Purpose of Review
This review discusses the current standard of care for incorporation of FLT3 TKIs and HCT into the treatment of FLT3-ITD AML. Additionally, this review provides an approach to the patient with relapsed/refractory disease.
Over the last decade, the routine use of HCT as consolidative therapy and the development of FLT3 TKIs have significantly improved remission rates and overall survival. The value and challenges of MRD assessment in FLT3 disease are discussed and current mechanisms of relapse are explored, as are the ongoing questions in the field that current clinical trials are seeking to answer.
FLT3-ITD mutations are common in acute myeloid leukemia and historically have been associated with a poor prognosis, but with the incorporation of FLT3 TKIs and routine use of allogeneic stem cell transplant as consolidative therapy, outcomes have improved dramatically. Ongoing research seeks to answer how and when to best use current therapies, and how to overcome resistance to FLT3 inhibition.
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Oran B, Cortes J, Beitinjaneh A, et al. Allogeneic transplantation in first remission improves outcomes irrespective of FLT3-ITD allelic ratio in FLT3-ITD-positive acute myelogenous leukemia. Biol Blood Marrow Transplant. 2016;22(7):1218–26.
DeZern AE, Sung A, Kim S, Smith BD, Karp JE, Gore SD, et al. Role of allogeneic transplantation for FLT3/ITD acute myeloid leukemia: outcomes from 133 consecutive newly diagnosed patients from a single institution. Biol Blood Marrow Transplant. 2011;17(9):1404–9.
Deol A, Sengsayadeth S, Ahn KW, 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(19):3005–14.
Kurosawa S, Yamaguchi H, Yamaguchi T, Fukunaga K, Yui S, Wakita S, et al. Decision analysis of postremission therapy in cytogenetically intermediate-risk acute myeloid leukemia: the impact of FLT3 internal tandem duplication, nucleophosmin, and CCAAT/enhancer binding protein alpha. Biol Blood Marrow Transplant. 2016;22(6):1125–32.
How J, Sykes J, Minden MD, et al. The prognostic impact of FLT3-ITD and NPM1 mutations in patients with relapsed acute myeloid leukemia and intermediate-risk cytogenetics. Blood Cancer J. 2013;3:e116.
Oran B, Jimenez AM, De Lima M, et al. Age and modified European LeukemiaNet classification to predict transplant outcomes: an integrated approach for acute myelogenous leukemia patients undergoing allogeneic stem cell transplantation. Biol Blood Marrow Transplant. 2015;21(8):1405–12.
Brunet S, Labopin M, Esteve J, Cornelissen J, Socié 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(7):735–41.
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(28):4339–45.
Stone RM, Fischer T, Paquette R, Schiller G, Schiffer CA, Ehninger G, et al. Phase IB study of the FLT3 kinase inhibitor midostaurin with chemotherapy in younger newly diagnosed adult patients with acute myeloid leukemia. Leukemia. 2012;26(9):2061–8.
•• Stone RM, Mandrekar SJ, Sanford BL, et al. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med. 2017;377(5):454–64 Randomized, phase III trial that showed a significant improvement in overall survival with the addition of midostaurin (FLT3 inhibitor) to standard induction therapy.
Serve H, Krug U, Wagner R, et al. Sorafenib in combination with intensive chemotherapy in elderly patients with acute myeloid leukemia: results from a randomized, placebo-controlled trial. J Clin Oncol. 2013;31(25):3110–8.
Macdonald DA, Assouline SE, Brandwein J, et al. A phase I/II study of sorafenib in combination with low dose cytarabine in elderly patients with acute myeloid leukemia or high-risk myelodysplastic syndrome from the National Cancer Institute of Canada Clinical Trials Group: trial IND.186. Leuk Lymphoma. 2013;54(4):760–6.
Rollig C, Serve H, Huttmann A, et al. Addition of sorafenib versus placebo to standard therapy in patients aged 60 years or younger with newly diagnosed acute myeloid leukaemia (SORAML): a multicentre, phase 2, randomised controlled trial. Lancet Oncol. 2015;16(16):1691–9.
Rollig C, Serve H, Hüttmann A, et al. The addition of sorafenib to standard AML treatment results in a substantial reduction in relapse risk and improved survival. Updated results from long-term follow-up of the randomized-controlled Soraml trial. Blood. 2017;130(S1):721.
Ohanian M, Garcia-Manero G, Levis M, Jabbour E, Daver N, Borthakur G, et al. Sorafenib combined with 5-azacytidine in older patients with untreated FLT3-ITD mutated acute myeloid leukemia. Am J Hematol. 2018;93(9):1136–41.
Altman JK, Foran JM, Pratz KW, Trone D, Cortes JE, Tallman MS. Phase 1 study of quizartinib in combination with induction and consolidation chemotherapy in patients with newly diagnosed acute myeloid leukemia. Am J Hematol. 2018;93(2):213–21.
Goldberg AD, Coombs CC, Wang ES, et al. Younger patients with newly diagnosed FLT3-mutant AML treated with crenolanib plus chemotherapy achieve adequate free crenolanib levels and durable remissions. Blood. 2019;134(S1):1326.
Pratz KW, Cherry M, Altman JK, et al. Updated results from a phase 1 study of gilteritinib in combination with induction and consolidation chemotherapy in subjects with newly diagnosed acute myeloid leukemia (AML). Blood. 2018;132(S1):564.
Bornhauser M, Illmer T, Schaich M, Soucek S, Ehninger G, Thiede C. Improved outcome after stem-cell transplantation in FLT3/ITD-positive AML. Blood. 2007;109(5):2264–5 author reply 2265.
Schlenk RF, Dohner K, Krauter J, et al. Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N Engl J Med. 2008;358(18):1909–18.
Sengsayadeth SM, Jagasia M, Engelhardt BG, et al. Allo-SCT for high-risk AML-CR1 in the molecular era: impact of FLT3/ITD outweighs the conventional markers. Bone Marrow Transplant. 2012;47(12):1535–7.
Schmid C, Labopin M, Socié G, Daguindau E, Volin L, Huynh A, et al. Outcome of patients with distinct molecular genotypes and cytogenetically normal AML after allogeneic transplantation. Blood. 2015;126(17):2062–9.
Poire X, Labopin M, Polge E, et al. Allogeneic stem cell transplantation benefits for patients >/= 60 years with acute myeloid leukemia and FLT3 internal tandem duplication: a study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation. Haematologica. 2018;103(2):256–65.
Schlenk RF, Weber D, Fiedler W, Salih HR, Wulf G, Salwender H, et al. Midostaurin added to chemotherapy and continued single-agent maintenance therapy in acute myeloid leukemia with FLT3-ITD. Blood. 2019;133(8):840–51.
Maziarz RT, Fernandez H, Patnaik MM, et al. Radius: midostaurin plus standard of care after allogeneic stem cell transplant in patients with FLT3 internal tandem duplication mutated acute myeloid leukemia. Biol Blood Marrow Transplant. 2019;25(3):S11–2.
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(12):2042–8.
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(3):496–504.
Pratz KW, Rudek MA, Smith BD, et al. A prospective study of peritransplant sorafenib for patients with FLT3-ITD acute myeloid leukemia undergoing allogeneic transplantation. Biol Blood Marrow Transplant. 2019.
•• Burchert A, Bug G, Finke J, et al. Sorafenib as maintenance therapy post allogeneic stem cell transplantation for FLT3-ITD positive AML: results from the randomized, double-blind, placebo-controlled multicentre Sormain trial. Blood. 2018;132(S1):661 Randomized trial showing overall survival benefit with the addition post-transplant sorafenib. Of note, the majority of these patients did not receicve any FLT3 inhibitors prior to transplant.
•• Perl AE, Martinelli G, Cortes JE, et al. Gilteritinib or chemotherapy for relapsed or refractory FLT3-mutated AML. N Engl J Med. 2019;381(18):1728–40 FLT3 inhibition with gilteritinib alone shown to be superior to investigator’s choice salvage chemotherapy.
Sandmaier BM, Khaled S, Oran B, Gammon G, Trone D, Frankfurt O. Results of a phase 1 study of quizartinib as maintenance therapy in subjects with acute myeloid leukemia in remission following allogeneic hematopoietic stem cell transplant. Am J Hematol. 2018;93(2):222–31.
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(26):6567–71.
Bazarbachi A, Labopin M, Battipaglia G, Djabali A, Passweg J, Socié G, et al. Sorafenib improves survival of FLT3-mutated acute myeloid leukemia in relapse after allogeneic stem cell transplantation: a report of the EBMT Acute Leukemia Working Party. Haematologica. 2019;104(9):e398–401.
Ravandi F, Alattar ML, Grunwald MR, et al. Phase 2 study of azacytidine plus sorafenib in patients with acute myeloid leukemia and FLT-3 internal tandem duplication mutation. Blood. 2013;121(23):4655–62.
Man CH, Fung TK, Ho C, Han HH, Chow HC, Ma AC, et al. Sorafenib treatment of FLT3-ITD(+) acute myeloid leukemia: favorable initial outcome and mechanisms of subsequent nonresponsiveness associated with the emergence of a D835 mutation. Blood. 2012;119(22):5133–43.
Rautenberg C, Nachtkamp K, Dienst A, Schmidt PV, Heyn C, Kondakci M, et al. Sorafenib and azacitidine as salvage therapy for relapse of FLT3-ITD mutated AML after allo-SCT. Eur J Haematol. 2017;98(4):348–54.
Xuan L, Wang Y, Chen J, Jiang E, Gao L, Wu B, et al. Sorafenib therapy is associated with improved outcomes for FMS-like tyrosine kinase 3 internal tandem duplication acute myeloid leukemia relapsing after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2019;25(8):1674–81.
Cortes JE, Tallman MS, Schiller GJ, et al. Phase 2b study of 2 dosing regimens of quizartinib monotherapy in FLT3-ITD-mutated, relapsed or refractory AML. Blood. 2018;132(6):598–607.
Cortes J, Perl AE, Dohner H, et al. Quizartinib, an FLT3 inhibitor, as monotherapy in patients with relapsed or refractory acute myeloid leukaemia: an open-label, multicentre, single-arm, phase 2 trial. Lancet Oncol. 2018;19(7):889–903.
Hills RK, Trone D, AK B. Quizartinib significantly improves overall survival in FLT3-ITD positive AML patients relapsed after stem cell transplantation or after failure of salvage chemotherapy: a comparison with historical AML database (UK NCRI data). Blood. 2015;126:2557.
Cortes J, Khaled S, Martinelli G, et al. Quizartinib significantly prolongs overall survival in patients with FLT3-internal tandem duplication–mutated (MUT) relapsed/refractory AML in the phase 3, randomized, controlled QUANTUM-R trial. 23rd Congress of the European Hematology Association. 2018.
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(23):3441–9.
Versluis J. In 't Hout FE, Devillier R, et al. Comparative value of post-remission treatment in cytogenetically normal AML subclassified by NPM1 and FLT3-ITD allelic ratio. Leukemia. 2017;31(1):26–33.
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.
Sakaguchi M, Yamaguchi H, Najima Y, Usuki K, Ueki T, Oh I, et al. Prognostic impact of low allelic ratio FLT3-ITD and NPM1 mutation in acute myeloid leukemia. Blood Adv. 2018;2(20):2744–54.
Chen F, Sun J, Yin C, et al. Impact of FLT3-ITD allele ratio and ITD length on therapeutic outcome in cytogenetically normal AML patients without NPM1 mutation. Bone Marrow Transplant 2019.
Taylor E, Morris K, Ellis M, et al. FLT3-ITD positive acute myeloid leukemia: a retrospective analysis of the role of allogeneic transplant and allelic ratio in patient management. Asia Pac J Clin Oncol. 2018;14(6):426–30.
Boddu P, Kantarjian H, Borthakur G, Kadia T, Daver N, Pierce S, et al. Co-occurrence of FLT3-TKD and NPM1 mutations defines a highly favorable prognostic AML group. Blood Adv. 2017;1(19):1546–50.
Ho AD, Schetelig J, Bochtler T, Schaich M, Schäfer-Eckart K, Hänel M, et al. Allogeneic stem cell transplantation improves survival in patients with acute myeloid leukemia characterized by a high allelic ratio of mutant FLT3-ITD. Biol Blood Marrow Transplant. 2016;22(3):462–9.
• Papaemmanuil E, Gerstung M, Bullinger L, et al. Genomic classification and prognosis in acute myeloid leukemia. N Engl J Med. 2016;374(23):2209–21 Informative overview of the mutational landscape of AML and associations of mutations with outcomes to current therapies.
Ahn JS, Kim HJ, Kim YK, Lee SS, Jung SH, Yang DH, et al. DNMT3A R882 mutation with FLT3-ITD positivity is an extremely poor prognostic factor in patients with normal-karyotype acute myeloid leukemia after allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2016;22(1):61–70.
Patel JP, Gonen M, Figueroa ME, et al. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N Engl J Med. 2012;366(12):1079–89.
Renneville A, Boissel N, Nibourel O, et al. Prognostic significance of DNA methyltransferase 3A mutations in cytogenetically normal acute myeloid leukemia: a study by the acute leukemia French association. Leukemia. 2012;26(6):1247–54.
Ivey A, Hills RK, Simpson MA, Jovanovic JV, Gilkes A, Grech A, et al. Assessment of minimal residual disease in standard-risk AML. N Engl J Med. 2016;374(5):422–33.
Kronke J, Schlenk RF, Jensen KO, et al. Monitoring of minimal residual disease in NPM1-mutated acute myeloid leukemia: a study from the German-Austrian acute myeloid leukemia study group. J Clin Oncol. 2011;29(19):2709–16.
Krauter J, Gorlich K, Ottmann O, Lubbert M, Dohner H, Heit W, et al. Prognostic value of minimal residual disease quantification by real-time reverse transcriptase polymerase chain reaction in patients with core binding factor leukemias. J Clin Oncol. 2003;21(23):4413–22.
Levis MJ, Perl AE, Altman JK, Gocke CD, Bahceci E, Hill J, et al. A next-generation sequencing-based assay for minimal residual disease assessment in AML patients with FLT3-ITD mutations. Blood Adv. 2018;2(8):825–31.
Thol F, Gabdoulline R, Liebich A, Klement P, Schiller J, Kandziora C, et al. Measurable residual disease monitoring by NGS before allogeneic hematopoietic cell transplantation in AML. Blood. 2018;132(16):1703–13.
Ossenkoppele G, Schuurhuis G. MRD in AML: does it already guide therapy decision-making? ASH Educ Program Book. 2016;1(356–365).
von Bubnoff N, Manley PW, Mestan J, Sanger J, Peschel C, Duyster J. Bcr-Abl resistance screening predicts a limited spectrum of point mutations to be associated with clinical resistance to the Abl kinase inhibitor nilotinib (AMN107). Blood. 2006;108(4):1328–33.
McMahon CM, Ferng T, Canaani J, Wang ES, Morrissette JJD, Eastburn DJ, et al. Clonal selection with RAS pathway activation mediates secondary clinical resistance to selective FLT3 inhibition in acute myeloid leukemia. Cancer Discov. 2019;9(8):1050–63.
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(1):48–58.
Gutierrez L, Jang M, Zhang T, Akhtari M, Alachkar H. Midostaurin reduces regulatory Tcells markers in acute myeloid leukemia. Sci Rep. 2018;8(1):17544.
Lange A, Jaskula E, Lange J, Dworacki G, Nowak D, Simiczyjew A, et al. The sorafenib anti-relapse effect after alloHSCT is associated with heightened alloreactivity and accumulation of CD8+PD-1+ (CD279+) lymphocytes in marrow. PLoS One. 2018;13(1):e0190525.
Mathew NR, Baumgartner F, Braun L, O'Sullivan D, Thomas S, Waterhouse M, et al. Sorafenib promotes graft-versus-leukemia activity in mice and humans through IL-15 production in FLT3-ITD-mutant leukemia cells. Nat Med. 2018;24(3):282–91.
Bucy T, Zoscak JM, Mori M, Borate U. Patients with FLT3-mutant AML needed to enroll on FLT3-targeted therapeutic clinical trials. Blood Adv. 2019;3(23):4055–64.
Badar T, Kantarjian HM, Nogueras-Gonzalez GM, et al. Improvement in clinical outcome of FLT3 ITD mutated acute myeloid leukemia patients over the last one and a half decade. Am J Hematol. 2015;90(11):1065–70.
Conflict of Interest
YBC has served as a consultant for Takeda, Incyte, and Magenta and on clinical trial adjudication committees for Equilium, Abbvie, and Daiichi. BDH has no conflicts of interest to report.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
This article is part of the Topical Collection on Stem Cell Transplantation
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Hunter, B.D., Chen, Y. Current Approaches to Transplantation for FLT3-ITD AML. Curr Hematol Malig Rep (2020). https://doi.org/10.1007/s11899-020-00558-5