A randomized assessment of adding the kinase inhibitor lestaurtinib to first-line chemotherapy for FLT3-mutated AML

Abstract

The clinical benefit of adding FMS-like tyrosine kinase-3 (FLT3)-directed small molecule therapy to standard first-line treatment of acute myeloid leukemia (AML) has not yet been established. As part of the UK AML15 and AML17 trials, patients with previously untreated AML and confirmed FLT3-activating mutations, mostly younger than 60 years, were randomly assigned either to receive oral lestaurtinib (CEP701) or not after each of 4 cycles of induction and consolidation chemotherapy. Lestaurtinib was commenced 2 days after completing chemotherapy and administered in cycles of up to 28 days. The trials ran consecutively. Primary endpoints were overall survival in AML15 and relapse-free survival in AML17; outcome data were meta-analyzed. Five hundred patients were randomly assigned between lestaurtinib and control: 74% had -internal tandem duplication mutations, 23%-tyrosine kinase domain point mutations, and 2% both types. No significant differences were seen in either 5-year overall survival (lestaurtinib 46% vs control 45%; hazard ratio, 0.90; 95% CI 0.70-1.15; = .3) or 5-year relapse-free survival (40% vs 36%; hazard ratio, 0.88; 95% CI 0.69-1.12; = .3). Exploratory subgroup analysis suggested survival benefit with lestaurtinib in patients receiving concomitant azole antifungal prophylaxis and gemtuzumab ozogamicin with the first course of chemotherapy. Correlative studies included analysis of in vivo FLT3 inhibition by plasma inhibitory activity assay and indicated improved overall survival and significantly reduced rates of relapse in lestaurtinib-treated patients who achieved sustained greater than 85% FLT3 inhibition. In conclusion, combining lestaurtinib with intensive chemotherapy proved feasible in younger patients with newly diagnosed -mutated AML, but yielded no overall clinical benefit. The improved clinical outcomes seen in patients achieving sustained FLT3 inhibition encourage continued evaluation of FLT3-directed therapy alongside front-line AML treatment. The UK AML15 and AML17 trials are registered at www.isrctn.com/ISRCTN17161961 and www.isrctn.com/ISRCTN55675535 respectively.

Sorafenib Dose Recommendation in Acute Myeloid Leukemia Based on Exposure‐FLT3 Relationship

“…Because the quantitative relationship between FLT3 activity and clinical outcome (i.e., overall survival and objective response rate) has been establised,8, 17, 18 it is appropriate to utlilize the degree of target inhibition from early clinical trials as a surrogate marker to support dosing selection. Sorafenib and its N‐oxide metabolite showed a concentration‐dependent inhibitory effect on both FLT3 and ERK activities 9.…”

“…FLT3 activating mutations are commonly present as internal tandem duplication (ITD) mutations (FLT3‐ITD) or point mutations in the second tyrosine kinase domain (FLT3‐TKD) in ∼25–30% or 5–10% of patients, respectively 5, 7. Currently, several FLT3 inhibitors are being investigated in patients with AML 8, 9. In 2017, the US Food and Drug Administration (FDA) approved the pan‐kinase/FLT3 inhibitor, midostaurin in patients with FLT3‐ITD and TKD‐positive AML based on prolongation of both event‐free and overall survival in the subgroup receiving midostaurin in combination with standard induction chemotherapy 10…”

“…Numerous phase I and phase II clinical trials have been conducted to evaluate sorafenib safety and efficacy as monotherapy or in combination with traditional antileukemic chemotherapy in newly diagnosed and refractory or relapsed adult AML as well as in pediatric AML 9, 12, 13, 14, 15, 16. Overall survival benefits for the incorporation of sorafenib into combinational therapies have yet to be demonstrated, possibly due to mixed FLT3 mutations status and to a sorafenib dosing regimen that has not been optimized to balance tolerability with the achievement of 85% FLT3 inhibition, which is a predictor for clinical response 8, 17, 18. All randomized studies to date have evaluated the use of sorafenib with chemotherapy in an unselected AML population with or without FLT3 mutations at the full maximum tolerate dose (MTD) dose of 400 mg b.i.d.…”

Targeting the FLT3 Mutation in Acute Myeloid Leukaemia

“…Within this trial, newly diagnosed AML patients with activating FLT3 mutations (median age, 49 years; range 5-68 years) were randomised to receive either oral lestaurtinib or placebo, for up to 28 days after each of the four courses of chemotherapy. 95 Recently published data showed that lestaurtinib yielded no improvements in 5-year RFS and OS when added to first-line chemotherapy. 95 Nevertheless, subgroup analysis indicated improved OS and significantly reduced rates of relapse in lestaurtinib-treated patients who sustained >85% FLT3 inhibition as assessed by the plasma inhibitory activity assay.…”

“…95 Recently published data showed that lestaurtinib yielded no improvements in 5-year RFS and OS when added to first-line chemotherapy. 95 Nevertheless, subgroup analysis indicated improved OS and significantly reduced rates of relapse in lestaurtinib-treated patients who sustained >85% FLT3 inhibition as assessed by the plasma inhibitory activity assay. 95 In addition, elevated FLT3 ligand had no impact on lestaurtinib plus chemotherapy treatment.…”