Azacitidine combined with low dose Venetoclax and Azole in treatment-naive, elderly patient with acute myeloid leukemia: A case report

Abstract

Introduction: Acute Myeloid Leukemia (AML) is the most common acute leukemia in adults with an increasing incidence with age. Patients older than 65 years respond less to standard intensive chemotherapy and develop more treatment related side effects. Therefore, treatment approaches are usually based on less intensive strategies which provide brief overall survival (OS). Recently, it has been demonstrated that the addition of Venetolcax, a BCL-2 inhibitor, to standard treatment may reinitiate the apoptosis and lead to better outcomes. Venetoclax is metabolized by the CYP3A. When administered with strong CYP3A inhibitors, such as azoles, drug’s concentration will increase by 2 to 7 folds empowering its effect. Methods: We will report, in what follows, the case of a 70-year-old frail patient with AML treated successfully with the combination of Azacitidine with modified dose of Venetoclax due to inaccessibility and refunding issues, in whom Fluconazole was added to potentiate the effect of Venetoclax in vivo, who reached a Complete Remission after four cycles of treatment. Results: Giving Venetoclax’s pharmacokinetics: CYP3A4 metabolization and considering the inadequate accessible dose of Venetoclax by the patient’s third party along with the current Lebanese economic crisis, we decided to combine 200mg of daily Fluconazole, a moderate CYP3A4 inhibitor, to the prefixed low dose Venetoclax in order to increase its bioavailability in the patient’s plasma and to increase his chance of response; schema extrapolated from the phase Ib sub-study evaluating Venetoclax-Posaconazole interaction in untreated AML patients resulting in an ORR of 67%. In fact, the patient reached a complete remission upon the end of the fourth cycle. He presented grade I febrile neutropenia after the first two cycles. No major adverse events were reported. To date, we believe it’s the first case described in the literature, reporting a complete remission after combining low dose Venetoclax and Azacitidine to a moderate CYP3A inhibitor. Conclusion Our experience showed that adding a CYP3A4 inhibitor to Venetoclax at lower doses was as effective as treating the patient with the recommended ones while decreasing the financial burden of the treatment. For that, we believe our case may open the floor for future prospective randomized clinical trials investigating the efficacy and tolerability of such combination.