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A randomised assessment of adding the kinase inhibitor lestaurtinib to 1st-line chemotherapy for FLT3-mutated AML.

Knapper, S; Russell, N; Gilkes, A; Hills, RK; Gale, RE; Cavenagh, JD; Jones, G; ... Burnett, AK; + view all (2017) A randomised assessment of adding the kinase inhibitor lestaurtinib to 1st-line chemotherapy for FLT3-mutated AML. Blood , 129 (9) pp. 1143-1154. 10.1182/blood-2016-07-730648. Green open access

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Abstract

The clinical benefit of adding 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 17 trials, patients with previously-untreated AML and confirmed FLT3-activating mutations, mostly aged <60 years, were randomised to receive oral Lestaurtinib (CEP701), or not, following each of four 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-analysed. 500 patients were randomised between Lestaurtinib and control; 74% had FLT3-ITD mutations, 23% FLT3-TKD point mutations, 2% both types. No significant differences were seen in either 5-year overall survival (Lestaurtinib 46% vs control 45%, HR 0.90 [0.70-1.15], p=0.3) or 5-year relapse-free survival (40% vs 36%, HR 0.88 [0.69-1.12], p=0.3). Exploratory sub-group analysis suggested survival benefit with Lestaurtinib in patients receiving concomitant azole anti-fungal 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 >85% FLT3 inhibition. In conclusion, combining Lestaurtinib with intensive chemotherapy proved feasible in younger patients with newly-diagnosed FLT3-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.

Type: Article
Title: A randomised assessment of adding the kinase inhibitor lestaurtinib to 1st-line chemotherapy for FLT3-mutated AML.
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1182/blood-2016-07-730648
Publisher version: https://doi.org/10.1182/blood-2016-07-730648
Language: English
Additional information: This research was originally published in Blood Online. Steven Knapper, Nigel Russell, Amanda Gilkes, Robert K. Hills, Rosemary E. Gale, James D. Cavenagh, Gail Jones, Lars Kjeldsen, Michael R. Grunwald, Ian Thomas, Heiko Konig, Mark J. Levis, Alan K. Burnett, A randomised assessment of adding the kinase inhibitor lestaurtinib to 1st-line chemotherapy for FLT3-mutated AML, in: Blood Jan 2016, blood-2016-07-730648; DOI: 10.1182/blood-2016-07-730648
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Haematology
URI: https://discovery.ucl.ac.uk/id/eprint/1533969
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