Recent advances in acute myeloid leukemia (AML) have been characterized by a better understanding of disease biology. As such, FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) have been recognized as conferring a poor prognosis. The FLT3-ITD molecular mutation is observed in about one-quarter of patients diagnosed with AML. Patients presenting with this abnormality are referred for early allogeneic stem-cell transplantation (allo-SCT). However, some data suggest that FLT3-ITD remains associated with a poor prognosis even after allo-SCT because of higher risk of relapse and strategies for preventing relapse in the post-transplant setting are required (Hu et al, Expert Rev Hematol, 2014). For example, in a large cohort of patients (Brunet et al, JCO, 2012), the incidence of relapse for FLT3-ITD AML patients after allo-SCT was 30% at 2-years, significantly higher compared to FLT3-ITD negative patients (p=0.006). Ponatinib (Iclusig®) is an orally available, tyrosine kinase inhibitor with a unique binding mechanism allowing inhibition of BCR-ABL kinases, including those with the T315I point mutation. Ponatinib also has in vitro inhibitory activity against a discrete set of kinases implicated in the pathogenesis of other hematologic malignancies, including FLT3, KIT, fibroblast growth factor receptor 1 (FGFR1), and platelet derived growth factor receptor α (PDGFRα). In vitro activity of ponatinib in AML has been already demonstrated (Gozgit et al, Mol Cancer Ther, 2011; Smith et al, Blood 2013). If some trials are on-going to test ponatinib alone or in combination with chemotherapy in FLT3-ITD AML (Clinical.trials.gov), no study is dedicated to the use of ponatinib in the post-transplant setting in order to prevent relapse in these patients. The main goal of this study will be to determine the maximal tolerated dose (MDT) of ponatinib after allo-SCT in FLT3-ITD AML patients, then to investigate the efficacy of ponatinib in a larger cohort of patients
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
23
Administration of ponatinib after allo-SCT transplant in FLT3-ITD AML patient
CHU Angers
Angers, France
CHu Brest
Brest, France
CHU Caen
Caen, France
CHU Clermont Ferrand
Clermont-Ferrand, France
CHU Grenoble
Grenoble, France
CHU Lille
Lille, France
CHU Limoges
Limoges, France
Chevallier
Nantes, France
Hopital St Antoine
Paris, France
Hopital St Louis
Paris, France
...and 4 more locations
Relapse incidence at 2 years from transplant
Time frame: 2 years
Overall survival
time interval from the graft (day 0) until the date of last follow-up or death
Time frame: 2 years
Leukemia free survival
time interval from the date of the graft (day 0) until the date of last follow-up, death or relapse
Time frame: 2 years
Non-relapse mortality (NRM)
incidence of mortality due to all causes except relapse after transplant, considering that cause of death for patients having relapsed but dying from another cause is relapse
Time frame: day 100
Acute and chronic GVHD
NIH score
Time frame: 2 years
Influence of Ponatinib on Immune reconstitution PB lymphocyte cells
an immunophenotype of PB lymphocytes will be performed by flow cytometry at +3, +6, +9 and +12 months post-transplant to study the reconstitutions of CD3, CD4 and CD8 T cells, B and NK cells. The results will be expressed as absolute counts (Giga/L). We want to establish the potential influence of ponatinib on the reconstitution of these cells
Time frame: 1 years
Inflence of Ponatinib on Chimerism of Donor peripheral blood and CD3 T cells
Donor peripheral blood and CD3 T cells chimerism will be studied using molecular markers and RT-PCR at day +30, +60, +90, and +6, +12 months post-transplant. We want to establish the potential influence of ponatinib on the chimerism post-transplant.
Time frame: 1 years
Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
Time frame: 2 years
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