(177) Optimization of Venetoclax Dosing with Posaconazole Prophylaxis in Acute Myeloid Leukemia

Poster Abstract: In November of 2018, the Food and Drug Administration granted accelerated approval for venetoclax in combination with hypomethylating agents (HMA) for patients with newly diagnosed acute myeloid leukemia (AML) who are elderly or whose comorbidities prevent them from receiving intensive induction (1). The target dose of venetoclax when combined with HMA is 400 mg once daily, when given in the absence of a cytochrome P450 (CYP) 3A4 inhibitor, such as posaconazole (2). The venetoclax package insert recommends dose reducing venetoclax to 100 mg when used concomitantly with strong CYP3A inhibitors, and it specifically mentions reducing venetoclax to 70 mg when used with posaconazole (2). However, in clinical practice there is no general consensus on a reduced dose of venetoclax to compensate for the drug-drug interaction between posaconazole and venetoclax. Multiple doses have been studied and referenced in the literature, including 50 mg (3), 70 mg (2,4), and 100 mg (5,6). Therefore, additional data is needed to clarify the most efficacious dose in order to optimize patient outcomes without compromising tolerability.

The purpose of this study is to identify if there is a difference in efficacy and safety between venetoclax 70 mg and 100 mg when combined with HMA and posaconazole prophylaxis in AML induction.

This is a retrospective cohort study evaluating patients treated with venetoclax and HMA induction therapy for newly diagnosed AML between August 1st, 2018 and July 31st, 2023. Data was collected through manual chart review in the electronic medical record by the study representatives.

Patients were included if they were greater than or equal to eighteen years of age and had newly diagnosed and previously untreated AML. Patients had to undergo induction therapy with venetoclax and HMA with posaconazole as antifungal prophylaxis. Patients were excluded from this study if they were lost to follow up after receiving initial treatment.

The primary outcomes involved a comparison of venetoclax 70mg to 100mg through two primary endpoints. The first being remission, defined as a complete response (CR) on bone marrow biopsy. The second primary endpoint is safety, which included a composite of toxicities, including neutropenic fever, infection, serious bleeding events, intensive care unit (ICU) admission, and death. The secondary outcomes include time to count recovery, the need for growth factor, length of hospital admission, number of cycles of venetoclax and HMA needed to induce remission, and total number of cycles received overall.

Results are pending.

References (must also be included in final poster): 1. Center for Drug Evaluation and Research. “FDA Approves Venetoclax in Combination for AML in Adults.” U.S. Food and Drug Administration, FDA, 14 Dec. 2018, www.fda.gov/drugs/fda-approves-venetoclax-combination-aml-adults.
2. Venetoclax [package insert]. North Chicago, IL and South San Francisco, CA; AbbVie Inc., Genentech USA, Inc. 2019, May
3. DiNardo CD, Jonas BA, Pullarkat V, Thirman MJ, Garcia JS, Wei AH, Konopleva M, Döhner H, Letai A, Fenaux P, Koller E, Havelange V, Leber B, Esteve J, Wang J, Pejsa V, Hájek R, Porkka K, Illés Á, Lavie D, Lemoli RM, Yamamoto K, Yoon SS, Jang JH, Yeh SP, Turgut M, Hong WJ, Zhou Y, Potluri J, Pratz KW. Azacitidine and Venetoclax in Previously Untreated Acute Myeloid Leukemia. N Engl J Med. 2020 Aug 13;383(7):617-629. doi: 10.1056/NEJMoa2012971. PMID: 32786187.
4. Maiti A, Konopleva MY. How We Incorporate Venetoclax in Treatment Regimens for Acute Myeloid Leukemia. Cancer J. 2022 Jan-Feb 01;28(1):2-13. doi: 10.1097/PPO.0000000000000567. PMID: 35072368; PMCID: PMC8785772.
5. Agarwal SK, DiNardo CD, Potluri J, Dunbar M, Kantarjian HM, Humerickhouse RA, Wong SL, Menon RM, Konopleva MY, Salem AH. Management of Venetoclax-Posaconazole Interaction in Acute Myeloid Leukemia Patients: Evaluation of Dose Adjustments. Clin Ther. 2017 Feb;39(2):359-367. doi: 10.1016/j.clinthera.2017.01.003. Epub 2017 Feb 1. PMID: 28161120.
6. DiNardo CD, Wei AH. How I treat acute myeloid leukemia in the era of new drugs. Blood. 2020 Jan 9;135(2):85-96. doi: 10.1182/blood.2019001239. PMID: 31765470.