FLT3 inhibitors in acute myeloid leukaemia: assessment of clinical effectiveness, adverse events and future research—a systematic review and meta-analysis

Abstract

Background FMS-like tyrosine kinase 3 (FLT3) is the most frequent mutation in AML. With two FLT3 inhibitors recently approved by the FDA (midostaurin and gilteritinib), there is a need to evaluate these targeted agents. Purpose To assess the clinical effectiveness of FLT3 inhibitors in AML patients. Methods Standard systematic review methods were utilised. Searches were conducted to July 2020 for completed and in-progress randomised controlled trials of FLT3 inhibitors in AML. A fixed-effect meta-analysis was undertaken. Results Eight completed trials involving 2656 patients and assessing five different FLT3 inhibitors (sorafenib, lestaurtinib, midostaurin, gilteritinib and quizartinib) were included. The pooled results were as follows (FLT3 inhibitor/control): overall survival hazard ratio (HR) = 0.83 (95% confidence interval [CI] 0.75 to 0.92, p = 0.0005), event-free survival HR = 0.85 (95% CI 0.77 to 0.94, p = 0.002), relapse-free survival HR = 0.76 (95% CI 0.64 to 0.90, p = 0.001), complete remission relative risk (RR) = 1.11 (95% CI 1.00 to 1.22. p = 0.05) and 60-day mortality RR = 1.04 (95% CI 0.77 to 1.40, p = 0.79). Relative risk of grade 3 and above vascular, dermatological, respiratory and hepatobiliary adverse events were found to be statistically significantly higher in the FLT3 inhibitor group compared to control, but the actual numbers of events were relatively small. Nineteen ongoing trials are still in progress, only one of which specifically targets older patients with AML. Conclusions There is evidence to support the use of FLT3 inhibitors in patients with AML, but more data is needed to verify the optimum use of the drugs regarding type of inhibitor, disease stage and patient characteristics, not only in relation to disease control, but adverse events and quality of life. There are a large number of ongoing trials; therefore, the results of this review are not a fait accompli; thus, is it recommended that the review be updated in a couple of years’ time. Given the challenges in extracting the complete data set required to assess clinical effectiveness, it is highly recommended that ongoing and future trials improve transparency and consistency of reporting of all trial outcomes, particularly disease control and adverse events, to enable a global clinical effectiveness assessment. Systematic review registration PROSPERO CRD42017055581

Advances in acute myeloid leukemia

“…Several recent reviews have summarized the evolving FLT3 landscape and identified important unanswered questions. [151][152][153] Additional tyrosine kinase inhibitors are being studied for targets other than FLT3 and are in various stages of development, as recently described. 154…”

Inhibitors of class I HDACs and of FLT3 combine synergistically against leukemia cells with mutant FLT3

“…The membrane-bound FMS-like tyrosine kinase-3 (FLT3) is activated by the FLT3 ligand and contributes to the development of hematopoietic cells. FLT3 is encoded on chromosome 13q12.2 and consists of five extracellular, immunoglobulin-like domains, a transmembrane domain, a juxtamembrane domain, and an intracellular tyrosine kinase domain (Majothi et al 2020 ; Marensi et al 2021 ; Scholl et al 2020 ). Mutations in FLT3 promote cell growth and chemoresistance and lead to AML with poor prognosis.…”

“…Mutations in FLT3 promote cell growth and chemoresistance and lead to AML with poor prognosis. Internal tandem duplications in FLT3 (FLT3-ITD) occur in 20–35% of patients with de novo AML and tyrosine kinase domain (FLT3-TKD) mutations occur in 5–10% of patients with de novo AML (Heidel et al 2006 ; Majothi et al 2020 ; Marensi et al 2021 ; Scholl et al 2020 ).…”

Small Molecule Inhibitors of MERTK and FLT3 Induce Cell Cycle Arrest in Human CD8+ T Cells

“…FLT3 is another highly attractive therapeutic target, due to the fact it is overexpressed in most AML cases with a high mutational rate [16,17]. Proven effects on tumor cell cycling by FLT3 inhibitors [18][19][20] have led to many clinical trials either as a monotherapy, or as combinatorial therapy with conventional chemotherapy, with early meta-analysis suggesting a statistically significant 17% improvement in survival [21].…”