
  42. Claxton DF, Ehmann C, Rybka W. Control of advanced and refractory acute myelogenous leukaemia with sirolimus-based non-myeloablative allogeneic stem cell transplantation. Br J Haematol 2005; 130:256.
  43. Schmid C, Schleuning M, Ledderose G, et al. 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.
  44. van Besien K, Artz A, Smith S, et al. Fludarabine, melphalan, and alemtuzumab conditioning in adults with standard-risk advanced acute myeloid leukemia and myelodysplastic syndrome. J Clin Oncol 2005; 23:5728.
  45. Tauro S, Craddock C, Peggs K, et al. Allogeneic stem-cell transplantation using a reduced-intensity conditioning regimen has the capacity to produce durable remissions and long-term disease-free survival in patients with high-risk acute myeloid leukemia and myelodysplasia. J Clin Oncol 2005; 23:9387.
  46. Schmid C, Schleuning M, Schwerdtfeger R, et al. Long-term survival in refractory acute myeloid leukemia after sequential treatment with chemotherapy and reduced-intensity conditioning for allogeneic stem cell transplantation. Blood 2006; 108:1092.
  47. Moore J, Nivison-Smith I, Goh K, et al. Equivalent survival for sibling and unrelated donor allogeneic stem cell transplantation for acute myelogenous leukemia. Biol Blood Marrow Transplant 2007; 13:601.
  48. Valcarcel D, Kan F, Wang T, et al. One antigen HLA-mismatched related and 8/8 allele matched unrelated donors are associated with similar survival after hematopoietic cell transplantation for acute leukemia (abstract). Blood 2008; 112:355.
  49. Appelbaum FR. Allogeneic hematopoietic cell transplantation for acute myeloid leukemia when a matched related donor is not available. Hematology Am Soc Hematol Educ Program 2008; :412.
  50. Rocha V, Labopin M, Sanz G, et al. Transplants of umbilical-cord blood or bone marrow from unrelated donors in adults with acute leukemia. N Engl J Med 2004; 351:2276.
  51. Schetelig J, Bornhäuser M, Schmid C, et al. Matched unrelated or matched sibling donors result in comparable survival after allogeneic stem-cell transplantation in elderly patients with acute myeloid leukemia: a report from the cooperative German Transplant Study Group. J Clin Oncol 2008; 26:5183.
  52. Atsuta Y, Suzuki R, Nagamura-Inoue T, et al. Disease-specific analyses of unrelated cord blood transplantation compared with unrelated bone marrow transplantation in adult patients with acute leukemia. Blood 2009; 113:1631.
  53. Basara N, Schulze A, Wedding U, et al. Early related or unrelated haematopoietic cell transplantation results in higher overall survival and leukaemia-free survival compared with conventional chemotherapy in high-risk acute myeloid leukaemia patients in first complete remission. Leukemia 2009; 23:635.
  54. Walter RB, Pagel JM, Gooley TA, et al. Comparison of matched unrelated and matched related donor myeloablative hematopoietic cell transplantation for adults with acute myeloid leukemia in first remission. Leukemia 2010; 24:1276.
  55. Gupta V, Tallman MS, He W, et al. Comparable survival after HLA-well-matched unrelated or matched sibling donor transplantation for acute myeloid leukemia in first remission with unfavorable cytogenetics at diagnosis. Blood 2010; 116:1839.
  56. Saber W, Opie S, Rizzo JD, et al. Outcomes after matched unrelated donor versus identical sibling hematopoietic cell transplantation in adults with acute myelogenous leukemia. Blood 2012; 119:3908.
  57. Mori M, Beatty PG, Graves M, et al. HLA gene and haplotype frequencies in the North American population: the National Marrow Donor Program Donor Registry. Transplantation 1997; 64:1017.
  58. Sanz J, Jaramillo FJ, Planelles D, et al. Impact on outcomes of human leukocyte antigen matching by allele-level typing in adults with acute myeloid leukemia undergoing umbilical cord blood transplantation. Biol Blood Marrow Transplant 2014; 20:106.
  59. Eapen M, Rocha V, Sanz G, et al. Effect of graft source on unrelated donor haemopoietic stem-cell transplantation in adults with acute leukaemia: a retrospective analysis. Lancet Oncol 2010; 11:653.
  60. Laughlin MJ, Eapen M, Rubinstein P, et al. Outcomes after transplantation of cord blood or bone marrow from unrelated donors in adults with leukemia. N Engl J Med 2004; 351:2265.
  61. Ooi J, Iseki T, Takahashi S, et al. Unrelated cord blood transplantation for adult patients with de novo acute myeloid leukemia. Blood 2004; 103:489.
  62. Wang Y, Liu DH, Liu KY, et al. Impact of pretransplantation risk factors on post transplantation outcome of patients with acute myeloid leukemia in remission after haploidentical hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2013; 19:283.
  63. Brunstein CG, Fuchs EJ, Carter SL, et al. Alternative donor transplantation after reduced intensity conditioning: results of parallel phase 2 trials using partially HLA-mismatched related bone marrow or unrelated double umbilical cord blood grafts. Blood 2011; 118:282.
  64. Liu H, Rich ES, Godley L, et al. Reduced-intensity conditioning with combined haploidentical and cord blood transplantation results in rapid engraftment, low GVHD, and durable remissions. Blood 2011; 118:6438.
  65. Van Besien K, Liu H, Jain N, et al. Umbilical cord blood transplantation supported by third-party donor cells: rationale, results, and applications. Biol Blood Marrow Transplant 2013; 19:682.
  66. Jain N, Liu H, Artz AS, et al. Immune reconstitution after combined haploidentical and umbilical cord blood transplant. Leuk Lymphoma 2013; 54:1242.
  67. Frassoni F, Barrett AJ, Grañena A, et al. Relapse after allogeneic bone marrow transplantation for acute leukaemia: a survey by the E.B.M.T. of 117 cases. Br J Haematol 1988; 70:317.
  68. Locatelli F. The role of repeat transplantation of haemopoietic stem cells and adoptive immunotherapy in treatment of leukaemia relapsing following allogeneic transplantation. Br J Haematol 1998; 102:633.
  69. Radich JP, Sanders JE, Buckner CD, et al. Second allogeneic marrow transplantation for patients with recurrent leukemia after initial transplant with total-body irradiation-containing regimens. J Clin Oncol 1993; 11:304.
  70. Barrett AJ, Locatelli F, Treleaven JG, et al. Second transplants for leukaemic relapse after bone marrow transplantation: high early mortality but favourable effect of chronic GVHD on continued remission. A report by the EBMT Leukaemia Working Party. Br J Haematol 1991; 79:567.
  71. Bosi A, Laszlo D, Labopin M, et al. Second allogeneic bone marrow transplantation in acute leukemia: results of a survey by the European Cooperative Group for Blood and Marrow Transplantation. J Clin Oncol 2001; 19:3675.
  72. Bosi A, Bacci S, Miniero R, et al. Second allogeneic bone marrow transplantation in acute leukemia: a multicenter study from the Gruppo Italiano Trapianto Di Midollo Osseo (GITMO). Leukemia 1997; 11:420.
  73. Christopeit M, Kuss O, Finke J, et al. Second allograft for hematologic relapse of acute leukemia after first allogeneic stem-cell transplantation from related and unrelated donors: the role of donor change. J Clin Oncol 2013; 31:3259.
  74. Michallet M, Tanguy ML, Socié G, et al. Second allogeneic haematopoietic stem cell transplantation in relapsed acute and chronic leukaemias for patients who underwent a first allogeneic bone marrow transplantation: a survey of the Société Française de Greffe de moelle (SFGM). Br J Haematol 2000; 108:400.
  75. Pawson R, Potter MN, Theocharous P, et al. Treatment of relapse after allogeneic bone marrow transplantation with reduced intensity conditioning (FLAG +/- Ida) and second allogeneic stem cell transplant. Br J Haematol 2001; 115:622.
  76. Leung AY, Tse E, Hwang YY, et al. Primary treatment of leukemia relapses after allogeneic hematopoietic stem cell transplantation with reduced-intensity conditioning second transplantation from the original donor. Am J Hematol 2013; 88:485.
  77. Collins RH Jr, 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.
  78. Verdonck LF, Petersen EJ, Lokhorst HM, et al. Donor leukocyte infusions for recurrent hematologic malignancies after allogeneic bone marrow transplantation: impact of infused and residual donor T cells. Bone Marrow Transplant 1998; 22:1057.
  79. Schmid C, Labopin M, Nagler A, et al. Treatment, risk factors, and outcome of adults with relapsed AML after reduced intensity conditioning for allogeneic stem cell transplantation. Blood 2012; 119:1599.
  80. 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.
  81. Vago L, Perna SK, Zanussi M, et al. Loss of mismatched HLA in leukemia after stem-cell transplantation. N Engl J Med 2009; 361:478.
  82. Giles F, O'Brien S, Cortes J, et al. Outcome of patients with acute myelogenous leukemia after second salvage therapy. Cancer 2005; 104:547.