Venetoclax-based lower-intensity regimens for acute myeloid leukemia

Abstract

Acute myeloid leukemia (AML) is a heterogeneous disease with variable genetic features and clinical outcomes. The main curative option for AML remains intensive chemotherapy and allogeneic hematopoietic stem cell transplant (HSCT) in selected patients. However, with a median age at diagnosis of 67 years old and frequent comorbidities, a large proportion of patients diagnosed with AML are not eligible for intensive chemotherapy. Until recently, the only treatments available for patients with AML ineligible for intensive chemotherapy were single-agent hypomethylating agents (HMAs) such as azacitidine and decitabine, or low-dose cytarabine (LDAC). In older patients with AML, these treatments have been reported to improve outcomes over best supportive care (BSC) alone. However, in clinical studies the expected median overall survival (OS) remained less than 12 months. Fortunately, our increasing knowledge of AML biology has accelerated the development of novel targeted drugs for AML. Among these, the anti-apoptotic protein B-cell lymphoma 2 (BCL2) inhibitor venetoclax has completely changed the therapeutic landscape of AML, especially for patients who are ineligible for intensive chemotherapy. Venetoclax is approved by Health Canada for use in combination with azacitidine or LDAC for the treatment of newly diagnosed untreated AML in patients who are 75 years or older or have comorbidities precluding the use of intensive chemotherapy. This approval is based on the two pivotal randomized, Phase 3 trials VIALE-A (azacitidine plus venetoclax) and VIALE-C (cytarabine plus venetoclax). Although seemingly easier to administer than intensive chemotherapy, venetoclax-based regimens are not as “non-intensive” as they are sometimes considered to be. They require the implementation of specific precautionary measures and monitoring to avoid excessive toxicity and optimize patients’ outcomes. We will review here practical points to safely administer venetoclax-based regimens to patients with AML who are ineligible for intensive chemotherapy.