The Emerging Role of Venetoclax-Based Treatments in Acute Lymphoblastic Leukemia

Abstract

Venetoclax, a B-cell lymphoma (BCL-2) inhibitor, in combination with hypomethylating agents has become the new standard of care in elderly and unfit patients with acute myeloid leukemia, with significantly improved overall survival and quality of life. Studies of venetoclax combined with high-dose chemotherapy are emerging with evidence of higher rates of molecular remission. Recently, a growing number of publications bring forth the use of venetoclax in patients with acute lymphoblastic leukemia (ALL). In the current review, we present the biological rationale of BCL-2 inhibition in ALL, how the interplay of BH3 proteins modulate the response and the current clinical experience with various combinations.

Venetoclax‐based salvage therapy for adult patients with relapsed/refractory acute lymphoblastic leukemia

“…Nonetheless, in most cases treatment was considered as a bridge to an allogeneic bone marrow transplant. Among the ven‐chemotherapy regimen, we report a CR/CRi rate of 55%, which is similar to previous reports in the r/r setting 4 . In the ven‐navitoclax‐based chemotherapy cohort, we report a similar ORR, but lower CR/CRi rate of 25%.…”

“…Among the ven-chemotherapy regimen, we report a CR/CRi rate of 55%, which is similar to previous reports in the r/r setting. 4 In the ven-navitoclax-based chemotherapy cohort, we report a similar ORR, but lower CR/CRi rate of 25%. None of the patients with previous exposure to venetoclax achieved CR.…”

“…In recent years, the advent of venetoclax, an orally available selective inhibitor of the anti-apoptosis protein BCL-2, has underscored the role of this anti-apoptotic machinery in hematological malignancies. Indeed, tumor dependency on BCL-2 proteins has been demonstrated in many hematological malignancies, [2][3][4] and venetoclax has been widely incorporated in the treatment of chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML), changing long practiced treatment paradigms. [5][6][7] Overexpression of BCL-2 and BCL-XL, another anti-apoptotic protein of the BCL-2 family, 8 has been reported in acute lymphoblastic leukemia (ALL), including T-ALL, B-ALL, TCF3-HLF ALL, and MLL-AF4 ALL, [9][10][11] suggesting BCL-2 inhibition is of significant clinical value.…”

Knockdown of MEF2D inhibits the development and progression of B-cell acute lymphoblastic leukemia

“…Moreover, it has been universally reported that the PI3K-AKT signaling pathway is hyperactive in ALL, promoting the survival of leukemic stem cells as well as the development of the leukemic bone marrow microenvironment and drug resistance (33)(34)(35). In addition, studies have confirmed that dysregulated expression of apoptosis TFs can promote the incidence of leukemia, and the overexpression of BCL2 is associated with leukemia drug resistance (36)(37)(38)(39).…”

Translational advances in the treatment of childhood acute lymphoblastic leukemia: narrative review of current and emerging molecular and immunotherapies

“…Given the encouraging results in adult populations, venetoclax holds the potential for promising results in pediatric patients as well. A phase I/II multicenter study (NCT04029688) is assessing the murine double minute 2 homolog (MDM2) inhibitor idasanutlin combined with chemotherapy or venetoclax in pediatric and young adult patients with r/r acute leukemias or solid tumors (61,62). Similarly, an additional phase I study is evaluating venetoclax in combination with CPX-351 in children, adolescents, and young adults with acute r/r leukemias (63).…”