BCL2 Expression at Post-Induction and Complete Remission Impact Outcome in Acute Myeloid Leukemia

Abstract

Advances in acute myeloid leukemia (AML) genomics and targeted therapies include the recently approved BCL2 inhibitor venetoclax. The association between BCL2 expression and patient outcome was analyzed in a series of 176 consecutive AML patients at diagnosis (Dx), post-induction (PI), complete remission (CR) and relapse (RL). Levels increased significantly at relapse (mean 1.07 PI/0.96 CR vs. 2.17 RL, p = 0.05/p = 0.03). In multivariate analysis, high BCL2-Dx were marginally associated with worse progression-free survival, while high PI levels or at CR had an independent negative impact on outcome (PI: HR 1.58, p = 0.014; CR: HR 1.96, p = 0.008). This behavior of high PI or CR BCL2 levels and increased risk was maintained in a homogeneous patient subgroup of age <70 and intermediate cytogenetic risk (PI: HR 2.44, p = 0.037; CR: HR 2.71, p = 0.049). Finally, for this subgroup, high BCL2 at relapse indicated worse overall survival (OS, HR 1.15, p = 0.05). In conclusion, high BCL2 levels PI or at CR had an independent negative impact on patient outcome. Therefore, BCL2 expression is a dynamic marker that may be useful during AML patient follow up, and BCL2 levels at PI and/or CR may influence response to anti-BCL2 therapy.

Transcript-Level Dysregulation of BCL2 Family Genes in Acute Myeloblastic Leukemia

“…Recently, Bilbao-Sieyro et al [88] reported a positive association between the absence of the NPM1 mutation and a higher BCL2 level. In our data, four other genes (pro-apoptotic BID, BIK, BNIP1, and BCL2L13 encoding a protein of controversial function) presented significantly higher expression in the NPM1-mutated samples.…”

“…A similar conclusion was drawn by Zhou et al [27] who noted an upregulation of BCL2 in AML, but without any impact on the patient outcome. Bilbao-Sieyro et al [88] documented a marginal association between a high BCL2 level at the time of AML diagnosis and worse progression-free survival, but not with OS. The association with the negative outcome was stronger when a high BCL2 level was detected directly after induction therapy or at CR.…”

“…Del Poeta et al [106] showed that a high BAX/BCL2 ratio level in the blast cells of de novo AML patients treated with standard induction and consolidation therapy was associated with a longer overall survival and disease-free survival. In addition, recently published data indicate that a high BCL2 mRNA level after induction therapy or at complete hematologic remission negatively affects the AML outcome [88]. On the contrary, low BCL2 level in the leukemic cells may help to identify patients with a favorable prognosis.…”

Can the Gene Expression Profile of Patients with Acute Myeloid Leukemia Predict Complete Remission Following Induction Therapy?

“…At PI, the expression levels of ASXL1 (p = 0.034) and BCL2 (p = 0.046) were associated with OS, with MYC expression of marginal significance (p = 0.062); while the levels of ASXL1 (p < 0.001), BCL2 (p = 0.012), MYC (p = 0.041) and EZH2 (p < 0.001) were associated with OS at CR, with BRD4 expression of marginal significance (0.48 in group of survivors vs. 0.66 in exitus group, p = 0.062). In the multivariate analysis, age and leukocyte count at diagnosis, ELN risk group 3, and BCL2 expression at both PI and CR retained significance [12]. Median PFS in our series was 12.5 months.…”

“…Between Dx and RL, MYC levels were significantly lower at RL (mean Dx 67.22 vs. RL 49.13, p = 0.01). When expression at either PI or CR was compared with RL, the only gene with significantly modified expression values was BCL2, which showed a significant increment at RL (mean PI 1.07 and CR 0.96 vs. RL 2.17, p = 0.05 and p = 0.03, respectively) [12].…”