Venetoclax-based chemotherapy in acute and chronic myeloid neoplasms: literature survey and practice points

Abstract

Venetoclax (VEN), a small-molecule inhibitor of B cell leukemia/lymphoma-2, is now FDA approved (November 2018) for use in acute myeloid leukemia (AML), specific to newly diagnosed elderly or unfit patients, in combination with a hypomethylating agent (HMA; including azacitidine or decitabine) or low-dose cytarabine. A recent phase-3 study compared VEN combined with either azacitidine or placebo, in the aforementioned study population; the complete remission (CR) and CR with incomplete count recovery (CRi) rates were 28.3% and 66.4%, respectively, and an improvement in overall survival was also demonstrated. VEN-based chemotherapy has also shown activity in relapsed/refractory AML (CR/CRi rates of 33–46%), high-risk myelodysplastic syndromes (CR 39% in treatment naïve, 5–14% in HMA failure), and blast-phase myeloproliferative neoplasm (CR 25%); in all instances, an additional fraction of patients met less stringent criteria for overall response. Regardless, venetoclax-induced remissions were often short-lived (less than a year) but long enough to allow some patients transition to allogeneic stem cell transplant. Herein, we review the current literature on the use of VEN-based combination therapy in both acute and chronic myeloid malignancies and also provide an outline of procedures we follow at our institution for drug administration, monitoring of adverse events and dose adjustments.

Outcomes of venetoclax‐based therapy in chronic phase and blast transformed chronic myelomonocytic leukemia

“…5 Based on the results of phase II and III studies of HMA/low-dose cytarabine (LDAC) and venetoclax, a novel bcl-2 inhibitor, these combination therapies have been approved by the U.S. FDA for the management of elderly or medically unfit patients with acute myeloid leukemia (AML). 6,7 While these combinations were associated with a median OS of 15 months in AML, based on preclinical data, these were not anticipated to be effective in CMML given the disease dependence on MCL-1 and the presence of factors shown to lead to resistance in AML, including monocytosis and oncogenic RASpathway mutations. 8 A recent retrospective study using venetoclax based regimens documented an overall response rate (ORR) of 67% in CMML and 81% in CMML-BT patients.…”

Acute myeloid leukemia after age 70 years: A retrospective comparison of survival following treatment with intensive versus HMA ± venetoclax chemotherapy

“…Instead, an increasing number of oncologists are currently preferring to use low-intensity chemotherapy (e.g., hypomethylating agents ± venetoclax) in older old patients with AML, with the intent to prolong short-term survival while at the same time avoid treatment-related morbidity from intensive induction chemotherapy. [2][3][4] However, while any form of treatment might be better than supportive care in prolonging survival in such patients, the possibility of additional survival benefit from intensive chemotherapy cannot be excluded and should not be ignored. 5 The current study seeks to provide additional information in this regard, based on retrospective analysis of data from 360 newly diagnosed AML patients above age 70 years, seen at our institution between January, 2004 and December, 2017.…”

Molecular Targeted Therapy and Immunotherapy for Myelodysplastic Syndrome

“…Venetoclax, approved by the FDA, is a BCL-2 inhibitor that can be used in combination with HMAs in HR-MDS patients and has been reported to have a good therapeutic response in a case study as a monotherapy (ClinicalTrials.gov (accessed on 21 September 2021) Identifier: NCT02966782) [ 204 ]. It acts as a BH3 mimetic that impedes the binding of BH3 proteins to BCL-2, hence releasing pro-apoptotic BAK and BAX proteins [ 205 , 206 ]. This results in mitochondrial outer membrane permeabilization (MOMP) with the release of cytochrome C into the cytoplasm, leading to the formation of cytosolic apoptosome complex, caspase activation, and subsequent cellular apoptosis [ 207 ].…”