A Randomised Comparison of the Sequential Addition of the FLT3 Inhibitor Lestaurtinib (CEP701) to Standard First Line Chemotherapy for FLT3-Mutated Acute Myeloid Leukemia: The UK Experience
Authors: Knapper Steven , Hills Robert K , Cavenagh James D , Kjeldsen Lars , Hunter Ann E. , Clark Richard E , Dennis Michael , Milligan Donald , Levis Mark J , Russell Nigel , Burnett Alan K. 
Published: October 2019

Abstract
Activating mutations of the receptor tyrosine kinase FLT3 are seen at diagnosis in one-third of younger adults with acute myeloid leukemia (AML) and are associated with an increased risk of relapse. FLT3 remains the subject of intense clinical interest as a therapeutic target. To date FLT3-targeted monotherapy has produced only transient clinical responses with no prospective trial producing an overall survival benefit. Here we report the results of the first randomised trial of a FLT3 inhibitor (Lestaurtinib, CEP701) given sequentially to chemotherapy as first line treatment for newly-diagnosed AML. FLT3-mutated patients entering the UK MRC AML15 and UK NCRI AML17 trials between January 2007 and October 2012 were randomised to receive either oral Lestaurtinib 80mg bid, or placebo, for up to 28 days after each of 4 courses of chemotherapy. Based on early pharmacokinetic data provision was made for dose reduction to 40mg bid for patients on concomitant azole anti-fungal drugs.
500 patients were randomised (175 AML15, 325 AML17). Median age was 49yrs (5-68, only 5 were <16yrs.). 94% patients had de novo AML, 5% secondary AML and 1% high risk MDS. The majority of patients (89%) had cytogenetically intermediate risk disease with 6% favourable and 5% adverse risk. Median presenting WBC was 28.0x109/l (0.2-363); 381 patients (74%) had FLT3-ITD mutations, 127 (23%) FLT3-TKD point mutations and 12 (2%) both types; 207 patients (41%) had concomitant mutated NPM1. All characteristics were balanced between the arms.
Results: No difference in remission rate was seen between the arms (CR/CRi: Lestaurtinib 92% vs Control 94%. OR 1.37 [0.68-2.78] p=0.4). The respective 5-year RFS was 40% vs 37%, HR 0.87 (0.68-1.12) p=0.3; cumulative incidence of relapse 52% vs 54%, HR 0.87 (0.67-1.13) p=0.3 and OS at 5 years 46% vs 43%, HR 0.89 (0.68-1.13) p=0.3 did not differ between arms.
Figure 1 Figure 1.
43% of patients were transplanted in both Lestaurtinib and control arms (130/300 and 85/200 respectively); 133 transplants were in CR1, 63 in CR2; 188 were allografts. When the data were censored at SCT the lack of difference in clinical outcome persisted (HR 0.97 [0.71-1.33] p=0.8).
Stratified analyses involving age, sex, diagnosis (de novo/secondary/MDS), cytogenetic group, performance status, ITD vs TKD, ITD allelic %, NPM1 status, Gemtuzumab ozogamicin (GO) or not in induction and concomitant use of azoles were undertaken to identify evidence of subgroup benefit with Lestaurtinib. No significant interactions were seen, with some evidence of survival benefit in patients receiving GO (p=0.09 for interaction). In patients receiving concomitant azole treatment there was a significant survival benefit with Lestaurtinib (HR 0.57 (0.36-0.92) p=0.02) although the test for interaction was not significant (p=0.2). Course 1 day 14 plasma trough Lestaurtinib levels were significantly higher in azole-treated patients than in those not receiving azoles (median 4517 vs 3085ng/ml, p=0.03). In AML17 patients treated with GO and azoles, survival with Lestaurtinib at 4 years was 61% compared to 28% in the control arm (p=0.02)
Minimal difference in toxicity was seen between the 2 arms, with the exception of slight excess nausea/diarrhea with Lestaurtinib in course 2. Supportive care requirements were slightly increased with Lestaurtinib with a borderline-significant 1-day increase in median time to platelet recovery following course 2 (p=0.05).
Conclusion: Lestaurtinib may be safely combined with intensive chemotherapy in younger patients with newly-diagnosed FLT3-mutated AML. No overall clinical improvement was seen with Lestaurtinib, although there was a suggestion of benefit in patients also receiving GO in induction: in Lestaurtinib-treated patients receiving both GO and azoles, survival was 61%. The potential clinical benefit of GO with adequate FLT3 inhibition requires prospective validation.
(We are grateful to Cephalon for the provision of Lestaurtinib for this study)

Disclosures
Knapper: Cephalon: Consultancy, Research Funding. Off Label Use: Tyrosine kinase inhibitor Lestaurtinib (CEP701) used off-label in a randomised controlled trial in FLT3-mutated acute myeloid leukemia.