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Review

The importance of FLT3 mutational analysis in acute myeloid leukemia

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Pages 2273-2286 | Received 19 Jul 2017, Accepted 24 Oct 2017, Published online: 22 Nov 2017

References

  • Rosnet O, Mattei MG, Marchetto S, et al. Isolation and chromosomal localization of a novel FMS-like tyrosine kinase gene. Genomics. 1991;9:380–385.
  • Agnes F, Shamoon B, Dina C, et al. Genomic structure of the downstream part of the human FLT3 gene: exon/intron structure conservation among genes encoding receptor tyrosine kinases (RTK) of subclass III. Gene. 1994;145:283–288.
  • Rosnet O, Buhring HJ, Marchetto S, et al. Human FLT3/FLK2 receptor tyrosine kinase is expressed at the surface of normal and malignant hematopoietic cells. Leukemia. 1996;10:238–248.
  • Carow CE, Levenstein M, Kaufmann SH, et al. Expression of the hematopoietic growth factor receptor FLT3 (STK-1/Flk2) in human leukemias. Blood. 1996;87:1089–1096.
  • Kayser S, Schlenk RF, Londono MC, 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;114:2386–2392.
  • Papaemmanuil E, Gerstung M, Bullinger L, et al. Genomic classification and prognosis in acute myeloid leukemia. N Engl J Med. 2016;374:2209–2221.
  • Stirewalt DL, Meshinchi S, Kussick SJ, et al. Novel FLT3 point mutations within exon 14 found in patients with acute myeloid leukaemia. Br J Haematol. 2004;124:481–484.
  • Reindl C, Bagrintseva K, Vempati S, et al. Point mutations in the juxtamembrane domain of FLT3 define a new class of activating mutations in AML. Blood. 2006;107:3700–3707.
  • Fröhling 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;12:501–513.
  • Spiekermann K, Bagrintseva K, Schoch C, et al. A new and recurrent activating length mutation in exon 20 of the FLT3 gene in acute myeloid leukemia. Blood. 2002;100:3423–3425.
  • Chatain N, Perera RC, Rossetti G, et al. Rare FLT3 deletion mutants may provide additional treatment options to patients with AML: an approach to individualized medicine. Leukemia. 2015;29:2434–2438.
  • Opatz S, Polzer H, Herold T, et al. Exome sequencing identifies recurring FLT3 N676K mutations in core-binding factor leukemia. Blood. 2013;122:1761–1769.
  • Bacher U, Haferlach C, Kern W, et al. Prognostic relevance of FLT3–TKD mutations in AML: the combination matters-an analysis of 3082 patients. Blood. 2008;111:2527–2537.
  • Patel JP, Gonen M, Figueroa ME, et al. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N Engl J Med. 2012;366:1079–1089.
  • Whitman SP, Archer KJ, Feng L, 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;61:7233–7239.
  • Döhner H, Estey E, Grimwade D, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017;129:424–447.
  • 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;99:4326–4335.
  • Stirewalt DL, Radich JP. The role of FLT3 in haematopoietic malignancies. Nat Rev Cancer. 2003;3:650–665.
  • Pratcorona M, Brunet S, Nomdedeu J, et al. Favorable outcome of patients with acute myeloid leukemia harboring a low-allelic burden FLT3-ITD mutation and concomitant NPM1 mutation: relevance to post-remission therapy. Blood. 2013;121:2734–2738.
  • Gale RE, Green C, Allen C, et al. The impact of FLT3 internal tandem duplication mutant level, number, size, and interaction with NPM1 mutations in a large cohort of young adult patients with acute myeloid leukemia. Blood. 2008;111:2776–2784.
  • Linch DC, Hills RK, Burnett AK, et al. Impact of FLT3(ITD) mutant allele level on relapse risk in intermediate-risk acute myeloid leukemia. Blood. 2014;124:273–276.
  • How J, Sykes J, Gupta V, et al. Influence of FLT3-internal tandem duplication allele burden and white blood cell count on the outcome in patients with intermediate-risk karyotype acute myeloid leukemia. Cancer. 2012;118:6110–6117.
  • Schneider F, Hoster E, Unterhalt M, et al. The FLT3ITD mRNA level has a high prognostic impact in NPM1 mutated, but not in NPM1 unmutated, AML with a normal karyotype. Blood. 2012;119:4383–4386.
  • Allen C, Hills RK, Lamb K, et al. The importance of relative mutant level for evaluating impact on outcome of KIT, FLT3 and CBL mutations in core-binding factor acute myeloid leukemia. Leukemia. 2013;27:1891–1901.
  • Koszarska M, Meggyesi N, Bors A, et al. Medium-sized FLT3 internal tandem duplications confer worse prognosis than short and long duplications in a non-elderly acute myeloid leukemia cohort. Leuk Lymphoma. 2014;55:1510–1517.
  • Fröhling S, Schlenk RF, Breitruck J, et al. Prognostic significance of activating FLT3 mutations in younger adults (16 to 60 years) with acute myeloid leukemia and normal cytogenetics: a study of the AML Study Group Ulm. Blood. 2002;100:4372–4380.
  • Smith CC, Wang Q, Chin CS, et al. Validation of ITD mutations in FLT3 as a therapeutic target in human acute myeloid leukaemia. Nature. 2012;485:260–263.
  • 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;98:1752–1759.
  • Schnittger S, Schoch C, Dugas M, et al. Analysis of FLT3 length mutations in 1003 patients with acute myeloid leukemia: correlation to cytogenetics, FAB subtype, and prognosis in the AMLCG study and usefulness as a marker for the detection of minimal residual disease. Blood. 2002;100:59–66.
  • Oyarzo MP, Lin P, Glassman A, et al. Acute myeloid leukemia with t(6;9) (p23;q34) is associated with dysplasia and a high frequency of flt3 gene mutations. Am J Clin Pathol. 2004;122:348–358.
  • Slovak ML, Gundacker H, Bloomfield CD, et al. A retrospective study of 69 patients with t(6;9)(p23;q34) AML emphasizes the need for a prospective, multicenter initiative for rare ‘poor prognosis’ myeloid malignancies. Leukemia. 2006;20:1295–1297.
  • Kainz B, Heintel D, Marculescu R, et al. Variable prognostic value of FLT3 internal tandem duplications in patients with de novo AML and a normal karyotype, t(15;17), t(8;21) or inv(16). Hematol J. 2002;3:283–289.
  • Slovak ML, Kopecky KJ, Cassileth PA, et al. Karyotypic analysis predicts outcome of preremission and postremission therapy in adult acute myeloid leukemia: a Southwest Oncology Group/Eastern Cooperative Oncology Group study. Blood. 2000;96:4075–4083.
  • Walter RB, Othus M, Burnett AK, et al. Resistance prediction in AML: analysis of 4601 patients from MRC/NCRI, HOVON/SAKK, SWOG and MD Anderson Cancer Center. Leukemia.2015;29:312–320.
  • Cheson BD, Bennett JM, Kopecky KJ, et al. Revised recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. J Clin Oncol. 2003;21:4642–4649.
  • Arber DA, Borowitz MJ, Cessna M, et al. Initial diagnostic workup of acute leukemia: guideline from the College of American Pathologists and the American Society of Hematology. Arch Pathol Lab Med. 2017;141:1342–1393.
  • Rydapt (midostaurin) [prescribing information]. East Hanover (NJ): Novartis Pharmaceuticals Corporation; April 2017.
  • Jones C, LeDay TV, Miller AM. Acute myelogenous leukemia at Baylor Charles A. Sammons Cancer Center, 2010 to 2012: retrospective analysis of molecular genetic evaluation. Proc (Bayl Univ Med Cent). 2014;27:299–304.
  • Lin TL, Williams T, He J, et al. Rates of complete diagnostic testing for patients with acute myeloid leukemia. Cancer Med. 2015;4:519–522.
  • Döhner H, Estey EH, Amadori S, 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;115:453–474.
  • George TI, Tworek JA, Thomas NE, et al. Evaluation of testing of acute leukemia samples: survey result from the College of American Pathologists. Arch Pathol Lab Med. 2017;141:1101–1106.
  • Invivoscribe. LeukoStrat® CDx FLT3 mutation assay [Internet]. San Diego (CA): Invivoscribe; 2017 [cited 2017 Sep 8]. Available from: https://invivoscribe.com/product/leukostrat-cdx-flt3-mutation-kit
  • Altman JK, Perl AE, Cortes JE, et al. Deep molecular response to gilteritinib improves survival in FLT3 mutation-positive relapsed/refractory acute myeloid leukemia. Paper presented at: European Hematology Association 22nd Congress: 2017 Jun 22–25; Madrid, Spain.
  • Kiyoi H, Naoe T, Nakano Y, et al. Prognostic implication of FLT3 and N-RAS gene mutations in acute myeloid leukemia. Blood. 1999;93:3074–3080.
  • McKerrell T, Moreno T, Ponstingl H, et al. Development and validation of a comprehensive genomic diagnostic tool for myeloid malignancies. Blood. 2016;128:e1–e9.
  • Duncavage EJ, Tandon B. The utility of next-generation sequencing in diagnosis and monitoring of acute myeloid leukemia and myelodysplastic syndromes. Int J Lab Hematol. 2015;37(Suppl 1):115–121.
  • Spencer DH, Abel HJ, Lockwood CM, et al. Detection of FLT3 internal tandem duplication in targeted, short-read-length, next-generation sequencing data. J Mol Diagn. 2013;15:81–93.
  • Au CH, Wa A, Ho DN, et al. Clinical evaluation of panel testing by next-generation sequencing (NGS) for gene mutations in myeloid neoplasms. Diagn Pathol. 2016;11:11.
  • Guan YF, Li GR, Wang RJ, et al. Application of next-generation sequencing in clinical oncology to advance personalized treatment of cancer. Chin J Cancer. 2012;31:463–470.
  • Murphy KM, Levis M, Hafez MJ, et al. Detection of FLT3 internal tandem duplication and D835 mutations by a multiplex polymerase chain reaction and capillary electrophoresis assay. J Mol Diagn. 2003;5:96–102.
  • Liu HE, Ko C, Lam F, et al. Establishment of a cost-effective method to detect FLT-ITD and D835 mutations in acute myeloid leukemia patients in the Taiwanese population. Tzu Chi Med J. 2015;27:18–24.
  • Gupta A, Viswanatha DS, Patnaik MM. FLT3 mutation testing in acute myeloid leukemia. JAMA Oncol. 2017;3:991–992.
  • Stirewalt DL, Willman CL, Radich JP. Quantitative, real-time polymerase chain reactions for FLT3 internal tandem duplications are highly sensitive and specific. Leuk Res. 2001;25:1085–1088.
  • Scholl S, Krause C, Loncarevic IF, et al. Specific detection of Flt3 point mutations by highly sensitive real-time polymerase chain reaction in acute myeloid leukemia. J Lab Clin Med. 2005;145:295–304.
  • Prasad V, Gale RP. Precision medicine in acute myeloid leukemia: hope, hype or both? Leuk Res. 2016;48:73–77.
  • Huang K, Yang M, Pan Z, et al. Leukemogenic potency of the novel FLT3-N676K mutant. Ann Hematol. 2016;95:783–791.
  • Schlenk RF, Döhner K, Salih 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). Paper presented at: 57th American Society of Hematology Annual Meeting and Exposition; 2015 Dec 5–8; Orlando, FL.
  • Stone RM, Mandrekar SJ, Sanford BL, et al. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med. 2017;377:454–464.
  • NCCN Clinical Practice Guidelines in Oncology. Acute Myeloid Leukemia. V3.2017 [Internet]. Fort Washington (PA): National Comprehensive Cancer Network; [cited 2017 Sep 8]. Available from: https://www.nccn.org/professionals/physician_gls/PDF/aml.pdf
  • Lin TL, Levy MY. Acute myeloid leukemia: focus on novel therapeutic strategies. Clin Med Insights Oncol. 2012;6:205–217.
  • Rydapt (midostaurin) [summary of product characteristics]. Basel, Switzerland: Novartis Pharmaceuticals AG; September 2017.
  • 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;90:1065–1070.
  • Schiller GJ, Tuttle P, Desai P. Allogeneic hematopoietic stem cell transplantation in FLT3-ITD-positive acute myelogenous leukemia: the role for FLT3 tyrosine kinase inhibitors post-transplantation. Biol Blood Marrow Transplant. 2016;22:982–990.
  • Ho AD, Schetelig J, Bochtler T, et al. Allogeneic stem cell transplantation improves survival in patients with AML characterized by a high allelic ratio of mutant FLT3-ITD. Biol Blood Marrow Transplant. 2016;22:462–469.
  • 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;22:1218–1226.
  • Gale RE, Hills R, Kottaridis PD, et al. No evidence that FLT3 status should be considered as an indicator for transplantation in acute myeloid leukemia (AML): an analysis of 1135 patients, excluding acute promyelocytic leukemia, from the UK MRC AML10 and 12 trials. Blood. 2005;106:3658–3665.
  • Bornhauser M, Illmer T, Schaich M, et al. Improved outcome after stem-cell transplantation in FLT3/ITD-positive AML. Blood. 2007;109:2264–2265.
  • Schlenk RF, Dohner K, Krauter J, et al. Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N Engl J Med. 2008;358:1909–1918.
  • Brunet S, Labopin M, Esteve J, 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;30:735–741.
  • Schlenk RF, Kayser S, Bullinger L, et al. Differential impact of allelic ratio and insertion site in FLT3-ITD-positive AML with respect to allogeneic transplantation. Blood. 2014;124:3441–3449.
  • Song Y, Magenau J, Li Y, et al. FLT3 mutational status is an independent risk factor for adverse outcomes after allogeneic transplantation in AML. Bone Marrow Transplant. 2016;51:511–520.
  • Chen Y, Li S, Lane AA, 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;20:2042–2048.
  • Antar A, Kharfan-Dabaja MA, Mahfouz R, et al. Sorafenib maintenance appears safe and improves clinical outcomes in FLT3-ITD acute myeloid leukemia after allogeneic hematopoietic cell transplantation. Clin. Lymphoma Myeloma Leuk. 2015;15:298–302.
  • Battipaglia G, Ruggeri A, Jestin M, 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. Poster presented at: 58th American Society of Hematology Annual Meeting and Exposition; 2016 Dec 3–6; San Diego, CA.
  • Brunner AM, Li S, Fathi AT, 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.
  • Maziarz RT, Patnaik MM, Scott BL, et al. Radius: a phase 2, randomized trial of standard of care with or without midostaurin to prevent relapse following allogeneic hematopoietic stem cell transplant in patients with FLT3-ITD–mutated acute myeloid leukemia. Poster presented at: 58th American Society of Hematology Annual Meeting and Exposition; 2016 Dec 3–6; San Diego, CA.
  • ClinicalTrials.gov. Crenolanib maintenance following allogeneic stem cell transplantation in FLT3-positive acute myeloid leukemia patients [Internet]. Bethesda (MD): US National Institutes of Health; 2017 Aug 8 [cited 2017 Sep 8]. Available from: https://clinicaltrials.gov/ct2/show/NCT02400255
  • ClinicalTrials.gov. A trial of the FMS-like tyrosine kinase 3 (FLT3) inhibitor gilteritinib administered as maintenance therapy following allogeneic transplant for patients with FLT3/internal tandem duplications (ITD) acute myeloid leukemia (AML) [Internet]. Bethesda (MD): US National Institutes of Health; 2017 Aug 7 [cited 2017 Sep 8]. Available from: https://clinicaltrials.gov/ct2/show/NCT02997202
  • ClinicalTrials.gov. Standard of care +/- midostaurin to prevent relapse post stem cell transplant in patients with FLT3-ITD mutated AML (RADIUS) [Internet]. Bethesda (MD): US National Institutes of Health; 2017 Mar 21 [cited 2017 Sep 8]. Available from: https://clinicaltrials.gov/ct2/show/NCT01883362
  • ClinicalTrials.gov. Sorafenib for prophylaxis of leukemia relapse in allo-HSCT recipients with FLT3-ITD positive AML [Internet]. Bethesda (MD): US National Institutes of Health; 2017 Jun 11 [cited 2017 Sep 8]. Available from: https://clinicaltrials.gov/ct2/show/NCT02474290
  • Pratz KW, Levis M. How I treat FLT3-mutated AML. Blood. 2017;129:565–571.
  • Kansagra AJ, Alkhateeb HB, Hefazi M, et al. Feasibility of allogeneic hematopoietic stem cell transplant for high risk FLT3-ITD mutant patients with acute myeloid leukemia in CR1—a real world analysis. Poster presented at: 58th American Society of Hematology Annual Meeting and Exposition; 2016 Dec 3–6; San Diego, CA.
  • Antar A, Otrock ZK, El-Cheikh J, et al. Inhibition of FLT3 in AML: a focus on sorafenib. Bone Marrow Transplant. 2017;52:344–351.
  • Zhang W, Konopleva M, Shi YX, et al. Mutant FLT3: a direct target of sorafenib in acute myelogenous leukemia. J Natl Cancer Inst. 2008;100:184–198.
  • Mori M, Kaneko N, Ueno Y, et al. Gilteritinib, a FLT3/AXL inhibitor, shows antileukemic activity in mouse models of FLT3 mutated acute myeloid leukemia. Invest New Drugs. 2017;35:556–565.
  • Zarrinkar PP, Gunawardane RN, Cramer MD, et al. AC220 is a uniquely potent and selective inhibitor of FLT3 for the treatment of acute myeloid leukemia (AML). Blood. 2009;114:2984–2992.
  • Cortes JE, Perl AE, Dombret H, et al. Final results of a phase 2 open-label, monotherapy efficacy and safety study of quizartinib (AC220) in patients > = 60 years of age with FLT3 ITD positive or negative relapsed/refractory acute myeloid leukemia. Paper presented at: 54th American Society of Hematology Annual Meeting and Exposition; 2012 Dec 8–11; Atlanta, GA.
  • Levis MJ, Perl AE, Dombret H, 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. Paper presented at: 54th American Society of Hematology Annual Meeting and Exposition; 2012 Dec 8–11; Atlanta, GA.
  • Schiller GJ, Tallman MS, Goldberg SL, 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. Poster presented at: 2014 American Society of Clinical Oncology Annual Meeting; 2014 May 30–Jun 3; Chicago, IL.
  • Altman JK, Foran JM, Pratz KW, et al. Results of a phase 1 study of quizartinib (AC220, ASP2689) in combination with induction and consolidation chemotherapy in younger patients with newly diagnosed acute myeloid leukemia. Paper presented at: 55th American Society of Hematology Annual Meeting and Exposition; 2013 Dec 7–10; New Orleans, LA.
  • 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;1:433–443.
  • von Bubnoff N, Engh RA, Åberg E, et al. FMS-like tyrosine kinase 3-internal tandem duplication tyrosine kinase inhibitors display a nonoverlapping profile of resistance mutations in vitro. Cancer Res. 2009;69:3032–3041.
  • 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;28:4339–4345.
  • Perl AE, Altman JK, Cortes J, 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;18:1061–1075.
  • Collins R, Kantarjian HM, Levis MJ, et al. Clinical activity of crenolanib in patients with D835 mutant FLT3-positive relapsed/refractory acute myeloid leukemia (AML). Poster presented at: 2014 American Society of Clinical Oncology Annual Meeting; 2014 May 30–Jun 3; Chicago, IL.
  • 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. Paper presented at: 56th American Society of Hematology Annual Meeting and Exposition; 2014 Dec 6–9; San Francisco, CA.
  • Wang ES, Stone RM, Tallman MS, et al. 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). Paper presented at: 58th American Society of Hematology Annual Meeting and Exposition; 2016 Dec 3–6; San Diego, CA.
  • Cortes JE, Kantarjian HM, Kadia TM, et al. Crenolanib besylate, a type I pan-FLT3 inhibitor, demonstrates clinical activity in multiple relapsed FLT3-ITD and D835 AML. Poster presented at: 2016 American Society of Clinical Oncology Annual Meeting; 2016 Jun 3–7; Chicago, IL.
  • ClinicalTrials.gov. A study of ASP2215 (gilteritinib), administered as maintenance therapy following induction/consolidation therapy for subjects with FMS-like tyrosine kinase 3 (FLT3/ITD) acute myeloid leukemia (AML) in first complete remission [Internet]. Bethesda (MD): US National Institutes of Health; 2017 Aug 18 [cited 2017 Sep 8]. Available from: https://clinicaltrials.gov/ct2/show/NCT02927262
  • ClinicalTrials.gov. Study of crenolanib in combination with chemotherapy in patients with relapsed or refractory acute myeloid leukemia and activating FLT3 mutations [Internet]. Bethesda (MD): US National Institutes of Health; 2017 May 15 [cited 2017 Sep 8]. Available from: https://clinicaltrials.gov/ct2/show/NCT02298166
  • ClinicalTrials.gov. A study of ASP2215 versus salvage chemotherapy in patients with relapsed or refractory acute myeloid leukemia (AML) with FMS-like tyrosine kinase (FLT3) mutation [Internet]. Bethesda (MD): US National Institutes of Health; 2017 Aug 23 [cited 2017 Sep 8]. Available from: https://clinicaltrials.gov/ct2/show/NCT02421939
  • ClinicalTrials.gov. (QuANTUM-R): an open-label study of quizartinib monotherapy vs salvage chemotherapy in acute myeloid leukemia (AML) subjects who are FLT3-ITD positive [Internet]. Bethesda (MD): US National Institutes of Health; 2017 Jun 23 [cited 2017 Sep 8]. Available from: https://clinicaltrials.gov/ct2/show/NCT02039726
  • ClinicalTrials.gov. Study investigating the efficacy of crenolanib with chemotherapy vs chemotherapy alone in R/R FLT3 mutated AML [Internet]. Bethesda (MD): US National Institutes of Health; 2017 Aug 14 [cited 2017 Sep 8]. Available from: https://clinicaltrials.gov/ct2/show/NCT03250338
  • ClinicalTrials.gov. A study of ASP2215 versus salvage chemotherapy in patients with relapsed or refractory acute myeloid leukemia (AML) with FLT3 mutation [Internet]. Bethesda (MD): US National Institutes of Health; 2017 Jun 22 [cited 2017 Sep 8]. Available from: https://clinicaltrials.gov/ct2/show/NCT03182244
  • ClinicalTrials.gov. A study of ASP2215 (gilteritinib), combination of ASP2215 plus azacitidine and azacitidine alone in the treatment of newly diagnosed acute myeloid leukemia with FMS-like tyrosine kinase (FLT3) mutation in patients not eligible for intensive induction chemotherapy [Internet]. Bethesda (MD): US National Institutes of Health; 2017 Aug 10 [cited 2017 Sep 8]. Available from: https://clinicaltrials.gov/ct2/show/NCT02752035
  • ClinicalTrials.gov. Quizartinib with standard of care chemotherapy and as maintenance therapy in patients with newly diagnosed FLT3-ITD (+) acute myeloid leukemia (AML) (QuANTUM-First) [Internet]. Bethesda (MD): US National Institutes of Health; 2017 Aug 30 [cited 2017 Sep 8]. Available from: https://clinicaltrials.gov/ct2/show/NCT02668653
  • ClinicalTrials.gov. Bortezomib and sorafenib tosylate in treating patients with newly diagnosed acute myeloid leukemia [Internet]. Bethesda (MD): US National Institutes of Health; 2017 Sep 4 [cited 2017 Sep 8]. Available from: https://clinicaltrials.gov/ct2/show/NCT01371981
  • ClinicalTrials.gov. Study of crenolanib vs midostaurin following induction chemotherapy and consolidation therapy in newly diagnosed FLT3 mutated AML [Internet]. Bethesda (MD): US National Institutes of Health; 2017 Aug 21 [cited 2017 Sep 8]. Available from: https://clinicaltrials.gov/ct2/show/NCT03258931
  • Albers C, Leischner H, Verbeek M, et al. The secondary FLT3-ITD F691L mutation induces resistance to AC220 in FLT3-ITD(+) AML but retains in vitro sensitivity to PKC412 and sunitinib. Leukemia. 2013;27:1416–1418.
  • Gallogly MM, Lazarus HM. Midostaurin: an emerging treatment for acute myeloid leukemia patients. J Blood Med. 2016;7:73–83.
  • ClinicalTrials.gov. Midostaurin and azacitidine in treating elderly patients with acute myelogenous leukemia [Internet]. Bethesda (MD): US National Institutes of Health; 2016 Jun 8 [cited 2017 Sep 8]. Available from: https://clinicaltrials.gov/ct2/show/NCT01093573
  • Röllig 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;16:1691–1699.
  • 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;31:3110–3118.
  • 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;121:4655–4662.
  • Muppidi MR, Portwood S, Griffiths EA, et al. Decitabine and sorafenib therapy in FLT-3 ITD-mutant acute myeloid leukemia. Clin Lymphoma Myeloma Leuk. 2015;15(Suppl):S73–S79.
  • ClinicalTrials.gov. Sorafenib plus 5-azacitidine initial therapy of patients with acute myeloid leukemia (AML) and high risk myelodysplastic syndrome (MS) with FLT3-ITD mutation [Internet]. Bethesda (MD): US National Institutes of Health; 2017 Mar 9 [cited 2017 Sep 8]. Available from: https://clinicaltrials.gov/ct2/show/NCT02196857
  • Smith CC, Lasater EA, Zhu X, et al. Activity of ponatinib against clinically-relevant AC220-resistant kinase domain mutants of FLT3-ITD. Blood. 2013;121:3165–3171.
  • Kihara R, Nagata Y, Kiyoi H, et al. Comprehensive analysis of genetic alterations and their prognostic impacts in adult acute myeloid leukemia patients. Leukemia. 2014;28:1586–1595.
  • Grossmann V, Schnittger S, Kohlmann A, et al. A novel hierarchical prognostic model of AML solely based on molecular mutations. Blood. 2012;120:2963–2972.
  • Fey MF, Buske C, ESMO Guidelines Working Group. Acute myeloblastic leukaemias in adult patients: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2013;24(Suppl 6):vi138–vi143.
  • Myers GL, Miller WG. The International Consortium for Harmonization of Clinical Laboratory Results (ICHCLR) – a pathway for harmonization. EJIFCC. 2016;27:30–36.
  • Plebani M. Harmonization of clinical laboratory information–current and future strategies. EJIFCC. 2016;27:15–22.
  • Kayser S, Walter RB, Stock W, et al. Minimal residual disease in acute myeloid leukemia—current status and future perspectives. Curr Hematol Malig Rep. 2015;10:132–144.
  • Ossenkoppele G, Schuurhuis GJ. MRD in AML: does it already guide therapy decision-making? Hematology Am Soc Hematol Educ Program. 2016;2016:356–365.
  • Shih LY, Huang CF, Wu JH, 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;100:2387–2392.
  • Kottaridis PD, Gale RE, Langabeer SE, et al. 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;100:2393–2398.
  • Schnittger S, Schoch C, Kern W, et al. FLT3 length mutations as marker for follow-up studies in acute myeloid leukaemia. Acta Haematol. 2004;112:68–78.
  • Cloos J, Goemans BF, Hess CJ, et al. Stability and prognostic influence of FLT3 mutations in paired initial and relapsed AML samples. Leukemia. 2006;20:1217–1220.
  • Palmisano M, Grafone T, Ottaviani E, et al. NPM1 mutations are more stable than FLT3 mutations during the course of disease in patients with acute myeloid leukemia. Haematologica. 2007;92:1268–1269.
  • Grunwald MR, Tseng LH, Lin MT, et al. Improved FLT3 internal tandem duplication PCR assay predicts outcome after allogeneic transplant for acute myeloid leukemia. Biol Blood Marrow Transplant. 2014;20:1989–1995.
  • Zuffa E, Franchini E, Papayannidis C, et al. Revealing very small FLT3 ITD mutated clones by ultra-deep sequencing analysis has important clinical implications in AML patients. Oncotarget. 2015;6:31284–31294.
  • Lin MT, Tseng LH, Dudley JC, et al. A novel tandem duplication assay to detect minimal residual disease in FLT3/ITD AML. Mol Diagn Ther. 2015;19:409–417.
  • Invivoscribe. FLT3 ITD MRD testing by NGS [Internet]. San Diego (CA): Invivoscribe; 2017 [cited 2017 Sep 11]. Available from: https://invivoscribe.com/clinical-services/flt3-itd-mrd-testing-by-ngs