Efficacy analysis of different FLT3 inhibitors in patients with relapsed/refractory acute myeloid leukemia and high‐risk myelodysplastic syndrome

Abstract

Several FLT3 inhibitors(i) are available to treat relapsed/refractory (R/R) FLT3-internal tandem duplicated acute myeloid leukemia (AML). This study analyzes the efficacies of various FLT3i (types 1 and 2) tested in clinical trials in treating R/R AML and high-risk myelodysplastic syndromes (HR-MDS). PubMed and EMBASE databases were searched for single/double-arm phase I/II/III R/R AML or HR-MDS clinical trials published between 1/1/2000 and 6/1/2021. The outcomes studied were composite response rate (CRc) and overall response rate (ORR). Toxicities were compared based on the organ system. The 28 studies analyzed had 1927 patients. The pooled ORR and (CRc) for all FLT3i were 53% (95% CI, 43%-63%) and 34% (95% CI, 26%-44%). Pooled ORR and CRc were 37% (95% CI, 25%-51%) and 35% (95% CI, 21%-52%) for type 1 and 58% (95% CI, 43%-71%) and 38% (95% CI, 27%-50%) for type 2, respectively. Gastrointestinal (GI) and hematological toxicity occurred in 22% (95% CI, 19%-25.4%) and 74.6% (95% CI, 70%-79%) with type 1 and 13.9% (95% CI, 12%-16%) and 57.7% (95% CI, 54.6%-60.8%) with type 2 FLT3i. QTc prolongation occurred in 2.06% (95% CI, 1.03%-3.65%) with type 1 and 7% (95% CI, 5.3%-9%) with type 2 FLT3i. Type 2 FLT3i had less GI toxicity but more QTc prolongation. Prospective studies are needed to compare the efficacy of type 1 and 2 FLT3i.

A Review of FLT3 Kinase Inhibitors in AML

“…Nevertheless, with the advent of FLT3 inhibitors, it is anticipated that this percentage will decrease. This noteworthy occurrence of FLT3 mutation during relapse is a sign that the FLT3-ITD clone, which was present during the initial diagnosis, can expand and cause a recurrence of AML [20].…”

“…These side effects can be severe in approximately 5-6% of patients. It is worth noting that both types of FLT3 inhibitors can cause such side effects [20,29].…”

“…Type 2 inhibitors have a 7% incidence of QTc prolongation (95% CI 5.3-9%), with quizartinib causing dose-dependent toxicity that can be severe. It is important to keep these potential side effects in mind when considering FLT3 inhibitors as a treatment option [20,29].…”