The Role of Venetoclax in Relapsed/Refractory Acute Myeloid Leukemia: Past, Present, and Future Directions

Abstract

Relapsed and/or refractory (R/R) acute myeloid leukemia (AML) is hallmarked by dramatic prognosis. Treatment remains challenging, with allogeneic hematopoietic stem cell transplantation (HSCT) as the only curative option. The BCL-2 inhibitor venetoclax (VEN) has proven to be a promising therapy for AML and is currently the standard of care in combination with hypomethylating agents (HMAs) for newly diagnosed AML patients ineligible for induction chemotherapy. Given its satisfactory safety profile, VEN-based combinations are increasingly being investigated as a part of the therapeutic strategy for R/R AML. The current paper aims to provide a comprehensive review of the main evidence regarding VEN in the setting of R/R AML, with a specific focus on combinational strategies, including HMAs and cytotoxic chemotherapy, as well as different clinical settings, especially in view of the crucial role of HSCT. A discussion of what is known about drug resistance mechanisms and future combinational strategies is also provided. Overall, VEN-based regimes (mainly VEN + HMA) have provided unprecedented salvage treatment opportunities in patients with R/R AML, with low extra-hematological toxicity. On the other hand, the issue of overcoming resistance is one of the most important fields to be addressed in upcoming clinical research.

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].…”

FLAG/FLAG-Ida Regimen in Secondary and Relapsed/Refractory Acute Myeloid Leukemia—Even in the Era of New Treatment Modalities Still a Significant Player

“…Relapsed and refractory (r/r) acute myeloid leukemia (AML) represent one of the most challenging conditions in hematology, with a 5-year survival rate of only 10% [1]. The advent of targeted drugs (gilteritinib, ivosidenib, etc.)…”