IS-free Treg HaploHCT

Inclusion Criteria:

• Cohort A: Histologically confirmed disease in the prior 4 weeks, despite at least 1prior line of therapy (e.g., 3+7 chemotherapy, HMA therapy): Rel/ref AML (de novo orsecondary) with ≥5% blasts in BM (or extramedullary sites); MDS EB-2 (BM ≥10%blasts, PB 5-19% blasts).

• Cohort B: Ultra high-risk AML or MDS that meets definition of 'Myeloid Neoplasmswith mutated TP53' per 2022 International Consensus Classification (Appendix L)regardless of response

• Cohort C: Ultra high-risk AML or MDS that meets definition of 'Myeloid Neoplasmswith multi-hit or complex karyotype (CK+) mutated TP53' per 2022 InternationalConsensus Classification (Appendix L) with response: AML (de novo or secondary) with <5% blasts in BM; MDS with <10% blasts in BM or PB.

• Available haploidentical HLA-matched (-A, -B, -C, -DRB1) related donor aged 18-65years.

• Age ≥18 to 65 years for Cohort A and B. Age ≥18 to 75 years for Cohort C. Because nodosing or adverse event data are currently available on the use of IS-free haploHCTin participants <18 years of age, children are excluded from this study but will beeligible for future pediatric trials.

• ECOG performance status ≤2 (Karnofsky ≥60, see Appendix A).

• Adequate organ and marrow function as defined below:

• Pulmonary Function: FEV1, FVC and DLCO ≥ 60% of predicted (corrected forhemoglobin)

• Cardiac Ejection Fraction ≥ 45%, and no evidence of pulmonary hypertension

• Hepatic: Total bilirubin within normal institutional limits (exceptionpermitted in Gilbert's Syndrome after discussion with study PI, on acase-by-case basis); and AST (SGOT)/ALT (SGPT) <2x institutional upper limit ofnormal

• Renal: Serum Creatinine within normal institutional limits or creatinineclearance >50 mL/min/1.73 m2 (see Appendix B) for participants with creatininelevels above institutional normal.

• The effects of IS-free haploHCT on the developing human fetus are unknown. For thisreason and because radiation and chemotherapeutic agents are known to beteratogenic, women of child-bearing potential and men must agree to use adequatecontraception (hormonal or barrier method of birth control; abstinence) prior tostudy entry and for the duration of study participation. Should a woman becomepregnant or suspect she is pregnant while she or her partner is participating inthis study, she should inform her treating physician immediately. Men treated orenrolled on this protocol must also agree to use adequate contraception prior to thestudy, for the duration of study participation, and a minimum of 4 months aftercompletion of study.

• Ability to understand and the willingness to sign a written informed consentdocument.

Exclusion Criteria:

• Participants who have had cytotoxic chemotherapy or radiotherapy within 2 weeks (4weeks for nitrosoureas or mitomycin C) prior to entering the study. Use ofhydroxyurea, HMA, e.g., azacytidine, decitabine) and/or FDA-approved novel targetedagents (e.g., venetoclax, FLT-3 inhibitors, IDH 1/2 inhibitors) are permitted up toa day prior to start of HCT conditioning.

• Participants who have not recovered from adverse events due to prior anti-cancertherapy (i.e., have residual non-hematologic toxicities > Grade 1) with exception ofalopecia, unless cleared by study PI.

• Participants who received Mylotarg or other therapies associated with increased riskof hepatic veno-occlusive disease (VOD) or have known prior or active VOD. All noveltherapies will be reviewed with PI.

• Participants who are receiving any other investigational agents within 21 days (or 5half-lives) prior to study entry, whichever is longer, unless cleared by the studyPI.

• Participants with extramedullary disease at immune privileged sites (e.g., CNS,testes, eye) are excluded, as these sites are less susceptible to the curative graftvs. leukemia effect of HCT.

• Myocardial infarction within 2 years prior to enrollment.

• Venous thromboembolic event (VTE) of DVT/ PE within 1 year prior to enrollment,unless approved by study PI. Patients with line-associated DVT within the past yearmay be enrolled if they have completed anticoagulation therapy.

• Stroke or transient ischemic attack (TIA) within 1 year prior to enrollment.

• History of bleeding peptic ulcer disease, erosive gastritis, intestinal perforationor clinically significant gastrointestinal (GI) hemorrhage or hemoptysis within theprior 6 months.

• Patients with a history of thrombotic microangiopathy (TMA) or hemolytic uremicsyndrome/thrombotic thrombocytopenic purpura (HUS/TTP).

• History of life-threatening reactions to iron infusions or murineantibody-containing products.

• Known donor-specific antibodies (DSA) in the recipient of clinical significance (e.g., requiring DSA depletion with plasmapheresis, rituximab) are excluded.

• Inability to withhold agents that may interact with hepatic cytochrome P450 enzymesinvolved in cyclophosphamide and/or thiotepa metabolism (see Section 5.5) during day -10 through day -5. It is acceptable use alternative non-interacting medicationsduring this period, and then restart prior medications

• Participants with uncontrolled bacterial, viral or fungal infections (i.e.,currently taking medications with progression of clinical symptoms or signs).

• Recipients of prior allogeneic or autologous hematopoietic cell transplantation, orsolid organ transplantation.

• Prior radiation exposure or other medical condition (e.g., Fanconi syndrome) thatprecludes use of myeloablative radiation (TMLI).

• HIV-positive participants on combination antiretroviral therapy are ineligiblebecause of the potential for pharmacokinetic interactions with the multiple agentsused routinely in myeloablative allogeneic stem cell transplantation. In addition,these individuals are at increased risk of lethal infections when treated withmarrow-suppressive therapy. Appropriate studies will be undertaken in participantsreceiving combination antiretroviral therapy when indicated.

• Participants seropositive for hepatitis B or C infection are ineligible as they areat high risk of lethal treatment-related hepatotoxicity after myeloablative HCT.

• Participants with psychiatric illness/social situations that would limit compliancewith study requirements.

• Pregnant women are excluded from this study because radiation and conditioningchemotherapy has the potential for teratogenic or abortifacient effects. A negativepregnancy test is required for females of childbearing potential. Because there isan unknown but potential risk for adverse events in nursing infants secondary totreatment of the mother with IS-free haploHCT breastfeeding should be discontinuedif the mother is treated with IS-free haploHCT.

• Participants with a history of another non-hematologic malignancy are ineligibleexcept for the following circumstances: Individuals with a history of othermalignancies are eligible if they have been disease-free for at least 5 years andare deemed by the investigator to be at low risk for recurrence of that malignancy.Individuals with the following cancers are eligible if diagnosed and treated withinthe past 5 years: cervical cancer in situ, and basal cell or squamous cell carcinomaof the skin.