This project is part of a joint ALFA and GOELAM strategy aiming to improve the survival of
patients with newly diagnosed Acute Myeloid Leukemia (AML) aged 18-70 years. The basis of
this strategy is to evaluate intensified conventional chemotherapy and targeted drugs in
selected disease-risk subgroups of adult patients with non promyelocytic AML. Participation
will be proposed to almost all adult patients in France aged 18-70 years and diagnosed with
AML.
FLT3 genetic alterations include FLT3 somatic point mutations within the second tyrosine
kinase domain and internal duplications of the juxta-membrane domain. This alteration is
refered to as FLT3-ITD. The FLT3-ITD mutation is found in around 30% of patients with
cytogenetically normal AML. Patients with the FLT3-ITD genotype have been reported to have a
poor outcome when treated with conventional chemotherapy with an estimated 4-year
relapse-free survival of 25% (Schlenk et al. N Engl J Med 2008). More recently, the
prognostic relevance of FLT3-ITD has been studied in the context of integrated genetic
profiling. This confirmed the genetic complexity of AML and also that FLT3-ITD was associated
with reduced overall survival in intermediate-risk AML. A multivariate analysis of several
genetic alterations revealed that FLT3-ITD was the primary predictor of patient outcome.
FLT3-ITD mutations were classified in 3 categories: 1) FLT3-ITD with +8, TET2, DNMT3A or
MLL-PTD mutations (3-year OS 14.5%); 2) FLT3-ITD with wild type CEBPA, TET2, DNMT3 and
MLL-PTD (3-year OS 35.2%) and 3) FLT3-ITD with CEBPA mutations (3-year OS 42%) (Patel JP et
al. N Engl J Med 2012). However, FLT3-ITD was not a predictor of response to induction
therapy, allowing the introduction of targeted therapies after the induction course.
Several FLT3 inhibitors have been evaluated or are currently being tested in the setting of
relapsing AML. In most trials to date, patients were only eligible if the FLT3-ITD mutation
was present. Disappointing results were reported with the first generation of FLT3
inhibitors, including lestaurtinib (CEP-701), midostaurin (PKC-412) and sorafenib. Second
generation FLT3 inhibitors such as quizartinib (AC220) are currently under investigation with
promising results. However, the hematologic toxicity of AC220 will likely present a major
limitation in evaluating AC220 combined with standard or high-dose chemotherapy.
Ponatinib (AP24534) is a third generation tyrosine kinase inhibitor targeting the BCR-ABL
tyrosine kinase domain. Ponatinib was rationally designed with an extensive network of
optimized molecular contacts and triple bonds to accommodate the T315I mutation, a major
cause of resistance to tyrosine kinase inhibitors in chronic and advanced phase chronic
myelogenous leukemia (CML). Ponatinib also inhibits SRC (IC50: 5.4 nM) and members of the
VEGFR, FGFR, and PDGFR families of receptor tyrosine kinases (O'Hare T, Cancer Cell 2009).
Despite low activity against FLT3 based on the IC50 value (FLT3 IC50: 12.6 nM compared to BCR
IC50: 0.37 nM), ponatinib has recently been reported to have significant cellular activity
against the MV4-11 cell line which harbors an FLT3-ITD activating mutation. Ponatinib-induced
apoptosis was maximal at 10 nM in vitro and a single dose of 5 and 10 mg/kg had a strong
inhibitory effect in vivo in mice bearing MV4-11 xenografts. Primary blast cells from 4
FLT3-ITD AML patients were also tested and ponatinib reduced their viability (IC50: 4 nM)
whereas no activity was shown on FLT3-ITD-negative blast cells (Gozgit JM et al. Mol Cancer
Ther 2011).
Preliminary data from the phase I clinical trial showed that 15 mg ponatinib was associated
with a Cmax of 51.1 nM. Cmax was increased to 111 nM and 149 nM in the 30 mg and 45 mg
cohorts respectively. The trough concentrations were 55.3 nM and 61.9 nM for the 30 mg and 45
mg doses respectively (Ariad clinical investigator's brochure, version 3). Results from the
ongoing phase II trial in CML patients suggest that the hematological toxicity profile of
ponatinib is comparable with that of nilotinib or dasatinib, both of which have been
successfully combined with conventional chemotherapy.
Investigators thus aim to combine ponatinib with cytarabine in FLT3-ITD AML patients in first
complete remission.