Background: In combination with hypomethylating drugs, venetoclax has recently changed the therapeutic management of patients with newly diagnosed acute myeloid leukemia (AML) for whom standard induction chemotherapy was not an option. Over and above the clinical benefits of this combination, the data show that more than half the patients did not show remission criteria, even after the first month's exposure to venetoclax.
Hypothesis: To compare the mean residual venetoclax plasma concentrations obtained in patients who went into complete composite remission versus those who did not go into remission at the end of the first cycle of venetoclax + azacitidine treatment.
Method: According to the French law, this is a multicenter, non-comparative, open-label, single-arm, interventional study with minimal risks and constraints. Selection, information and inclusion will concern adult patients (≥60 years) with a confirmed diagnosis of AML according to ELN 2022 guidelines. Included patients will be treated as standard care with a combination of venetoclax+azacitidine. This research protocol will not modify their usual care.
Subject must have a confirmed diagnosis of previously untreated AML (ELN 2022 criteria) within 28 days of the onset of symptoms. Only previous cytoreductive treatments (e.g. hydroxyurea) are authorized.
Subject aged ≥ 75 years.
ECOG performance status: of 2 or 3.
cardiac history: heart failure requiring treatment, left ventricular ejection fraction ≤ 50%, chronic stable angina.
blood leukocytes >25 G/L.
Subject has already received anticancer treatment (drugs, surgery, radiotherapy) for AML, hematological malignancy or malignant cancer (within the last 2 years).
Subjects with AML with central nervous system involvement or promyelocytic type (AML-M3).
infection (viral, bacterial or fungal) requiring treatment;
adult patients with untreated AML and ineligible for standard cytarabine and anthracycline induction therapy
Cohort
Prospective
Blood sampling for venetoclax drug dosage (venous puncture)
Biological/Vaccine8 blood samples for venetoclax and azole antifungal drugs identification and dosage will be taken by venous and capillary punctures throughout management of patients
Comparison of mean plasma residual concentration of venetoclax
To compare the mean plasma residual concentration (ng/mL) of venetoclax (determined by LC-MS-MS) between patients who have entered composite complete remission (defined by the presence of remission criteria ≥ CRi, according to ELN 2022 guidelines) versus those who have not at the end of the first cycle of venetoclax+azacitidine treatment.
Study relationship between mean plasma residual concentration of venetoclax and remission occurrence
To estimate mean residual plasma concentrations (Cres, ng/mL) of venetoclax and azole antifungals during patients' usual care. Then study the relationship between mean venetoclax Cres and the achievement (or non-achievement) of remission over time (according to ELN 2022 guidelines) .
Study performance of mean venetoclax Cres
To evaluate the performance (ROC curve) of mean venetoclax Cres (ng/mL) as a predictive biomarker of event-free survival (EFS) at 6 and 12 months.
Study survival
To estimate event-free survival (EFS), relapse-free survival (RFS) and overall survival (OS).
Study early deaths
To estimate the proportion of early deaths at 30 and 60 days post-inclusion.
ancillary study 1: study a medical device (VAMS Mitra, Neoteryx) to collect blood capillary sample as an alternative to venous puncture
To compare venetoclax Cres (ng/mL) values obtained with the Mitra® (Neoteryx) medical device (CE) with those obtained after conventional venipuncture (ng/mL).
ancillary study 2: study exposure of plasma venetoclax over 24h
To compute the total integrated area under the plasma venetoclax concentration-time curve (AUC) over 24h in 30 patients cared in CHU of Caen only and to identify the best time of sampling. Pharmacokinetic sampling (day 2 or 3 of cycle 2): Cres (prédose, ng/mL) and post-dose: 2h, 4h, 6h, 8h, 12h, 18h, 24h.
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