Targeting FLT3 mutations in AML: review of current knowledge and evidence

Naval Daver, Richard F Schlenk, Nigel H Russell, Mark J Levis, Naval Daver, Richard F Schlenk, Nigel H Russell, Mark J Levis

Abstract

Genomic investigations of acute myeloid leukemia (AML) have demonstrated that several genes are recurrently mutated, leading to new genomic classifications, predictive biomarkers, and new therapeutic targets. Mutations of the FMS-like tyrosine kinase 3 (FLT3) gene occur in approximately 30% of all AML cases, with the internal tandem duplication (ITD) representing the most common type of FLT3 mutation (FLT3-ITD; approximately 25% of all AML cases). FLT3-ITD is a common driver mutation that presents with a high leukemic burden and confers a poor prognosis in patients with AML. The prognostic value of a FLT3 mutation in the tyrosine kinase domain (FLT3-TKD), which has a lower incidence in AML (approximately 7-10% of all cases), is uncertain. Accumulating evidence demonstrates that FLT3 mutational status evolves throughout the disease continuum. This so-called clonal evolution, together with the identification of FLT3-ITD as a negative prognostic marker, serves to highlight the importance of FLT3-ITD testing at diagnosis and again at relapse. Earlier identification of FLT3 mutations will help provide a better understanding of the patient's disease and enable targeted treatment that may help patients achieve longer and more durable remissions. First-generation FLT3 inhibitors developed for clinical use are broad-spectrum, multikinase inhibitors; however, next-generation FLT3 inhibitors are more specific, more potent, and have fewer toxicities associated with off-target effects. Primary and secondary acquired resistance to FLT3 inhibitors remains a challenge and provides a rationale for combining FLT3 inhibitors with other therapies, both conventional and investigational. This review focuses on the pathological and prognostic role of FLT3 mutations in AML, clinical classification of the disease, recent progress with next-generation FLT3 inhibitors, and mechanisms of resistance to FLT3 inhibitors.

Conflict of interest statement

ND has received research funding from Daiichi Sankyo, Bristol-Myers Squibb, Pfizer, Karyopharm, Sevier, Genentech, and ImmunoGen and has served in a consulting or advisory role for Daiichi Sankyo, Bristol-Myers Squibb, Pfizer, Novartis, Celgene, AbbVie, and Agios. RFS has received honoraria from Daiichi Sankyo, Novartis, Pfizer, Janssen, and Arog; has served in a consulting or advisory role for Daiichi Sankyo, Novartis, and Pfizer; and has received research funding from Pfizer, AstraZeneca, PharmaMar, and Novartis. NHR has received honoraria from and has served in an advisory role for Jazz, Teva, Pfizer, and Daiichi Sankyo. MJL has received honoraria from Daiichi Sankyo, Novartis, and Agios; has served in a consulting or advisory role for Daiichi Sankyo, Novartis, and Agios; and has received research funding from Astellas and Novartis.

Figures

Fig. 1
Fig. 1
Type I FLT3: inhibitors bind the FLT3 receptor in the active conformation, either near the activation loop or the ATP-binding pocket, and are active against ITD and TKD mutations. Type II FLT3 inhibitors bind the FLT3 receptor in the inactive conformation in a region adjacent to the ATP-binding domain. As a result of this binding affinity, type II FLT3 inhibitors prevent activity of ITD mutations but do not target TKD mutations [81]. FLT3, FMS-like tyrosine kinase; ITD, internal tandem duplication; JMD, juxtamembrane domain; TK, tyrosine kinase; TKD, tyrosine kinase domain

References

    1. Ding L, Ley TJ, Larson DE, Miller CA, Koboldt DC, Welch JS, et al. Clonal evolution in relapsed acute myeloid leukaemia revealed by whole-genome sequencing. Nature. 2012;481:506–10.
    1. Döhner H, Weisdorf DJ, Bloomfield CD. Acute myeloid leukemia. N Engl J Med. 2015;373:1136–52.
    1. Walter MJ, Payton JE, Ries RE, Shannon WD, Deshmukh H, Zhao Y, et al. Acquired copy number alterations in adult acute myeloid leukemia genomes. Proc Natl Acad Sci USA. 2009;106:12950–5.
    1. Döhner H, Estey E, Grimwade D, Amadori S, Appelbaum FR, Buchner T, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017;129:424–47.
    1. O’Donnell MR, Tallman MS, Abboud CN, Altman JK, Appelbaum FR, Arber DA, et al. Acute myeloid leukemia, version 3.2017, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2017;15:926–57.
    1. Grimwade D, Mrozek K. Diagnostic and prognostic value of cytogenetics in acute myeloid leukemia. Hematol Oncol Clin North Am. 2011;25:61.
    1. Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127:2391–405.
    1. Schetelig J, Rollig C, Kayser S, Stoelzel F, Schaefer-Eckart K, Haenel M, et al. Validation of the ELN 2017 Classification for AML with intermediate risk cytogenetics with or without NPM1-mutations and high or low Ratio FLT3-ITDs. Blood. 2017;130:2694.
    1. 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.
    1. Döhner H, Estey EH, Amadori S, Appelbaum FR, Buchner T, Burnett AK, et al. Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood. 2010;115:453–74.
    1. Grunwald MR, Tseng LH, Lin MT, Pratz KW, Eshleman JR, Levis MJ, et al. Improved FLT3 internal tandem duplication PCR assay predicts outcome after allogeneic transplant for acute myeloid leukemia. Biol Blood Marrow Transplant. 2014;20:1989–95.
    1. Lin TL, Williams T, He J, Aljitawi OS, Ganguly S, Abhyankar S, et al. Rates of complete diagnostic testing for patients with acute myeloid leukemia. Cancer Med. 2015;4:519–22.
    1. George TI, Tworek JA, Thomas NE, Fatheree LA, Souers RJ, Nakhleh RE, et al. Evaluation of testing of acute leukemia samples: survey result from the College of American Pathologists. Arch Pathol Lab Med. 2017;141:1101–6.
    1. Grafone T, Palmisano M, Nicci C, Storti S. An overview on the role of FLT3-tyrosine kinase receptor in acute myeloid leukemia: biology and treatment. Oncol Rev. 2012;6:e8.
    1. Kottaridis PD, Gale RE, Linch DC. Flt3 mutations and leukaemia. Br J Haematol. 2003;122:523–38.
    1. Nagel G, Weber D, Fromm E, Erhardt S, Lubbert M, Fiedler W, et al. Epidemiological, genetic, and clinical characterization by age of newly diagnosed acute myeloid leukemia based on an academic population-based registry study (AMLSG BiO) Ann Hematol. 2017;96:1993–2003.
    1. Whitman SP, Archer KJ, Feng L, Baldus C, Becknell B, Carlson BD, et al. Absence of the wild-type allele predicts poor prognosis in adult de novo acute myeloid leukemia with normal cytogenetics and the internal tandem duplication of FLT3: a cancer and leukemia group B study. Cancer Res. 2001;61:7233–9.
    1. Thiede C, Steudel C, Mohr B, Schaich M, Schakel U, Platzbecker U, et al. Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis. Blood. 2002;99:4326–35.
    1. Khaled S, Al Malki M, Marcucci G. Acute myeloid leukemia: biologic, prognostic, and therapeutic insights. Oncology. 2016;30:318–29.
    1. Kottaridis PD, Gale RE, Langabeer SE, Frew ME, Bowen DT, Linch DC. Studies of FLT3 mutations in paired presentation and relapse samples from patients with acute myeloid leukemia: implications for the role of FLT3 mutations in leukemogenesis, minimal residual disease detection, and possible therapy with FLT3 inhibitors. Blood. 2002;100:2393–8.
    1. Shih LY, Huang CF, Wu JH, Lin TL, Dunn P, Wang PN, et al. Internal tandem duplication of FLT3 in relapsed acute myeloid leukemia: a comparative analysis of bone marrow samples from 108 adult patients at diagnosis and relapse. Blood. 2002;100:2387–92.
    1. Kronke J, Bullinger L, Teleanu V, Tschurtz F, Gaidzik VI, Kuhn MW, et al. Clonal evolution in relapsed NPM1-mutated acute myeloid leukemia. Blood. 2013;122:100–8.
    1. Metzeler KH, Herold T, Rothenberg-Thurley M, Amler S, Sauerland MC, Gorlich D, et al. Spectrum and prognostic relevance of driver gene mutations in acute myeloid leukemia. Blood. 2016;128:686–98.
    1. Papaemmanuil E, Gerstung M, Bullinger L, Gaidzik VI, Paschka P, Roberts ND, et al. Genomic classification and prognosis in acute myeloid leukemia. N Engl J Med. 2016;374:2209–21.
    1. 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.
    1. Cortes JE, Kantarjian HM, Kadia TM, Borthakur G, Konopleva M, Garcia-Manero G, et al. Crenolanib besylate, a type I pan-FLT3 inhibitor, to demonstrate clinical activity in multiply relapsed FLT3-ITD and D835 AML. JCO. 2016;34:7008.
    1. Cortes J, Perl AE, Döhner H, Kantarjian H, Martinelli G, Kovacsovics T, 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;19:889–903.
    1. Cortes JE, Tallman MS, Schiller GJ, Trone D, Gammon G, Goldberg SL, et al. Phase 2b study of two dosing regimens of quizartinib monotherapy in FLT3-ITD mutated, relapsed or refractory AML. Blood. 2018;132:598–607.
    1. 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.
    1. 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.
    1. Stone RM, DeAngelo DJ, Klimek V, Galinsky I, Estey E, Nimer SD, et al. Patients with acute myeloid leukemia and an activating mutation in FLT3 respond to a small-molecule FLT3 tyrosine kinase inhibitor, PKC412. Blood. 2005;105:54–60.
    1. Borthakur G, Kantarjian H, Ravandi F, Zhang W, Konopleva M, Wright JJ, et al. Phase I study of sorafenib in patients with refractory or relapsed acute leukemias. Haematologica. 2011;96:62–8.
    1. 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;26:2061–8.
    1. Ravandi F, Arana YiC, Cortes JE, Levis M, Faderl S, Garcia-Manero G, et al. Final report of phase II study of sorafenib, cytarabine and idarubicin for initial therapy in younger patients with acute myeloid leukemia. Leukemia. 2014;28:1543–5.
    1. Kiyoi H, Naoe T, Nakano Y, Yokota S, Minami S, Miyawaki S, et al. Prognostic implication of FLT3 and N-RAS gene mutations in acute myeloid leukemia. Blood. 1999;93:3074–80.
    1. 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.
    1. Port M, Bottcher M, Thol F, Ganser A, Schlenk R, Wasem J, et al. Prognostic significance of FLT3 internal tandem duplication, nucleophosmin 1, and CEBPA gene mutations for acute myeloid leukemia patients with normal karyotype and younger than 60 years: a systematic review and meta-analysis. Ann Hematol. 2014;93:1279–86.
    1. Bacher U, Haferlach C, Kern W, Haferlach T, Schnittger S. Prognostic relevance of FLT3-TKD mutations in AML: the combination matters—an analysis of 3082 patients. Blood. 2008;111:2527–37.
    1. 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.
    1. Linch DC, Hills RK, Burnett AK, Khwaja A, Gale RE. Impact of FLT3(ITD) mutant allele level on relapse risk in intermediate-risk acute myeloid leukemia. Blood. 2014;124:273–6.
    1. 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.
    1. Stirewalt DL, Kopecky KJ, Meshinchi S, Engel JH, Pogosova-Agadjanyan EL, Linsley J, et al. Size of FLT3 internal tandem duplication has prognostic significance in patients with acute myeloid leukemia. Blood. 2006;107:3724–6.
    1. Kayser S, Schlenk RF, Londono MC, Breitenbuecher F, Wittke K, Du J, et al. Insertion of FLT3 internal tandem duplication in the tyrosine kinase domain-1 is associated with resistance to chemotherapy and inferior outcome. Blood. 2009;114:2386–92.
    1. Liu Song-Bai, Dong Hao-Jie, Bao Xie-Bing, Qiu Qiao-Cheng, Li Hong-Zhi, Shen Hong-Jie, Ding Zi-Xuan, Wang Chao, Chu Xiao-Ling, Yu Jing-Qiu, Tao Tao, Li Zheng, Tang Xiao-Wen, Chen Su-Ning, Wu De-Pei, Li Ling, Xue Sheng-Li. Impact of FLT3-ITD length on prognosis of acute myeloid leukemia. Haematologica. 2018;104(1):e9–e12.
    1. Cloos J, Goemans BF, Hess CJ, van Oostveen JW, Waisfisz Q, Corthals S, et al. Stability and prognostic influence of FLT3 mutations in paired initial and relapsed AML samples. Leukemia. 2006;20:1217–20.
    1. McCormick SR, McCormick MJ, Grutkoski PS, Ducker GS, Banerji N, Higgins RR, et al. FLT3 mutations at diagnosis and relapse in acute myeloid leukemia: cytogenetic and pathologic correlations, including cuplike blast morphology. Arch Pathol Lab Med. 2010;134:1143–51.
    1. Nazha A, Cortes J, Faderl S, Pierce S, Daver N, Kadia T, et al. Activating internal tandem duplication mutations of the fms-like tyrosine kinase-3 (FLT3-ITD) at complete response and relapse in patients with acute myeloid leukemia. Haematologica. 2012;97:1242–5.
    1. Pratz KW, Sato T, Murphy KM, Stine A, Rajkhowa T, Levis M. FLT3-mutant allelic burden and clinical status are predictive of response to FLT3 inhibitors in AML. Blood. 2010;115:1425–32.
    1. Warren M, Luthra R, Yin CC, Ravandi F, Cortes JE, Kantarjian HM, et al. Clinical impact of change of FLT3 mutation status in acute myeloid leukemia patients. Mod Pathol. 2012;25:1405–12.
    1. Wattad M, Weber D, Döhner K, Krauter J, Gaidzik VI, Paschka P, et al. Impact of salvage regimens on response and overall survival in acute myeloid leukemia with induction failure. Leukemia. 2017;31:1306–13.
    1. Schlenk RF, Frech P, Weber D, Brossart P, Horst HA, Kraemer D, et al. Impact of pretreatment characteristics and salvage strategy on outcome in patients with relapsed acute myeloid leukemia. Leukemia. 2017;31:1217–20.
    1. Oran B, Cortes J, Beitinjaneh A, Chen HC, de Lima M, Patel K, 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;22:1218–26.
    1. Ho AD, Schetelig J, Bochtler T, Schaich M, Schafer-Eckart K, Hanel 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;22:462–9.
    1. Gaidzik VI, Teleanu V, Papaemmanuil E, Weber D, Paschka P, Hahn J, et al. RUNX1 mutations in acute myeloid leukemia are associated with distinct clinico-pathologic and genetic features. Leukemia. 2016;30:2160–8.
    1. Badar T, Kantarjian HM, Nogueras-Gonzalez GM, Borthakur G, Garcia Manero G, Andreeff M, 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;90:1065–70.
    1. Zarrinkar PP, Gunawardane RN, Cramer MD, Gardner MF, Brigham D, Belli B, et al. AC220 is a uniquely potent and selective inhibitor of FLT3 for the treatment of acute myeloid leukemia (AML) Blood. 2009;114:2984–92.
    1. Hills RK, Gammon G, Trone D, Burnett AK. 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.
    1. Wander SA, Levis MJ, Fathi AT. The evolving role of FLT3 inhibitors in acute myeloid leukemia: quizartinib and beyond. Ther Adv Hematol. 2014;5:65–77.
    1. Smith BD, Levis M, Beran M, Giles F, Kantarjian H, Berg K, et al. Single-agent CEP-701, a novel FLT3 inhibitor, shows biologic and clinical activity in patients with relapsed or refractory acute myeloid leukemia. Blood. 2004;103:3669–76.
    1. Pratz KW, Cortes J, Roboz GJ, Rao N, Arowojolu O, Stine A, et al. A pharmacodynamic study of the FLT3 inhibitor KW-2449 yields insight into the basis for clinical response. Blood. 2009;113:3938–46.
    1. Fiedler W, Kayser S, Kebenko M, Janning M, Krauter J, Schittenhelm M, et al. A phase I/II study of sunitinib and intensive chemotherapy in patients over 60 years of age with acute myeloid leukaemia and activating FLT3 mutations. Br J Haematol. 2015;169:694–700.
    1. Rollig C, Serve H, Huttmann A, Noppeney R, Muller-Tidow C, Krug U, 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;16:1691–9.
    1. Levis M, Ravandi F, Wang ES, Baer MR, Perl A, Coutre S, et al. Results from a randomized trial of salvage chemotherapy followed by lestaurtinib for patients with FLT3 mutant AML in first relapse. Blood. 2011;117:3294–301.
    1. Knapper S, Russell N, Gilkes A, Hills RK, Gale RE, Cavenagh JD, et al. A randomized assessment of adding the kinase inhibitor lestaurtinib to first-line chemotherapy for FLT3-mutated AML. Blood. 2017;129:1143–54.
    1. Fiedler W, Serve H, Döhner H, Schwittay M, Ottmann OG, O’Farrell AM, et al. A phase 1 study of SU11248 in the treatment of patients with refractory or resistant acute myeloid leukemia (AML) or not amenable to conventional therapy for the disease. Blood. 2005;105:986–93.
    1. Serve H, Krug U, Wagner R, Sauerland MC, Heinecke A, Brunnberg U, 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;31:3110–8.
    1. Ravandi F, Alattar ML, Grunwald MR, Rudek MA, Rajkhowa T, Richie MA, et al. Phase 2 study of azacytidine plus sorafenib in patients with acute myeloid leukemia and FLT-3 internal tandem duplication mutation. Blood. 2013;121:4655–62.
    1. 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.
    1. 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.
    1. Stone RM, Mandrekar SJ, Sanford BL, Laumann K, Geyer SM, Bloomfield CD, et al. The addition of midostaurin to standard chemotherapy decreases cumulative incidence of relapse (CIR) in the International Prospective Randomized, Placebo-Controlled, Double-Blind Trial (CALGB 10603 / RATIFY [Alliance]) for newly diagnosed acute myeloid leukemia (AML) patients with FLT3 mutations. Blood. 2017;130:2580.
    1. Rydapt PI. 2018. ; Accessed 2018.
    1. Novartis Pharmaceuticals Corporation. Novartis receives FDA approval for Rydapt® in newly diagnosed FLT3-mutated acute myeloid leukemia (AML) and three types of systemic mastocytosis (SM). 2018. . Accessed 2018.
    1. Rydapt SMC. 2017. . Accessed 2018.
    1. Rydapt SMC. 2018. ; Accessed 2018.
    1. Döhner K, Thiede C, Larson RA, Prior TW, Marcucci G, Jones D, et al. Prognostic impact of NPM1/FLT3-ITD genotypes from randomized patients with acute myeloid leukemia (AML) treated within the International Ratify Study. Blood. 2017;130:467.
    1. Schlenk R, Döhner K, Salih H, Kündgen A, Fiedler W, Salwender H, 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.
    1. Schlenk RF, Fiedler W, Salih HR, Wulf G, Thol F, Kündgen A, et al. Impact of age and midostaurin-dose on response and outcome in acute myeloid leukemia with FLT3-ITD: interim-analyses of the AMLSG 16-10 Trial. Blood. 2016;128:449.
    1. Larson RA, Mandrekar SJ, Sanford BL, Laumann K, Geyer SM, Bloomfield CD, et al. An analysis of maintenance therapy and post-midostaurin outcomes in the International Prospective Randomized, Placebo-Controlled, Double-Blind Trial (CALGB 10603/RATIFY [Alliance]) for newly diagnosed acute myeloid leukemia (AML) patients with FLT3 mutations. Blood. 2017;130:145.
    1. National Institutes of Health. . . Accessed 2018.
    1. Maziarz RT, Patnaik MM, Scott BL, Mohan SR, Deol A, Rowley SD, et al. Radius: A Phase 2, Randomized Trial of Standard of Care (SOC) with or without midostaurin to prevent relapse following allogeneic hematopoietic stem cell transplant (alloHSCT) in patients (pts) with FLT3-Itd-mutated acute myeloid leukemia (AML) Blood. 2016;128:2248.
    1. Daver N, Cortes J, Ravandi F, Patel KP, Burger JA, Konopleva M, et al. Secondary mutations as mediators of resistance to targeted therapy in leukemia. Blood. 2015;125:3236–45.
    1. Chao Q, Sprankle KG, Grotzfeld RM, Lai AG, Carter TA, Velasco AM, et al. Identification of N-(5-tert-butyl-isoxazol-3-yl)-N’-{4-[7-(2-morpholin-4-yl-ethoxy)imidazo[2,1-b][1, 3]benzothiazol-2-yl]phenyl}urea dihydrochloride (AC220), a uniquely potent, selective, and efficacious FMS-like tyrosine kinase-3 (FLT3) inhibitor. J Med Chem. 2009;52:7808–16.
    1. Gunawardane RN, Nepomuceno RR, Rooks AM, Hunt JP, Ricono JM, Belli B, et al. Transient exposure to quizartinib mediates sustained inhibition of FLT3 signaling while specifically inducing apoptosis in FLT3-activated leukemia cells. Mol Cancer Ther. 2013;12:438–47.
    1. 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;93:213–21.
    1. Bowen D, Russell N, Knapper S, Milligan D, Hunter AE, Khwaja A, et al. AC220 (Quizartinib) can be safely combined with conventional chemotherapy in older patients with newly diagnosed acute myeloid leukaemia: experience from the AML18 Pilot Trial. Blood. 2013;122:622.
    1. Swaminathan M, Kantarjian HM, Daver N, Borthakur G, Ohanian M, Kadia T, et al. The combination of quizartinib with azacitidine or low dose cytarabine is highly active in patients (Pts) with FLT3-ITD mutated myeloid leukemias: Interim Report of a Phase I/II Trial. Blood. 2017;130:723.
    1. 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;93:222–31.
    1. Shah NP, Talpaz M, Deininger MW, Mauro MJ, Flinn IW, Bixby D, et al. Ponatinib in patients with refractory acute myeloid leukaemia: findings from a phase 1 study. Br J Haematol. 2013;162:548–52.
    1. Daver N, Pollyea DA, Rizzieri DA, Palmer J, Rampal RK, Dinner S, et al. A Phase I Study of FLX925, a dual FLT3 and CDK4/6 inhibitor in patients with relapsed or refractory acute myeloid leukemia (AML) Blood. 2017;130:1343.
    1. Sato T, Yang X, Knapper S, White P, Smith BD, Galkin S, et al. FLT3 ligand impedes the efficacy of FLT3 inhibitors in vitro and in vivo. Blood. 2011;117:3286–93.
    1. Yang X, Sexauer A, Levis M. Bone marrow stroma-mediated resistance to FLT3 inhibitors in FLT3-ITD AML is mediated by persistent activation of extracellular regulated kinase. Br J Haematol. 2014;164:61–72.
    1. Piloto O, Wright M, Brown P, Kim KT, Levis M, Small D. Prolonged exposure to FLT3 inhibitors leads to resistance via activation of parallel signaling pathways. Blood. 2007;109:1643–52.
    1. Traer E, Martinez J, Javidi-Sharifi N, Agarwal A, Dunlap J, English I, et al. FGF2 from marrow microenvironment promotes resistance to FLT3 inhibitors in acute myeloid leukemia. Cancer Res. 2016;76:6471–82.
    1. Dutreix C, Munarini F, Lorenzo S, Roesel J, Wang Y. Investigation into CYP3A4-mediated drug–drug interactions on midostaurin in healthy volunteers. Cancer Chemother Pharmacol. 2013;72:1223–34.
    1. Chang Y, Hernandez D, Ghiaur G, Levis MJ, Jones RJ. Bone marrow stroma protects FLT3 acute myeloid leukemia (AML) through CYP3A4-mediated drug metabolization of FLT3 tyrosine kinase inhibitors (TKIs) Blood. 2017;130:2519.
    1. Heidel F, Solem FK, Breitenbuecher F, Lipka DB, Kasper S, Thiede MH, et al. Clinical resistance to the kinase inhibitor PKC412 in acute myeloid leukemia by mutation of Asn-676 in the FLT3 tyrosine kinase domain. Blood. 2006;107:293–300.
    1. von Bubnoff N, Engh RA, Aberg E, Sanger J, Peschel C, Duyster J. FMS-like tyrosine kinase 3-internal tandem duplication tyrosine kinase inhibitors display a nonoverlapping profile of resistance mutations in vitro. Cancer Res. 2009;69:3032–41.
    1. Patnaik Mrinal M. The importance of FLT3 mutational analysis in acute myeloid leukemia. Leukemia & Lymphoma. 2017;59(10):2273–2286.
    1. Kampa-Schittenhelm KM, Heinrich MC, Akmut F, Döhner H, Döhner K, Schittenhelm MM. Quizartinib (AC220) is a potent second generation class III tyrosine kinase inhibitor that displays a distinct inhibition profile against mutant-FLT3, -PDGFRA and -KIT isoforms. Mol Cancer. 2013;12:4598–12-19.
    1. Lee LY, Hernandez D, Rajkhowa T, Smith SC, Raman JR, Nguyen B, et al. Preclinical studies of gilteritinib, a next-generation FLT3 inhibitor. Blood. 2017;129:257–60.

Source: PubMed

Sponsor e collaboratori

Condizioni mediche

Interventi farmacologici

3
Sottoscrivi