Magrolimab-Azacitidine Combo vs. Venetoclax-Azacitidine: A Study for TP53 Mutant AML

Magrolimab (Hu5F9-G4) kills leukemia stem cells by stimulating tumor phagocytosis by inhibiting CD47, a macrophage immune checkpoint, and the “don’t eat me” signal on cancer cells. By increasing phagocytosis of leukemic blasts by triggering “eat me” signals on those cells, hypomethylating drugs work synergistically with magrolimab. In the frontline treatment of AML in patients unable to tolerate intense chemotherapy and in treating myelodysplastic syndrome, the combination of magrolimab and azacitidine (AZA) has demonstrated promising activity. It showed an objective response rate of 69%, a complete response rate of 45%, and median overall survival (OS) of 12.9 months in TP53-mutant (TP53m) AML. Mutations in the TP53 gene are found in about 10-15% of newly diagnosed cases of AML, and they are correlated with a low chance of survival. Whether patients receive intense chemotherapy or less intensive treatments, such as a hypomethylating drug with venetoclax, the documented first-line median OS in TP53m AML is 4-7 months (VEN). There is a large unmet medical need for TP53 mutation carriers of AML.

In patients with untreated TP53m AML, we compared the effectiveness, safety, and tolerability of magrolimab+AZA to the physician’s choice of VEN+AZA or “7+3” chemotherapy. This multicenter, open-label, randomized study is in its third and final phase. 346 patients will be randomly assigned to receive either VEN+AZA or 7+3 chemotherapy (depending on patient fitness) or magrolimab+AZA (experimental arm). Patients will be randomly assigned based on age (75 vs. 75), geographic location (US vs. non-US sites), and appropriateness for non-intensive vs. intensive therapy. Patients must have a TP53 gene mutation that is not benign or likely benign (confirmed by the central laboratory) or biallelic 17p deletions (based on a locally evaluated karyotype/fluorescence in situ hybridization report) be younger than 18 years old with histologically confirmed AML and no prior antileukemic therapy.

Intravenous (IV) magrolimab will be given to patients assigned to the magrolimab+AZA arm at a priming dose of 1 mg/kg on days 1 and 4, 15 mg/kg on day 8, and 30 mg/kg on days 11, 15, and then weekly for 5 doses, followed by every other week beginning 1 week after the fifth weekly 30 mg/kg dose, throughout the first 28-day cycle. Patients assigned to the VEN+AZA group will receive VEN and AZA following their approved uses. Patients undergoing 7+3 chemotherapy will have one to two induction cycles consisting of intravenous (IV) daunorubicin or idarubicin on days 1-3 and cytarabine 100 mg/m2 or 200 mg/m2 on days 1-7 and then up to four consolidation cycles consisting of high-dose cytarabine (3000 mg/m2). Patients who are given magrolimab+AZA or VEN+AZA will continue to take the drugs until they either experience disease progression, relapse, no longer benefit from them, or develop intolerable side effects. Stem cell transplantation is an option for patients if doctors decide it will benefit their patients. Overall survival (OS) in patients who are candidates for non-intensive therapy is the primary aim, while OS in all patients is a key secondary endpoint. The trial has begun. Patients are still enrolled.

Source: https://library.ehaweb.org/eha/2022/eha2022-congress/357414/naval.g.daver.a.phase.3.randomized.open-label.study.evaluating.the.safety.and.html?f=menu%3D6%2Abrowseby%3D8%2Asortby%3D2%2Amedia%3D3%2Ace_id%3D2233%2Aot_id%3D26840%2Amarker%3D1769%2Afeatured%3D17676

Clinical Trial: https://clinicaltrials.gov/ct2/show/NCT04778397

Inc, M. G. (n.d.). A PHASE 3, RANDOMIZED, OPEN-LABEL STUDY EVALUATING THE SAFETY AND… by Dr Naval G Daver. Library.ehaweb.org. Retrieved March 25, 2023, from https://library.ehaweb.org/eha/2022/eha2022-congress/357414/naval.g.daver.a.phase.3.randomized.open-label.study.evaluating.the.safety.and.html?f=menu%3D6%2Abrowseby%3D8%2Asortby%3D2%2Amedia%3D3%2Ace_id%3D2233%2Aot_id%3D26840%2Amarker%3D1769%2Afeatured%3D17676

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