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Abstract
The past decade has witnessed major advances in our understanding of molecular biology, which led to breakthrough novel therapies, importantly including the B-cell lymphoma-2 (BCL-2) inhibitor venetoclax. Notably, venetoclax-based combinations have improved outcomes, including both remission rates and overall survival, of older patients with acute myeloid leukemia (AML) deemed “unfit” for intensive chemotherapy due to age or comorbidities. This has translated into a rapid and widespread use of venetoclax-based combinations in both academic and community-based settings. Other venetoclax-based combinations are being investigated in AML with the ultimate goal of improving cure rates across many subgroups; frontline and relapsed/refractory, in combination with intensive chemotherapy, in the post-transplant setting, or as maintenance strategy. In this article, we summarize the current available data on venetoclax-based combinations. We also highlight areas of unmet medical need, and we offer practical clinical pearls for management of patients receiving such therapy.
Highlights
Acute myeloid leukemia (AML) is a disease of older patients; the incidence increases with age and the median age at diagnosis is 68 years [1]
While the original hypomethylating agents (HMA) + VEN clinical trial and the subsequent Food and Drug Administration (FDA) approved schedule is daily dosing, given the high efficacy and the associated significant myelosuppression, we have found that holding venetoclax once marrow remission or aplasia is confirmed around day 21–25 has been an effective strategy to mitigate prolonged cytopenias [70]
The advent of venetoclax-based combinations has been revolutionary in the treatment of adult patients with AML and are considered standard of care for older patients ineligible for intensive chemotherapy
Summary
Acute myeloid leukemia (AML) is a disease of older patients; the incidence increases with age and the median age at diagnosis is 68 years [1]. The combination of venetoclax with either HMA or LDAC has received accelerated FDA approval trials for newly diagnosed (ND) patients with AML older than 75 years or unfit for intensive chemotherapy, based on two multicenter independent early phase clinical trials This advance is considered by most experts to be the most impactful of all other new approvals for such population with high unmet need, with favorable safety profile and dramatic improvement in CR, MRD negativity and OS rates, compared with historical controls [20]. A phase I trial of escalating dose of venetoclax in combination with standard 7 + 3 induction (7-day cytarabine and 3-day anthracycline) has shown that 200 mg daily for 4 days can be safely given in patients with ND AML 18–60 years of age [44].
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