The University of Texas MD Anderson Cancer Center
Project Term: October 1, 2021 - September 30, 2026
My ultimate goal is to develop more effective, better tolerated, and individualized treatment for patients with AML. This project focuses on AML patients with IDH1 or IDH2 mutations, with a clinical trial evaluating a combination of three agents which are effective in IDH-mutated AML. While these therapies are not curative on their own, my hope is that this combination will lead to a practice changing all-oral, outpatient, and well-tolerated curative strategy for patients with IDH-mutated AML.
Treatment options for AML have improved rapidly, with nearly a dozen new approvals within the past 5 years. Yet despite these advances, unfortunately most AML patients are not cured, and long-term AML outcomes remain poor. Efforts to improve both the rate of remission and the durability of remission with improved treatment regimens are of paramount importance. Mutations in IDH1 or IDH2 occur in approximately 20% of patients with acute myeloid leukemia (AML), and occur with increasing frequency in older patients. Several new and effective treatment strategies for patients with IDH1/2 mutated AML now exist; the targeted IDH1 inhibitor ivosidenib and the targeted IDH2 inhibitor enasidenib are both approved as single agents. These agents are associated with an overall response rate of approximately 40%, and ~ 20% of patients experience complete remissions. The oral BCL-2 inhibitor venetoclax in combination with a hypomethylating agent (i.e. azacitidine or decitabine) has recently become a paradigm-shifting new standard of care for older patients with AML who are ineligible for intensive chemotherapy. Patients with AML harboring IDH1 or IDH2 mutations respond particularly well to venetoclax-combination therapy, with a remission rate of ~70% and median survival of 24 months. Yet despite these “favorable outcomes”, relapse is nearly inevitable and the outcomes of patients at the time of venetoclax-combination therapy are particularly dismal. Thus, further improvements to available treatment regimens are needed to augment efficacy and potentially overcome resistance patterns, which may provide enduring leukemia cures. Improving the convenience of leukemia therapy with oral and primarily outpatient treatment regimens are also particularly valuable to enhance patient satisfaction. We hypothesize that the all-oral combination regimen of decitabine/cedazuridine, venetoclax, and ivosidenib or enasidenib will be well tolerated, and lead to deeper and more durable remissions in patients with IDH1 or IDH2-mutated AML. Innovative laboratory analyses will help determine the depth of response and evaluate shifts in leukemia subpopulations on the clinical study, through single-cell sequencing and proteomic analyses of patient study samples. Ultimately, we are hopeful this treatment regimen will lead to a practicing changing all-oral outpatient, and well-tolerated curative strategy for patients with IDH-mutated AML.