Current Position of Venetoclax in the Treatment of AML − Hope for a Better Prognosis?
The treatment of acute myeloid leukemia (AML) remained stagnant for a long time, with many new drugs emerging only in the past few years. One of the newest and most important is the Bcl-2 anti-apoptotic protein inhibitor venetoclax.
Role of Bcl-2
The Bcl-2 protein prevents cells from entering apoptosis, and its pathologically increased expression has been demonstrated in a number of cancers, which may also relate to chemotherapy resistance. Venetoclax inhibits Bcl-2 and thereby restores the cells' crucial ability to initiate apoptosis. Its great advantage is its effectiveness even in the case of TP53 gene mutation.
Preclinical studies have shown that the survival of AML cells, particularly leukemic stem cells, depends on Bcl-2, and its inhibition by venetoclax leads to the rapid entry of leukemic cells into apoptosis. Subsequently, a synergy of venetoclax with both hypomethylating agents (azacitidine, decitabine) and also with cytarabine was preclinically demonstrated.
Primary Diagnosis of AML in Elderly or Unfit Patients
Favorable results from non-randomized phase I/II studies in newly diagnosed AML patients over 75 years old or with severe comorbidities (unfit), where combinations of venetoclax with azacitidine or decitabine or in another study with low-dose cytarabine were administered, led to confirmatory phase III studies VIALE-A (venetoclax 400 mg/day + azacitidine) and VIALE-C (venetoclax 600 mg/day + low-dose cytarabine). Again, these were previously untreated AML patients not eligible for intensive therapy. These studies were randomized, double-blind, and placebo-controlled. Both included almost identical patient groups: median age 76 years, high cytogenetic risk in 32% (VIALE-A) and 36% (VIALE-C) of patients, secondary AML in 25% and 38% of participants, and TP53 mutation in 23% and 19% of patients.
In the VIALE-C study, 48% of patients on the venetoclax and cytarabine combination achieved composite complete remission (CR/CRi, i.e., complete remission and complete remission with incomplete hematologic recovery) compared to 13% in the cytarabine-only group, with 27% achieving CR in the venetoclax group compared to 7% in the control group. Remission was rapidly achieved with venetoclax, with 34% achieving CR/CRi after the first cycle compared to 3% in the control group. Median overall survival (OS) was 7.2 months in the venetoclax group compared to 4.1 months in the control group (hazard ratio [HR] 0.75; 95% confidence interval [CI] 0.52–1.07; p = 0.11). Median event-free survival (EFS) was 4.7 months with venetoclax compared to 2.0 months in the control group. Overall, the results were rather disappointing as the planned goal (extension of OS) was not achieved.
The results were far better in the VIALE-A study. Composite complete remission was achieved in 66.4% of patients on the venetoclax and azacitidine combination compared to 28.3% in the azacitidine-only group (p < 0.001). CR was seen in 36.7% of the venetoclax group compared to 17.9% in the control group (p < 0.001). Remission occurred very quickly in venetoclax patients, often after the first treatment cycle. With a median follow-up of 20.5 months, median OS was 14.7 months in the venetoclax group versus 9.6 months in the control group (p < 0.001). Median EFS was 9.8 months with venetoclax versus 7.0 months in the control group. Both stated goals were achieved: the combination of venetoclax with azacitidine led to significantly more frequent remissions and extended OS compared to azacitidine alone.
Younger Patients and Refractory Patients
Venetoclax has the potential to be very important for younger patients with primary refractory AML who do not achieve adequate response after induction. In these individuals, the disease is highly likely to involve overexpression of Bcl-2, and the insensitivity of cancer cells to chemotherapy may be related to dysfunctional apoptosis mechanisms. In younger patients with relapsed/refractory (R/R) AML, the combination of venetoclax with intensive chemotherapy showed very good results, achieving CR/CRi in 69% of cases.
Retrospective comparisons also suggested that even in healthy patients with newly diagnosed AML, a lower-intensity approach based on a combination of hypomethylating agents with venetoclax could be beneficial.
Conclusion and Discussion
Venetoclax seems to be a breakthrough drug in AML therapy after decades. It has found its place, especially in palliative treatment for older patients and patients unsuitable for intensive therapy. Here, in combination with azacitidine, it achieves rapid and very good results. Based on published analyses, it can be assumed that the combination of venetoclax and hypomethylating agents is at least as effective as standard induction therapy even in younger patients. Additionally, we have fairly good data confirming the high efficacy of combining venetoclax with intensive chemotherapy in patients with R/R AML.
There is great hope that the treatment of AML patients will be more effective thanks to venetoclax, allowing more patients to be cured than before. Similarly, palliatively treated patients will have hope for longer survival and better quality of life.
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Source: Kořístek Z. Venetoclax in the treatment of acute myeloid leukemia. Acta medicinae 2022; 11 (3): 100−102.
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