Venetoclax for the treatment of newly diagnosed acute myeloid leukemia in patients who are ineligible for intensive chemotherapy

Abstract

Acute myeloid leukemia (AML) is an aggressive hematological malignancy with a globally poor outcome, especially in patients ineligible for intensive chemotherapy. Until recently, therapeutic options for these patients included low-dose cytarabine (LDAC) or the hypomethylating agents (HMA) azacitidine and decitabine, which have historically provided only short-lived and modest benefits. The oral B-cell lymphoma 2 inhibitor, venetoclax, Venetoclax, an oral B-cell lymphoma 2 (BCL2) inhibitor, is now approved by the USA Food and Drug Administration (FDA) in combination with LDAC or HMA in older AML patients ineligible for intensive chemotherapy. Is now approved by the US Food and Drug Administration for this indication. In the pivotal clinical trials evaluating venetoclax either in combination with LDAC or with HMA, the rates of complete remission (CR) plus CR with incomplete hematological recovery were 54% and 67%, respectively and the median overall survival (OS) was 10.4 months and 17.5 months, respectively, comparing favorably with outcomes in clinical trials evaluating single-agent LDAC or HMA. The most common adverse events with venetoclax combinations are gastrointestinal symptoms, which are primarily low grade and easily manageable, and myelosuppression, which may require delays between cycles, granulocyte colony-stimulating factor (G-CSF) administration, or decreased duration of venetoclax administration per cycle. A bone marrow assessment after the first cycle of treatment is critical to determine dosing and timing of subsequent cycles, as most patients will achieve their best response after one cycle. Appropriate prophylactic measures can reduce the risk of venetoclax-induced tumor lysis syndrome. In this review, we present clinical data from the pivotal trials evaluating venetoclax-based combinations in older patients ineligible for intensive chemotherapy, and provide practical recommendations for the prevention and management of adverse events associated with venetoclax.

Venetoclax and decitabine for relapsed paediatric myelodysplastic syndrome‐related acute myeloid leukaemia with complex aberrant karyotype after second stem cell transplantation

“…Our patient exhibited prolonged neutropenia during venetoclax therapy, possibly enhanced by concomitant posaconazole administration 8,12 . It is debatable whether antifungal prophylaxis was necessary, as invasive fungal infections during venetoclax/HMA treatment are rare 13 .…”

“…The oral BCL‐2 inhibitor venetoclax targets anti‐apoptotic mechanisms in myeloid blasts, triggering a mitochondrial‐dependent apoptotic pathway 7 . HMAs, such as azacitidine or decitabine, or LDAC, constitute lower intensity treatments for patients ineligible for intensive chemotherapy, but are associated with low response rates when administered as monotherapy 4,8 . Alternatively, individualised targeted‐therapy options for mutated NRAS (neuroblastoma RAS) would have been available for this patient.…”

“…However, these results were available only after beginning therapy with venetoclax and decitabine. Numerous targeted therapies combined with venetoclax are currently under investigation and may lead to further treatment options in our patient 8 …”

“…It is debatable whether antifungal prophylaxis was necessary, as invasive fungal infections during venetoclax/HMA treatment are rare 13 . Dose reduction by 50% of venetoclax was performed instead of the 75% reduction recommended by the manufacturer and literature, 8,12 with only moderate recovery of neutrophil count. Beneficial anti‐leukaemic effects of increased venetoclax exposure are speculative; therapeutic drug monitoring (TDM) was not performed.…”

Double agents of cell death: novel emerging functions of apoptotic regulators

“…The first FDA-approved BCL-2 selective inhibitor, venetoclax, is in clinical use for the treatment of chronic lymphocytic leukemia (CLL) [8,30]. More recently, venetoclax was approved in combination with demethylating chemotherapeutic agents for the treatment of acute myeloid leukemia (AML) [31]. However, the recent emergence of venetoclax-refractory tumors has reinforced the need for the development of additional treatment strategies [32][33][34].…”