Allogeneic Engineered Hematopoietic Stem Cell Transplant (HCT) Lacking the CD33 Protein, and Post-HCT Treatment With Mylotarg, for Patients With CD33+ AML or MDS

Open to people ages 18-70

1. Must be ≥18 and ≤70 years of age. 2.

2. Patients with AML must have one of the following groups of features that are known to be a risk factor for leukemia relapse:

   • BM in morphological remission (<5% blasts) with adverse-risk disease related genetics at presentation (according to European Leukemia-Net guidelines [ELN, Döhner 2017]), or

   • Intermediate risk genetics in morphologic remission (<5% blasts) with other recognized high risk criteria such as MRD+ following therapy, or

   • BM with evidence of persistent leukemia 5-10% blasts post induction/salvage therapy. Patients with BM Blast count >10% may participate with Sponsor Medical

     Monitor approval. (Note: these patients may have disease-related genetics of any risk criteria at presentation), or

   • Any patient in second or greater remission.
3. Patients with MDS must have all of the following:
   • Previous or current IPSS-R score of High or Very High risk; AND
   • Previous or current MDS-IB1 or MDS-IB2 per the 2022 WHO criteria (Khoury 2022)
     1. AML sample from the patient must have evidence of CD33 expression (>0%) 4. Candidate for HLA-matched allogeneic HCT using a myeloablative conditioning regimen.
     2. Must have a related or unrelated stem cell donor that is a 8/8 match for HLA-A, -B, -C, and -DRB1.
     3. Must have adequate performance status and organ function as defined below:

a) Performance Status: Karnofsky score of ≥70. b) Cardiac: left ventricular ejection fraction (LVEF) ≥50% c) Pulmonary: diffusing capacity of lung for carbon monoxide (DLCO), forced vital capacity (FVC), and forced expiratory volume in one second (FEV1) ≥66%.

d) Renal: estimated glomerular filtration rate (GFR) >60 mL/min e) Hepatic: total bilirubin <1.5 × ULN, or if ≥1.5 × ULN direct bilirubin <ULN and ALT/AST <1.5 × ULN (per institutional criteria).

1. Prior autologous or allogeneic stem cell transplantation.
2. Presence of the following disease-related genetics: t(15; 17)(q22; q21), or t(9; 22)(q34; q11), or other evidence of acute promyelocytic leukemia or chronic myeloid leukemia.
3. Prior treatment with Mylotarg™ (gemtuzumab ozogamicin) in the past 3.5 months.
4. Active central nervous system (CNS) leukemia.
5. Patients diagnosed with Gilbert's syndrome.
6. Uncontrolled bacterial, viral, or fungal infections; or known human immunodeficiency virus (HIV), Hepatitis B, or Hepatitis C infection.