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

Eligibility Criteria

• * Age ≥ 18 years
• * Diagnosis of untreated AML other than acute promyelocytic leukemia (APL) with t(15;17)(q22;q12) or variants according to the 5th edition of the World Health Organization (WHO) classification of hematolymphoid tumors. Patients with myelodysplastic, myeloproliferative, or myelodysplastic/myeloproliferative neoplasms and ≥ 10% blasts in blood and/or bone marrow, are also eligible, as are patients with mixed phenotype acute leukemia (MPAL). Outside diagnostic material is acceptable to establish diagnosis; submission of peripheral blood specimen for flow cytometry performed at the study institution should be considered. Diagnostic material must have been submitted for cytogenetic and/or molecular testing as clinically appropriate
• * Cytogenetically/molecularly adverse-risk disease (European LeukemiaNet \[ELN\] 2022 criteria)
• * Expression of CD123 on immunophenotypically abnormal blasts, as assessed by local multiparameter flow cytometry. Evaluation of CD123 expression via immunohistochemistry is permissible, for example if flow cytometric assessment is not available
• * Medically fit, as defined by treatment-related mortality (TRM) score ≤ 13.1 calculated with simplified model
• * The use of hydroxyurea prior to start of study therapy is allowed. Patients with symptoms/signs of hyperleukocytosis, white blood cell count (WBC) \> 100,000/μL or with concern for other complications of high tumor burden (e.g. disseminated intravascular coagulation) can be treated with leukapheresis prior to start of study therapy
• * 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 is thought to be due to hepatic infiltration by AML, Gilbert's syndrome, or hemolysis
• * Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =\< 3.0 x IULN unless 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 clinical evidence of congestive heart failure
• * Fertile male and female subjects must be willing to use an effective contraceptive method before, during, and for at least 3 months after receiving the investigational agent
• * Provide written informed consent
• * 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 is under treatment with antimicrobials, and/or controlled or stable (e.g. if specific, effective therapy is not available/feasible or desired \[e.g. known chronic viral hepatitis, human immunodeficiency virus (HIV)\]). Patient needs to be clinically stable 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 hypersensitivity reactions to monoclonal antibodies
• * Confirmed or suspected pregnancy or active breast feeding
• * Treatment with any other investigational anti-leukemia agent