PB1689 LEVELS OF BCL2 EXPRESSION AT POST-INDUCTION AND AT COMPLETE REMISSION IMPACT THE OUTCOME IN AML AND MAY IDENTIFY THOSE PATIENTS THAT WOULD BENEFIT OF BCL2 INHIBITORS
Authors: C. Bilbao, C. Rodríguez Medina, S. Sánchez Sosa, Y. Florido Ortega, M. D. L. N. Saez Perdomo, J. M. González Martín, E. González Pérez, R. Stuckey, R. Fernández, V. Peri, M. T. Molero Labarta, M. T. Gómez Casares
Journal: HemaSphere (2019)

Background: Despite the great progress in the understanding of acute myeloid leukemia (AML) pathogenesis, the frontline therapy has not substantially changed in 40 years and altough 40% to 65% will achieve remission, current outcomes remain unsatisfactory due to the high relapse rate. Advances in genomics of AML using massive sequence technologies have revealed the broad biological heterogeneity of the disease leading to new risk stratification of the pathology and to a personalized management. This has allowed the incorporation of targeted therapies, and among them, the use of BCL2 inhibitors has been recently aproved. Aims: In the present work we aimed to analyze mRNA BCL2 expression in a series of 176 AML at diagnosis and also at post-induction, at complete remission and at relapse, and study its influence over the clincs and outcome. Methods: Ours was a consecutive series of 176 AML diagnosed and treated at the 2 Hospitals of Gran Canaria from January of 2014 to July of 2017, with a median age of 59 years (range 16-82). RT-qPCR was conducted with Perfecta SYBR Green FastMix (Quanta Bioscience) on the Light Cycler 480 platform (Roche). Relative expression of genes was determine by the 2-ΔΔCt method normalized to ABL as reference gene and relative to the normal cDNA pool as internal calibrator. BCL2 expression level was considered either as continuous and also it was dichotomized by the receiver operating characteristic (ROC) curve and area under the ROC (AUC) for overall survival (OS) and progression free survival (PFS). Univariate and multivariate survival analyses were carried out using the Cox proportional hazard model. Analyses were performed using Statistical software R. Results: When comparing expression levels at the moment of diagnosis (Dx) with post-induction (PI), BCL2 levels showed a marked descent after induction treatment (mean 1.64 Dx vs.1.18 PI, p < 0.001) and the same was observed when comparing levels at Dx vs. at complete remission, CR (mean 1.57 at Dx vs. 0.95 at CR, p < 0.001). When we compared expression in either PI or CR with relapse, a significant increment at relapse was oberved (mean 1.07 at PI and 0.96 at CR vs. 2.17 at RL, p = 0.05 and p = 0.03 respectively). BCL2 levels at Dx over the established AUC cutoff marginally associated with worse PFS in the multivariate analysis (HR, 1.589, 95% CI 0.96 - 2.62, p = 0.07). At PI in the multivariate survival analysis, higher BCL2 levels influence negatively in OS and DFS and this behaviour was mantained for OS in the homogeneous subgroup of patiens with age below 70 and intermediate cytogenetic risk (HR, 2.44, 95% CI 1.06 – 5.64; p = 0.037). The independent association with worse OS was more evident and stronger in patients with high BCL2 levels at the time of CR, and this relationship was maintained in the subgroup of patients under 70 and of intermediate cytogenetic risk despite the smaller series size (HR, 2.71, 95% CI 1 – 7.33, p = 0.049). At last, we had a very limited series with expression levels measured at relapse but when the analysis was focussed on patients <70 and intermediate risk, high amount of BCL2 at relapse also related, altough marignally, with worse OS (HR,1.15, 95% CI 1-1.32, p = 0.05). Summary/Conclusion: Therfore, it seems that BCL2 expression level is a dinamic marker that may be usefull during follow up. Also high levels at PI or when achieving CR independently impacted in the outcome. It has been reported that BCL2 levels correlate with sensitivity against BCL2-inhibition (ABT-199), therefore this group of patients with higher levels of BCL2 at PI or at CR may benefit of anti-BCL2 therapy.