Donor Stem Cell Transplant after TCR Alpha-Beta+ T Cells/CD19+ B Cell Depletion for the Treatment of Children and Young Adults with Malignant or Non-malignant Hematological Disorders

Inclusion Criteria

• COHORT MALIGNANT (M) AND COHORT NON-MALIGNANT (NM): Age < 60 years and > 1 month
• COHORT M AND COHORT NM: Life expectancy > 10 weeks
• COHORT M AND COHORT NM: Patients deemed eligible for allogeneic HSCT per institutional guidelines
• COHORT M AND COHORT NM: Patients with life-threatening hematological malignancies and non-malignant disorders that could benefit from HSCT; * For malignant patients: ** High-risk acute lymphoblastic leukemia (ALL) in 1st complete remission (CR), ALL in 2nd CR; or ** High-risk acute myeloid leukemia (AML) in 1st CR, AML in 2nd CR; or ** Childhood myelodysplastic syndrome (cMDS)- with low blasts (LB) or cMDS-with increased blasts (IB); or ** Juvenile myelomonocytic leukemia (JMML); or ** Mixed-phenotype acute leukemia (MPAL); or ** Non-Hodgkin lymphomas in 2nd CR; or ** Other hematologic malignancies in 1st or 2nd CR eligible for stem cell transplantation per institutional standard * Patients with non-malignant disorders receiving first HSCT: ** Receiving a first HSCT using mis-matched donors, due to the absence of suitable HLA identical sibling or HLA phenotypically identical relative; or ** whose disease put them at increased risk of graft rejection or GvHD (e.g., Fanconi Anemia, STAT1 gain of function) and therefore can benefit from receiving alpha beta−depleted HSCT using as a donor either an HLA identical sibling or an HLA phenotypically identical (10/10 matched) donor
• COHORT M AND COHORT NM: A minimum genotypic identical match of 5/10 is required
• COHORT M AND COHORT NM: The donor and recipient must be identical, as determined by high resolution typing, in at least one allele of each of the following genetic loci: HLA-A, HLA-B, HLA-C, HLA-DQB1 and HLA-DRB1
• COHORT M AND COHORT NM: Lansky/Karnofsky score > 50; the Karnofsky scale will be used in subjects >= 16 years of age, and the Lansky Scale will be used for those < 16 years of age
• COHORT M AND COHORT NM: All subjects >= 18 years of age must be able to give informed consent or adults lacking capacity to consent must have a legally authorized representative (LAR) available to provide consent. For subjects < 18 years old their legal authorized representative (LAR) (i.e. parent or guardian) must give informed consent. Pediatric subjects will be included in age appropriate discussion and written assent will be obtained for those > 7 years of age, when appropriate
• COHORT M AND COHORT NM: Male and female subjects of childbearing potential must agree to use an effective means of birth control to avoid pregnancy throughout the transplant procedure, while on immunosuppression, and if the subject experiences any chronic GvHD
• COHORT C: Since the purpose of cohort C is to provide treatment on a compassionate basis, patients with malignant or non-malignant disorders who do not qualify for cohort M or cohort NM, and who require TCR alpha beta+ T cell/CD19+ B cell depleted HSCT may be enrolled under this cohort. Some examples of patients who may get treated under this cohort are: * Patients receiving second or subsequent HSCT, * Patients with active malignant disease at the time of HSCT, * Patients with malignant disease with hypocellular/aplastic marrow at the time of disease evaluation for HSCT, * Patients with malignant disease in 3rd CR or more * Secondary MDS or AML or treatment related MDS or AML * Patients with Fanconi Anemia with MDS/AML * Any other reason that makes the patient ineligible for cohort M or NM but require TCR alpha beta + T cell/CD19+ B cell depleted HSCT for treatment of their disease. Patients on the compassionate use arm must meet local institutional standards for suitability for transplant, and donors for these patients will meet the eligibility criteria below.
• DONOR INCLUSION: Age < 65 years for adult donors; for pediatric donors, weight greater than 10 kg
• DONOR INCLUSION: Sufficiently healthy not to be at increased risk from the mobilization procedure
• DONOR INCLUSION: Must meet the selection criteria as defined by the Foundation for the Accreditation of Cell Therapy (FACT) and will be screened as applicable per the Food and Drug Administration (FDA) and American Association of Blood Banks (AABB) guidelines
• DONOR INCLUSION: Donor must have adequate peripheral venous access for leukapheresis or must agree to placement of a central venous catheter
• DONOR INCLUSION: Signed informed consent
• DONOR INCLUSION: Female donors of childbearing potential must agree to use an effective means of birth control to avoid pregnancy throughout the stem cell mobilization and collection procedure
• DONOR INCLUSION: Negative Pregnancy Test (negative serum or urine beta-human chorionic gonadotropin [HCG]) at the time of donor eligibility
• DONOR INCLUSION: Should more than one “equally” major histocompatibility complex (MHC) compatible donor be identified, other selection criteria may include natural killer cell (NK) alloreactivity, NK cell killer cell immunoglobulin-like receptor (KIR)-haplotype, B-content for B-haplotype donors, size of the NK alloreactive subset, gender, age, cytomegalovirus (CMV) status, health status and body weight of donor. The physician treating the subject will make the final decision

Exclusion Criteria

• COHORT M AND COHORT NM: Pregnant or lactating females
• COHORT M AND COHORT NM: Has received a prior allogenic HSCT
• COHORT M AND COHORT NM: Secondary MDS or AML or treatment related MDS or AML
• COHORT M AND COHORT NM: Dysfunction of liver (alanine aminotransferase [ALT]/aspartate aminotransferase [AST] > 10 times upper normal value, or direct bilirubin > 3 times upper normal value)
• COHORT M AND COHORT NM: Serum creatinine > 1.5 times upper limit of normal (ULN) (for patients not on dialysis) or unmanageable dysfunction of renal function while undergoing dialysis (for patients on dialysis)
• COHORT M AND COHORT NM: Severe cardiovascular disease (congestive heart failure or left ventricular ejection fraction < 30%)
• COHORT M AND COHORT NM: Current active infectious disease (including positive human immunodeficiency virus [HIV] serology or viral ribonucleic acid [RNA])
• COHORT M AND COHORT NM: Serious concurrent uncontrolled medical disorders
• COHORT M AND COHORT NM: Lack of patient’s/parents’/guardian’s informed consent
• COHORT M AND COHORT NM: Any severe concurrent disease which, in the judgement of the principal investigator (PI), would place the patient at increased risk during participation in the study
• DONOR EXCLUSION: Evidence of active infection (including urinary tract infection, or upper respiratory tract infection) or viral hepatitis exposure (on screening), unless hepatitis B surface antibody positive (HBs Ab+) and hepatitis B virus (HBV) deoxyribonucleic acid (DNA) negative
• DONOR EXCLUSION: Factors which place the donor at increased risk for complications from leukapheresis or granulocyte colony-stimulating factor (G-CSF) therapy (e.g., autoimmune disease, symptomatic coronary artery disease requiring therapy, previous thrombotic events)
• DONOR EXCLUSION: Breastfeeding at the time of G-CSF mobilization. Note: consider suspending breastfeeding during the G-CSF mobilization in situation where most suitable donor is breast feeding