A combination regimen consisting of azacitidine with venetoclax and magrolimab showed clinical activity in older and high-risk patients with newly diagnosed acute myeloid leukemia (AML), according to results of a study presented during the 2021 ASH Annual Meeting by Naval Daver, MD, of the MD Anderson Cancer Center in Houston.
According to Dr. Daver and colleagues, most patients with AML experience relapse despite high frontline response rates with azacitidine and venetoclax. In the phase I study, the investigators assessed whether the addition of magrolimab, a monoclonal antibody against CD47 and macrophage checkpoint inhibitor, to azacitidine and venetoclax in adults with AML could improve disease outcomes. Only patients with relapsed/refractory AML were enrolled in the study.
After establishing the recommended phase II dose, an expanded protocol allowed for the enrollment of frontline, venetoclax-naïve, and venetoclax-exposed patients with relapsed/refractory AML. Patients in the frontline cohort were 75 years or older, had comorbidities that made them ineligible for intensive therapy, or had adverse-risk karyotype and/or TP53 mutation regardless of age/fitness.
On days 1 through 28, patients were treated with azacitidine 75 mg/m2 (days 1-7) and venetoclax 400 mg (days 1-28). Magrolimab was dosed on days 1, 4, 8, 11, 15, and 22 of cycle 1. Additionally, magrolimab was dosed weekly in cycle 2 as well as every two weeks in cycle 3 onward. There were no dose-limiting toxicities at the end of the phase Ib portion of the study, which enrolled six patients. The established recommended phase II doses of magrolimab were 1 mg/kg on days 1 and 4 of cycle 1; 15 mg/kg on day 8 of cycle 1; and 30 mg/kg on day 11 of cycle 1.
For the phase II portion of the study, the investigators focused on assessing the triplet combination’s safety and maximum tolerated dose (MTD). Additionally secondary objectives were the rates of complete response (CR)/CR with incomplete hematologic recovery (CRi), duration of response (DOR), and overall survival (OS).
Overall, the study included 17 newly diagnosed patients with AML, eight venetoclax-naïve patients with relapsed/refractory disease, and 13 patients with relapsed/refractory AML who experienced treatment failure with venetoclax. Another six patients were enrolled after the data cutoff point of July 1, 2021.
The median age of the newly diagnosed patients was 70 years and ranged between 33 and 84 years. Most patients had high-risk features, including 82% who were categorized as European LeukemiaNet adverse-risk, 45% who had Eastern Cooperative Oncology Group performance status of 2 or greater, and 47% who had TP53 mutation.
In 15 of 16 newly diagnosed patients, the CR/CRi rate was 94%, and the eight-week mortality was 0. All patients had a response after the first cycle. Among the patients with CR/CRi, the median time to absolute neutrophil count recovery >0.5 was 28 days, and the median time to platelet recovery >50×109/L was 24 days.
During a median follow-up period of 3.4 months, one of the 17 frontline patients had died from disease relapse. In seven newly diagnosed evaluable patients with TP53 mutation, the investigators reported a CR/CRi in 100%, CR in 86%, measurable residual disease negativity in 57%, complete cytogenetic response in three patients, and remission in six patients.
In the relapsed/refractory venetoclax-naïve patients, the CR/CRi rate was 63%, and the median OS was not reached. In contrast, the relapsed/refractory patients with prior venetoclax failure had a CR/CRi rate of 27% and a median OS of 3.1 months.
The eight-week mortality rate among all 38 patients was 9.7%, and all deaths occurred in patients with relapsed/refractory disease. The most frequent treatment-emergent non-hematologic adverse events (AEs) included hypokalemia (58%), hypophosphatemia (55%), hyperbilirubinemia (53%), hyponatremia (53%) and sinus tachycardia (47%). Grade 3/4 AEs included pneumonia (32%), febrile neutropenia (32%), hyperbilirubinemia (11%), elevated ALT (11), and skin infection (11%).
Limitations of the study included the small sample size, as well as the lack of a randomized control group.
The authors report no relevant conflicts of interest.
Daver N, Konopleva M, Maiti A, et al. Phase I/II Study of Azacitidine (AZA) with Venetoclax (VEN) and Magrolimab (Magro) in Patients (pts) with Newly Diagnosed Older/Unfit or High-Risk Acute Myeloid Leukemia (AML) and Relapsed/Refractory (R/R) AML. Abstract #371. Presented at the 2021 American Society of Hematology Annual Meeting, December 12, 2021.