Optimising Therapy in FLT3-Mutated Acute Myeloid Leukaemia

Background Substantial progress has been made in the treatment of Acute myeloid leukaemia (AML) with changes to chemotherapy schedules and the addition of novel targeted therapies(Burnett et al. Br J Haematol 2020;188:86-100). Recently approved therapies have demonstrated efficacy that is restricted to cytogenetic or molecular subgroups of patients.

Optimise-FLT3 will concentrate exclusively on the large subgroup of patients with activating somatic mutations in the gene encoding the FLT3 receptor tyrosine kinase (FLT3). These mutations are present in 1/3 of AML patients(Schnittger et al. Blood 2002;100:59-66, Schnittger et al. Blood 2002;100:59-66, Thiede et al. Blood 2002;99:4326-35) and are associated with a high risk of early relapse, occurring in 40-50% of intensively treated patients (Stone et al. N Engl J Med 2017;377:454-464). Separate studies have identified beneficial therapeutic strategies in this group, namely: 1)intensification of the chemotherapy backbone, 2)addition of FLT3 kinase inhibition and 3)incorporation of the anti-CD33 immunoconjugate Gemtuzumab Ozogamicin (GO). These approaches have not yet been optimally combined. Optimise-FLT3 seeks to improve clinical outcomes by defining the best combination of these strategies, while simultaneously evaluating the clinical utility of highly sensitive and specific next generation sequencing (NGS) based methods to track the FLT3 mutation during treatment for detection of measurable residual disease (MRD).

Method Optimise-FLT3 is a phase II/III randomised three-arm, multi-stage, controlled trial comparing two experimental regimens, DA-GO-Mido and FLAG-Ida-GO-Mido, against the current standard of care, DA-Mido.

Patients aged ≥16yrs with newly diagnosed FLT3-mutated AML who are considered suitable for intensive therapy with curative intent will be recruited to the trial from across 80 UK centres and 8-10 sites internationally.

Patients that have undergone any previous therapy for AML (or any antecedent haematological condition) or have other active malignancy requiring treatment will not be eligible for the trial.

The Primary objective is to compare event free survival between trial arms. Specific events include death from any cause, failure to achieve CR, CRh or CRi after two chemotherapy cycles, MRD relapse and frank relapse. Secondary objectives include incidence of complete remission within 2 courses, death within 30 and 60 days, overall survival, time to haematological relapse, incidence of MRD negativity after cycle 2, MRD levels after cycle 1 and 2, time to MRD relapse, cumulative incidence of grade 3 and 4 toxicity, resource use, rate and timing of allogeneic stem cell transplant and QOL.

At trial entry patients will be randomised (1:1:1) between the three treatment arms (DA-Mido, DA-GO-Mido and FLAG-Ida-GO-Mido), balancing randomisation by FLT3 mutation type, NPM1 status and age. In each arm, patients will receive two cycles of induction chemotherapy and will then undergo MRD assessment (by RT-qPCR if NPM1 is co-mutated or by flow cytometry if NPM1 is unmutated). Patients testing MRD positive, and those with baseline FLT3 ITD >5% with unmutated NPM1 will be recommended for allogeneic haematopoietic stem cell transplant. The remaining patients will receive consolidation chemotherapy with two cycles of high dose cytarabine (HIDAC) and midostaurin, followed by maintenance treatment with midostaurin monotherapy for 12 months.

The study incorporates an initial pilot phase for FLAG-Ida-GO-Mido with a safety review by the independent data monitoring committee planned after 10 and 20 patients have been treated. Stage 1 is the phase II part of the trial which will establish whether either of the experimental arms demonstrate an efficacy signal based on EFS with a target hazard ratio (HR) of 0.64. 236 patients will be recruited by the end of stage 1 at month 34 when interim analysis will determine whether both experimental arms should continue and whether either of the interventions should be restricted according to NPM1 co-mutation status. Stage 2 is a phase III trial which will aim to confirm the efficacy signal in EFS with a target HR of 0.64. 390 patients will be recruited in total by the end of stage 2. It is expected that recruitment will take 3 years 8 months to complete. Following completion of scheduled treatment, patients will be followed up 6-monthly until 2 years after the final patient completes therapy.