Midostaurin In Acute Myeloid Leukemia: An Evidence-Based Review And Patient Selection

References

• Papaemmanuil E, Gerstung M, Bullinger L, et al. Genomic classification and prognosis in acute myeloid Leukemia. N Engl J Med. 2016;374(23):2209–2221. doi:10.1056/NEJMoa151619227276561
   PubMed Web of Science ®Google Scholar
• Dohner 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(4):424–447. doi:10.1182/blood-2016-08-73319627895058
   PubMed Web of Science ®Google Scholar
• Available from: https://www.nccn.org/professionals/physician_gls/pdf/aml.pdf. Accessed 914, 2019.
   Google Scholar
• Kottaridis PD, Gale RE, Frew ME, 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(6):1752–1759. doi:10.1182/blood.v98.6.175211535508
   PubMed Web of Science ®Google Scholar
• Levis M. FLT3 mutations in acute myeloid leukemia: what is the best approach in 2013? Hematology Am Soc Hematol Educ Program. 2013;2013:220–226. doi:10.1182/asheducation-2013.1.22024319184
   PubMed Web of Science ®Google Scholar
• Thiede C, Steudel C, Mohr B, 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(12):4326–4335. doi:10.1182/blood.v99.12.432612036858
   PubMed Web of Science ®Google Scholar
• Rosnet O, Birnbaum D. Hematopoietic receptors of class III receptor-type tyrosine kinases. Crit Rev Oncog. 1993;4(6):595–613.7506935
   PubMed Web of Science ®Google Scholar
• Gabbianelli M, Pelosi E, Montesoro E, et al. Multi-level effects of flt3 ligand on human hematopoiesis: expansion of putative stem cells and proliferation of granulomonocytic progenitors/monocytic precursors. Blood. 1995;86(5):1661–1670.7544638
   PubMed Web of Science ®Google Scholar
• Rusten LS, Lyman SD, Veiby OP, Jacobsen SE. The FLT3 ligand is a direct and potent stimulator of the growth of primitive and committed human CD34+ bone marrow progenitor cells in vitro. Blood. 1996;87(4):1317–1325.8608220
   PubMed Web of Science ®Google Scholar
• Shah AJ, Smogorzewska EM, Hannum C, Crooks GM. Flt3 ligand induces proliferation of quiescent human bone marrow CD34+CD38- cells and maintains progenitor cells in vitro. Blood. 1996;87(9):3563–3570.8611678
   PubMed Web of Science ®Google Scholar
• Frohling S, Scholl C, Levine RL, et al. Identification of driver and passenger mutations of FLT3 by high-throughput DNA sequence analysis and functional assessment of candidate alleles. Cancer Cell. 2007;12(6):501–513. doi:10.1016/j.ccr.2007.11.00518068628
   PubMed Web of Science ®Google Scholar
• Nakao M, Yokota S, Iwai T, et al. Internal tandem duplication of the flt3 gene found in acute myeloid leukemia. Leukemia. 1996;10(12):1911–1918.8946930
   PubMed Web of Science ®Google Scholar
• Brandts CH, Sargin B, Rode M, et al. Constitutive activation of Akt by Flt3 internal tandem duplications is necessary for increased survival, proliferation, and myeloid transformation. Cancer Res. 2005;65(21):9643–9650. doi:10.1158/0008-5472.CAN-05-042216266983
   PubMed Web of Science ®Google Scholar
• Mizuki M, Fenski R, Halfter H, et al. Flt3 mutations from patients with acute myeloid leukemia induce transformation of 32D cells mediated by the Ras and STAT5 pathways. Blood. 2000;96(12):3907–3914.11090077
   PubMed Web of Science ®Google Scholar
• Yamamoto Y, Kiyoi H, Nakano Y, et al. Activating mutation of D835 within the activation loop of FLT3 in human hematologic malignancies. Blood. 2001;97(8):2434–2439. doi:10.1182/blood.v97.8.243411290608
   PubMed Web of Science ®Google Scholar
• Chou SC, Tang JL, Hou HA, et al. Prognostic implication of gene mutations on overall survival in the adult acute myeloid leukemia patients receiving or not receiving allogeneic hematopoietic stem cell transplantations. Leuk Res. 2014;38(11):1278–1284. doi:10.1016/j.leukres.2014.08.01225260824
   PubMed Web of Science ®Google Scholar
• Ravandi F, Kantarjian H, Faderl S, et al. Outcome of patients with FLT3-mutated acute myeloid leukemia in first relapse. Leuk Res. 2010;34(6):752–756. doi:10.1016/j.leukres.2009.10.00119878996
   PubMed Web of Science ®Google Scholar
• Bienz M, Ludwig M, Leibundgut EO, et al. Risk assessment in patients with acute myeloid leukemia and a normal karyotype. Clin Cancer Res. 2005;11(4):1416–1424. doi:10.1158/1078-0432.CCR-04-155215746041
   PubMed Web of Science ®Google Scholar
• Levis M, Small D. FLT3: ITDoes matter in leukemia. Leukemia. 2003;17(9):1738–1752. doi:10.1038/sj.leu.240309912970773
   PubMed Web of Science ®Google Scholar
• Levis M. FLT3 as a marker of minimal residual disease: time to re-think? Am J Hematol. 2017;92(4):329–330. doi:10.1002/ajh.2466728142203
   PubMed Web of Science ®Google Scholar
• Levis MJ, Perl AE, Altman JK, 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):825–831. doi:10.1182/bloodadvances.201801592529643105
   PubMed Web of Science ®Google Scholar
• Levis M, Brown P, Smith BD, et al. Plasma inhibitory activity (PIA): a pharmacodynamic assay reveals insights into the basis for cytotoxic response to FLT3 inhibitors. Blood. 2006;108(10):3477–3483. doi:10.1182/blood-2006-04-01574316857987
   PubMed Web of Science ®Google Scholar
• Daver N, Schlenk RF, Russell NH, Levis MJ. Targeting FLT3 mutations in AML: review of current knowledge and evidence. Leukemia. 2019;33(2):299–312. doi:10.1038/s41375-018-0357-930651634
   PubMed Web of Science ®Google Scholar
• Thomas CM, Campbell P. FLT3 inhibitors in acute myeloid leukemia: current and future. J Oncol Pharm Pract. 2019;25(1):163–171. doi:10.1177/107815521880262030270754
   PubMed Web of Science ®Google Scholar
• O’Farrell AM, Foran JM, Fiedler W, et al. An innovative phase I clinical study demonstrates inhibition of FLT3 phosphorylation by SU11248 in acute myeloid leukemia patients. Clin Cancer Res. 2003;9(15):5465–5476.14654525
   PubMed Web of Science ®Google Scholar
• Shah NP, Talpaz M, Deininger MW, et al. Ponatinib in patients with refractory acute myeloid leukaemia: findings from a phase 1 study. Br J Haematol. 2013;162(4):548–552. doi:10.1111/bjh.1238223691988
   PubMed Web of Science ®Google Scholar
• Fiedler W, Serve H, Dohner H, 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(3):986–993. doi:10.1182/blood-2004-05-184615459012
   PubMed Web of Science ®Google Scholar
• Burchert A. 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;132:661.
   Web of Science ®Google Scholar
• Antar A, Kharfan-Dabaja MA, Mahfouz R, Bazarbachi A. Sorafenib maintenance appears safe and improves clinical outcomes in FLT3-ITD acute myeloid leukemia after allogeneic hematopoietic cell transplantation. Clin Lymphoma Myeloma Leuk. 2015;15(5):298–302. doi:10.1016/j.clml.2014.12.00525550214
   PubMed Web of Science ®Google Scholar
• Ravandi F, Cortes JE, Jones D, et al. Phase I/II study of combination therapy with sorafenib, idarubicin, and cytarabine in younger patients with acute myeloid leukemia. J Clin Oncol. 2010;28(11):1856–1862. doi:10.1200/JCO.2009.25.488820212254
   PubMed Web of Science ®Google Scholar
• 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):1691–1699. doi:10.1016/S1470-2045(15)00362-926549589
   PubMed Web of Science ®Google Scholar
• Perl A. Gilteritinib significantly prolongs overall survival in patients with FLT3-mutated (FLT3mut+) relapsed/refractory (R/R) acute myeloid leukemia (AML): results from the phase III ADMIRAL trial. AACR Annual Meeting 2019; 2019; doi:10.1097/01.HS9.0000561784.84381.11 Atlanta, Georgia
   Google Scholar
• Fabbro D, Ruetz S, Bodis S, et al. PKC412 – a protein kinase inhibitor with a broad therapeutic potential. Anticancer Drug Des. 2000;15(1):17–28.10888033
   PubMedGoogle Scholar
• Meyer T, Regenass U, Fabbro D, et al. A derivative of staurosporine (CGP 41 251) shows selectivity for protein kinase C inhibition and in vitro anti-proliferative as well as in vivo anti-tumor activity. Int J Cancer. 1989;43(5):851–856. doi:10.1002/ijc.29104305192714889
   PubMed Web of Science ®Google Scholar
• Bahlis NJ, Miao Y, Koc ON, Lee K, Boise LH, Gerson SL. N-benzoylstaurosporine (PKC412) inhibits Akt kinase inducing apoptosis in multiple myeloma cells. Leuk Lymphoma. 2005;46(6):899–908. doi:10.1080/1042819050008059516019536
   PubMed Web of Science ®Google Scholar
• Ganeshaguru K, Wickremasinghe RG, Jones DT, et al. Actions of the selective protein kinase C inhibitor PKC412 on B-chronic lymphocytic leukemia cells in vitro. Haematologica. 2002;87(2):167–176.11836167
   PubMed Web of Science ®Google Scholar
• Nakamura K, Yoshikawa N, Yamaguchi Y, Kagota S, Shinozuka K, Kunitomo M. Effect of PKC412, an inhibitor of protein kinase C, on spontaneous metastatic model mice. Anticancer Res. 2003;23(2B):1395–1399.12820400
   PubMed Web of Science ®Google Scholar
• Yoshikawa N, Nakamura K, Yamaguchi Y, Kagota S, Shinozuka K, Kunitomo M. Effect of PKC412, a selective inhibitor of protein kinase C, on lung metastasis in mice injected with B16 melanoma cells. Life Sci. 2003;72(12):1377–1387. doi:10.1016/s0024-3205(02)02407-412527035
   PubMed Web of Science ®Google Scholar
• Propper DJ, McDonald AC, Man A, et al. Phase I and pharmacokinetic study of PKC412, an inhibitor of protein kinase C. J Clin Oncol. 2001;19(5):1485–1492. doi:10.1200/JCO.2001.19.5.148511230495
   PubMed Web of Science ®Google Scholar
• Virchis A, Ganeshaguru K, Hart S, et al. A novel treatment approach for low grade lymphoproliferative disorders using PKC412 (CGP41251), an inhibitor of protein kinase C. Hematol J. 2002;3(3):131–136. doi:10.1038/sj.thj.620016512111648
   PubMedGoogle Scholar
• Eder JP Jr, Garcia-Carbonero R, Clark JW, et al. A phase I trial of daily oral 4ʹ-N -benzoyl-staurosporine in combination with protracted continuous infusion 5-fluorouracil in patients with advanced solid malignancies. Invest New Drugs. 2004;22(2):139–150. doi:10.1023/B:DRUG.0000011790.31292.ef14739662
   PubMed Web of Science ®Google Scholar
• Monnerat C, Henriksson R, Le Chevalier T, et al. Phase I study of PKC412 (N-benzoyl-staurosporine), a novel oral protein kinase C inhibitor, combined with gemcitabine and cisplatin in patients with non-small-cell lung cancer. Ann Oncol. 2004;15(2):316–323. doi:10.1093/annonc/mdh05214760128
   PubMed Web of Science ®Google Scholar
• Millward MJ, House C, Bowtell D, et al. The multikinase inhibitor midostaurin (PKC412A) lacks activity in metastatic melanoma: a phase IIA clinical and biologic study. Br J Cancer. 2006;95(7):829–834. doi:10.1038/sj.bjc.660333116969355
   PubMed Web of Science ®Google Scholar
• Saishin Y, Saishin Y, Takahashi K, Seo MS, Melia M, Campochiaro PA. The kinase inhibitor PKC412 suppresses epiretinal membrane formation and retinal detachment in mice with proliferative retinopathies. Invest Ophthalmol Vis Sci. 2003;44(8):3656–3662. doi:10.1167/iovs.02-114312882820
   PubMed Web of Science ®Google Scholar
• Saishin Y, Silva RL, Saishin Y, et al. Periocular injection of microspheres containing PKC412 inhibits choroidal neovascularization in a porcine model. Invest Ophthalmol Vis Sci. 2003;44(11):4989–4993. doi:10.1167/iovs.03-060014578426
   PubMed Web of Science ®Google Scholar
• Campochiaro PA, Group CPS. Reduction of diabetic macular edema by oral administration of the kinase inhibitor PKC412. Invest Ophthalmol Vis Sci. 2004;45(3):922–931. doi:10.1167/iovs.03-095514985312
   PubMed Web of Science ®Google Scholar
• Weisberg E, Boulton C, Kelly LM, et al. Inhibition of mutant FLT3 receptors in leukemia cells by the small molecule tyrosine kinase inhibitor PKC412. Cancer Cell. 2002;1(5):433–443.12124173
   PubMed Web of Science ®Google Scholar
• Grundler R, Thiede C, Miething C, Steudel C, Peschel C, Duyster J. Sensitivity toward tyrosine kinase inhibitors varies between different activating mutations of the FLT3 receptor. Blood. 2003;102(2):646–651. doi:10.1182/blood-2002-11-344112663439
   PubMed Web of Science ®Google Scholar
• Bali P, George P, Cohen P, et al. Superior activity of the combination of histone deacetylase inhibitor LAQ824 and the FLT-3 kinase inhibitor PKC412 against human acute myelogenous leukemia cells with mutant FLT-3. Clin Cancer Res. 2004;10(15):4991–4997. doi:10.1158/1078-0432.CCR-04-021015297399
   PubMed Web of Science ®Google Scholar
• Furukawa Y, Vu HA, Akutsu M, et al. Divergent cytotoxic effects of PKC412 in combination with conventional antileukemic agents in FLT3 mutation-positive versus -negative leukemia cell lines. Leukemia. 2007;21(5):1005–1014. doi:10.1038/sj.leu.240459317330105
   PubMed Web of Science ®Google Scholar
• Mollgard L, Deneberg S, Nahi H, et al. The FLT3 inhibitor PKC412 in combination with cytostatic drugs in vitro in acute myeloid leukemia. Cancer Chemother Pharmacol. 2008;62(3):439–448. doi:10.1007/s00280-007-0623-417960382
   PubMed Web of Science ®Google Scholar
• Odgerel T, Kikuchi J, Wada T, et al. The FLT3 inhibitor PKC412 exerts differential cell cycle effects on leukemic cells depending on the presence of FLT3 mutations. Oncogene. 2008;27(22):3102–3110. doi:10.1038/sj.onc.121098018071308
   PubMed Web of Science ®Google Scholar
• Stone RM, DeAngelo DJ, Klimek V, 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(1):54–60. doi:10.1182/blood-2004-03-089115345597
   PubMed Web of Science ®Google Scholar
• Fischer T, Stone RM, Deangelo DJ, 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):4339–4345. doi:10.1200/JCO.2010.28.967820733134
   PubMed Web of Science ®Google Scholar
• Strati P, Kantarjian H, Ravandi F, et al. Phase I/II trial of the combination of midostaurin (PKC412) and 5-azacytidine for patients with acute myeloid leukemia and myelodysplastic syndrome. Am J Hematol. 2015;90(4):276–281. doi:10.1002/ajh.2392425530214
   PubMed Web of Science ®Google Scholar
• Stone RM, Fischer T, Paquette R, 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):2061–2068. doi:10.1038/leu.2012.11522627678
   PubMed Web of Science ®Google Scholar
• 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):454–464. doi:10.1056/NEJMoa161435928644114
   PubMed Web of Science ®Google Scholar
• Stone RM, Manley PW, Larson RA, Capdeville R. Midostaurin: its odyssey from discovery to approval for treating acute myeloid leukemia and advanced systemic mastocytosis. Blood Adv. 2018;2(4):444–453. doi:10.1182/bloodadvances.201701108029487059
   PubMed Web of Science ®Google Scholar
• Larson RA, Mandrekar SJ, Sanford BL, 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.
   Web of Science ®Google Scholar
• Schlenk RF, Weber D, Fiedler W, et al. Midostaurin added to chemotherapy and continued single-agent maintenance therapy in acute myeloid leukemia with FLT3-ITD. Blood. 2019;133(8):840–851. doi:10.1182/blood-2018-08-86945330563875
   PubMed Web of Science ®Google Scholar
• Kim ES. Midostaurin: first global approval. Drugs. 2017;77(11):1251–1259. doi:10.1007/s40265-017-0779-028612232
   PubMed Web of Science ®Google Scholar
• 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(6):1223–1234. doi:10.1007/s00280-013-2287-624085261
   PubMed Web of Science ®Google Scholar
• Outas T, Duval V, Sinclair K, Berkowitz N. Concomitant use of midostaurin with strong CYP3A4 inhibitors: an analysis from the ratify trial. Blood. 2017;130:3814.
   Web of Science ®Google Scholar
• Breitenbuecher F, Markova B, Kasper S, et al. A novel molecular mechanism of primary resistance to FLT3-kinase inhibitors in AML. Blood. 2009;113(17):4063–4073. doi:10.1182/blood-2007-11-12666419144992
   PubMed Web of Science ®Google Scholar
• Stolzel F, Steudel C, Oelschlagel U, et al. Mechanisms of resistance against PKC412 in resistant FLT3-ITD positive human acute myeloid leukemia cells. Ann Hematol. 2010;89(7):653–662. doi:10.1007/s00277-009-0889-120119833
   PubMed Web of Science ®Google Scholar
• Heidel F, Solem FK, Breitenbuecher F, 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(1):293–300. doi:10.1182/blood-2005-06-246916150941
   PubMed Web of Science ®Google Scholar
• 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(7):1425–1432. doi:10.1182/blood-2009-09-24285920007803
   PubMed Web of Science ®Google Scholar
• Perl AE. Gilteritinib significantly prolongs overall survival in patients with FLT3-mutated (FLT3mut+) relapsed/refractory (R/R) acute myeloid leukemia (AML): results from the phase III ADMIRAL trial. Proceedings of the 110th Annual Meeting of the American Association for Cancer Research; 2019; Atlanta, GA. doi:10.1097/01.HS9.0000561784.84381.11
   Google Scholar
• Cortes JE, Khaled SK, Martinelli G, et al. Efficacy and safety of single-agent Quizartinib (Q), a potent and selective FLT3 Inhibitor (FLT3i), in patients (pts) with FLT3-Internal Tandem Duplication (FLT3-ITD)-mutated Relapsed/Refractory (R/R) Acute Myeloid Leukemia (AML) enrolled in the global, phase 3, randomized controlled quantum-R trial. Blood. 2018;132(Suppl 1):563.
   Google Scholar
• Cortes J, Perl AE, Döhner 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. doi:10.1016/S1470-2045(18)30240-729859851
   PubMed Web of Science ®Google Scholar
• Smith CC, Lasater EA, Lin KC, et al. Crenolanib is a selective type I pan-FLT3 inhibitor. Proc Natl Acad Sci U S A. 2014;111(14):5319–5324. doi:10.1073/pnas.132066111124623852
   PubMed Web of Science ®Google Scholar
• Randhawa JK, Kantarjian HM, Borthakur G, 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(21):389.
   Web of Science ®Google Scholar
• 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):213–221. doi:10.1002/ajh.2497429139135
   PubMed Web of Science ®Google Scholar
• 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(Suppl 1):564.
   Google Scholar
• Wang ES, Stone RM, Tallman MS, Walter RB, Eckardt JR, Collins R. Crenolanib, a type I FLT3 TKI, can be safely combined with cytarabine and anthracycline induction chemotherapy and results in high response rates in patients with newly diagnosed FLT3 Mutant Acute Myeloid Leukemia (AML). Blood. 2016;128(22):1071.
   Web of Science ®Google Scholar
• Williams CB, Kambhampati S, Fiskus W, et al. Preclinical and phase I results of decitabine in combination with midostaurin (PKC412) for newly diagnosed elderly or relapsed/refractory adult patients with acute myeloid leukemia. Pharmacotherapy. 2013;33(12):1341–1352. doi:10.1002/phar.131623798029
   PubMed Web of Science ®Google Scholar
• Chen W, Xie H, Wang H, et al. Prognostic significance of KIT mutations in core-binding factor acute myeloid leukemia: a systematic review and meta-analysis. PLoS One. 2016;11(1):e0146614. doi:10.1371/journal.pone.014661426771376
   PubMed Web of Science ®Google Scholar
• Qin Y-Z, Zhu H, Jiang Q, et al. Prevalence and prognostic significance of c-KIT mutations in core binding factor acute myeloid leukemia: a comprehensive large-scale study from a single chinese center. Blood. 2014;124(21):1000.
   Web of Science ®Google Scholar
• Maziarz RTT, Patnaik MM, Scott BL, et al. Radius: a phase 2 randomized trial investigating standard of care ± midostaurin after allogeneic stem cell transplant in FLT3-ITD-mutated AML. Blood. 2018;132(Suppl 1):662. doi:10.1182/blood-2018-05-84642829954750
   PubMedGoogle Scholar
• Sobhanifar MA, Mashkani B, Saadatmandzadeh M, Sadeghnia HR, Mousavi SH. Induction of cytotoxicity and apoptosis in FLT3 mutant expressing cells using novel pyrimido cyanoacrylates and quinoline derivatives. Biomed Pharmacother. 2018;108:893–905. doi:10.1016/j.biopha.2018.09.00130372901
   PubMed Web of Science ®Google Scholar
• Chyla B, Daver N, Doyle K, et al. Genetic biomarkers of sensitivity and resistance to venetoclax monotherapy in patients with relapsed acute myeloid leukemia. Am J Hematol. 2018. doi:10.1002/ajh.25146
   PubMed Web of Science ®Google Scholar
• Kasper S, Breitenbuecher F, Heidel F, et al. Targeting MCL-1 sensitizes FLT3-ITD-positive leukemias to cytotoxic therapies. Blood Cancer J. 2012;2(3):e60. doi:10.1038/bcj.2012.522829255
   PubMedGoogle Scholar
• Kohl TM, Hellinger C, Ahmed F, et al. BH3 mimetic ABT-737 neutralizes resistance to FLT3 inhibitor treatment mediated by FLT3-independent expression of BCL2 in primary AML blasts. Leukemia. 2007;21(8):1763–1772. doi:10.1038/sj.leu.240477617554384
   PubMed Web of Science ®Google Scholar