In May 2023, Professor Jianxiang Wang , the Chief Clinical Expert at the Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences, and his team, published a paper in The Lancet titled "Quizartinib Plus Chemotherapy in Newly Diagnosed Patients with FLT3-internal-tandem-duplication-positive Acute Myeloid Leukemia: A Phase 3 Trial." The study introduces Quizartinib as an anti-FLT3 drug, demonstrating significant safety and efficacy in the QuANTUM-First trial, with the potential to improve the prognosis of patients with FLT3-mutated AML.
Acute myeloid leukemia (AML) is a genetically heterogeneous disease associated with poor clinical outcomes. Mutations in FMS-related receptor tyrosine kinase 3 (FLT3) are common in AML, with FLT3-internal-tandem-duplication (ITD) mutations being particularly poor prognostic indicators. Standard treatments for FLT3-ITD-positive AML include chemotherapy and allogeneic hematopoietic cell transplantation (allo-HCT). In recent years, FLT3-targeted agents, such as multikinase inhibitors, have shown promise in improving outcomes for patients with FLT3-mutated AML. Quizartinib, a highly potent and selective type 2 FLT3 inhibitor, has demonstrated antileukemic activity and an acceptable safety profile in previous trials.
The QuANTUM-First study was a multicenter, randomized, double-blind, placebo-controlled, phase 3 trial conducted at 193 hospitals and clinics in 26 countries. The study aimed to compare the effect of quizartinib versus placebo on overall survival in newly diagnosed FLT3-ITD-positive AML patients aged 18-75 years. Patients were randomly assigned to receive either quizartinib or placebo in combination with chemotherapy during the induction and consolidation phases. After consolidation, patients received quizartinib or placebo as single-agent continuation therapy for up to 3 years. The primary outcome was overall survival, while secondary outcomes included event-free survival, complete remission rates, and safety profiles.
A total of 539 patients with FLT3-ITD-positive AML were included in the study, with 268 patients in the quizartinib group and 271 patients in the placebo group. The median age of the patients was 56 years. At a median follow-up of 39.2 months, the quizartinib group showed a median overall survival of 31.9 months (95% CI 21.0-not estimable), compared to 15.1 months (95% CI 13.2-26.2) in the placebo group. The hazard ratio for overall survival was 0.78 (95% CI 0.62-0.98, P=0.032), indicating a significantly improved overall survival with quizartinib. The safety profiles were similar between the two groups, with febrile neutropenia, hypokalemia, and pneumonia being the most common grade 3 or 4 adverse events.
The addition of quizartinib to standard chemotherapy, followed by continuation monotherapy for up to 3 years, significantly improved overall survival in newly diagnosed FLT3-ITD-positive AML patients aged 18-75 years. The results from the QuANTUM-First trial provide evidence for the efficacy and safety of quizartinib as a treatment option for adult patients with this high-risk subtype of AML.
