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Review Haematological Malignancies Targeting the FLT3 Mutation in Acute Myeloid Leukaemia Sabine Kayser 1 and Richard F Schlenk 2,3 1. University of Heidelberg, Heidelberg, Germany; 2. Department of Internal Medicine V, University Hospital of Heidelberg, Heidelberg, Germany; 3. Department of Internal Medicine V, Clinical Cooperation Unit Molecular Hematology/Oncology, German Cancer Research Center (DKFZ), University of Heidelberg, Heidelberg, Germany A cute myeloid leukaemia (AML) exhibiting an internal tandem duplication of the FLT3 gene (FLT3-ITD) is an aggressive haematologic malignancy with a poor prognosis due to a high relapse rate and very limited options after relapse with conventional salvage regimens, whereas the prognostic impact of point mutations in the tyrosine kinase domain of the FLT3 gene (FLT3-TKD) are less clear. A number of tyrosine kinase inhibitors (TKIs) have been developed that inhibit the constitutively activated kinase activity caused by the FLT3 mutation, thus interrupting signalling pathways. Early clinical trials of these agents as monotherapy failed to elicit enduring complete responses, leading to clinical testing of FLT3 TKI in combination with conventional chemotherapy. Midostaurin has demonstrated improved survival in combination with standard intensive chemotherapy as compared to standard chemotherapy alone in younger adult patients with newly diagnosed FLT3-mutated AML and is the first and currently the only approved FLT3 TKI. Newer, more selective compounds, such as gilteritinib and crenolanib, have also demonstrated significant potency and specificity. Several combination trials are ongoing or planned in both relapsed and newly diagnosed AML patients with activating FLT3 mutations. Keywords Acute myeloid leukaemia, FLT3 mutations, tyrosine kinase inhibitors, intensive chemotherapy, allogeneic stem cell transplantation Disclosure: Sabine Kayser is a member of the speakers’ bureau of Novartis, and Teva, and also gratefully acknowledges the support of the Olympia-Morata programme from the Medical Faculty of the University Heidelberg. Richard Schlenk has received research funding from Novartis, Pfizer, Amgen, Teva, AstraZeneca, and PharmaMar, is a member of the speakers’ bureau of Novartis, Pfizer, Amgen, Celgene, Teva, AROG, and is on the advisory boards for Daiichi Sankyo, Novartis, Pfizer. Acknowledgements: Medical writing support was provided by Katrina Mountfort and supported by Novartis. Authorship: All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship of this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval to the version to be published. Compliance with Ethics: This study involves a review of the literature and did not involve any studies with human or animal subjects performed by any of the authors. Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any non-commercial use, distribution, adaptation and reproduction provided the original author(s) and source are given appropriate credit. Received: May 5, 2017 Acute myeloid leukaemia (AML) is a heterogeneous clonal disorder of haematopoietic progenitor cells resulting in uncontrolled growth and accumulation of malignant white blood cells. It is the most common myeloid leukaemia in adults, with a prevalence of 3–8 cases per 100,000 adults rising to 9–17 cases per 100,000 adults aged 65 years and older. The median age at presentation is about 70 years. 1 AML affects both male as well as female patients with a slight predominance of the male gender (m/f: 3:2). According to the American Cancer Society, AML accounted for approximately 33% of all new leukaemia cases in the United States in 2016. Almost 20,000 patients had been newly diagnosed with AML in 2016 in the United States and over 10,000 died of the disease (www.cancer.org). The median overall survival (OS) after 5 years in younger (18–60 years) adult AML patients is roughly 40% with the disease being even more detrimental in older individuals with only around 10% surviving patients above the age of 60 years. 2 Hence, there is a high medical need to improve the outcome of AML patients. The prognosis for patients with AML is determined to a large degree by the biology of the disease. In recent years, the identification and characterisation of genetic aberrations has vastly improved our understanding of the pathogenesis of AML. These genetic alterations allow for the stratification of patient populations into different risk groups, thus guiding treatment. Based on the currently updated version of the European LeukemiaNet (ELN) risk stratification by genetics, the risk groups consist of the favourable, intermediate and adverse risk categories (Table 1). 3–7 AML with normal karyotype (accounting for roughly 50% of the patients) can be categorised according to molecular abnormalities. Of these, the most frequently affected gene mutations are NPM1 and FLT3. 8 Accepted: May 31, 2017 Citation: European Oncology & Haematology, 2017;13(2):139–46 Corresponding Author: Richard F Schlenk, NCT Trial Center, National Center for Tumor Diseases, Im Neuenheimer Feld 130.3, 69120 Heidelberg, Germany. E: richard.schlenk@nct-heidelberg.de Support: The publication of this article was supported by Novartis. TOU CH MED ICA L MEDIA Despite the fact that AML is a clinically and genetically heterogeneous disease, until recently most patients have been treated by similar chemotherapeutic regimens. 9 To date, the only approved targeted therapies for patients with AML are all-trans retinoic acid 10 and arsenic trioxide 11 for acute promyelocytic leukaemia (APL), which accounts for 10–15% of AML cases. 12 There is a clear need for more targeted therapies and a more individualised approach in the treatment of AML. However, in the last decade the treatment options for AML have expanded as a result of the discovery of cytogenetic abnormalities as well as molecular mutations, but only two new nontargeted drugs have been approved in the EU in this period. This article aims to discuss mutations of the FLT3 gene, as well as the therapeutic interventions targeting these mutations. 139