Midostaurin approved for FLT3-mutated AML.

Midostaurin was recently approved by the US Food and Drug Administration for the treatment of FLT3-mutant acute myeloid leukemia (AML). This is the first drug to receive regulatory approval for AML in the United States since the year 2000. Midostaurin is a small-molecule kinase inhibitor with activity against the receptor tyrosine kinase FLT3, and its approval will hopefully mark the beginning of an era of targeted agents for the treatment of molecularly defined subtypes of AML.

[1]  G. Ehninger,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 , 2022 .

[2]  Axel Benner,et al.  Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. , 2008, The New England journal of medicine.

[3]  T. Naoe,et al.  Prognostic significance of FLT3 internal tandem duplication and tyrosine kinase domain mutations for acute myeloid leukemia: a meta-analysis , 2005, Leukemia.

[4]  Hwai I. Yang,et al.  Prognostic impact of allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia patients with internal tandem duplication of FLT3. , 2013, Leukemia research.

[5]  P. Zarrinkar,et al.  AC220 is a uniquely potent and selective inhibitor of FLT3 for the treatment of acute myeloid leukemia (AML). , 2009, Blood.

[6]  T. Tamaoki,et al.  Staurosporine, a potent inhibitor of phospholipid/Ca++dependent protein kinase. , 1986, Biochemical and biophysical research communications.

[7]  M. Levis,et al.  Preclinical studies of gilteritinib, a next-generation FLT3 inhibitor. , 2017, Blood.

[8]  M. Levis,et al.  FLT3: ITDoes matter in leukemia , 2003, Leukemia.

[9]  P. Bolufer,et al.  Incidence and prognostic value of FLT3 internal tandem duplication and D835 mutations in acute myeloid leukemia. , 2003, Haematologica.

[10]  J. Esteve,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. , 2012, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[11]  M. Levis,et al.  How I treat FLT3-mutated AML. , 2017, Blood.

[12]  M. Levis.  FLT3 mutations in acute myeloid leukemia: what is the best approach in 2013? , 2013, Hematology. American Society of Hematology. Education Program.

[13]  L. Bullinger,et al.  Differential impact of allelic ratio and insertion site in FLT3-ITD-positive AML with respect to allogeneic transplantation. , 2014, Blood.

[14]  E. Estey,et al.  Addition of gemtuzumab ozogamicin to induction chemotherapy in adult patients with acute myeloid leukaemia: a meta-analysis of individual patient data from randomised controlled trials. , 2014, The Lancet. Oncology.

[15]  M. Labopin,et al.  Potent graft-versus-leukemia effect after reduced-intensity allogeneic SCT for intermediate-risk AML with FLT3-ITD or wild-type NPM1 and CEBPA without FLT3-ITD. , 2012, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[16]  E. Estey.  Why Is Progress in Acute Myeloid Leukemia So Slow? , 2015, Seminars in hematology.

[17]  Doriano Fabbro,et al.  Inhibition of mutant FLT3 receptors in leukemia cells by the small molecule tyrosine kinase inhibitor PKC412. , 2002, Cancer cell.

[18]  M. Patnaik,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) , 2016 .

[19]  N. Schmitz,et al.  Allogeneic Stem Cell Transplantation Improves Survival in Patients with Acute Myeloid Leukemia Characterized by a High Allelic Ratio of Mutant FLT3-ITD. , 2016, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[20]  S. Meshinchi,et al.  The outcome of allogeneic hematopoietic cell transplantation for children with FMS-like tyrosine kinase 3 internal tandem duplication-positive acute myelogenous leukemia. , 2015, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[21]  Mindy I. Davis,et al.  Comprehensive analysis of kinase inhibitor selectivity , 2011, Nature Biotechnology.

[22]  R. Greil,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 , 2016 .

[23]  F. Awan,et al.  Efficacy and Safety of Midostaurin in Advanced Systemic Mastocytosis. , 2016, The New England journal of medicine.

[24]  T. Naoe,et al.  Prognostic implication of FLT3 and N-RAS gene mutations in acute myeloid leukemia. , 1999, Blood.

[25]  H. Kantarjian,et al.  Allogeneic Transplantation in First Remission Improves Outcomes Irrespective of FLT3-ITD Allelic Ratio in FLT3-ITD-Positive Acute Myelogenous Leukemia. , 2016, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[26]  E. Estey,et al.  Plasma inhibitory activity (PIA): a pharmacodynamic assay reveals insights into the basis for cytotoxic response to FLT3 inhibitors. , 2006, Blood.

[27]  B. Wood,et al.  Comparison of Minimal Residual Disease as Outcome Predictor for AML Patients in First Complete Remission Undergoing Myeloablative or Nonmyeloablative Allogeneic Hematopoietic Cell Transplantation , 2013, Leukemia.

[28]  R. Hills,et al.  A randomized assessment of adding the kinase inhibitor lestaurtinib to first-line chemotherapy for FLT3-mutated AML. , 2017, Blood.

[29]  M. Caligiuri,et al.  FLT3 D835/I836 mutations are associated with poor disease-free survival and a distinct gene-expression signature among younger adults with de novo cytogenetically normal acute myeloid leukemia lacking FLT3 internal tandem duplications. , 2008, Blood.

[30]  D. Linch,et al.  Improved outcome after stem-cell transplantation in FLT3/ITD-positive AML , 2007 .

[31]  I. Buño,et al.  Prognostic impact of minimal residual disease analysis by flow cytometry in patients with acute myeloid leukemia before and after allogeneic hemopoietic stem cell transplantation , 2014, European journal of haematology.

[32]  Joshua F. McMichael,et al.  The Origin and Evolution of Mutations in Acute Myeloid Leukemia , 2012, Cell.

[33]  A. Harris,et al.  Phase I and pharmacokinetic study of PKC412, an inhibitor of protein kinase C. , 2001, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[34]  Axel Benner,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. , 2002, Blood.

[35]  M. McDevitt,et al.  Role of allogeneic transplantation for FLT3/ITD acute myeloid leukemia: outcomes from 133 consecutive newly diagnosed patients from a single institution. , 2011, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[36]  M. Levis,et al.  Crenolanib is a potent inhibitor of FLT3 with activity against resistance-conferring point mutants. , 2014, Blood.

[37]  J. Esteve,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. , 2013, Blood.

[38]  Martin Dugas,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. , 2002 .

[39]  E. Estey,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. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[40]  M. Levis,et al.  The Future of Targeting FLT3 Activation in AML , 2017, Current Hematologic Malignancy Reports.

[41]  A. Mead,et al.  FLT3 tyrosine kinase domain mutations are biologically distinct from and have a significantly more favorable prognosis than FLT3 internal tandem duplications in patients with acute myeloid leukemia. , 2007, Blood.

[42]  Joshua F. McMichael,et al.  Clonal evolution in relapsed acute myeloid leukemia revealed by whole genome sequencing , 2011, Nature.

[43]  E. Estey,et al.  Patients with acute myeloid leukemia and an activating mutation in FLT3 respond to a small-molecule FLT3 tyrosine kinase inhibitor, PKC412 , 2004 .

[44]  C. Schiffer,et al.  Phase IB study of the FLT3 kinase inhibitor midostaurin with chemotherapy in younger newly diagnosed adult patients with acute myeloid leukemia , 2012, Leukemia.