Clinical Trials

Overview

About this study

Acute myeloid leukemia (AML) is a heterogeneous clonal disease with significant disease-specific mortality. While most patients (pts) who are eligible for induction chemotherapy achieve complete remission (CR)/CR with incomplete hematologic recovery (CRi), long-term outcomes remain poor, especially in older pts and those unable to withstand intensive therapy. With the relatively recent addition of the doublet of hypomethylating agent (HMA), decitabine or azacitidine, plus BCL2 inhibitor venetoclax to the therapeutic toolbox in AML, especially in older and unfit pts, rates of CR/CRi have improved to about 66% based on phase III data. The doublet seems to exhibit synergism surpassing the efficacy of single-agent venetoclax or HMA therapy. Recent work has shown that azacitidine activates the integrated stress signal pathway to induce expression of the pro-apoptotic BCL2 family members NOXA and PUMA in AML cell lines in vitro and in xenografts. These observations have not been extended to AML pts receiving therapy with HMA/venetoclax. Moreover, it is unclear what happens to interactions involving other BCL2 family members upon treatment with HMA/venetoclax. Our group has previously observed that BAK is constitutively activated in certain AML cell lines and clinical samples, increasing the susceptibility of cells to specific BH3 mimetics and possibly other agents. Our studies have also shown that upregulation of NOXA, e.g., after treatment of AML cells with pevonedistat, displaces BAK from preformed complexes with MCL1. To determine whether induction of NOXA and disruption of other BCL2 family interactions are associated with a favorable outcome in AML treated with HMA/venetoclax, we propose to examine BCL2 family expression and interactions at days 0, 1, and 4-6 of therapy in a cohort of 30 pts with previously untreated AML receiving HMA/venetoclax. Using a combination of Western blotting on whole cell lysates, immunoprecipitation followed by Western blotting, and proximity ligation assays, we will examine dynamic changes in interactions between anti-apoptotic BCL2 family members (BCL2, BCLXL, and MCL1) and pro-apoptotic binding partners, including BAK, BAX, NOXA, BIM, PUMA, and BID. This study will improve our understanding of the factors that determine sensitivity to the HMA/venetoclax doublet, suggest potential mechanisms of resistance for future investigation, and point toward novel three-drug combinations designed to overcome this resistance. We will also use this study to ensure that two different assays developed to detect DNMT1-DNA covalent complexes (one based on mass spectometry and one involving custom-made monoclonal antibodies) can detect DNMT1-DNA covalent complexes in blood samples from patients treated with HMA.

Participation eligibility

Participant eligibility includes age, gender, type and stage of disease, and previous treatments or health concerns. Guidelines differ from study to study, and identify who can or cannot participate. There is no guarantee that every individual who qualifies and wants to participate in a trial will be enrolled. Contact the study team to discuss study eligibility and potential participation.

Participating Mayo Clinic locations

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