The treatment of older unfit patients with acute myeloid leukemia (AML) is challenging. The hypomethylating agents (HMA) azacitidine and decitabine have relatively mild side effects and have proven to be feasible for the treatment of older patients and patients with co-morbidities. Currently, venetoclax added to an HMA agent is the new standard of treatment. Since this new standard comes with a substantial societal financial burden, there is a rational to optimize the venetoclax dosing schedule. The CYP3A4 inhibitor cobicistat (COBI) can be used to increase venetoclax exposure, thereby allowing to reduce the dose of venetoclax and thus costs substantially.
Patients with: a diagnosis of AML and related precursor neoplasms according to ICC-2022 classification (excluding acute promyelocytic leukaemia) (appendix A). Patients may have had previous treatment with erythropoiesis stimulating agents (ESA) for an antecedent phase of MDS. ESAs must be stopped at least two weeks before registration.
Patients 18 years and older who are considered not fit for intensive chemotherapy or who decline the option of intensive chemotherapy.
WHO performance status 0, 1 or 2 (appendix E).
Leukocytes < 30 x109/L
Acute promyelocytic leukemia.
Myelodysplastic syndrome (MDS).
Patients previously treated for AML or MDS (any anti-leukemic therapy including investigational agents; excluding: 1) erythropoiesis stimulating agents (ESAs); 2) hydroxyurea ((previous treatment with hydroxyurea is allowed for the control of peripheral leukemic blasts in patients with leukocytosis).
except when the patient successfully completed treatment (chemotherapy and/or surgery and/or radiotherapy) with curative intent for this malignancy at least 24 months prior to registration;
Sequential
azacitidine
Drugduring run-in and extention phase: from Cycle 1 until relapse
Venetoclax
Drugduring run-in and extention phase: from Cycle 1 until relapse
Cobicistat
Drugduring run-in phase: from cycle 2 until relapse during extension phase: from cycle 1 until relapse
Pharmacokinetic equivalence of cobicistat boosted venetoclax and unboosted venetoclax (PK cycle 1 vs PK cycle 2).venetoclax and unboosted venetoclax (PK cycle 1 vs PK cycle 2).
run-in phase
Overall survival (OS).
extension phase
Venetoclax and cobicistat CL, Cmax, Tmax, Cmin and AUC0-24.
run-in phase
Complete remission (CR) rate defined as CR as best response during or at completion of the treatment, as determined by the Investigator, based on the European LeukemiaNet (ELN2022) recommended response criteria (see Appendix B).
extension phase
CR with incomplete hematologic recovery (CRi) rate, based on the European LeukemiaNet (ELN2022) recommended response criteria (see Appendix B).
extension phase
CR and CR with incomplete hematologic recovery (CRi) rate, based on the European LeukemiaNet (ELN2022) recommended response criteria (see Appendix B).
extension phase
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