[en] Patients with acute myeloid leukemia (AML) ineligible for intensive chemotherapy (IC) have limited treatment options. The phase 3 ENHANCE-3 study aimed to determine whether magrolimab (magrolimab arm) was superior to placebo (control arm) when either was combined with venetoclax and azacitidine. Adults with previously untreated AML who were ineligible for IC were randomized to receive magrolimab (1 mg/kg on days 1 and 4, 15 mg/kg on day 8, 30 mg/kg on days 11 and 15, then weekly for 5 weeks, then every 2 weeks) or placebo, venetoclax (100 mg on day 1, 200 mg on day 2, and 400 mg daily thereafter), and azacitidine (75 mg/m2 days 1-7) in 28-day cycles. The primary endpoint was overall survival (OS); key secondary endpoints included complete remission (CR) rate and safety. After randomization of 378 patients, the trial was stopped at a prespecified interim analysis due to futility. At final analysis, with median follow-up of 7.6 months (magrolimab arm) vs 7.4 months (control arm), median OS was 10.7 vs 14.1 months (HR, 1.178 [95% CI, 0.848-1.637]). The CR rate within 6 cycles was 41.3% vs 46.0%. Addition of magrolimab to venetoclax and azacitidine resulted in more fatal adverse events (19.0% vs 11.4%), primarily driven by grade 5 infections (11.1% vs 6.5%) and respiratory events (2.6% vs 0%). There were similar incidences of any-grade infections, febrile neutropenia, and neutropenia between arms. These results highlight the difficulty in improving outcomes for patients with AML ineligible for IC. This trial was registered at www.clinicaltrials.gov as #NCT05079230.
Disciplines :
Hematology
Author, co-author :
Daver, Naval G ; University of Texas, MD Anderson Cancer Center, Houston, Texas, United States
Vyas, Paresh ; MRC Molecular Haematology Unit, Radcliffe Department of Medicine, Weatherall Institute of Medicine, University of Oxford, Oxford, United Kingdom
Huls, Gerwin A; University Medical Center Groningen, Groningen, Netherlands
Döhner, Hartmut ; University Hospital Ulm, Ulm, Germany
Maury, Sebastien ; Hopital Henri Mondor, Créteil, France
Novak, Jan ; Fakultní Nemocnice Královské Vinohrady, Vinohrady, Czech Republic
Papayannidis, Cristina ; IRCCS, Azienda Ospedaliero Universitaria di Bologna, Istituto di Ematologia, Bologna, Italy
Montesinos, Pau ; Hospital Universitari i Politècnic La Fe, Valencia, Spain
Niroula, Rabin; Brown University Health Cancer Institute, The Warren Alpert Medical School of Brown University, Providence, Rhode Island, United States
Fenaux, Pierre; hôpital St Louis, Paris, PARIS, France
Esteve, Jordi; Hospital Clínic of Barcelona, Barcelona, Spain
Wu, Shang-Ju ; National Taiwan University Hospital, Taipei City, Taiwan
Lin, TL, Pagano, L, The important role of intensive induction chemotherapy in the treatment of acute myeloid leukemia. Expert Rev Hematol 14:3 (2021), 303–314.
National Cancer Institute. Cancer stat facts—acute myeloid leukemia (AML). https://seer.cancer.gov/statfacts/html/amyl.html. (Accessed 16 October 2024)
Grinblatt, DL, Roboz, GJ, Pollyea, DA, et al. Treatment patterns and outcomes of patients with acute myeloid leukemia (AML) from 2013 to 2022: a Connect Myeloid Registry study [abstract]. Blood, 142(suppl 1), 2023, 593.
Döhner, H, Wei, AH, Appelbaum, FR, et al. Diagnosis and management of AML in adults: 2022 recommendations from an international expert panel on behalf of the ELN. Blood 140:12 (2022), 1345–1377.
Pratz, KW, Jonas, BA, Pullarkat, V, et al. Long-term follow-up of VIALE-A: venetoclax and azacitidine in chemotherapy-ineligible untreated acute myeloid leukemia. Am J Hematol 99:4 (2024), 615–624.
DiNardo, CD, Jonas, BA, Pullarkat, V, et al. Azacitidine and venetoclax in previously untreated acute myeloid leukemia. N Engl J Med 383:7 (2020), 617–629.
Bataller, A, Bazinet, A, DiNardo, CD, et al. Prognostic risk signature in patients with acute myeloid leukemia treated with hypomethylating agents and venetoclax. Blood Adv 8:4 (2024), 927–935.
Döhner, H, Pratz, KW, DiNardo, CD, et al. Genetic risk stratification and outcomes among treatment-naive patients with AML treated with venetoclax and azacitidine. Blood 144:21 (2024), 2211–2222.
Döhner, H, DiNardo, CD, Appelbaum, FR, et al. Genetic risk classification for adults with AML receiving less-intensive therapies: the 2024 ELN recommendations. Blood 144:21 (2024), 2169–2173.
Liu, J, Wang, L, Zhao, F, et al. Pre-clinical development of a humanized anti-CD47 antibody with anti-cancer therapeutic potential. PLoS One, 10(9), 2015, e0137345.
Feng, D, Gip, P, McKenna, KM, et al. Combination treatment with 5F9 and azacitidine enhances phagocytic elimination of acute myeloid leukemia [abstract]. Blood, 132(suppl 1), 2018, 2729.
Jia, Y, Zhang, Q, Weng, C, et al. Combined blockade of CD47-SIRPa interaction by 5F9 (magrolimab) and azacitidine/venetoclax therapy facilitates macrophage-mediated anti-leukemia efficacy in AML pre-clinical models [abstract]. Blood, 138(suppl 1), 2021, 510.
Daver, N, Senapati, J, Maiti, A, et al. Phase I/II study of azacitidine (aza) with venetoclax (ven) and magrolimab (magro) in patients (pts) with newly diagnosed (ND) older/unfit or high-risk acute myeloid leukemia (AML) and relapsed/refractory (RR) AML [abstract]. Blood 140:suppl 1 (2022), 141–144.
Daver, NG, Vyas, P, Kambhampati, S, et al. Tolerability and efficacy of the anticluster of differentiation 47 antibody magrolimab combined with azacitidine in patients with previously untreated AML: phase Ib results. J Clin Oncol 41:31 (2023), 4893–4904.
Cheson, BD, Bennett, JM, Kopecky, KJ, et al. Revised recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. J Clin Oncol 21:24 (2003), 4642–4649.
Cheson, BD, Greenberg, PL, Bennett, JM, et al. Clinical application and proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia. Blood 108:2 (2006), 419–425.
Döhner, H, Estey, E, Grimwade, D, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood 129:4 (2017), 424–447.
Jahn, E, Saadati, M, Fenaux, P, et al. Clinical impact of the genomic landscape and leukemogenic trajectories in non-intensively treated elderly acute myeloid leukemia patients. Leukemia 37:11 (2023), 2187–2196.
Othman, J, Lam, HPJ, Leong, S, et al. Real-world outcomes of newly diagnosed AML treated with venetoclax and azacitidine or low-dose cytarabine in the UK NHS. Blood Neoplasia, 1(3), 2024, 100017.
Banerjee, R, Khandelwal, S, Kozakai, Y, Sahu, B, Kumar, S, CD47 regulates the phagocytic clearance and replication of the Plasmodium yoelii malaria parasite. Proc Natl Acad Sci U S A 112:10 (2015), 3062–3067.
Moon, S, Han, S, Jang, IH, et al. Airway epithelial CD47 plays a critical role in inducing influenza virus-mediated bacterial super-infection. Nat Commun, 15(1), 2024, 3666.
Su, X, Johansen, M, Looney, MR, Brown, EJ, Matthay, MA, CD47 deficiency protects mice from lipopolysaccharide-induced acute lung injury and Escherichia coli pneumonia. J Immunol 180:10 (2008), 6947–6953.
Wenzek, C, Steinbach, P, Wirsdörfer, F, et al. CD47 restricts antiviral function of alveolar macrophages during influenza virus infection. iScience, 25(12), 2022, 105540.
Sallman, D, Garcia-Manero, G, Daver, NG, et al. Magrolimab (magro) + azacitidine (aza) vs placebo (pbo) + aza in patients (pts) with untreated higher-risk (HR) myelodysplastic syndromes (MDS): phase 3 ENHANCE study final analysis. HemaSphere, 8(S1), 2024, e104.
Kantarjian, H, O'Brien, S, Cortes, J, et al. Results of intensive chemotherapy in 998 patients age 65 years or older with acute myeloid leukemia or high-risk myelodysplastic syndrome: predictive prognostic models for outcome. Cancer 106:5 (2006), 1090–1098.
Othman, J, Lam, HPJ, Leong, S, et al. Real-world outcomes of newly diagnosed AML treated with venetoclax and azacitidine or low-dose cytarabine in the UK NHS. Blood Neoplasia, 1(3), 2024, 100017.
Hoff, FW, Blum, WG, Huang, Y, et al. Beat-AML 2024 ELN-refined risk stratification for older adults with newly diagnosed AML given lower-intensity therapy. Blood Adv 8:20 (2024), 5297–5305.
