Effect of Concomitant Azole Antifungals on Duration of Myelosuppression in Newly Diagnosed Patients with AML Receiving Venetoclax in Combination with Cladribine and Low-Dose Cytarabine

Presenter: Caitlin R. Rausch, PharmD, BCOP, Clinical Pharmacy Specialist, Leukemia, University of Texas M.D. Anderson Cancer Center, Houston

Co-Authors: Patrick Reville, MD, Fellow, Division of Cancer Medicine, University of Texas M.D. Anderson Cancer Center; Tapan Kadia, MD, Professor, Department of Leukemia, University of Texas M.D. Anderson Cancer Center; Kayleigh Marx, PharmD, BCOP, Clinical Pharmacy Specialist, Leukemia, University of Texas M.D. Anderson Cancer Center

BACKGROUND: The addition of venetoclax to cladribine and low-dose cytarabine (Clad/LDAC) alternating with azacitidine is being investigated for the treatment of patients with newly diagnosed acute myeloid leukemia (AML).¹ Prophylaxis with mold-active antifungals is recommended for patients with AML undergoing induction therapy associated with prolonged and profound neutropenia.² The triazole antifungals (azoles) inhibit CYP3A4, the enzyme responsible for venetoclax metabolism. With the combination of venetoclax and hypomethylating agents, concomitant azoles increase the duration of thrombocytopenia.³ The impact of concomitant azoles on the duration of myelosuppression with Clad/LDAC and venetoclax has not been previously described.

OBJECTIVE: To describe the duration of neutropenia and thrombocytopenia in patients receiving Clad/LDAC and venetoclax with concomitant azoles.

METHOD: We evaluated newly diagnosed patients with AML treated with intravenous cladribine 5 mg/m² on days 1 to 5, subcutaneous cytarabine 20 mg twice a day on days 1 to 10, and venetoclax 400 mg, or equivalent, on days 1 to 21 as part of a clinical trial.¹ Venetoclax 100 mg with posaconazole or with voriconazole (strong CYP3A4 inhibitor); 200 mg with isavuconazole (moderate CYP3A4 inhibitor) were considered equivalent. Time to absolute neutrophil count (ANC) and platelet count was counted from day 1 of each course of therapy.

RESULTS: A total of 50 patients who achieved complete remission with or without complete blood count recovery after induction were included in the study. During induction, 8 (16%) patients received venetoclax 400 mg without an azole. The remaining 42 received either posaconazole (N = 26; 52%), voriconazole (N = 14; 28%), or isavuconazole (N = 2; 4%). The median time to ANC >1000 µL^-1 was 27 days for patients receiving no azole or moderate CYP3A4 inhibitor, and 26 days for those receiving a strong CYP3A4 inhibitor. The median time to platelet count >100,000 µL^-1 was 27, 18, and 22 days for patients receiving no azole, a moderate CYP3A4 inhibitor, or a strong CYP3A4 inhibitor, respectively. One patient did not achieve ANC >1000 cells/µL, and 4 patients did not achieve platelet count >100,000 µL^-1 after induction; 4 of them were receiving posaconazole and 1 received voriconazole. All patients received a concomitant CYP3A4 inhibitor during consolidation. Patients receiving posaconazole had prolonged median time to ANC >500 µL^-1 of 49 days (95% confidence interval [CI], 35.43-62.57) and platelet count >50,000 µL^-1 of 74 days (95% CI, 24.25-123.75).

CONCLUSION: Concomitant azoles did not significantly affect the duration of myelosuppression during induction; however, the only 4 patients who did not achieve platelet count recovery were receiving a strong CYP3A4 inhibitor. Patients receiving posaconazole had prolonged count recovery during consolidation. Pharmacokinetic analysis of serum venetoclax concentrations when combined with azoles is ongoing. Given the need for concomitant azoles in this patient population, therapeutic drug monitoring may be necessary to optimize venetoclax-based therapies.

1. ClinicalTrials.gov. Identifier: NCT03586609. Venetoclax, cladribine, low dose cytarabine, and azacitidine in treating patients with previously untreated acute myeloid leukemia. https://clinicaltrials.gov/ct2/show/NCT03586609?term=NCT03586609&draw=2&rank=1.
2. Maertens JA, Girmenia C, Brüggemann RJ, et al. European guidelines for primary antifungal prophylaxis in adult haematology patients: summary of the updated recommendations from the European Conference on Infections in Leukaemia. J Antimicrob Chemother. 2018;73:3221-3230.
3. Rausch CR, DiNardo CD, Maiti A, et al. Duration of cytopenias with concomitant venetoclax and azole antifungals in acute myeloid leukemia. Cancer. 2021;127:2489-2499.