magrolimab (ONO-7913) / Ono Pharma, Gilead - LARVOL DELTA

Rhabdomyolysis in patients taking isocitrate dehydrogenase inhibitors for R/R Acute Myeloid Leukemia (ASH 2025) - "She was started on treatment with azacitidine, venetoclax, and magrolimab and achieved MRD-negative CR after cycle 1, then went on to complete 6 cycles of therapy, followed by 4 cycles of maintenance therapy with combination decitabine/cedazuridine and venetoclax prior to relapse. She was then treated with combination decitabine/cedazuridine, venetoclax, and ivosidenib...Azacitidine was discontinued after C33, at which time she continued on enasidenib monotherapy...She was on a stable dose of atorvastatin at the time of this event and had recently started azithromycin for symptoms of upper respiratory tract infection...al 2015). We hypothesize that rhabdomyolysis observed with IDH inhibitors may reflect a convergence of metabolic stressors, particularly in susceptible populations such as elderly patients with low muscle mass, and those on concomitant statins."

Clinical • Acute Myelogenous Leukemia • Brain Cancer • Constipation • Gastroenterology • Gastrointestinal Disorder • Glioma • Hematological Disorders • Hematological Malignancies • Hepatology • Infectious Disease • Leukemia • Musculoskeletal Pain • Myelodysplastic Syndrome • Respiratory Diseases • Solid Tumor • Thrombocytopenia • IDH1 • IDH2

Efficacy of novel agents in the treatment of acute myeloid leukemia and myelodysplastic syndrome: A systematic review and meta-analysis (ASH 2025) - "Newer agents included for AML were Guadectiabine, Magrolimab, Alvocidib, Enasidenib, Flotetuzumab, Vadastuximab, Mitoxantrone, Pevonedistat, Entospletinib, Eprenetapopt, Belinostat, Onvansertib, Panobinostat, Cediranib Maleate, Nilotinib, Emavusertib, and anti-CD45 antibody (DOTA-BC8). The newer agents investigated for MDS included Rigosertib, Imetelstat, Pembrolizumab, Enasidenib, Sabatolimab, Ivosidenib, Elitercept, Pevonedistat, Emavusertib, Atezolizumab, and Olutasidenib...All patients were treated concomitantly with either azacitidine (77%) or decitabine (23%)... This meta-analysis and systematic review demonstrate promising efficacy for novel agents in AML and MDS patients. There is a need for prospective trials with larger patient populations to investigate these agents further."

Retrospective data • Review • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Neutropenia • TP53

Dichotomy of TP53 mutant AML MRD microenvironment: Spatially segregated immunosuppressive mechanisms and niche-specific structural support (ASH 2025) - "Patients received either Aza/Ven- or Ara-C/Idarubicin-based regimens combined with magrolimab or gilteritinib. single-cell proteomics analysis of bone marrow biopsies provides a spatially resolved view of the TP53mut AML microenvironment, uncovering persistent p53+ MRD cells enriched for erythroid phenotypes. Their structural niches suggest MRD-protective roles of MSCs and adipocytes, and immunosuppressive features such as spatial separation between T-cell clusters and p53+ cells, involvement of Tregs within lymphocyte clusters and a distance-dependent TIGIT surge of T and NK-cells in proximity to p53+ cells. This comprehensive spatial analysis offers new insights into the mechanisms of immune escape and MRD persistence in TP53mut AML."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • CD14 • CD34 • FOXP3 • NPM1 • TFRC • TIGIT • TP53

CD43 functions as a CD47 independent "don't eat me" signal and novel immune checkpoint in AML (ASH 2025) - "However, the CD47-targeting monoclonal antibody magrolimab recentlyfailed to meet its primary endpoint in Phase III ENHANCE trial in myeloid malignancies...These findings for the first timesuggest that CD43 on AML blasts promotes an immunosuppressive tumor microenvironment andcontributes to poor patient outcomes. Collectively, our work identifies O-glycosylated CD43 as a novel "don't eat me" immune checkpoint thatoperates independently of CD47, providing a promising therapeutic target to enhance macrophage-mediated tumor clearance in hematologic malignancies."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Lymphoma • ADAM10 • ADAM17 • CD4 • CD47 • GLI2 • SIGLEC1 • SIRPA • SLC35C1 • SPN

CD47-blockade induces programmed necroptosis and complements the effects of BCL-2 inhibition in lymphoid malignancies (ASH 2025) - "Methodology: The fully humanized anti-CD47 monoclonal antibodies, SRF231, magrolimab, as well as themouse monoclonal anti-CD47 antibody, B6H12, were evaluated in this study. Our study unravels a novel, critical non-canonical cell death mechanism of targeting CD47 vianecroptosis. We also demonstrate the complementary and distinct cell death mechanisms of SRF231-induced necroptosis and venetoclax-induced apoptosis, a combination worthy of further study in theclinic specifically against BCL-2-dependent lymphoid malignancies."

Acute Lymphocytic Leukemia • B Cell Lymphoma • Burkitt Lymphoma • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • ANXA5

Durability of complete response outperforms complete response rates as a surrogate endpoint for advancing to phase III trials in high-risk myelodysplastic syndromes (ASH 2025) - "The HMA plus venetoclax cohort (n=59) had a CRrate of 11.9% (7/59) with 8.5% (5/59) durable CR, equating to 71% (5/7) of CRs durable. Clinical trial pts(n=41) receiving HMA plus novel agents (magrolimab, eprenetapopt, or tamibarotene) had a higher CRrate of 29.3% (12/41) with 24.4% (10/41) durable CR, translating into 83% (10/12) of CRs being durable.In subgroup analysis of pts with TP53-mutated MDS treated with HMA alone (n=242), achieving a durableCR was associated with a 38% reduction in risk of death (HR 0.62; 95% CI 0.39–0.97; p=0.037). Only durable CR translates into a survival benefit in HR-MDS. CR >6 months is a practical, clinicallymeaningful surrogate endpoint and may improve assessment of treatment efficacy and accelerate drugdevelopment in HR-MDS."

Clinical • P3 data • Hematological Malignancies • Myelodysplastic Syndrome • TP53

PNOC025: A phase 1 study assessing the safety and tolerability of magrolimab in children and adults with recurrent or progressive malignant brain tumors (SNO 2025) - "Magrolimab is safe and well-tolerated in children and adults with recurrent or progressive malignant brain tumors. Unfortunately, the magrolimab program was discontinued by the Sponsor before enrollment was completed, for reasons unassociated with this trial. Biologic and clinical correlate analyses are underway."

Clinical • P1 data • Brain Cancer • Ependymoma • Glioblastoma • Glioma • High Grade Glioma • Oncology • Primary Spinal Cord Tumor • Solid Tumor

CD47 BLOCKADE SYNERGIZES WITH CHEMOTHERAPY IN ENHANCING MACROPHAGE PHAGOCYTOSIS OF EWING SARCOMA CELLS (CTOS 2025) - "We demonstrated that enhancing csCRT by chemotherapy doxorubicin (DOX) and blocking CD47 by magrolimab (MAG) significantly enhanced macrophage phagocytosis of ES cells and had synergistic anti-tumor effects against ES xenograft tumors...Cyclophosphamide (CP), another common chemotherapy regimen for ES and was reported to enhance csCRT level on cancer cells, was utilized to enhance csCRT on ES cells (0-20 mg/mL for 24 hrs). Lemzoparlimab (LEM) (1 μg/mL), a next generation therapeutic CD47 blockade that does not produce substantial hematologic toxicity, was used to block CD47 signal... Our data demonstrates a synergistic effect of CP and LEM in increasing macrophage phagocytosis of ES cells that is comparable to the combination of DOX and MAG. This provides a rationale to move this combinatorial therapy to preclinical investigation."

Ewing Sarcoma • Oncology • Sarcoma • Solid Tumor • CALR • CD47 • CSF1

PNOC025: A phase 1 study assessing the safety and tolerability of magrolimab in children and adults with recurrent or progressive malignant brain tumors (WFNOS 2025) - "Magrolimab is safe and well-tolerated in children and adults with recurrent or progressive malignant brain tumors. Unfortunately, the magrolimab program was discontinued by the Sponsor before enrollment was completed, for reasons unassociated with this trial. Biologic and clinical correlate analyses are underway."

Clinical • P1 data • Brain Cancer • Ependymoma • Glioblastoma • Glioma • High Grade Glioma • Oncology • Primary Spinal Cord Tumor • Solid Tumor

Safety and Tolerability of Magrolimab Combinations in Patients with Relapsed/Refractory Multiple Myeloma (RRMM): Safety Run-in Results from a Phase 2 Study (ASH 2023) - P2 | "In the SRI cohorts, pts received Magro in the following combinations: with daratumumab (Magro + D), pomalidomide/dexamethasone (Magro + Pd), or carfilzomib/dexamethasone (Magro + Kd). No TEAEs leading to death occurred. Conclusion Magro demonstrated an acceptable safety profile with minimal additive toxicity when given in combination with SOC regimens for pts with heavily pretreated RRMM."

Clinical • P2 data • Anemia • Fatigue • Febrile Neutropenia • Hematological Disorders • Hematological Malignancies • Infectious Disease • Multiple Myeloma • Neutropenia • Oncology • Pneumonia • Pulmonary Disease • Respiratory Diseases • Thrombocytopenia

Clinical outcomes and safety of CD47-targeted immunotherapies across hematologic malignancies: a systematic review of monoclonal antibodies and fusion proteins in combination strategies. (PubMed, Clin Exp Med) - "CD47-targeted combinations demonstrate encouraging early phase efficacy and manageable safety in hematologic malignancies, with signals of benefit in higher-risk MDS, TP53-mutant AML, relapsed/refractory DLBCL, and rituximab-refractory iNHL. However, recent Phase III trials in newly diagnosed AML Daver et al. [27], and Zeidner et al. [26] did not confirm this benefit, underscoring that CD47 blockade remains investigational and requires validation in rigorously designed randomized studies."

Clinical data • IO biomarker • Journal • Review • Acute Myelogenous Leukemia • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Disorders • Hematological Malignancies • Indolent Lymphoma • Leukemia • Lymphoma • Multiple Myeloma • Myelodysplastic Syndrome • Non-Hodgkin’s Lymphoma • Oncology • CD47 • SIRPA • TP53

Pyroglutamation of cell surface proteins CD47 and TRP1 by glutaminyl cyclase modulates therapeutic antibody binding. (PubMed, Commun Biol) - "Here, we show that pyroglutamation on CD47 and TRP1 modulates the binding of anti(α)-CD47 magrolimab and αTRP1 TA99 and flanvotumab. Furthermore, the N-terminal glutamine on CD47 is crucial for effective antibody recognition, while pyroglutamation of TRP1 is involved in trafficking to the cell surface. These findings highlight that the pyroglutamation by glutaminyl cyclase can modulate the binding affinity of antibodies with therapeutic potential."

Journal • Oncology

Phase 1b/2 Study of Magrolimab (Magro), Azacitidine (AZA) and Venetoclax (VEN) in Patients (pts) with Newly Diagnosed (ND) Older/Unfit or High Risk Acute Myeloid Leukemia (AML) and Relapsed Refractory (R/R) AML: Final Clinical Data and Genomic Markers of Resistance/Relapse (ASH 2024) - "Interestingly, pts with TP53mut AML who underwent alloSCT had med EFS 12 mos and med OS NR. Potential mechanisms of resistance/relapse included erythroid differentiation, inflammatory tumor microenvironment, and CD47 upregulation."

Clinical data • P1/2 data • Acute Myelogenous Leukemia • Anemia • Febrile Neutropenia • Hematological Disorders • Hematological Malignancies • Leukemia • Neutropenia • Oncology • CD47 • IFNG • TNFA • TP53

Single-Cell Genomics and Proteomics Reveals Venetoclax-Resistant Monocytic Differentiation of TP53 LOH Clones in TP53 Mutant AML (ASH 2023) - " Patients 1 and 3 received treatment with CD47AB (Magrolimab), 5'-Azacitidine (Aza), and Venetoclax (Ven); Patient 2 received IMGN632 (CD123-targeting ADC), Aza and Ven. Patient 4 received p97 Inhibitor CB-5339; Patient 5 received CD47 inhibitor (ALX148), Aza, Ven... This study establishes a genotype-phenotype connection through single-cell proteogenomic profiling of TP53-mutated AML, describing the clonal evolution and immunophenotypic dynamics during treatment while proposing a potential mechanism of resistance."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • BCL2L1 • CD123 • CD14 • CD33 • CD34 • CD36 • CD68 • CD8 • EIF4EBP1 • ETV6 • IDH1 • IL3RA • ITGAM • KIT • SCARB1 • TP53

Enhancing Macrophage Mediated Phagocytosis in AML: The Complementary Mechanisms of Venetoclax and Azacitidine Combination Therapy (ASH 2024) - "We have previously reported that the combination of venetoclax and azacitidine (VEN/AZA) increased macrophage phagocytosis in preclinical models, with or without CD47 antibody (5F9, magrolimab) (Jia et al., Blood 2021). These findings provide a rationale for combining VEN/AZA with macrophage-based therapies in AML treatment, particularly in TP53-mutant cases. Further validation of the identified pathways is ongoing and will be reported."

Combination therapy • Acute Myelogenous Leukemia • Hematological Malignancies • Idiopathic Arthritis • Leukemia • Oncology • AKT2 • CD47 • DNMT3A • FLT3 • MRC1 • NPM1 • POU4F2 • PTPRC • SIRPA

Single-Cell Characterization of TP53-Mutated AML Patients Treated with Frontline Azacitidine, Venetoclax, and Magrolimab Reveals Mechanisms of Response and Resistance (ASH 2023) - P1/2 | "Through single cell transcriptomic profiling of TP53-mutated AML patients treated with the triplet combination of AVM on protocol we identified erythroid differentiation and oxidative phosphorylation as possible intrinsic resistance mechanisms. Additionally, non-responders exhibited a dysfunctional T cell state prior to treatment, while relapses were associated with development of CD8 dysfunction. Overall, this data provides valuable insight into the mechanisms of response and resistance to magrolimab-based therapy."

Clinical • Acute Myelogenous Leukemia • Inflammation • CD47 • CD8 • IFNG • TNFA • TP53

Mutational Landscape and Depth of Response in Patients with Acute Myeloid Leukemia (AML) Treated with Magrolimab in Combination with Venetoclax and Azacitidine Compared to Placebo (ASH 2024) - "Patients with a TET2 mutation likely fare worse with magrolimab treatment, including an increased rate of respiratory tract infection. It is noteworthy that TET2m mature myeloid cells have pro-inflammatory features raising the hypothesis that magrolimab and TET2 mutant myeloid cells may synergise to exacerbate a maladapted innate response to infection."

Clinical • Combination therapy • Acute Myelogenous Leukemia • Hematological Malignancies • Infectious Disease • Leukemia • Oncology • Pneumonia • Pulmonary Disease • Respiratory Diseases • ASXL1 • DNMT3A • FLT3 • KRAS • NPM1 • TET2 • TP53

Phase I Study of Response-Adapted Treatment with Venetoclax, Obinutuzumab, and Magrolimab (VENOM) in Relapsed and Refractory Indolent B-Cell Malignancies (ASH 2023) - P1 | "Magrolimab is a fully humanized IgG4 anti-human CD47 antibody, with high activity in FL when combined with rituximab (Advani NEJM 2018). The primary objective is safety, with secondary endpoints of overall response rate, duration of response, and PFS. Exploratory objectives include the identification of a molecular signature that predicts response to magrolimab and obinutuzumab, and correlation of response with circulating tumor DNA levels."

IO biomarker • P1 data • Anemia • Autoimmune Hemolytic Anemia • B Cell Lymphoma • Chronic Lymphocytic Leukemia • Follicular Lymphoma • Hematological Disorders • Hematological Malignancies • Hepatitis B • Hepatology • Human Immunodeficiency Virus • Immune Thrombocytopenic Purpura • Immunology • Indolent Lymphoma • Infectious Disease • Leukemia • Lymphoma • Mantle Cell Lymphoma • Marginal Zone Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Thrombocytopenia • Thrombocytopenic Purpura • TP53

Combination of the potentially immunogenic therapeutics Venetoclax, Azacitidine and Magrolimab induces an additive T-cell response in acute myeloid leukemia (DGHO 2025) - "Seven therapeutic agents in various combinations showed promising results those are Nivolumab, ATRA, Ipilimumab and Lenalidomide as well as the BCL2-inhibitor Venetoclax, the demethylating agent Azacitidine and the anti-CD47 antibody Magrolimab. Magrolimab induces an additive T cell response in comparison to Venetoclax and Azacitidine alone. Selecting the ideal patients for this form of therapy is important, warranting additional studies with modified patient criteria.Taken together, combinations of immunotherapeutic approaches increase antigen-specific immune responses against leukemic cells especially the combination of LAA-peptides with a triple mix of Venetoclax, Azacitidine and Magrolimab could be an interesting option for further studies."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia

The Potent Dihydroorotate Dehydrogenase Inhibitor, Hosu-53, Exhibits Compelling Monotherapy Efficacy in Multiple Myeloma and Augments CD47 Targeted Therapy (ASH 2023) - "Among the most promising MM SOC agents is monoclonal antibodies (mAb) such as the CD38 antibody daratumumab, which significantly improved the management of newly diagnosed and relapsed/refractory MM...We further verified HOSU-53 efficacy using the disseminated MM1.S luciferase CDX model and found a significant prolonged survival in the HOSU-53 cohort (median survival53-days) compared to vehicle (median survival28-days) that was further enhanced with isatuximab combination resulting in superior survival benefit (median survival 69-days)...Currently there is significant clinical interest in CD47 antibody therapy such as magrolimab for both solid tumors and hematological malignancies...In summary, we show compelling survival benefit for HOSU-53 as a monotherapy which is further enhanced when combined with anti-CD38 or anti-CD47 therapies. HOSU-53 is expected to enter phase 1 clinical trials in 2024 and our data is supportive for its expansion into MM."

Clinical • IO biomarker • Monotherapy • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Multiple Myeloma • Oncology • Solid Tumor • CALR

The CD47-Blocking Immune Checkpoint Inhibitor Maplirpacept Does Not Interfere with Blood Transfusion Compatibility Testing (ASH 2023) - "CD47 expression on RBCs was shown to interfere with pre-transfusion laboratory testing in patients treated with the anti-CD47 mAb, Hu5F9-G4 (Velliquette et al. Here we demonstrate that interference with blood compatibility testing is dependent upon the type of CD47-blocking agent. Decoy receptors such as Maplirpacept, unlike anti-CD47 mAb, do not interfere with blood group serologic testing, which may confer a significant clinical advantage by negating the need for additional approaches to prevent interference."

Checkpoint inhibition • IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Multiple Myeloma • Oncology • Ovarian Cancer • Solid Tumor • CD47 • SIRPA

Magrolimab (Hu5F9-G4) promotes macrophage M1 polarization and is associated with enhanced autophagy in colorectal cancer. (PubMed, Transl Oncol) - "Hu5F9-G4 demonstrates potential as a therapeutic agent in CRC by promoting M2d-to-M1 macrophage polarization, suppressing tumor progression, and influencing the autophagy pathway. These findings highlight CDKN1A and MAP1LC3B as promising targets for CRC therapy."

Journal • Colorectal Cancer • Oncology • Solid Tumor • CDKN1A • MAP1LC3B

Trial in Progress: A Randomized, Double-Blind, Placebo-Controlled, Multicenter Phase 2 Study of AK117/Placebo in Combination with Azacitidine in Patients with Newly Diagnosed Higher-Risk Myelodysplastic Syndromes (AK117-205) (ASH 2024) - P2 | "Additionally, unlike the first generation anti-CD47 agents such as magrolimab, AK117 does not cause red blood cell agglutination and on-target anemia. Stratification factors will be based on IPSS-R scores : ≤4.5, >4.5-6, and >6.The primary endpoint is complete remission rate (CRR) assessed by investigators based on 2023 International Working Group (IWG 2023) response criteria (Zeidan A et al, Blood, 2023), and to determine the optimal dose of AK117 for future confirmatory trials (can expand this Phase 2 trial to a Phase 3 trial). Key secondary endpoints include overall response rate (ORR), duration of response (DoR), event-free survival (EFS), overall survival (OS), rate and duration of transfusion independence (TI), time to transformation to acute myeloid leukemia (AML), safety assessed by incidence and severity of adverse events (AEs), pharmacokinetics (PK) and immunogenicity."

Clinical • Combination therapy • P2 data • Acute Myelogenous Leukemia • Anemia • Bone Marrow Transplantation • Hematological Disorders • Hematological Malignancies • Immunology • Infectious Disease • Leukemia • Myelodysplastic Syndrome • Myeloproliferative Neoplasm • Oncology • SIRPA

Impact of Mutational Landscape and CD47 Levels in the Magrolimab + Azacitidine Vs Placebo + Azacitidine Trial in Patients with Untreated Higher Risk Myelodysplastic Syndrome (ASH 2024) - P3 | "Given the imbalanced cytogenetic risk between CD47 high and CD47 low in the magrolimab+ aza arm, the observation warrants further investigation into the connection between cytogenetic risk, CD47 levels, and CD47 blockade. Additional data with respect to the mutational landscape will be forthcoming, including central evaluation of TP53 status."

Clinical • Hematological Malignancies • Myelodysplastic Syndrome • Oncology • CALR • CD47 • SIRPA • TP53

Effects of Magrolimab Therapy in Conjunction with Conventional Chemotherapeutics in Pediatric Acute Myeloid Leukemia Patient Derived Xenograft Models (ASH 2024) - P3 | "In this project, Magro was tested as a single agent and in combination with backbone chemotherapy drugs, cytarabine (AraC) or azacitidine (Aza), in three different pediatric AML (pAML) patient derived xenograft (PDX) models – AML006 (KMT2A : : MLLT1), AML010 (+10, WT1), AML013 (KMT2A : : MLLT4) - in order to evaluate its pre-clinical efficacy in vivo. Interestingly, the two models that demonstrated improvement in survival with magrolimab both harbored KMT2A rearrangements, suggesting a subset of patients that may be more responsive to the effects of CD47 blockade. As this drug is still being evaluated for use in other malignancies, future studies may focus on investigating the possible importance of biomarker-based selection of patients."

Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Pediatrics • AFDN • KMT2A • PTPRC • PTPRCAP • SIRPA • WT1