TY - JOUR
T1 - Azacitidine plus venetoclax in patients with high-risk myelodysplastic syndromes or chronic myelomonocytic leukaemia
T2 - phase 1 results of a single-centre, dose-escalation, dose-expansion, phase 1–2 study
AU - Bazinet, Alexandre
AU - Darbaniyan, Faezeh
AU - Jabbour, Elias
AU - Montalban-Bravo, Guillermo
AU - Ohanian, Maro
AU - Chien, Kelly
AU - Kadia, Tapan
AU - Takahashi, Koichi
AU - Masarova, Lucia
AU - Short, Nicholas
AU - Alvarado, Yesid
AU - Yilmaz, Musa
AU - Ravandi, Farhad
AU - Andreeff, Michael
AU - Kanagal-Shamanna, Rashmi
AU - Ganan-Gomez, Irene
AU - Colla, Simona
AU - Qiao, Wei
AU - Huang, Xuelin
AU - McCue, Deborah
AU - Mirabella, Bailey
AU - Kantarjian, Hagop
AU - Garcia-Manero, Guillermo
N1 - Funding Information:
This study was funded by the University of Texas MD Anderson Cancer Center Support Grant (CA016672) and the University of Texas MD Anderson Cancer Center Myelodysplastic Syndromes/Acute Myeloid Leukaemia Moon Shot. We thank the patients who participated in this trial, their families, and the clinical and research staff at MD Anderson Cancer Center.
Publisher Copyright:
© 2022 Elsevier Ltd
PY - 2022/10
Y1 - 2022/10
N2 - Background: Therapies beyond hypomethylating agents such as azacitidine are needed in high-risk myelodysplastic syndromes. Venetoclax is an orally bioavailable small molecule BCL-2 inhibitor that is synergistic with hypomethylating agents. We therefore aimed to evaluate the safety, tolerability, and preliminary activity of azacitidine combined with venetoclax for 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 University of Texas MD Anderson Cancer Center (Houston, TX, USA). This Article details the phase 1 results. We enrolled patients (≥18 years) with treatment-naive or relapsed or refractory high-risk myelodysplastic syndromes or chronic myelomonocytic leukaemia and bone marrow blasts of more than 5%. No specific Eastern Cooperative Oncology Group status restriction was 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 was safety and tolerability as well as determination of the maximum tolerated dose and recommended phase 2 dose of the azacitidine and venetoclax combination using a 3 + 3 study design. All patients who received one dose of study drug were included in the analyses. 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%) were female; 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 phase 2 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-emergent adverse events were neutropenia (nine [39%] of 23), thrombocytopenia (nine [39%]), lung infection (seven [30%]), and febrile neutropenia (four [17%]). Three deaths due to sepsis, which were not deemed treatment-related, occurred on the study drugs. The overall response rate was 87% (95% CI 66–97; 20 of 23 patients). Interpretation: Azacitidine with venetoclax is safe and shows encouraging activity in patients with high-risk myelodysplastic syndromes or chronic myelomonocytic leukaemia. Funding: MD Anderson Cancer Center.
AB - Background: Therapies beyond hypomethylating agents such as azacitidine are needed in high-risk myelodysplastic syndromes. Venetoclax is an orally bioavailable small molecule BCL-2 inhibitor that is synergistic with hypomethylating agents. We therefore aimed to evaluate the safety, tolerability, and preliminary activity of azacitidine combined with venetoclax for 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 University of Texas MD Anderson Cancer Center (Houston, TX, USA). This Article details the phase 1 results. We enrolled patients (≥18 years) with treatment-naive or relapsed or refractory high-risk myelodysplastic syndromes or chronic myelomonocytic leukaemia and bone marrow blasts of more than 5%. No specific Eastern Cooperative Oncology Group status restriction was 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 was safety and tolerability as well as determination of the maximum tolerated dose and recommended phase 2 dose of the azacitidine and venetoclax combination using a 3 + 3 study design. All patients who received one dose of study drug were included in the analyses. 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%) were female; 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 phase 2 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-emergent adverse events were neutropenia (nine [39%] of 23), thrombocytopenia (nine [39%]), lung infection (seven [30%]), and febrile neutropenia (four [17%]). Three deaths due to sepsis, which were not deemed treatment-related, occurred on the study drugs. The overall response rate was 87% (95% CI 66–97; 20 of 23 patients). Interpretation: Azacitidine with venetoclax is safe and shows encouraging activity in patients with high-risk myelodysplastic syndromes or chronic myelomonocytic leukaemia. Funding: MD Anderson Cancer Center.
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U2 - 10.1016/S2352-3026(22)00216-2
DO - 10.1016/S2352-3026(22)00216-2
M3 - Article
C2 - 36063832
AN - SCOPUS:85138752499
SN - 2352-3026
VL - 9
SP - e756-e765
JO - The Lancet Haematology
JF - The Lancet Haematology
IS - 10
ER -