flotetuzumab (MGD006) / MacroGenics - LARVOL DELTA

Flotetuzumab as Salvage Immunotherapy for Refractory Acute Myeloid Leukemia. (PubMed, Blood) - P1/2 | "We have recently shown an association between an immune-infiltrated tumor microenvironment (TME) and resistance to cytarabine-based chemotherapy but responsiveness to flotetuzumab, a bispecific DART® antibody-based molecule to CD3ε and CD123...Stepwise dosing during week 1, pre-treatment dexamethasone, prompt use of tocilizumab and temporary dose reductions/interruptions successfully prevented severe IRR/CRS, resulting in acceptable tolerability...Flotetuzumab represents an innovative experimental approach associated with acceptable safety and encouraging evidence of activity in PIF/ER AML patients. Trial registration number: NCT02152956."

IO biomarker • Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CD123

Flotetuzumab for the Treatment of Relapsed or Refractory Advanced CD123-Positive Hematological Malignancies (clinicaltrials.gov) - P1 | N=13 | Completed | Sponsor: City of Hope Medical Center | Active, not recruiting ➔ Completed | Trial completion date: May 2026 ➔ Aug 2025 | Trial primary completion date: May 2026 ➔ Aug 2025

Trial completion • Trial completion date • Trial primary completion date • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • B Acute Lymphoblastic Leukemia • Chronic Myeloid Leukemia • Hairy Cell Leukemia • Hematological Malignancies • Hodgkin Lymphoma • Leukemia • Lymphoma • Myelodysplastic Syndrome • Oncology • T Acute Lymphoblastic Leukemia • IL3RA • PD-L1

PEPN1812: Flotetuzumab for the Treatment of Pediatric Recurrent or Refractory Acute Myeloid Leukemia (clinicaltrials.gov) - P1 | N=16 | Active, not recruiting | Sponsor: Children's Oncology Group | Trial completion date: Sep 2025 ➔ Mar 2026

Trial completion date • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Pediatrics

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

Current status and future potential of CD123-based targeted therapies for acute leukemia. (PubMed, Expert Opin Biol Ther) - "It discusses completed and ongoing clinical trials for agents such as tagraxofusp, pivekimab sunirine, flotetuzumab, vibecotamab, and investigational CAR T-cell therapies (e.g. MB-102, UCART123v1.2). While clinical activity has been demonstrated, especially in BPDCN, therapeutic durability and safety remain hurdles. Precision in antigen targeting, combination strategies, and toxicity management will be critical for successful integration of CD123-directed therapies into standard clinical practice."

Journal • Review • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • CD123 • IL3RA

Spatial Technologies Reveal the Immune Landscape of Pediatric Acute Myeloid Leukemia (ASH 2023) - P1/2 | "Moreover, we acquired an additional dataset of pre-treatment immune-related gene expression profiling obtained from the BM of 30 flotetuzumab-treated (CD3 x CD123 bispecific antibody) refractory/relapsed (R/R) adult AML patients (NCT02152956; Vadakekolathu et al., 2020) for TIDE-based immune deconvolution (Jiang et al., 2018)...Lastly, for the first time, we identified TLS-like aggregates in the BM of AML patients, which have been associated with immunotherapy response in many cancers (Schumacher & Thommen, 2022). Additional studies to further characterize the function and relevance of these lymphoid aggregates are ongoing."

Clinical • IO biomarker • Tumor mutational burden • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Pediatrics • Rhabdomyosarcoma • Sarcoma • Solid Tumor • CD123 • CD8 • IL3RA • KMT2A • TMB

Spatially Resolved Transcriptomics Unveils Unique T-Cell Dysfunctional States and Prognostic Gene Expression Signatures in TP53-Mutated Acute Myeloid Leukemia (ASH 2023) - "We have previously shown that TP53 abnormalities are associated with a pro-inflammatory and immunosuppressive tumor microenvironment (TME), including high CD274 and FoxP3 expression, with dysfunctional natural killer (NK)/CD8+ T-cell states and with response to flotetuzumab, a CD123 × CD3 bispecific T-cell engager...Conclusions Spatial gene programs of leukemia stemness, T-cell dysfunction and immune suppression are enriched in TP53-m AML. It remains to be determined whether TP53-m AML with a pre-existing but ineffective T-cell response may be amenable to T cell-targeting immunotherapies."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CD123 • CD3D • CD4 • CD8 • CDCP1 • FOXP3 • IL1B • IL3RA • PD-L1 • PRDM1 • S100A8 • S100A9 • TP53 • ZEB2

Curing the Incurable: TP53 Mutated Myeloid Neoplasms. (PubMed, Clin Lymphoma Myeloma Leuk) - "The differential prognosis of the mutation in various chromosomal and VAF settings will be explored. Lastly, we will outline therapeutic options, promising treatments on the horizon, and whether allogeneic stem cell transplant is curative."

Journal • Review • Acute Myelogenous Leukemia • Genetic Disorders • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • Transplantation • TP53

Novel HLA-mediated mechanisms of GVHD: multifaceted roles of HLA class II in GVHD and GVL (PubMed, Rinsho Ketsueki) - "In acute myeloid leukemia relapse, downregulation of HLA class II on leukemic cells allows immune evasion, but this suppression can be reversed by IFN-γ or flotetuzumab, a CD123×CD3 bispecific antibody, restoring immunogenicity and potentially enhancing the graft versus leukemia (GVL) effect. Collectively, HLA class II molecules function not only in conventional antigen presentation to CD4+ T cells but also in neo-self antigen recognition, immune evasion, and tissue-specific disease expression. A deeper understanding of HLA class II biology may pave the way toward therapeutic strategies that separate GVHD from the GVL effect."

Journal • Review • Acute Graft versus Host Disease • Acute Myelogenous Leukemia • Bone Marrow Transplantation • Chronic Graft versus Host Disease • Fibrosis • Graft versus Host Disease • Hematological Malignancies • Immunology • Leukemia • Transplantation • CD123 • CD4 • IFNG • IL3RA

EFFICACY AND OUTCOMES OF NOVEL THERAPEUTIC AGENTS AS MONOTHERAPY OR IN COMBINATION WITH CONVENTIONAL THERAPY IN ACUTE MYELOID LEUKEMIA: A SYSTEMATIC REVIEW AND META-ANALYSIS (EHA 2025) - "Agents included Guadectiabine 28%, Magrolimab 7% Alvocidib 3%, Enasidenib 23%,, Flotetuzumab 4%, Vadastuximab 9%, Mitoxantrone 9%, Pevonedistat 2%, Entospletinib 3%, Eprenetapopt 20%, Belinostat 0.5%, Onvansertib 3%, Panobinostat 2%, Cediranib Maleate 1%, Nilotinib 2%, Emavusertib 0.5%, and anti-CD45 antibody (DOTA-BC8) 0.5%. The conventional therapies were azacitidine 20% and cytarabine 17%... This study shows the promising efficacy of novel agents in AML and highlights the need for further prospective trials with larger patient populations to better understand the efficacy and safety outcomes of these agents in patients with AML."

Combination therapy • Monotherapy • Retrospective data • Review • Acute Myelogenous Leukemia • Anemia • Hematological Disorders • Hematological Malignancies • Infectious Disease • Leukemia • Neutropenia • Oncology • Thrombocytopenia • TP53

PEPN1812: Flotetuzumab for the Treatment of Pediatric Recurrent or Refractory Acute Myeloid Leukemia (clinicaltrials.gov) - P1 | N=16 | Active, not recruiting | Sponsor: Children's Oncology Group | Trial completion date: Sep 2024 ➔ Sep 2025

Trial completion date • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Pediatrics • CD123 • IL3RA

Post-transplant Flotetuzumab for AML (clinicaltrials.gov) - P1 | N=3 | Completed | Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Recruiting ➔ Completed | N=16 ➔ 3 | Trial completion date: Dec 2027 ➔ Jun 2024 | Trial primary completion date: Dec 2025 ➔ Jun 2024

Enrollment change • Post-transplantation • Trial completion • Trial completion date • Trial primary completion date • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Transplantation • IL3RA

Flotetuzumab for Relapsed Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS) Following Allogeneic Hematopoietic Cell Transplantation (Allo-HCT) (clinicaltrials.gov) - P2 | N=11 | Terminated | Sponsor: Washington University School of Medicine | Trial completion date: Mar 2026 ➔ Jul 2024 | Active, not recruiting ➔ Terminated; The sponsor is no longer supporting the drug

Trial completion date • Trial termination • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • Transplantation

Flotetuzumab for Relapsed Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS) Following Allogeneic Hematopoietic Cell Transplantation (Allo-HCT) (clinicaltrials.gov) - P2 | N=11 | Active, not recruiting | Sponsor: Washington University School of Medicine | Recruiting ➔ Active, not recruiting | N=25 ➔ 11 | Trial completion date: Jun 2029 ➔ Mar 2026 | Trial primary completion date: Jul 2028 ➔ Mar 2024

Enrollment change • Enrollment closed • Trial completion date • Trial primary completion date • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • Transplantation

OUTCOMES WITH IMMUNE-BASED THERAPIES FOR TP53 MUTATED ACUTE MYELOID LEUKEMIA: A SYSTEMATIC REVIEW AND META-ANALYSIS (EHA 2024) - "Immune therapies were Magrolimab 4 (40%), Durvalumab 1 10%),Nivolumab 1 (10%), Flotetuzumab 1 (10%), Pembrolizumab 1 (10%), CLL1-CD33 CAR-T 1 (10%), and APVO436 1(10%). Non-allogeneic transplant immune-based therapies show encouraging response rates, offering a potential treatmentoption for patients with TP53 mutated AML for whom options are limited. Prospective randomized studies withreasonable long follow up are needed to establish the efficacy of immune-based therapies in this difficult to treat population."

IO biomarker • Retrospective data • Review • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CD33 • TP53

Flotetuzumab for Relapsed Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS) Following Allogeneic Hematopoietic Cell Transplantation (Allo-HCT) (clinicaltrials.gov) - P2 | N=25 | Recruiting | Sponsor: Washington University School of Medicine | Trial completion date: Dec 2027 ➔ Jun 2029 | Trial primary completion date: Jan 2026 ➔ Jul 2028

Trial completion date • Trial primary completion date • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • Transplantation

Flotetuzumab as a salvage immunotherapy in advanced CD123-positive hematological malignancies, a phase 1 pilot study. (PubMed, Leuk Lymphoma) - "Responses only occurred in Cohort B, with a partial response in one patient with Hodgkin's lymphoma and morphological complete remission in the bone marrow in one patient with blastic plasmacytoid dendritic cell neoplasm. In conclusion, flotetuzumab had a manageable safety profile in advanced CD123-positive hematological malignancies."

IO biomarker • Journal • Metastases • P1 data • Acute Lymphocytic Leukemia • Hematological Disorders • Hematological Malignancies • Hodgkin Lymphoma • Leukemia • Lymphoma • Neutropenia • Oncology • Thrombocytopenia • CD123 • IL3RA

Flotetuzumab for the Treatment of Relapsed or Refractory Advanced CD123-Positive Hematological Malignancies (clinicaltrials.gov) - P1 | N=13 | Active, not recruiting | Sponsor: City of Hope Medical Center | Trial completion date: Nov 2023 ➔ May 2026 | Trial primary completion date: Nov 2023 ➔ May 2026

Metastases • Trial completion date • Trial primary completion date • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • B Acute Lymphoblastic Leukemia • Chronic Myeloid Leukemia • Hairy Cell Leukemia • Hematological Disorders • Hematological Malignancies • Hodgkin Lymphoma • Leukemia • Lymphoma • Myelodysplastic Syndrome • Oncology • T Acute Lymphoblastic Leukemia • IL3RA • PD-L1

PEPN1812: Flotetuzumab for the Treatment of Pediatric Recurrent or Refractory Acute Myeloid Leukemia (clinicaltrials.gov) - P1 | N=16 | Active, not recruiting | Sponsor: Children's Oncology Group | N=47 ➔ 16 | Trial completion date: Oct 2023 ➔ Sep 2024

Enrollment change • Trial completion date • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Pediatrics • CD123 • IL3RA

Modeling Flotetuzumab‑Associated Cytokine Release Syndrome (CRS) in AML Using In Vitro and In Vivo Preclinical Models (SOHO 2023) - "The in vitro killing assay shows that T-cells from the spleens of immune competent C57/Bl6 hCD123eHOM mice bind to both FLZ and hCD123 on transduced murine leukemia cells. Co- culture with T-cells + target cells + FLZ showed killing at 24 hours compared to controls. T-cell activation and proliferation were noted based on cell surface markers."

Cytokine release syndrome • IO biomarker • Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CD123 • CD8 • IL3RA

Flotetuzumab for the Treatment of Relapsed or Refractory Advanced CD123-Positive Hematological Malignancies (clinicaltrials.gov) - P1 | N=13 | Active, not recruiting | Sponsor: City of Hope Medical Center | Recruiting ➔ Active, not recruiting | N=40 ➔ 13

Enrollment change • Enrollment closed • Metastases • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • B Acute Lymphoblastic Leukemia • Chronic Myeloid Leukemia • Hairy Cell Leukemia • Hematological Disorders • Hematological Malignancies • Hodgkin Lymphoma • Leukemia • Lymphoma • Myelodysplastic Syndrome • Oncology • T Acute Lymphoblastic Leukemia • IL3RA • PD-L1

"It failed in MDS, FLAG or CLIA kinda regimens , else flotetuzumab bi specific or MDM2i trial navtemadlin/ milademetan/ siremadlin MIRROS trial failed though" (@RenoHemonc)

[VIRTUAL] Targeting p53 in MDS (SOHO 2021) - P1, P1b, P1b/2, P2, P3 | "Lastly, a 2nd generation oral agent (APR-548) will enter the clinic in 2021...These data support the planned Phase 3 open-label study of azacitidine + magrolimab versus azacitidine + venetoclax in unfit AML patients and versus induction chemotherapy in fit patients with a primary endpoint of OS in the non-intensive group (NCT04778397). Other novel HMA combinations have recently had high ORR/CR rates as frontline therapy, which include sabatolimab and pevonedistat, although unclear molecular subset data in TP53 mutant patients...Specifically, PDL1 has been shown to be upregulated on TP53 mutant hematopoietic stem cells and bone marrow blasts.17,18 Importantly, TP53 mutant AML patients have been strongly associated with an adverse immune microenvironment and potentially may be an optimal molecular subset for novel immunomodulatory agents.19 In this regard the bispecific agent flotetuzumab targeting CD123 has had activity in TP53 mutant relpased..."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Myelodysplastic Syndrome • Oncology • CD123 • TP53

Interim results from a phase 1 first-in-human study of flotetuzumab, a CD123 x CD3 bispecific DART molecule, in AML/MDS (ESMO 2017) - P1; "...Flotetuzumab (MGD006/S80880), a novel CD123 x CD3 bispecific DART protein, is designed to target CD123+ cells for elimination by T cells...A LID strategy and early use of tocilizumab ameliorated this toxicity and limits corticosteroid use...To date flotetuzumab has an acceptable safety profile and demonstrated early evidence of anti-leukemic activity."

Clinical • P1 data • Acute Myelogenous Leukemia • Myelodysplastic Syndrome

A Phase 1, First-in-Human, Dose-Escalation Study of MGD024, a CD123 x CD3 Bispecific Dart® Molecule, in Patients with Relapsed or Refractory CD123-Positive (+) Hematologic Malignancies (ASH 2022) - P1 | "Of note, the CD123-directed therapy tagraxofusp has now become the standard of care (SoC) for blastic plasmacytoid dendritic cell neoplasm (BPDCN) (Pemmaraju NEJM 2019)...This new construct permits intermittent intravenous (IV) dosing due to a longer half-life (Alderson ASH 2021) compared with the first-generation DART molecule flotetuzumab, a continuous-infusion molecule that showed preliminary single-agent activity in refractory acute myeloid leukemia (AML) (Uy Blood 2021)...Secondary objectives include pharmacokinetics, immunogenicity, preliminary assessment of MGD024 clinical activity, and preliminary evaluation of safety/efficacy of tocilizumab in the management of MGD024-induced CRS...Response evaluation is determined using modified European LeukemiaNet (ELN) 2017 criteria for ALM and ALL; International Working Group (IWG) 2006 criteria for MDS; Lugano 2014 criteria for cHL; ELN 2020 criteria for CML; 2017 consensus criteria for HCL; IWG-Myeloproliferative..."

Clinical • P1 data • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Chronic Myeloid Leukemia • Hairy Cell Leukemia • Hematological Malignancies • Hodgkin Lymphoma • Inflammation • Lymphoma • Myelodysplastic Syndrome • Myeloproliferative Neoplasm • CD123