allogeneic engineered hematopoietic stem cell transplant (hct) lacking the cd33 protein, and post-hct treatment with mylotarg, for patients with cd33+ aml or mds

Conditions: Leukemia, Myeloid, Acute; Myelodysplastic Syndromes

Summary: this is a phase 1/2a, multicenter, open-label, first-in-human (fih) study of vor33 in participants with aml or mds who are undergoing human leukocyte antigen (hla)-matched allogeneic hematopoietic cell transplant (hct).

high risk acute myeloid leukemia (aml) and myelodysplastic syndromes (mds) frequently relapses despite hematopoietic stem cell transplant (hct). post-hct targeted therapy to reduce relapse is limited by toxicity to the engrafted cells. vor33, an allogeneic crispr/cas9 genome-edited hematopoietic stem and progenitor cell (hspc) therapy product, lacking the cd33 protein, is being investigated for participants with cd33+ aml or mds at high risk for relapse after hct to allow post-hct targeting of residual cd33+ acute aml cells using mylotarg™ without toxicity to engrafted vor33 cells. participants will undergo a myeloablative hct with matched related or unrelated donor cd34+-selected hematopoietic stem and progenitor cells (hspcs) engineered to remove cd33 expression (vor33 product). mylotarg™ will be given after engraftment for up to 4 cycles. the primary endpoint assessing safety of vor33 will be the incidence of successful engraftment at 28 days. part 1 of this study will evaluate the safety of escalating mylotarg™ dose levels to determine the maximum tolerated dose (mtd) and recommended phase 2 dose (rp2d). part 2 will expand the number of participants to evaluate the mylotarg™ rp2d.

Eligibility criteria:
inclusion criteria: 1. must be ≥18 and ≤70 years of age. 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) 4. aml sample from the patient must have evidence of cd33 expression (\>0%) 5. candidate for hla-matched allogeneic hct using a myeloablative conditioning regimen. 6. must have a related or unrelated stem cell donor that is a 8/8 match for hla-a, -b, -c, and -drb1. 7. must have adequate performance status and organ function as defined below: 1. performance status: karnofsky score of ≥70. 2. cardiac: left ventricular ejection fraction (lvef) ≥50% 3. pulmonary: diffusing capacity of lung for carbon monoxide (dlco), forced vital capacity (fvc), and forced expiratory volume in one second (fev1) ≥66%. 4. renal: estimated glomerular filtration rate (gfr) \>60 ml/min 5. hepatic: total bilirubin \<1.5 × uln, or if ≥1.5 × uln direct bilirubin \<uln and alt/ast \<1.5 × uln (per institutional criteria). exclusion 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.

Keywords: leukemia acute myeloid leukemia aml hematopoietic stem cell transplant hct cd33 allogeneic myelodysplastic syndromes myelodysplastic syndromes with excess blasts mds mds-eb cell therapy