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Post-remission strategies for the prevention of relapse following allogeneic hematopoietic cell transplantation for high-risk acute myeloid leukemia: expert review from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation

Bone Marrow Transplantation volume 54, pages 519–530 (2019)Cite this article

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Abstract

Acute myeloid leukemia (AML) is an aggressive hematopoietic malignancy generally associated with poor prognosis. Allogeneic hematopoietic cell transplantation (alloHCT) continues to be the most potent anti-leukemia treatment for adult patients with intermediate and high-risk AML. However, disease relapse after alloHCT remains unacceptably high and is the primary cause of treatment failure and mortality following alloHCT. It is therefore that post-transplant early cellular or pharmacologic maintenance or preemptive strategies to enhance the graft-versus-leukemia effect or to eradicate persistent minimal residual disease have been of renewed interest, particularly with the availability of more sensitive technologies to measure residual AML. Although preliminary studies have demonstrated improved outcomes with the use of post-alloHCT remission therapies, prospective randomized trials are required to determine their clinical efficacy and role in the treatment of AML. On behalf of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation, we summarize the available evidence on the use and efficacy of available pharmacologic post-remission therapies, including hypomethylating agents, deacetylase inhibitors, and tyrosine kinase inhibitors, as well as cellular therapies, including preemptive and prophylactic donor lymphocyte infusions for the prevention of relapse of AML.

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References

  1. Cornelissen JJ, Gratwohl A, Schlenk RF, Sierra J, Bornhauser M, Juliusson G, et al. The European LeukemiaNet AML Working Party consensus statement on allogeneic HSCT for patients with AML in remission: an integrated-risk adapted approach. Nat Rev Clin Oncol. 2012;9:579–90.

    Article  CAS  PubMed  Google Scholar 

  2. Zuckerman T, Rowe JM. Transplantation in acute myeloid leukemia. Hematol Oncol Clin North Am. 2014;28:983–94.

    Article  PubMed  Google Scholar 

  3. Pemmaraju N, Kantarjian H, Garcia-Manero G, Pierce S, Cardenas-Turanzas M, Cortes J, et al. Improving outcomes for patients with acute myeloid leukemia in first relapse: a single center experience. Am J Hematol. 2015;90:27–30.

    Article  PubMed  Google Scholar 

  4. Bejanyan N, Weisdorf DJ, Logan BR, Wang HL, Devine SM, de Lima M, et al. Survival of patients with acute myeloid leukemia relapsing after allogeneic hematopoietic cell transplantation: a center for international blood and marrow transplant research study. Biol Blood Marrow Transplant. 2015;21:454–9.

    Article  PubMed  Google Scholar 

  5. Schmid C, Labopin M, Nagler A, Niederwieser D, Castagna L, Tabrizi R, et al. Treatment, risk factors, and outcome of adults with relapsed AML after reduced intensity conditioning for allogeneic stem cell transplantation. Blood. 2012;119:1599–606.

    Article  CAS  PubMed  Google Scholar 

  6. Andreola G, Labopin M, Beelen D, Chevallier P, Tabrizi R, Bosi A, et al. Long-term outcome and prognostic factors of second allogeneic hematopoietic stem cell transplant for acute leukemia in patients with a median follow-up of 10 years. Bone Marrow Transplant. 2015;50:1508–12.

    Article  CAS  PubMed  Google Scholar 

  7. Yafour N, Beckerich F, Bulabois CE, Chevallier P, Daguindau E, Dumesnil C, et al. How to prevent relapse after allogeneic hematopoietic stem cell transplantation in patients with acute leukemia and myelodysplastic syndrome. Curr Res Transl Med. 2017;65:65–69.

    Article  CAS  PubMed  Google Scholar 

  8. Ruggeri A, Sun Y, Labopin M, Bacigalupo A, Lorentino F, Arcese W, et al. Post-transplant cyclophosphamide versus anti-thymocyte globulin as graft- versus-host disease prophylaxis in haploidentical transplant. Haematologica. 2017;102:401–10.

    Article  PubMed  PubMed Central  Google Scholar 

  9. de Lima M, Bonamino M, Vasconcelos Z, Colares M, Diamond H, Zalcberg I, et al. Prophylactic donor lymphocyte infusions after moderately ablative chemotherapy and stem cell transplantation for hematological malignancies: high remission rate among poor prognosis patients at the expense of graft-versus-host disease. Bone Marrow Transplant. 2001;27:73–78.

    Article  PubMed  Google Scholar 

  10. Schmid C, Labopin M, Nagler A, Bornhauser M, Finke J, Fassas 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.

    Article  CAS  PubMed  Google Scholar 

  11. Schroeder T, Czibere A, Platzbecker U, Bug G, Uharek L, Luft T, et al. Azacitidine and donor lymphocyte infusions as first salvage therapy for relapse of AML or MDS after allogeneic stem cell transplantation. Leukemia. 2013;27:1229–35.

    Article  CAS  PubMed  Google Scholar 

  12. Esteller M. Cancer epigenomics: DNA methylomes and histone-modification maps. Nat Rev Genet. 2007;8:286–98.

    Article  CAS  PubMed  Google Scholar 

  13. Kantarjian HM, Thomas XG, Dmoszynska A, Wierzbowska A, Mazur G, Mayer J, et al. Multicenter, randomized, open-label, phase III trial of decitabine versus patient choice, with physician advice, of either supportive care or low-dose cytarabine for the treatment of older patients with newly diagnosed acute myeloid leukemia. J Clin Oncol. 2012;30:2670–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Dombret H, Seymour JF, Butrym A, Wierzbowska A, Selleslag D, Jang JH, et al. International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with > 30% blasts. Blood. 2015;126:291–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Sanchez-Abarca LI, Gutierrez-Cosio S, Santamaria C, Caballero-Velazquez T, Blanco B, Herrero-Sanchez C, et al. Immunomodulatory effect of 5-azacytidine (5-azaC): potential role in the transplantation setting. Blood. 2010;115:107–21.

    Article  CAS  PubMed  Google Scholar 

  16. Goodyear OC, Dennis M, Jilani NY, Loke J, Siddique S, Ryan G, et al. Azacitidine augments expansion of regulatory T cells after allogeneic stem cell transplantation in patients with acute myeloid leukemia (AML). Blood. 2012;119:3361–9.

    Article  CAS  PubMed  Google Scholar 

  17. Liu Y, Kuick R, Hanash S, Richardson B. DNA methylation inhibition increases T cell KIR expression through effects on both promoter methylation and transcription factors. Clin Immunol. 2009;130:213–24.

    Article  CAS  PubMed  Google Scholar 

  18. Jabbour E, Giralt S, Kantarjian H, Garcia-Manero G, Jagasia M, Kebriaei P, et al. Low-dose azacitidine after allogeneic stem cell transplantation for acute leukemia. Cancer. 2009;115:1899–905.

    Article  CAS  PubMed  Google Scholar 

  19. Czibere A, Bruns I, Kroger N, Platzbecker U, Lind J, Zohren F, et al. 5-Azacytidine for the treatment of patients with acute myeloid leukemia or myelodysplastic syndrome who relapse after allo-SCT: a retrospective analysis. Bone Marrow Transplant. 2010;45:872–6.

    Article  CAS  PubMed  Google Scholar 

  20. Bolanos-Meade J, Smith BD, Gore SD, McDevitt MA, Luznik L, Fuchs EJ, et al. 5-azacytidine as salvage treatment in relapsed myeloid tumors after allogeneic bone marrow transplantation. Biol Blood Marrow Transplant. 2011;17:754–8.

    Article  CAS  PubMed  Google Scholar 

  21. Schroeder T, Rachlis E, Bug G, Stelljes M, Klein S, Steckel NK, et al. Treatment of acute myeloid leukemia or myelodysplastic syndrome relapse after allogeneic stem cell transplantation with azacitidine and donor lymphocyte infusions--a retrospective multicenter analysis from the German Cooperative Transplant Study Group. Biol Blood Marrow Transplant. 2015;21:653–60.

    Article  CAS  PubMed  Google Scholar 

  22. Craddock C, Labopin M, Robin M, Finke J, Chevallier P, Yakoub-Agha I, et al. Clinical activity of azacitidine in patients who relapse after allogeneic stem cell transplantation for acute myeloid leukemia. Haematologica. 2016;101:879–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Choi J, Ritchey J, Prior JL, Holt M, Shannon WD, Deych E, et al. In vivo administration of hypomethylating agents mitigate graft-versus-host disease without sacrificing graft-versus-leukemia. Blood. 2010;116:129–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Schroeder T, Frobel J, Cadeddu RP, Czibere A, Dienst A, Platzbecker U, et al. Salvage therapy with azacitidine increases regulatory T cells in peripheral blood of patients with AML or MDS and early relapse after allogeneic blood stem cell transplantation. Leukemia. 2013;27:1910–3.

    Article  CAS  PubMed  Google Scholar 

  25. de Lima M, Giralt S, Thall PF, de Padua Silva L, Jones RB, Komanduri K, 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.

    Article  PubMed  Google Scholar 

  26. Craddock C, Jilani N, Siddique S, Yap C, Khan J, Nagra S, et al. Tolerability and clinical activity of post-transplantation azacitidine in patients allografted for acute myeloid leukemia treated on the RICAZA trial. Biol Blood Marrow Transplant. 2016;22:385–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Platzbecker U, Wermke M, Radke J, Oelschlaegel U, Seltmann F, Kiani A, et al. Azacitidine for treatment of imminent relapse in MDS or AML patients after allogeneic HSCT: results of the RELAZA trial. Leukemia. 2012;26:381–9.

    Article  CAS  PubMed  Google Scholar 

  28. de Lima M, Oran B, Champlin RE, Papadopoulos EB, Giralt SA, Scott BL, et al. Final analysis of the phase I/II study of CC-486 (oral azacitidine) maintenance therapy after allogeneic stem cell transplantation (Allo-SCT) in patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS). Blood. 2017;130:4512.

    Google Scholar 

  29. Pusic I, Choi J, Fiala MA, Gao F, Holt M, Cashen AF, et al. Maintenance therapy with decitabine after allogeneic stem cell transplantation for acute myelogenous leukemia and myelodysplastic syndrome. Biol Blood Marrow Transplant. 2015;21:1761–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Shen L, Pili R. Class I histone deacetylase inhibition is a novel mechanism to target regulatory T cells in immunotherapy. Oncoimmunology. 2012;1:948–50.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Stahl M, Gore SD, Vey N, Prebet T. Lost in translation? Ten years of development of histone deacetylase inhibitors in acute myeloid leukemia and myelodysplastic syndromes. Expert Opin Investig Drugs. 2016;25:307–17.

    Article  CAS  PubMed  Google Scholar 

  32. DeAngelo DJ, Spencer A, Bhalla KN, Prince HM, Fischer T, Kindler T, et al. Phase Ia/II, two-arm, open-label, dose-escalation study of oral panobinostat administered via two dosing schedules in patients with advanced hematologic malignancies. Leukemia. 2013;27:1628–36.

    Article  CAS  PubMed  Google Scholar 

  33. Bug G, Burchert A, Wagner E, Kroeger N, Jedlickova Z, Gueller S et al. Phase I/II study of the deacetylase inhibitor panobinostat as maintenance therapy after an allogeneic stem cell transplantation in patients with high-risk MDS or AML: The Panobest-Trial [abstract]. In: Blood, 2015.

  34. Fukushima N, Minami Y, Kakiuchi S, Kuwatsuka Y, Hayakawa F, Jamieson C, et al. Small-molecule Hedgehog inhibitor attenuates the leukemia-initiation potential of acute myeloid leukemia cells. Cancer Sci. 2016;107:1422–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Cortes JE, Heidel FH, Heuser M, Fiedler W, Smith BD, Robak T. A phase 2 randomized study of low dose Ara-C with or without Glasdegib (PF-04449913) in untreated patients with acute myeloid leukemia or high-risk myelodysplastic syndrome. Blood. 2016;128:99.

  36. Levis M, Small D. FLT3: it does matter in leukemia. Leukemia. 2003;17:1738–52.

    Article  CAS  PubMed  Google Scholar 

  37. Brandts CH, Sargin B, Rode M, Biermann C, Lindtner B, Schwable J, et al. Constitutive activation of Akt by Flt3 internal tandem duplications is necessary for increased survival, proliferation, and myeloid transformation. Cancer Res. 2005;65:9643–50.

    Article  CAS  PubMed  Google Scholar 

  38. Kelly LM, Liu Q, Kutok JL, Williams IR, Boulton CL, Gilliland DG. FLT3 internal tandem duplication mutations associated with human acute myeloid leukemias induce myeloproliferative disease in a murine bone marrow transplant model. Blood. 2002;99:310–8.

    Article  CAS  PubMed  Google Scholar 

  39. Schlenk RF, Kayser S, Bullinger L, Kobbe G, Casper J, Ringhoffer M, et al. Differential impact of allelic ratio and insertion site in FLT3-ITD-positive AML with respect to allogeneic transplantation. Blood. 2014;124:3441–9.

    Article  CAS  PubMed  Google Scholar 

  40. Kim Y, Lee GD, Park J, Yoon JH, Kim HJ, Min WS, et al. Quantitative fragment analysis of FLT3-ITD efficiently identifying poor prognostic group with high mutant allele burden or long ITD length. Blood Cancer J. 2015;5:e336.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Kottaridis PD, Gale RE, Frew ME, Harrison G, Langabeer SE, Belton AA, et al. The presence of a FLT3 internal tandem duplication in patients with acute myeloid leukemia (AML) adds important prognostic information to cytogenetic risk group and response to the first cycle of chemotherapy: analysis of 854 patients from the United Kingdom Medical Research Council AML 10 and 12 trials. Blood. 2001;98:1752–9.

    Article  CAS  PubMed  Google Scholar 

  42. Meshinchi S, Alonzo TA, Stirewalt DL, Zwaan M, Zimmerman M, Reinhardt D, et al. Clinical implications of FLT3 mutations in pediatric AML. Blood. 2006;108:3654–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Burnett AK, Goldstone A, Hills RK, Milligan D, Prentice A, Yin J, et al. Curability of patients with acute myeloid leukemia who did not undergo transplantation in first remission. J Clin Oncol. 2013;31:1293–301.

    Article  PubMed  Google Scholar 

  44. Levis M. FLT3 mutations in acute myeloid leukemia: what is the best approach in 2013? Hematol Am Soc Hematol Educ Program. 2013;2013:220–6.

    Article  Google Scholar 

  45. Brunet S, Labopin M, Esteve J, Cornelissen J, Socie G, Iori AP, et al. Impact of FLT3 internal tandem duplication on the outcome of related and unrelated hematopoietic transplantation for adult acute myeloid leukemia in first remission: a retrospective analysis. J Clin Oncol. 2012;30:735–41.

    Article  PubMed  Google Scholar 

  46. Deol A, Sengsayadeth S, Ahn KW, Wang HL, Aljurf M, Antin JH, et al. Does FLT3 mutation impact survival after hematopoietic stem cell transplantation for acute myeloid leukemia? A Center for International Blood and Marrow Transplant Research (CIBMTR) analysis. Cancer. 2016;122:3005–14.

    Article  CAS  PubMed  Google Scholar 

  47. Konig H, Levis M. Targeting FLT3 to treat leukemia. Expert Opin Ther Targets. 2015;19:37–54.

    Article  CAS  PubMed  Google Scholar 

  48. Carpenter PA, Snyder DS, Flowers ME, Sanders JE, Gooley TA, Martin PJ, et al. Prophylactic administration of imatinib after hematopoietic cell transplantation for high-risk Philadelphia chromosome-positive leukemia. Blood. 2007;109:2791–3.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Giebel S, Czyz A, Ottmann O, Baron F, Brissot E, Ciceri F, et al. Use of tyrosine kinase inhibitors to prevent relapse after allogeneic hematopoietic stem cell transplantation for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia: A position statement of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation. Cancer. 2016;122:2941–51.

    Article  CAS  PubMed  Google Scholar 

  50. Metzelder SK, Schroeder T, Finck A, Scholl S, Fey M, Gotze K, et al. High activity of sorafenib in FLT3-ITD-positive acute myeloid leukemia synergizes with allo-immune effects to induce sustained responses. Leukemia. 2012;26:2353–9.

    Article  CAS  PubMed  Google Scholar 

  51. Wilhelm SM, Carter C, Tang L, Wilkie D, McNabola A, Rong H, et al. BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res. 2004;64:7099–109.

    Article  CAS  PubMed  Google Scholar 

  52. Metzelder S, Wang Y, Wollmer E, Wanzel M, Teichler S, Chaturvedi A, 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.

    Article  CAS  PubMed  Google Scholar 

  53. Sharma M, Ravandi F, Bayraktar UD, Chiattone A, Bashir Q, Giralt S, 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Chen YB, Li S, Lane AA, Connolly C, Del Rio C, Valles B, et al. Phase I trial of maintenance sorafenib after allogeneic hematopoietic stem cell transplantation for fms-like tyrosine kinase 3 internal tandem duplication acute myeloid leukemia. Biol Blood Marrow Transplant. 2014;20:2042–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Brunner AM, Li S, Fathi AT, Wadleigh M, Ho VT, Collier K, et al. Haematopoietic cell transplantation with and without sorafenib maintenance for patients with FLT3-ITD acute myeloid leukaemia in first complete remission. Br J Haematol. 2016;175:496–504.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Battipaglia G, Ruggeri A, Massoud R, El Cheikh J, Jestin M, Antar A, et al. Efficacy and feasibility of sorafenib as a maintenance agent after allogeneic hematopoietic stem cell transplantation for Fms-like tyrosine kinase 3-mutated acute myeloid leukemia. Cancer. 2017;123:2867–74.

    Article  CAS  PubMed  Google Scholar 

  57. Tarlock K, Chang B, Cooper T, Gross T, Gupta S, Neudorf S, et al. Sorafenib treatment following hematopoietic stem cell transplant in pediatric FLT3/ITD acute myeloid leukemia. Pediatr Blood Cancer. 2015;62:1048–54.

    Article  CAS  PubMed  Google Scholar 

  58. Pratz KW, Gojo I, Karp JE. Luznik L, Smith BD, Jones RJ, et al. Prospective study of peri-transplant use of sorafenib as remission maintenance for FLT3-ITD patients undergoing allogeneic transplantation. Blood. 2015;126:3164.

  59. Weisberg E, Boulton C, Kelly LM, Manley P, Fabbro D, Meyer T, et al. Inhibition of mutant FLT3 receptors in leukemia cells by the small molecule tyrosine kinase inhibitor PKC412. Cancer Cell. 2002;1:433–43.

    Article  CAS  PubMed  Google Scholar 

  60. Fischer T, Stone RM, Deangelo DJ, Galinsky I, Estey E, Lanza C, et al. Phase IIB trial of oral Midostaurin (PKC412), the FMS-like tyrosine kinase 3 receptor (FLT3) and multi-targeted kinase inhibitor, in patients with acute myeloid leukemia and high-risk myelodysplastic syndrome with either wild-type or mutated FLT3. J Clin Oncol. 2010;28:4339–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Stone RM, Mandrekar SJ, Sanford BL, Laumann K, Geyer S, Bloomfield CD, et al. Midostaurin plus Chemotherapy for Acute Myeloid Leukemia with a FLT3 Mutation. N Engl J Med. 2017;377:454–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Schlenk R, Dohner K, Salih H, Kundgen A, Fiedler W, Salwender HJ et al. Midostaurin in combination with intensive induction and as single agent maintenance therapy after consolidation therapy with allogeneic hematopoietic stem cell transplantation or high-dose cytarabine (NCT01477606). Blood. 2015;126:322.

  63. Levis M. Quizartinib for the treatment of FLT3/ITD acute myeloid leukemia. Future Oncol. 2014;10:1571–9.

    Article  CAS  PubMed  Google Scholar 

  64. Levis MJ, Perl AE, Dombret H, Dohner H, Steffen B, Rousselot P et al. Final results of a phase 2 open-label, monotherapy efficacy and safety study of quizartinib (AC220) in patients with FLT3-ITD positive or negative relapsed/refractory acute myeloid leukemia after second-line chemotherapy or hematopoietic stem cell transplantation. Blood. 2012;120:673.

  65. Schiller GJ, Tallman MS, Goldberg SL, Perl AE, Marie J, Martinelli G et al. Final results of a randomized phase 2 study showing the clinical benefit of quizartinib (AC220) in patients with FLT3-ITD positive relapsed or refractory acute myeloid leukemia. J Clin Oncol. 2014;32:7100.

    Article  Google Scholar 

  66. Sandmaier BM, Khaled SK, Oran B, Gammon G, Trone D, Frankfurt O. Results of a phase 1 study of quizartinib (AC220) as maintenance therapy in subjects with acute myeloid leukemia in remission following allogeneic hematopoietic cell transplantation. Blood. 2014;124:428.

  67. Smith CC, Wang Q, Chin CS, Salerno S, Damon LE, Levis MJ, et al. Validation of ITD mutations in FLT3 as a therapeutic target in human acute myeloid leukaemia. Nature. 2012;485:260–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Smith CC, Paguirigan A, Jeschke GR, Lin KC, Massi E, Tarver T, et al. Heterogeneous resistance to quizartinib in acute myeloid leukemia revealed by single-cell analysis. Blood. 2017;130:48–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Galanis A, Ma H, Rajkhowa T, Ramachandran A, Small D, Cortes J, et al. Crenolanib is a potent inhibitor of FLT3 with activity against resistance-conferring point mutants. Blood. 2014;123:94–100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Randhawa JK, Kantarjian HM, Borthakur G, Thompson PA, Konopleva M, Daver N et al. Results of a phase II study of crenolanib in relapsed/refractory acute myeloid leukemia patients (Pts) with activating FLT3 mutations. Blood. 2014;124:389.

  71. Collins R, Kantarjian HM, Levis MJ, Perl AE, Ramachandran A, Ravandi F et al. Clinical activity of crenolanib in patients with D835 mutant FLT3-positive relapsed/refractory acute myeloid leukemia (AML). J Clin Oncol. 2014;32:7027.

    Article  Google Scholar 

  72. Altman JK, Perl AE, Cortes JE, Levis MJ, Smith CC, Litzow MR et al. Antileukemic activity and tolerability of ASP2215 80mg and greater in FLT3 mutation-positive subjects with relapsed or refractory acute myeloid leukemia: results from a Phase 1/2, open-label, dose-escalation/dose-response study. Blood. 2015;126:321.

  73. Levis MJ, Perl AE, Altman JK, Cortes JE, Ritchie EK. Results of a first-in-human, phase I/II trial of ASP2215, a selective, potent inhibitor of FLT3/Axl in patients with relapsed or refractory (R/R) acute myeloid leukemia (AML). J Clin Oncol. 2015;33:7003.

    Article  Google Scholar 

  74. Perl AE, Altman JK, Cortes J, Smith C, Litzow M, Baer MR, et al. Selective inhibition of FLT3 by gilteritinib in relapsed or refractory acute myeloid leukaemia: a multicentre, first-in-human, open-label, phase 1-2 study. Lancet Oncol. 2017;18:1061–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. 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.

    Article  PubMed  Google Scholar 

  76. Jedlickova Z, Schmid C, Koenecke C, Hertenstein B, Baurmann H, Schwerdtfeger R, et al. Long-term results of adjuvant donor lymphocyte transfusion in AML after allogeneic stem cell transplantation. Bone Marrow Transplant. 2016;51:663–7.

    Article  CAS  PubMed  Google Scholar 

  77. Guillaume T, Yakoub-Agha I, Tabrizi R, Borel C, Chevallier P, Magro L, et al. Prospective phase II study of prophylactic azacitidine and donor lymphocyte infusions following allogeneic hematopoietic stem cell transplantation for high risk acute myeloid leukemia and myelodysplastic syndrome. Blood. 2016;128:1162.

    Article  Google Scholar 

  78. Bachanova V, Cooley S, Defor TE, Verneris MR, Zhang B, McKenna DH, et al. Clearance of acute myeloid leukemia by haploidentical natural killer cells is improved using IL-2 diphtheria toxin fusion protein. Blood. 2014;123:3855–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Bachanova V, Miller JS. NK cells in therapy of cancer. Crit Rev Oncog. 2014;19:133–41.

    Article  PubMed  PubMed Central  Google Scholar 

  80. Chapuis AG, Ragnarsson GB, Nguyen HN, Chaney CN, Pufnock JS, Schmitt TM, et al. Transferred WT1-reactive CD8 + T cells can mediate antileukemic activity and persist in post-transplant patients. Sci Transl Med. 2013;5:174ra27.

    Article  PubMed  PubMed Central  Google Scholar 

  81. Mardiros A, Dos Santos C, McDonald T, Brown CE, Wang X, Budde LE, et al. T cells expressing CD123-specific chimeric antigen receptors exhibit specific cytolytic effector functions and antitumor effects against human acute myeloid leukemia. Blood. 2013;122:3138–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Kenderian SS, Ruella M, Shestova O, Klichinsky M, Aikawa V, Morrissette JJ, et al. CD33-specific chimeric antigen receptor T cells exhibit potent preclinical activity against human acute myeloid leukemia. Leukemia. 2015;29:1637–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Lynn RC, Poussin M, Kalota A, Feng Y, Low PS, Dimitrov DS, et al. Targeting of folate receptor beta on acute myeloid leukemia blasts with chimeric antigen receptor-expressing T cells. Blood. 2015;125:3466–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Lichtenegger FS, Krupka C, Kohnke T, Subklewe M. Immunotherapy for acute myeloid leukemia. Semin Hematol. 2015;52:207–14.

    Article  CAS  PubMed  Google Scholar 

  85. Gillissen MA, Kedde M, Yasuda E, Levie SE, Bakker AQ, YBC et al. Donor-derived B cells produce potent AML-specific antibodies that recognize novel tumor-specific antigens and mediate graft-versus-leukemia immunity. Blood. 2015;126:3146.

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Authors and Affiliations

  1. Utah Blood and Marrow Transplant Program, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA

    Catherine J. Lee

  2. Vanderbilt University Medical Center, Nashville, TN, USA

    Bipin N. Savani

  3. Department of Hematology, Hopital Saint-Antoine, APHP and University UPMC, Paris, France

    Mohamad Mohty & Norbert C. Gorin

  4. Department of Haematology, Hopital Saint-Antoine, INSERM, Paris, France

    Myriam Labopin & Annalisa Ruggeri

  5. Klinikum Augsburg, Dept. of Hematology and Oncology, University of Munich, Augsburg, Germany

    Christoph Schmid

  6. Department of Medicine, Division of Hematology, University of Liège, Liège, Belgium

    Frédéric Baron

  7. Department of Hematology, Hospital Clinic, IDIBAPS, Barcelona, Spain

    Jordi Esteve

  8. Maria Sklodowska-Curie Cancer Center and Institute of Oncology, Gliwice Branch, Gliwice, Poland

    Sebastian Giebel

  9. Department of Hematology, IRCCS San Raffaele Scientific Institute, Milano, Italy

    Fabio Ciceri

  10. Hematology Division, Chaim Sheba Medical Center, Tel Hashomer, Israel

    Arnon Nagler

  11. Acute Leukemia Working Party – EBMT Paris office, Hȏpital Saint-Antoine, Paris, France

    Arnon Nagler

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Contributions

Catherine Lee: conceptualization and writing—original draft. Catherine Lee, Bipin Savani, Mohamed Mohty, Norbert Gorin, Myriam Labopin, Annalisa Ruggeri, Christoph Schmid, Frédéric Baron, Jordi Esteve, Sebastian Giebel, Fabio Ciceri, and Arnon Nagler: writing—review and editing. All authors guarantee the content of this manuscript

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Correspondence to Catherine J. Lee.

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Lee, C.J., Savani, B.N., Mohty, M. et al. Post-remission strategies for the prevention of relapse following allogeneic hematopoietic cell transplantation for high-risk acute myeloid leukemia: expert review from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation. Bone Marrow Transplant 54, 519–530 (2019). https://doi.org/10.1038/s41409-018-0286-2

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  • DOI: https://doi.org/10.1038/s41409-018-0286-2

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