Fresh from ASH 2021: Promising results of the combination of azacitidine with venetoclax and magrolimab in the treatment of AML

Introduction

The authors noted that while the combination of AZA + VEN achieves a high response rate in AML patients, most eventually relapse, and overall survival (OS) in R/R AML is very short. Therefore, Daver et al. evaluated the effects of the combination of AZA + VEN with magrolimab, an anti-CD47 antibody that blocks the 'don't eat me' signal on macrophages, in a phase I/II study. During the annual ASH 2021 congress, Dr. Daver explained that ongoing phase II study results show that the combination AZA + VEN + magrolimab exhibits clinical activity in older patients and high-risk individuals newly diagnosed with AML.

Study Methodology and Progress

In the phase I study, the authors evaluated whether adding magrolimab to AZA + VEN in adults with AML could improve therapy outcomes. Only patients with R/R AML were included. After determining the recommended dose for the phase II study, an expanded protocol allowed the inclusion of patients with newly diagnosed AML and R/R AML, including some who had not previously taken venetoclax and others who had undergone treatment failure with a VEN-including regimen. The data presented at ASH 2021 covered a cohort of 38 patients (17 newly diagnosed AML, 8 R/R AML who hadn’t taken venetoclax, and 13 R/R AML with prior VEN-including treatment failures) with information collected up to July 1, 2021.

In phase II, investigators assessed the safety and maximum tolerated dose of the combination. Secondary endpoints included response rate (complete remission/incomplete hematologic recovery [CR/CRi]), duration of response (DOR), and overall survival (OS).

Participants received AZA at 75 mg/m² on days 1–7, VEN at 400 mg (or an approved equivalent dose) on days 1–28, and magro on days 1, 4, 8, 11, 15, and 22 in the first cycle, weekly in the second cycle, and every two weeks in the third and subsequent cycles.

Results

In the newly diagnosed AML group, the median age was 70 years (range 33–84), and many had high-risk AML characteristics. Responses and toxicity were evaluated in the intention-to-treat (ITT) population. One patient was still in their first cycle, so their early treatment phase wasn’t assessable, but in the remaining 16 newly diagnosed AML patients, the CR/CRi rate was 94% (15 out of 16) and CR was 81%. All patients achieved a response after one cycle. During a median follow-up period of 3.4 months, one of the 17 first-line patients died due to relapse. Among the 7 newly diagnosed AML patients with TP53 mutations who could be evaluated, the investigators reported a CR/CRi rate of 100% and CR of 86%, MRD-negativity of 57%, complete cytogenetic response in 3 patients, and remission in 6.

In the R/R AML cases, the CR/CRi rate was 63% among those who had not previously used VEN, and the median OS was not reached. In contrast, among those with VEN regimen failures, the CR/CRi rate was 27%, and the median OS was 3.1 months.

In the entire cohort of 38 patients, mortality rates at 4 weeks (0%) and 8 weeks (9.7%; n = 4) were recorded. All four deceased patients had R/R AML.

The most common treatment-related non-hematologic adverse events included hypokalemia (58%), hypophosphatemia (55%), hyperbilirubinemia (53%), hyponatremia (53%), and sinus tachycardia (47%). Grade 3/4 adverse events included pneumonia (32%), febrile neutropenia (32%), hyperbilirubinemia (11%), elevated ALT (11%), and skin infections (11%).

Careful monitoring for anemia was conducted in the study participants, resulting in no severe cases or treatment interruptions/cessations due to anemia.

Conclusion

The study demonstrated that the combination of venetoclax, azacitidine, and magrolimab is particularly effective in newly diagnosed AML patients who are older or have high-risk characteristics. 

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Sources:
1. Daver N., Konopleva M., Maiti A. et al. Abstract #371. 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. ASH, 2021 Dec 12. Available at: https://ashpublications.org/ashclinicalnews/news/1697/Azacitidine-With-Venetoclax-and-Magrolimab-Shows
2. 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. Blood 2021; 138 (suppl. 1): 371, doi: 10.1182/blood-2021-153638.