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

1. To determine the maximum tolerated dose (MTD) of lintuzumab-Ac225 added to venetoclax for patients with CD33 positive relapsed/refractory AML. (Phase 1 portion)
2. To assess the percentage of patients with CR, CRh, or Overall Response (CR + CRh), up to 6 months after the start of treatment without receiving other AML therapies. (Phase 2 portion)

The study is a multicenter, open label Phase I and Phase II trial combining lintuzumab-Ac225 with venetoclax in patients who have relapsed or refractory AML.

The Phase I portion is a dose-finding study which will enroll at least three patients at each dose level. Patients in a dose level will be observed for a minimum of 4 weeks before dose escalation occurs. There is no dose escalation for any individual patient.

The Phase II portion of the study will enroll patients at the MTD dose level of lintuzumab-Ac225 as determined in the Phase I portion of the study. The goal of the Phase II portion will be to further characterize the safety and efficacy of the MTD dose of lintuzumab-Ac225.

Inclusion Criteria:

1. 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.

2. Circulating blast count ≤ 200/μL within 10 days prior to first cycle of treatment. Hydroxyurea should be used to keep the peripheral blast count ≤ 200/μL until the first day of protocol treatment, to the extent that this is possible

3. ECOG ≤ 2

4. Estimated creatinine clearance ≥ 50 mL/min

5. AST and ALT ≤ 3.0 x ULN

6. Bilirubin ≤ 3.0 x ULN

Exclusion Criteria:

1. Active CNS Leukemia.

2. Known HIV infection or known hepatitis B or hepatitis C infection (with a detectable viral load).

3. Participant has received strong and/or moderate CYP3A inducers within 7 days prior to the initiation of study treatment.

4. Secondary refractory AML (e.g., treated for current relapse without achieving remission);

   a. With the exception that single agent FLT3 inhibitors, IDH1/IDH2 inhibitors are allowed for current relapse without achieving remission.

5. Have received prior radiation to maximally tolerated levels to any critical normal organ.

6. Clinically significant cardiac disease.

7. Active, uncontrolled serious infection.

8. Have other non-myeloid malignancy within 2 years of entry (with exceptions).

9. Psychiatric disorder that would preclude study participation

10. Previous solid organ transplant (prior treatment with SCT is allowed but not if patient has GVHD or is still receiving immunosuppression/GVHD therapy).