• Phase I: Maximum Tolerated Dose (MTD) of Lintuzumab-Ac225 [ Time Frame: Cycle 1, up to 48 days ]
  To determine the maximum tolerated dose (MTD) of lintuzumab-Ac225 when given in combination with venetoclax and azacitidine for patients with CD33 positive AML
• Phase II: Overall Response (CR + CRh + CRi + MLFS) [ Time Frame: Up to 6 months ]
  To assess the percentage of patients achieving CR, CRh, CRi, morphologic leukemia-free state (MLFS), or Overall Response (CR + CRh + CRi + MLFS), up to 6 months after the start of treatment without receiving other AML therapies

• Phase I: Overall Response [ Time Frame: Up to 6 months ]
  Number of patients who's overall response is CR or CRh or CRi or MLFS
• Phase I: OS [ Time Frame: Phase I: End of 6 months, 12 months, 24 months. ]
  Number of patients who died
• Phase II: OS [ Time Frame: Phase II: End of 6 months, 12 months, 24 months ]
  Number of patients who died
• Phase I and II: DFS [ Time Frame: Through study completion, up to 2 years ]
  Disease-free survival
• Phase I and II: Evaluate incidence of AEs and SAEs [ Time Frame: Through study completion, up to 2 years ]
  Rate of AEs and SAEs, including infusion-related reactions
• Phase I and II: Lab abnormalities (other than hematologic indices) [ Time Frame: Through study completion, up to 2 years ]
  Summary of rate of Grade 3/4 lab abnormalities
• Phase I and II: Evaluate BH3 priming assay results [ Time Frame: Completion of Cycle 1, estimated 1 month ]
  Summary of assay results
• Phase I and II: MRD status [ Time Frame: From date of first dose until the date of first documented response, first assessment at 6 months ]
  Number of patients who are MRD negative

The study is a multicenter, open label Phase I/II trial.

1. To determine the maximum tolerated dose (MTD) of lintuzumab-Ac225 when given in combination with venetoclax and azacitidine for patients with CD33 positive AML. (Phase I portion)
2. To assess the percentage of patients with CR, CRh, CRi, MLFS or Overall Response (CR + CRh + CRi + MLFS), up to 6 months after the start of treatment without receiving other AML therapies.. (Phase 2 portion)

• Acute Myeloid Leukemia
• Relapsed Adult AML

• Biological: Lintuzumab-Ac225
  In the Phase I, patients will be enrolled into the following dose escalation cohorts: 0.50 μCi/kg, 1.0 μCi/kg, and 1.5 μCi/kg. If the 0.50 μCi/kg dose is determined to exceed the MTD, a 0.25 μCi/kg dose will be explored.
  Other Name: Actimab
• Drug: Venetoclax
  400 mg daily will be taken orally on Days 1-21 of a 28-day cycle. There will be a ramp up of venetoclax dosing in the first cycle, with 100 mg administered on Day 1, 200 mg on Day 2, and 400 mg on Day 3 and Day 4 and later. Patients on antifungal azoles should receive one-half these doses, up to a maximum of 200 mg of venetoclax.
  Other Name: Venclexta
• Drug: Azacitidine
  75 mg/m2 will be administered on days 1-7 of a 28-day cycle.
  Other Name: Vidaza

Inclusion Criteria:

1. Histologically confirmed acute myeloid leukemia

2. Refractory or relapsed AML which will include:

   1. Refractory disease will be defined as at least 1 prior treatment with no remission.
   2. Relapsed disease will be defined as 5% or more blasts in bone marrow seen after remission.
   3. Patients with AML arising from myelodysplastic syndromes (including CMML) or myeloproliferative neoplasms (secondary AML, ts-AML) are also eligible.

3. White blood cell (WBC) count < 10 x 109/L;

   a. Use of hydroxyurea, prior to Cycle 1 and during Cycles 1 and 2, is permitted to lower the WBC count in the peripheral blood.

4. Age > 18 years.
5. Estimated creatinine clearance ≥ 50 mL/min calculated by the Cockroft-Gault formula.
6. AST and ALT ≤ 3.0 x ULN (unless considered to be due to leukemic organ involvement).
7. Bilirubin ≤ 3.0 x ULN (unless considered to be due to leukemic organ involvement).
8. Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 2.

Exclusion Criteria:

1. Have acute promyelocytic leukemia (APL).
2. Active CNS leukemia. Patients with symptoms of CNS involvement, particularly those with M4 or M5 subtypes, should undergo lumbar puncture prior to treatment on study to exclude CNS disease. Symptoms include cranial neuropathies, other neurologic deficits, and headache.
3. Have received prior radiation to maximally tolerated levels to any critical normal organ.
4. Participant has received strong and/or moderate CYP3A inducers within 7 days prior to the initiation of study treatment.
5. Clinically significant cardiac disease.
6. Active, uncontrolled serious infection.
7. Have other non-myeloid malignancy within 2 years of entry (with exceptions).
8. Psychiatric disorder that would preclude study participation
9. Previous solid organ transplant (prior treatment with SCT is allowed but not if patient as GVHD or is still receiving immunosuppression/GVHD therapy).