Constitutive Phosphoinositide-3kinase Activation Represents a Good Prognostic Factor in De Novo AML Patients under 60 Years.
Authors: Tamburini Jerome , Elie Caroline , Bardet Valerie , Park Sophie , Broet Philippe , Cornillet Lefebvre Pascale , Lioure Bruno , Ifrah Norbert , Witz Francis , Luc Harousseau Jean , Dreyfus Francois , Mayeux Patrick , Lacombe Catherine , Bouscary Didier 
Published: October 2019

Abstract
Abnormal activation of kinases may promote leukemogenesis by conferring cell proliferation and survival advantage in acute myelogenous leukemia (AML). New targeted therapies are currently developed to disrupt such kinases activation to improve the long term prognosis of AML patients. However, the prognosis impact on AML patients has only been evaluated for a few kinases, including FLT3 and ERK/MAPK. Recent reports suggest that PI3K activation may confer poor survival to AML patients. Pre-treatment primary bone marrow blast cells samples from 92 patients registered for the LAM2001 trial of the French GOELAMS group were analyzed and PI3 kinase constitutive activation was correlated with outcome. As previously reported (V Bardet, Haematologica, 2006, 91, 757–764), the status of AKT phosphorylation on Ser 473 was determined using either Western Blot analysis (in samples >90% blasts) or flow cytometry in the CD45Low positive population of blast cells. Phosphorylation of AKT on Ser473 was determined after a 4 hour period of deprivation in cytokine and serum-free medium. In such conditions, we can clearly define to groups of patients, one with constitutive activation of PI3K (PI3K+) and the other without detectable phosphorylation of AKT (PI3K−). At inclusion, 42 patients were males and 50 were females. Median age at diagnosis was 46 (17,3–64,5) years. Leukocytosis was 12000/μL (range 400–251800). Patients were classified in low-risk, standard-risk and high-risk cytogenetic subgroups in respectively 16%, 61% and 23%. 16/61 (25%) had FLT3-ITD mutation, 9/60 (15%) had Ras (N-Ras or K-Ras) mutations and 15/59 (25%) had NPM mutations. 46 of 92 (50%) patients had constitutive PI3K activation (PI3K+ group). No difference was observed between the PI3K+ and PI3K− groups for all previously descripted parameters, except concerning FLT3 mutational status: 5/32 (16%) PI3K+ patients had FLT3-ITD versus 11/29 (38%) in the PI3K− (p = 0,048). All patients received one course of induction chemotherapy (3+7 regimen), and 31 (34%) a second induction course at day 15. Complete remission was obtained in 74 patients (80%) with no difference between the two groups (p = 0,60). Among responders, 30 (41%) had autologous stem cell transplantation, 24 (32%) had allogenic bone marrow transplantation and 16 (22%) had consolidation chemotherapy. With a median follow-up of 26 months (range 3 days–37 months), 48 patients died. Overall survival was 56% in the PI3K+ group and 33% in the PI3K− group (p=0.007). Among responders, 30 patients had relapse. Relapse free survival was 72% in the PI3K+ group and 41% in the PI3K− group (p=0.001). Thus constitutive PI3K activity detected in leukemic cells at diagnosis confer a better prognosis in AML. We observed significantly more relapses in PI3K− patients. These results suggest that PI3K activity in AML may confer a particular sensitivity to chemotherapy, the demonstration of which remain to be made. Furthermore, inhibition of PI3K signaling pathway may not be as beneficial as expected, and a better understanding of downstream effectors is clearly needed before targeting PI3K in AML.