Azacitidine plus venetoclax in patients with high-risk myelodysplastic syndromes or chronic myelomonocytic leukaemia: phase 1 results of a single-centre, dose-escalation, dose-expansion, phase 1-2 study
Mené sur 23 patients atteints d'un syndrome myélodysplasique à haut risque de récidive ou d'une leucémie myélomonocytaire chronique (durée médiane de suivi : 13,2 mois), cet essai de phase I/II évalue la dose maximale tolérée de l'azacitidine en combinaison avec le vénétoclax
Background : Therapies beyond hypomethylating agents such as azacitidine are needed in high-riskmyelodysplastic syndromes. Venetoclax is an orally bioavailable small molecule BCL-2inhibitor that is synergistic with hypomethylating agents. We therefore aimed to evaluatethe safety, tolerability, and preliminary activity of azacitidine combined with venetoclaxfor treatment-naive and relapsed or refractory high-risk myelodysplastic syndromes or chronic myelomonocytic leukaemia.
Methods : We did a single centre, dose-escalation, dose-expansion, phase 1–2 trial at the Universityof Texas MD Anderson Cancer Center (Houston, TX, USA). This Article details the phase1 results. We enrolled patients (≥18 years) with treatment-naive or relapsed or refractoryhigh-risk myelodysplastic syndromes or chronic myelomonocytic leukaemia and bone marrowblasts of more than 5%. No specific Eastern Cooperative Oncology Group status restrictionwas used. Patients were treated with intravenous or subcutaneous azacitidine (75 mg/m2) for 5 days and oral venetoclax (100–400 mg) for 7–14 days. The primary outcome wassafety and tolerability as well as determination of the maximum tolerated dose andrecommended phase 2 dose of the azacitidine and venetoclax combination using a 3 + 3study design. All patients who received one dose of study drug were included in theanalyses. This study is registered with ClinicalTrials.gov, number NCT04160052. The phase 2 dose-expansion part of the trial is ongoing.
Findings : Between Nov 12, 2019, and Dec 17, 2021, a total of 23 patients were enrolled in the phase 1 portion of this study (17 [74%] hypomethylating agent naive and six [26%]post-hypomethylating agent failure). 18 (78%) patients were male and five (22%) werefemale; 21 (91%) were white and two (9%) were Asian. Median follow-up was 13·2 months(IQR 6·8–18·3). The maximum tolerated dose was not reached and the recommended phase2 dose was established as azacitidine 75 mg/m2 for 5 days plus venetoclax 400 mg for 14 days. The most common grade 3–4 treatment-emergentadverse events were neutropenia (nine [39%] of 23), thrombocytopenia (nine [39%]),lung infection (seven [30%]), and febrile neutropenia (four [17%]). Three deaths dueto sepsis, which were not deemed treatment-related, occurred on the study drugs. Theoverall response rate was 87% (95% CI 66–97; 20 of 23 patients).
Interpretation : Azacitidine with venetoclax is safe and shows encouraging activity in patients withhigh-risk myelodysplastic syndromes or chronic myelomonocytic leukaemia.
The Lancet Haematology , résumé, 2021