Inclusion Criteria:

• Adult (age ≥ 18 years).
• Diagnosis of 1 of the following diseases:
  • Primary or secondary acute myelogenous leukemia (AML; including erythroleukemia and eosinophilic leukemia, but excluding acute promyelocytic leukemia);
  • B-cell acute lymphoblastic leukemia (B-cell ALL);
  • Blastic plasmacytoid dendritic cell neoplasm (BPDCN);
  • Chronic myeloid leukemia (CML) in blast phase, resistant or intolerant to tyrosine kinase inhibitor therapy.
• Patients with relapsed or refractory disease with no available standard therapy. For AML, this includes patients with:
  • newly diagnosed leukemia refractory to ≥ 2 induction attempts;
  • leukemia in first relapse with initial complete response duration of < 6 months;
  • leukemia in first relapse following ≥ 1 unsuccessful salvage attempts;
  • leukemia in second or higher relapse; or
  • patients who are not candidates for aggressive induction therapies (i.e., "7+3" or similar regimens) who have relapsed after initial treatment.
• Eastern Cooperative Oncology Group performance status 0-2.
• Not a candidate for, or refusing treatment with hematopoietic stem cell transplantation .
• Female patients of childbearing potential must agree to use a highly effective method of birth control during and for 4 weeks after the last dose of XmAb14045. Women are considered to be of childbearing potential unless it is documented that they are over the age of 60 OR postmenopausal by history with no menses for 1 year and confirmed by follicle-stimulating hormone ( using local reference ranges) OR have a history of hysterectomy and/or bilateral oophorectomy OR have a history of bilateral tubal ligation. Highly effective methods of birth control include hormonal birth control (oral, intravaginal, transdermal, implantable, or intrauterine), intrauterine devices, vasectomized partner, or any double-barrier methods (combination of male condom and spermicide with either cap, diaphragm, or sponge). Male patients must agree to use highly effective contraception, as above, and refrain from donating sperm during the treatment period and for at least 4 weeks after the last dose of XmAb14045.
• Able and willing to complete the entire study according to the study schedule.
• Patients must give written informed consent. A copy of the signed informed consent form will be retained in the patient’s chart.

Exclusion Criteria: 

• Systemic antineoplastic therapy (including cytotoxic chemotherapy and toxin immunoconjugates, but excluding hydroxyurea), unconjugated antibody therapy, or radiotherapy within 2 weeks of the first dose of study treatment, or small molecule kinase inhibitors within 6 elimination half-lives of the first dose of study treatment.
• Prior therapy with CD123- or IL-3R-directed immunotherapies, including monospecific and bsAbs, immunoconjugates, or chimeric antigen receptor-modified T-cell therapy.
• Failure to recover from Grade 3 or 4 toxicity from previous treatment (unrelated to malignant bone marrow involvement).
• Known uncontrolled central nervous system involvement by malignant disease.
• Absolute blast count ≥ 10,000/mm3 or symptoms of leukostasis (hydroxyurea or other therapies may be used to control leukocytosis through the first month of study therapy).
• Diagnosis of promyelocytic leukemia (French-American-British M3).
• Aspartate aminotransferase or alanine aminotransferase at screening > 3.0 x upper limit of normal (ULN) unless considered due to leukemic organ involvement.
• Bilirubin > 1.5 x ULN, unless prior diagnosis and documentation of leukemic organ involvement, ongoing hemolysis, or Gilbert's syndrome has been made.
• Serum creatinine > 2.0 x ULN OR estimated creatinine clearance < 40 mL/min calculated by either the Cockcroft Gault or Modification of Diet in Renal Disease (Levey, 1999) formula at screening.
• Active heart failure of New York Heart Association Functional Capacity Class III or IV or Objective Assessment C or D.
• History or evidence of a clinically unstable/uncontrolled disorder, condition or disease (including but not limited to cardiopulmonary, renal, metabolic, hematologic or neurologic) other than their primary malignancy, that in the opinion of the Investigator would pose a risk to patient safety or interfere with the study evaluation, procedures or completion.
• Evidence of any active, uncontrolled bacterial, viral, parasitic or systemic fungal infections within 1 week of first dose of study drug.
• Positive test for human immunodeficiency virus -I or -II antibodies, hepatitis B surface antigen, hepatitis B core antibody (HBcAb), or hepatitis C virus (HCV) antibody (unless HCV viral load test by polymerase chain reaction is negative). HBcAb positivity will be allowed if one or more of the following is true:
  • hepatitis B surface antibody is present; or
  • hepatitis B DNA testing is negative and the patient is receiving hepatitis B reactivation prophylaxis with entecavir, tenofovir, or lamivudine.
• Patient is pregnant or breast-feeding, or planning to become pregnant while enrolled in the study, up to end of study visit.
• Positive urine pregnancy test (ie, urine beta human chorionic gonadotropin at screening.
• Patients with substance abuse or other medical or psychiatric conditions that, in the opinion of the Investigator, would confound study interpretation or affect the patient’s ability to tolerate or complete the study.