Combination Chemotherapy (FLAG-Ida) With Pivekimab Sunirine (PVEK [IMGN632]) for the Treatment of Newly Diagnosed Adverse Risk Acute Myeloid Leukemia and Other High-Grade Myeloid Neoplasms

Inclusion Criteria:

• Age ≥ 18 years

• Diagnosis of untreated AML other than acute promyelocytic leukemia (APL) witht(15;17)(q22;q12) or variants according to the 5th edition of the World HealthOrganization (WHO) classification of hematolymphoid tumors. Patients withmyelodysplastic, myeloproliferative, or myelodysplastic/myeloproliferative neoplasmsand ≥ 10% blasts in blood and/or bone marrow, are also eligible, as are patientswith mixed phenotype acute leukemia (MPAL). Outside diagnostic material isacceptable to establish diagnosis; submission of peripheral blood specimen for flowcytometry performed at the study institution should be considered. Diagnosticmaterial must have been submitted for cytogenetic and/or molecular testing asclinically appropriate

• Cytogenetically/molecularly adverse-risk disease (European LeukemiaNet [ELN] 2022criteria)

• Expression of CD123 on immunophenotypically abnormal blasts, as assessed by localmultiparameter flow cytometry. Evaluation of CD123 expression viaimmunohistochemistry is permissible, for example if flow cytometric assessment isnot available

• Medically fit, as defined by treatment-related mortality (TRM) score ≤ 13.1calculated with simplified model

• The use of hydroxyurea prior to start of study therapy is allowed. Patients withsymptoms/signs of hyperleukocytosis, white blood cell count (WBC) > 100,000/μL orwith concern for other complications of high tumor burden (e.g. disseminatedintravascular coagulation) can be treated with leukapheresis prior to start of studytherapy

• Patients may have received low-intensity treatment (e.g. azacitidine/decitabine,lenalidomide, growth factors) for antecedent low-grade myeloid neoplasm (i.e. < 10%blasts in blood and bone marrow)

• Bilirubin =< 1.5 x institutional upper limit of normal (IULN) unless elevation isthought to be due to hepatic infiltration by AML, Gilbert's syndrome, or hemolysis

• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3.0 x IULNunless elevation is thought to be due to hepatic infiltration by AML

• Creatinine clearance >= 60 mL/min

• Left ventricular ejection fraction >= 45%, assessed by multigated acquisition (MUGA)scan or echocardiography or other appropriate diagnostic modality and no clinicalevidence of congestive heart failure

• Fertile male and female subjects must be willing to use an effective contraceptivemethod before, during, and for at least 3 months after receiving the investigationalagent

• Provide written informed consent

Exclusion Criteria:

• Diagnosis of blast phase chronic myeloid leukemia (CML)

• Patients with FLT3-mutated AML

• Concomitant illness associated with a likely survival of < 1 year

• Active systemic fungal, bacterial, viral, or other infection, unless disease isunder treatment with antimicrobials, and/or controlled or stable (e.g. if specific,effective therapy is not available/feasible or desired [e.g. known chronic viralhepatitis, human immunodeficiency virus (HIV)]). Patient needs to be clinicallystable as defined as being afebrile and hemodynamically stable for 24 hours.Patients with fever thought to be likely secondary to leukemia are eligible

• Known hypersensitivity to any study drug or prior >= grade 3 hypersensitivityreactions to monoclonal antibodies

• Confirmed or suspected pregnancy or active breast feeding

• Treatment with any other investigational anti-leukemia agent