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Lestaurtinib As a FLT3 Inhibitor Xdepartment of Haematology, School of Medicine, Cardiff University, UK

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Lestaurtinib As a FLT3 Inhibitor Xdepartment of Haematology, School of Medicine, Cardiff University, UK Hematology Meeting Reports 2008;2(5):162-163 SESSION X xA.K. Burnett Lestaurtinib as a FLT3 inhibitor xDepartment of Haematology, School of Medicine, Cardiff University, UK Overexpression of the FLT-3 does not significantly reduce sur- receptor is common in Acute vival. Its impact in that context is Myeloid Leukaemia (AML) and difficult to distinguish from the mutations represent one of the presence of a high white count. commonest mutations which Point (TK) mutations do not have occur in approximately 30% of an adverse prognosis, and indeed adult cases, although less frequent may indicate a favourable feature. in older patients. The most fre- The mutation characteristics quently detected mutation is an patients with proliferative disor- Internal Tandem Duplication ders ie with high WBC’s and (ITD) in the juxtamembrane posi- hypercellular marrows. Several tion of the receptor (24%), and a agents with pre-clinical in vivo point mutation in the activation and in vitro activity have been loop usually at positive 385 (7%). developed. None of the agents The mutations are in frame and who are furthest down the clinical constitutively activate via STAT5. development path are specific for Mutations are unevenly distrib- FLT3 mutations. Lestaurtinib uted in FAB and cytogenetic (CEP-701) is a small molecule groups. They have highest fre- kinase inhibitor which has shown quency in Acute Promyelocytic impressive preclinical activity in Leukaemia (35-40%), and are in vivo models, against cell lines associated with a normal kary- bearing the mutation and against otypic or trisomy 8. They are less primary cells where it is active frequent in poor risk karyotypes against both mutated and non- or in core binding leukaemias. mutated cases, although at a lower The association with normal kary- IC against mutants. tyope has the additional interest of In phase I/II studies which being associated with mutations recruited mutated AML cases of the nucleophosmin 1 mutation with relapsed disease a maximum in approximately two-thirds of tolerated dose was not reached at cases. Whether these mutations doses capable of inhibition. are themselves leukaemogenic is Clinical activity was seen as thought to be unlikely. clearance of blasts in approxi- The major clinical interest is mately half of patients and reduc- that the presence of an ITD pre- tion in bone marrow blasts but no dicts a significantly increased risk complete remissions. It was sug- of relapse, but does not reduce the gested that greater benefit would prospect of initial response. The be seen in combination with stan- frequent association with the APL dard chemotherapy, and some subtype, which is highly curable, pre-clinical studies suggested | 162 | New Drugs in Hematology synergy, but also that sequencing of ing. Since Lestaurtinib is highly protein bound Lestaurtinib was important with the chemo- direct pharmacokinetics are not informative. therapy. Antagonism was seen when cells were Levis and colleagues have developed a bioas- treated before chemotherapy, whereas simulta- say of “Plasma Inhibitory Activity”, which neous or sequential administration resulted in demonstrates the extent to which patients’ synergy. plasma can dephosphorylate the FLT-3 recep- Two major randomised trials are underway. tor. Defining these parameters in the context A potential registration trial in relapsed of these prospective trials will be important in patients compared chemotherapy (MAC or assessing efficacy. Ara-C) with or without Lestaurtinib which was The interpretation of inhibitor trials will also given after the course of chemotherapy. This require to take into account the relapse risk of study is close to completing accrual of over individual patients. This depends on whether 200 patients. An amendment of the UK MRC or not the mutation co-exists with an NPM1 AML15 Trial assesses CEP-701 in first line mutation which tends to neutralise the negative use of 80 mgs bid commencing two days after impact of FLT3, and what level of FLT-3 allel- chemotherapy daily until two days before the next course of chemotherapy or for up to four ic ratio exists. High level mutations have a courses. Patients are aged 15-60. Four courses greater risk of relapse are planned. The toxicity is predominantly gas- While molecular therapy in AML will be tro-intestinal (nausea) and has caused patients complicated because of the heterogeneous to discontinue therapy or require a dose reduc- molecular basis of the disease. FLT-3 inhibi- tion. Because of interaction with CP3A metab- tion is clearly a priority aim for which efficacy olism azoles tend to potentiate toxicity, and if will be determined in ongoing randomised tri- used dose reduction is usually needed. To be a als. Many inhibitory agents are in various responder two aspects require to be achieved. stages of development, but none is yet proven Cells have to show sensitivity in in vitro test- to have clinical benefit. Hematology Meeting Reports 2008;2(5) | 163 | .
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