Venetoclax: A New Partner in the Novel Treatment Era for Acute Myeloid Leukemia and Myelodysplastic Syndrome

Abstract

Background Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS) are two closely related blood cancers that are more frequent in older adults. AML is the most common type of adult acute leukemia, and MDS is characterized by ineffective blood cell production and abnormalities in the bone marrow and blood. Both can be resistant to treatment, often due to dysfunction in the process of apoptosis, the body’s natural mechanism for cell death. Venetoclax, an orally-administered medication that selectively targets the BCL-2 protein, has shown promise in enhancing treatment sensitivity in some hematological malignancies by reducing the apoptotic threshold. This review aims to evaluate the effectiveness of venetoclax in treating AML and MDS, as well as potential mechanisms of resistance to the medication. Methods A literature search was conducted utilizing PUBMED to capture all relevant research articles on the use of venetoclax as a therapy for both diseases. The MeSH terms “acute myeloid leukemia”, “myelodysplastic syndrome” and “venetoclax” were searched. Furthermore, Clinicaltrials.gov was accessed to ensure the inclusion of all ongoing clinical trials. Results Although Venetoclax showed modest results as a single-agent therapy in AML, venetoclax-based combination therapies? mainly with hypomethylating agents or low-dose cytarabine? yielded significantly positive results. Preliminary results oN the use of venetoclax-based combination therapy with HMA, mainly azacitidine, in unfit high-risk MDS also yielded optimistic results. Identification of mutations for which various drugs have been approved has spurred active investigation of venetoclax in combination trials. Conclusion Venetoclax-based combination therapies have been shown to induce rapid responses and increase overall survival in AML patients unfit for intensive chemotherapy. These therapies are also yielding positive preliminary results in high-risk MDS patients in phase I trials. Resistance to venetoclax and drug-related toxicity are two main obstacles that need to be overcome to reap the full benefits of this therapy.

Mitochondria Deregulations in Cancer Offer Several Potential Targets of Therapeutic Interventions

“…As a consequence, free Bim can activate Bak/Bax on the surface of mitochondria, inducing PTP opening and the death of cancer cells [ 87 , 88 , 89 ]. Preclinical studies demonstrated that these inhibitors were able to inhibit tumor growth in vivo and in vitro; however, clinical studies are needed to prove their real efficacy [ 90 ].…”

Casein Kinase 2 (CK2): A Possible Therapeutic Target in Acute Myeloid Leukemia

“…The Bcl2-inhibitor venetoclax is used in the treatment of various malignancies, including AML, and various lymphoid malignancies [103][104][105][106][107][108][109]. A recent study identified CK2 as a major regulator of resistance to venetoclax in mantle cell lymphoma; additional experimental studies have demonstrated that even though the CK2 inhibitor CX-4945/silmitasertib alone does not affect the viability of mantle cell lymphoma cell lines or primary samples, CK2 inhibition strongly synergizes with the antilymphoma effects of venetoclax and the Bruton's tyrosine kinase inhibitor ibrutinib [106][107][108].…”

“…Venetoclax has direct antileukemic effects on AML cells and is now used in the treatment of AML [103][104][105] and mantle cell lymphoma [106][107][108][109], and MSCs support the proliferation and survival of both AML cells and mantle cell lymphoma cells [92,93,[106][107][108][109][110]. Furthermore, CK2 inhibition causes a similar modulation of intracellular proapoptotic signaling including Mcl1 reduction in AML cells and mantle cell lymphoma cells [61,65,[106][107][108][109].…”

CXCR4-Mediated Codelivery of FLT3 and BCL-2 Inhibitors for Enhanced Targeted Combination Therapy of FLT3-ITD Acute Myeloid Leukemia

“…BCL-2 is an antiapoptotic protein that is overexpressed in AML cells and promotes leukemic blast survival through regulation of the mitochondrial apoptotic pathway . Venetoclax (VEN), a highly selective BCL-2 inhibitor, in combination with hypomethylating agents or low-dose cytarabine has been approved as a standard option for newly diagnosed AML patients who are unfit for intensive chemotherapy. − Recent studies have indicated the synergistic effect of VEN in combination with FLT3 inhibitors in FLT3-ITD AML models, , likely due to the simultaneous downregulation of MCL-1 and BCL-XL antiapoptotic proteins, which can facilitate VEN resistance. , Moreover, early phase clinical trials have shown encouraging response rates and survival benefits in FLT3 mutant AML patients after combination therapy with VEN and FLT3 inhibitors. − Nevertheless, this combination is associated with poor bioavailability, dose-dependent myelosuppression, overlapping systemic toxicity, and drug resistance, limiting its clinical benefits.…”