All content on this site is intended for healthcare professionals only. By acknowledging this message and accessing the information on this website you are confirming that you are a Healthcare Professional. If you are a patient or carer, please visit Know AML.
In patients over the age of 60, the prognosis of acute myeloid leukemia (AML) remains poor, often due to comorbid conditions and age-related changes in tumor biology that makes them refractory to, or less tolerant of intensive chemotherapy. There continues to be a need for novel treatment options for older patients with AML.
Venetoclax was recently approved by the US Food and Drug Administration (FDA) for the treatment of elderly patients with newly diagnosed AML, or for patients who have comorbidities, in combination with hypomethylating agents (HMAs) or low-dose cytarabine (LDAC). First indicated for the treatment of patients with chronic lymphocytic leukemia (CLL), it is a potent, selective B-cell lymphoma-2 (BCL-2) inhibitor.
Suresh Agarwal, and colleagues, conducted a study to characterize the exposure-efficacy and exposure-safety relationships in order to identify the optimal dose of venetoclax combined with low-intensity therapies in elderly patients with newly diagnosed acute myeloid leukemia (AML). Low-intensity therapies consisted of a HMA (azacitidine or decitabine) or LDAC.
Patients were enrolled to either a phase Ib exposure-response analyses of venetoclax in combination with azacitidine or decitabine (NCT02203773, n=212) or a phase I/II study of venetoclax in combination with LDAC (NCT02287233, n=92). As food increases venetoclax plasma concentrations, it was administered orally once daily (QD) within 30 minutes after a meal, and before patients received HMA or LDAC therapies.
The starting dose of venetoclax was 20–100mg, which was then increased daily to mitigate the risk of tumor lysis syndrome (TLS). The target dose was 400–1200mg (venetoclax + HMA), or 600–800mg (venetoclax + LDAC). When the target dose was reached, it was continued daily in 28-day cycles.
Data from all patients who had at least one efficacy assessment were included in the exposure-efficacy analyses (n=201 from HMA study; n=83 from LDAC study).
Venetoclax plus HMA
Venetoclax plus LDAC
Venetoclax plus HMA
No significant association between the probability of neutropenia or serious treatment-emergent adverse events (STEAEs) and venetoclax exposure. At 400mg and 800mg a slight increasing trend was identified in the probability of infections, with 51% (95% CI, 43%–58%) and 59% (95% CI, 50%–66%) respectively.
Venetoclax plus LDAC
Higher venetoclax exposures seemed to show a decreasing probability of STEAEs, but no relationship of venetoclax dosing with any of the evaluated AEs was identified.
The administration of 400mg venetoclax QD in combination with a HMA, and 600mg QD in combination with LDAC was supported by the exposure-response and exposure-safety analysis to safely maximize the probability of response in elderly patients with newly diagnosed AML.
These results provide the justification for the dose of venetoclax used the global, double-blind, phase III studies investigating venetoclax, in combination with azacitidine vs azacitidine alone (NCT02993523), and in combination with LDAC vs LDAC alone (NCT03069352). These studies will enroll elderly patients with AML who are unfit for standard induction therapy.
Treatment of older or unfit patients with AML
Prof. Courtney DiNardo, MD Anderson Cancer Center, Houston, US, discussed the optimal treatment strategy for elderly or frail patients with AML at the 1st NCRI AML academy.
Venetoclax for the treatment of AML: Developments and progress in 2020
Venetoclax (Ven) was first approved by the U.S. Food and Drug Administration (FDA) for the treatment of chronic lymphocytic leukemia in January, 2016. Since then, it has...
Subscribe to get the best content related to AML delivered to your inbox