2 Step ATG with Preparative Chemotherapy and Methotrexate for the Prevention of Acute GVHD for Patients Undergoing Myeloablative Allogeneic Stem Cell Transplant for Hematopoietic Disorders

Inclusion Criteria

• Adult male or female, age 18-60 years
• Patients must have a related or unrelated peripheral blood stem cell donor. Sibling donor must be a 6/6 match for human leukocyte antigen (HLA)-A and -B at intermediate (or higher) resolution, and -DRB1 at high resolution using deoxyribonucleic acid (DNA)-based typing, and must be willing to donate peripheral blood stem cells and meet institutional criteria for donation. Unrelated donor must be 8/8 match at HLA-A, -B, -C and –DRB1 at high resolution using DNA-based typing. Unrelated donor must be willing to donate peripheral blood stem cells and be medically eligible to donate stem cells according to National Marrow Donor Program (NMDP) criteria
• A candidate for myeloablative preparative regimen, based on age ≤ 60, or Hematopoietic Cell Transplantation-Comorbidity Index (HCT-CI) of ≤ 4, and considered by the treating physician to be a candidate for such regimen
• Cardiac function: ejection fraction ≥ 45%
• Calculated creatinine clearance greater than 50 mL/minute (using the Cockcroft-Gault formula and actual body weight)
• Pulmonary function: Diffusion Capacity of the Lung for Carbon Monoxide (DLCO) ≥ 50% (adjusted for hemoglobin) and forced expiratory volume 1 (FEV1) ≥ 50%
• Total bilirubin < 1.5 x the upper limit of normal. Patients who have been diagnosed with Gilbert’s Disease are allowed to exceed the defined bilirubin value up to < 3mg/dl
• Alanine aminotransferase (ALT) /aspartate aminotransferase (AST) < 2.5 x the upper normal limit
• Female subjects (unless postmenopausal for at least 1 year before the screening visit, or surgically sterilized), agree to practice two effective methods of contraception (hormonal contraception and male partner to use condom) or agree to complete abstain from heterosexual intercourse from the time of signing the informed consent through 12 months post-transplant
• Male subjects (even if surgically sterilized), of partners of women of childbearing potential must agree to practice effective barrier contraception or abstain from heterosexual intercourse from the time of signing the informed consent through 12 months post-transplant
• Karnofsky performance status (KPS) ≥ 80
• Patients must have a diagnosis of one of the following: * Acute myeloid leukemia (AML) in complete remission (CR) 1 with intermediate or high risk for relapse as defined by European Leukemia Network (ELN) 2022 criteria (Dohner et al., 2022), or deemed to be at high risk for relapse by treating physician, based on, therapy related, or extra medullary presentation * AML in >CR1 * Myelodysplastic syndrome (MDS) with Molecular International Prognostic Scoring System (IPSS-M) ≥ intermediate-low.(Bernard et al., 2022; Mohty et al., 2022) * Chronic myeloproliferative disorder (essential thrombocytopenia [ET], polycythemia vera [PV], myelofibrosis) with bone marrow blasts > 5% and/or other evidence of progression to acute leukemia or Int or high-risk disease by MIPPS version (v) 2 score.(Ali et al., 2019; Guglielmelli et al., 2018) * Chronic myelomonocytic leukemia (CMML) especially those with high-risk features based in: The CMML-specific prognostic scoring system with molecular features (Specific Prognostic Scoring System-molecular [CPSS-Mol]) - high risk and intermediate-2 risk, Mayo molecular model - high risk and Intermediate-2 risk, Groupe Francophone des Myélodysplasies (GFM) - high risk and selected patients with intermediate risk.(Elena et al., 2016; Itzykson et al., 2013; Patnaik et al., 2014) * Acute lymphoblastic leukemia (ALL) in CR1 with high risk for relapse ** B-cell ALL: High white blood cell count at diagnosis (ie, >30,000/µl), Clonalcytogenetic abnormalities – t(4;11), t(1;19), t(9;22), or BCR-ABL gene positivity, BCR-ABL1-like (Ph-like) gene signature, progenitor-B cell immunophenotype (eg, blasts expressing membrane CD19, CD79a, and cytoplasmic CD22, but not CD10), Length of time from start of induction therapy to attainment of CR greater than four weeks, and minimal residual disease (MRD) post-remission bone marrow MRD+.(Akabane & Logan, 2020; Lafage-Pochitaloff et al., 2017) ** T-cell ALL: Failure to achieve CR after one induction, MRD > 1X 10^-4 after 2 courses of induction, Presenting white blood cell (WBC) > 100 X 10^9/L, complex cytogenetics ≥ 5,early T-cell Precursor ALL, poor risk genetics including lack of NOTCH1 ith/FBXW7 or presence of N-RAS & K-RAS, EZH2 and age > 40 years.(Marks & Rowntree, 2017) * ALL in > CR1
• The subject is willing and able to sign informed consent and abide by the protocol requirements

Exclusion Criteria

• Autologous hematopoietic stem cell transplant < 3 months prior to enrollment
• Patients with florid residual AML with > 5% blast in the marrow or circulating blast in the peripheral blood are not eligible for this study
• Previous allogeneic stem cell transplant
• Uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiogram (EKG) suggestive of acute ischemia or active conduction system abnormalities
• Known hypersensitivity to the study agent (ATG)
• Received any investigational drugs within the 14 days prior to the first day of transplant conditioning
• Pregnant and/or breastfeeding
• Evidence of HIV infection or known HIV positive serology
• Current uncontrolled bacterial, viral or fungal infection (currently taking medication with evidence of progression of clinical symptoms or radiologic findings)
• Non-hematologic malignancy within prior three (3) years, with the exception of squamous cell or basal cell skin carcinoma
• Participation in another clinical study with an investigational product during the last 28 days