Venetoclax Dosing in Combination with Antifungal Agents: Real World Experience in Patients with Acute Myeloid Leukemia
Authors: Rausch Caitlin R. , DiNardo Courtney D. , Maiti Abhishek , Jammal Nadya , Kadia Tapan M. , Marx Kayleigh , Borthakur Gautam M. , Savoy J Michael , Pemmaraju Naveen , Dipippo Adam , Daver Naval G. , Chew Serena , Sasaki Koji , Issa Ghayas C. , Naqvi Kiran , Ravandi Farhad , Kantarjian Hagop M. , Konopleva Marina Y 
Published: November 2019

Introduction: Venetoclax (VEN) is approved for the treatment of acute myeloid leukemia (AML) in combination with hypomethylating agents (HMAs) or low-dose cytarabine and commonly used for patients (pts) unfit for intensive chemotherapy. Prophylaxis with triazole antifungals (azoles) during induction treatment in pts with AML has decreased mortality and is the standard of care for pts receiving treatment regimens associated with prolonged myelosuppression (Cornely et al, 2007). Azoles inhibit CYP3A4 (CYP3A4i), the enzyme responsible for the metabolism of VEN, and p-glycoprotein to varying degrees, which VEN is a substrate. Based on this interaction and the results of a small pharmacokinetic study, significant VEN dosage reductions are recommended (Agarwal et al, 2017). Little real-world data exists to demonstrate the tolerability of VEN in combination with azoles during induction treatment with VEN and HMAs.
Methods: All pts with newly diagnosed AML treated at our institution with VEN and HMAs from 11/2014-1/2019 were retrospectively reviewed. Pts were treated as standard of care or as part of clinical trial in combination with azacitidine (NCT02203773) or decitabine (NCT03404193; NCT02203773). Pts who received concomitant antifungal for >5 days while also receiving VEN for >7 days were included. VEN 100mg daily with posaconazole or voriconazole (strong CYP3A4i) and VEN 200mg daily with isavuconazole or fluconazole (moderate CYP3A4i) were considered 400mg equivalent dosages. Higher doses of VEN in these combinations were considered >VEN 400mg equivalent. To determine the clinical impact of concomitant azoles, time to absolute neutrophil count (ANC) and platelet (PLT) recovery after induction was analyzed, in addition to response rates, episodes of febrile neutropenia (FN) and documented infections.
Results:One-hundred twenty-one pts treated with HMA and VEN were identified (Table 1). The median age was 72 years (48-86) and 35% were > 75 years. Forty pts (33%) had secondary AML, and 10% had therapy-related AML. Most were treated with decitabine 20mg/m2 administered for 10 days (67%) or 5 (22%). VEN was administered for a median of 23 days (7-30) at a 400mg daily dose equivalent in 74 pts (62%) and >400mg dose equivalent in 40 pts (33%). Eighty-nine (74%) received a concomitant azole with VEN including posaconazole (38%), isavuconazole (21%), voriconazole (13%), or fluconazole (2%). Following induction therapy with VEN and HMA, 37% achieved a complete response (CR) and 22% achieved a CR with incomplete blood count recovery (CRi). An additional 10% achieved a morphologic leukemia free state (MLFS) (Table 2). Prior to cycle 2, 55% of pts achieved ANC>500 cells/mm3 and 64% achieved PLT>50,000 cells/mm3 after a median of 34 days and 24 days, respectively. No difference in response was observed based on VEN dosage or duration (Table 3). Pts achieving CR/CRi received VEN for a median of 22 days (7-29), and 38% at the 400mg equivalent VEN dosage with an azole.
When analyzing VEN dosage by the use of an azole, duration of neutropenia (ANC<1000 cells/mm3) was 5 days longer in pts receiving an azole compared to those who were not (p>0.05) (Table 4). Number of pts achieving PLT>50,000 cells/mm3 was not affected by concomitant antifungal or VEN dosage, but duration of thrombocytopenia was. Time to PLT>50,000 cells/mm3 was significantly longer for pts receiving VEN 400mg equivalent with an azole (25 vs 20 days, p=0.01) as well as time to PLT>100,000 cells/mm3 (27 vs 22 days, p=0.03). Despite prolonged cytopenias, all pts receiving the VEN 400mg equivalent dosage had similar rates of FN, documented infections, and hospital duration regardless of the use of an azole (Table 4). Those receiving >400mg VEN equivalent had numerically higher rates of FN, infections, and duration of hospitalization.
Conclusion: The combination of VEN with HMA is an effective treatment option in pts with newly diagnosed AML. VEN is associated with significant myelosuppression which can be enhanced by concomitant CYP3A4i, such as the azoles. The combination of VEN and azoles resulted in prolonged cytopenias, namely thrombocytopenia, compared to the use of VEN without an azole. This did not result in higher rates of FN, infections, or duration of hospitalization, therefore the concomitant use of VEN and azole appear to provide a clinically safe and effective therapeutic regimen. Higher doses of VEN do not appear to be advantageous in this setting.

Disclosures
DiNardo: daiichi sankyo: Honoraria; jazz: Honoraria; syros: Honoraria; medimmune: Honoraria; notable labs: Membership on an entity's Board of Directors or advisory committees; abbvie: Consultancy, Honoraria; agios: Consultancy, Honoraria; celgene: Consultancy, Honoraria. Maiti:Celgene: Other: research funding. Kadia:Celgene: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bioline RX: Research Funding; BMS: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Research Funding. Borthakur:Polaris: Research Funding; Strategia Therapeutics: Research Funding; Tetralogic Pharmaceuticals: Research Funding; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Xbiotech USA: Research Funding; Bayer Healthcare AG: Research Funding; AstraZeneca: Research Funding; BMS: Research Funding; Eli Lilly and Co.: Research Funding; Oncoceutics, Inc.: Research Funding; PTC Therapeutics: Consultancy; NKarta: Consultancy; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cyclacel: Research Funding; GSK: Research Funding; Janssen: Research Funding; Incyte: Research Funding; AbbVie: Research Funding; Argenx: Membership on an entity's Board of Directors or advisory committees; Eisai: Research Funding; Novartis: Research Funding; Cantargia AB: Research Funding; Arvinas: Research Funding; Oncoceutics: Research Funding; BioTheryX: Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Agensys: Research Funding. Pemmaraju:affymetrix: Research Funding; sagerstrong: Research Funding; Daiichi-Sankyo: Research Funding; plexxikon: Research Funding; novartis: Consultancy, Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; cellectis: Research Funding; celgene: Consultancy, Honoraria; samus: Research Funding; abbvie: Consultancy, Honoraria, Research Funding; mustangbio: Consultancy, Research Funding; incyte: Consultancy, Research Funding. Sasaki:Pfizer: Consultancy; Otsuka: Honoraria. Ravandi:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Menarini Ricerche: Research Funding; Cyclacel LTD: Research Funding; Selvita: Research Funding; Xencor: Consultancy, Research Funding; Macrogenix: Consultancy, Research Funding. Kantarjian:Astex: Research Funding; AbbVie: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Immunogen: Research Funding; Takeda: Honoraria; Agios: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; BMS: Research Funding; Cyclacel: Research Funding; Daiichi-Sankyo: Research Funding; Novartis: Research Funding; Jazz Pharma: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Ariad: Research Funding. Konopleva:Astra Zeneca: Research Funding; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Ablynx: Research Funding; Agios: Research Funding; Kisoji: Consultancy, Honoraria; Ascentage: Research Funding; Calithera: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Forty-Seven: Consultancy, Honoraria; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; Cellectis: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Eli Lilly: Research Funding.