PB1834: CLEVO: A NON-INTERVENTIONAL STUDY TO INVESTIGATE CLONAL EVOLUTION OF FMS-LIKE TYROSINE KINASE 3 (FLT3) GENE MUTATIONS DURING DISEASE PROGRESSION IN PATIENTS WITH ACUTE MYELOID LEUKEMIA

Abstract

Background: Acute myeloid leukemia (AML) is clinically heterogeneous, with differing response to treatment and patient survival reflecting the diverse cytogenetic abnormalities and genetic mutations that give rise to the disease. Clonal evolution means that genetic characteristics of the leukemic cells and the proportions of individual cell clones can change because of disease progression and selection by therapy. Fms-like tyrosine kinase 3 (FLT3) gene mutations are found in approximately 30% of the general AML population and are often secondary events associated with leukemic transformation. These mutations are known to either develop or become undetectable during the disease course, and the mutant-to-wild-type allelic ratio also typically changes. This clonal evolution is not well understood but may have clinical consequences. Aims: The aim of this study is to characterize FLT3 mutations at AML diagnosis and chart the clonal evolution of FLT3 mutations (gain or loss) through treatment. Methods: This non-interventional, descriptive study will prospectively enroll approximately 650 adults (aged ≥18 years) with AML diagnosed within 30 days of enrollment at oncology or oncology/hematology specialist sites in Belgium, France, Germany, Israel, Italy, Spain, the UK and the USA, with follow-up for 36 months. Patients will be excluded if they have relapsed or refractory AML at enrollment, acute promyelocytic leukemia, or clinically active central nervous system leukemia. Patients will undergo treatment according to local standard of care and treatment guidelines, at the treating physician’s discretion. Patients will undergo routine FLT3 genetic testing at diagnosis and at relapse/refractory disease, and all AML treatments (including hematopoietic stem cell transplantation) received will be recorded. The primary objective is to determine the proportion of relapsed/refractory AML patients with FLT3 clonal evolution (gain/loss of FLT3 mutations) from diagnosis. Secondary objectives include a description of the: frequency, allelic ratio, length and location of FLT3-internal tandem duplication mutations and frequency of other FLT3 mutations at diagnosis and at relapse/refractory disease; frequency of FLT3 clonal evolution of FLT3 mutations at relapse/refractory disease by mutation type and treatment(s) received; patient survival (overall 3-year survival rate, disease-free survival and event-free survival) in relation to FLT3 mutation status at diagnosis, FLT3 clonal evolution and treatment received; frequency of composite complete remission in relation to FLT3 mutation status at diagnosis, FLT3 clonal evolution (relapsed patients only) and treatment received; and frequency and characteristics of other AML-associated genetic mutations at diagnosis and relapse/refractory disease. Interim analyses are planned for ~1 and ~3 years following study initiation to provide an estimate of FLT3 mutation frequencies in the study population, and potentially an early estimate of the rate of clonal evolution. The first patient was enrolled in September 2020. Results: The trial is in progress. Summary/Conclusion: The information generated by this study will help to better understand the clonal evolution of FLT3 throughout the course of the disease for AML patients.