T Cell Receptor Alpha/Beta Depletion Peripheral Blood Stem Cell Transplantation for the Prevention of Graft Versus Host Disease in Children and Adults with Hematological Malignancies

Inclusion Criteria

• PATIENTS: Histological confirmation of hematological malignancies as below: * Acute leukemias as described below must be in remission by morphology (=< 5% blasts). However, a small percentage of blasts that is equivocal between marrow regeneration versus (vs.) early relapse are acceptable. Minimal residual disease as detected by flow cytometry or molecular methods is allowed, however every reasonable effort (balancing the potential risks and toxicities of additional chemotherapy) should be made to reduce the disease burden to its lowest possible level prior to transplant * Acute Myeloid Leukemia (AML) and related precursor neoplasms: 2nd or greater complete remission (CR); CR1 that is NOT considered as favorable-risk ** Favorable risk AML is defined as having one of the following: *** t(8,21) without cKIT mutation *** inv(16) or t(16;16) without cKIT mutation *** Normal karyotype with mutated NPM1 and wild type FLT-ITD *** Normal karyotype with double mutated CEBPA *** Acute prolymphocytic leukemia (APL) in first molecular remission at the end of consolidation * Very high risk pediatric patients with AML: Patients < 21 years, however, are eligible with (M2 marrow) with < 25% blasts in marrow after having failed one or more cycles of chemotherapy * Acute lymphoblastic leukemia (ALL): second or greater CR; CR1 unable to tolerate consolidation chemotherapy due to chemotherapy-related toxicities; CR1 high-risk ALL * High risk ALL is defined as having one of the following: ** 30 years of age or older at diagnosis ** Intrachromosomal amplification of chromosome 21 (iAMP21) ** t(17:19): TCF3-HLF fusion ** TP53 mutated ** t(v;14q32/IgH) ** ALL with IKAROS deletion ** ALL with (v;11q23) or KMT2a rearrangements ** Evidence of high risk cytogenetics, e.g. t(9;22), t(1;19), t(4;11), other MLL rearrangements, IKZF1 ** White blood cell counts of greater than 30,000/mcL (B-ALL) or greater than 100,000/mcL (T-ALL) at diagnosis ** Central nervous system (CNS) leukemia involvement during the course of disease ** Slow cytologic response (> 10% lymphoblasts in bone marrow on day 14 of induction therapy) ** Evidence of persistent immonophenotypic or molecular minimal residual disease (MRD) at the end of induction and consolidation therapy * Very high risk pediatric patients with ALL: patients < 21 years are also considered high risk CR1 if they had M2 or M3 marrow at day 42 from the initiation of induction or M3 marrow at the end of induction. They are eligible once they achieve a complete remission * Myelodysplasia (MDS) International Prognostic Scoring System (IPSS) intermediate (INT-2) or high risk (i.e. refractory anemia with excessive blasts [RAEB], refractory anemia with excessive blasts in transformation [RAEBt]) or refractory anemia with severe pancytopenia, transfusion dependence, or high risk cytogenetics or molecular features. Blasts must be < 10% by a representative bone marrow aspirate morphology * Biphenotypic/Undifferentiated/Prolymphocytic Leukemias in first or subsequent CR * Juvenile myelomonocytic leukemia: A diagnosis of juvenile myelomonocytic leukemia (JMML) requires the presence of the following: ** Clinical and hematological features (all 4 mandatory) *** Peripheral blood monocyte count of > 1x10^9/L *** Blast percentage in peripheral blood and bone marrow < 20% *** Splenomegaly *** Absence of Philadelphia chromosome (BCR/ABL rearrangement) ** Oncogenetic studies (1 finding is sufficient) *** Somatic mutation of PTPN11, or K-RAS, or N-RAS *** Clinical diagnosis of neurofibromatosis-1 or NF1 mutation *** Germline CBL mutation and loss of heterozygosity of CBL ** If none of the category 2 criteria are met, the child must have at least two of the following category 3 criteria: *** Monosomy 7 or any other chromosomal abnormality *** Fetal hemoglobin increased for age *** Myeloid precursors in peripheral blood smear *** Spontaneous growth or GM-CSF hypersensitivity in colony assay *** Hyperphosphorylation of STAT5 * Infant Leukemia ** Age =< 3 years at diagnosis (not age of transplant) ** Meeting of one of the following disease criteria: *** Acute myeloid leukemia: high risk CR1 as evidenced by: **** High risk cytogenetics **** t(4;11) or other MLL rearrangements chromosome 5, 7, or 19 abnormalities complex karyotype (> 5 distinct changes) **** >= 2 cycles to obtain CR; CR2 or higher preceding MDS **** All patients must be in CR or early relapse (i.e., < 15% blasts in bone marrow [BM]) *** Acute lymphocytic leukemia: high risk CR1 as evidenced by: **** High-risk cytogenetics: ***** t(4;11) or other MLL rearrangements hypodiploid ***** t(9;22) **** > 1 cycle to obtain CR CR2 or higher **** All patients must be in CR as defined by hematological recovery, AND **** < 5% blasts by light microscopy within the bone marrow with a cellularity of >= 15% *** Myelodysplasia (MDS) IPSS Int-2 or high risk (i.e. RAEB, RAEBt) or refractory anemia with severe pancytopenia or high risk cytogenetics. Blasts must be < 10% by a representative bone marrow aspirate morphology * Chronic Myelogenous Leukemia excluding refractory blast crisis: To be eligible in first chronic phase (CP1) patient must have failed or be intolerant to one or more tyrosine kinase inhibitors
• PATIENTS: Age 60 years of age or younger at the time of consent
• PATIENTS: Karnofsky performance status >= 70% or Lansky play score 50% for < 16 years of age
• PATIENTS: Adequate organ function defined as: * Cardiac: Absence of decompensated congestive heart failure, or uncontrolled arrhythmia and left ventricular ejection fraction >= 45% * Pulmonary: Diffusing capacity for carbon monoxide (DLCO), forced expiratory volume (FEV1), forced vital capacity (FVC) > 40% predicted, and absence of oxygen (O2) requirements. For children that are not able to cooperate with pulmonary function tests (PFTs), a pulse oximetry with exercise should be attempted. If neither test can be obtained it should be clearly stated in the provider’s note * Liver: Transaminases < 5 x upper limit of normal (ULN) and total bilirubin =< 2.5 mg/dL except for patients with Gilbert’s syndrome or hemolysis * Renal: Creatinine =< 2.0 mg/dL (adults) and creatinine clearance > 40 mL/min (pediatrics). Adults with a creatinine > 1.2 or a history of renal dysfunction must have estimated creatinine clearance > 40 ml/min/1.73m^2
• PATIENTS: Participants with partners of childbearing potential must be willing to use at least two forms of effective birth control (one form must be a barrier method) for the duration of treatment during study treatment and for 4 months completion of therapy. Persons are considered to be of childbearing potential unless one or the following applies: * Is postmenopausal, defined as no menses for at least 12 months without an alternative medical cause * Considered permanently sterile. Permanent sterilization includes hysterectomy, bilateral salpingectomy, and/or bilateral oophorectomy * Pre-pubertal
• PATIENTS: Suitable haploidentical, matched sibling or unrelated donor
• PATIENTS: Voluntary written consent prior to the performance of any research related activity
• DONORS: Meets one of the following match criteria: * an HLA-A, B, DRB1 matched sibling donor (matched sibling) * an HLA-A, B, DRB1 matched related donor (other than sibling) * a related donor mismatched at 1 HLA-A, B, C and DRB1 antigen * 7-8/8 HLA-A, B, C, DRB1 allele matched unrelated donor per current institutional guidelines * An HLA-haploidentical relative of the patient (biological parents, siblings, half-siblings or offspring), defined as having a shared HLA haplotype between donor and patient at HLA-A, -B, -C, and -DRB1 Patients and donors are typed as per institutional guidelines
• DONORS: Body weight of at least 20 kilograms and at least 8 years of age
• DONORS: Recipient needs =< 15% of the donor's total blood volume to achieve required target cell count
• DONORS: Willing and able to undergo mobilized peripheral blood apheresis
• DONORS: In general good health as determined by the medical provider
• DONORS: Hematologic: hemoglobin, white blood cell (WBC), platelet within 10% of upper and lower limit of normal range of test (gender based for hemoglobin)
• DONORS: Hepatic: alanine aminotransferase (ALT) < 2 x upper limit of normal
• DONORS: Renal: serum creatinine < 1.8 mg/dl
• DONORS: Performance of a donor infectious disease screen panel per current standard institutional donor screen – must be negative for HIV and active hepatitis B
• DONORS: Not pregnant - females of childbearing potential must have a negative pregnancy test within 7 days of mobilization start
• DONORS: Voluntary written consent (parent/guardian and minor assent, if < 18 years) prior to the performance of any research related procedure

Exclusion Criteria

• PATIENTS: Pregnant or breastfeeding. The chemotherapy regimens used in this study is Pregnancy Category D - there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks. Persons of child-bearing potential must have a negative pregnancy test (serum or urine) with 14 days of study enrollment
• PATIENTS: Active uncontrolled infection within 1 week of starting preparative therapy
• PATIENTS: Known seropositive for HIV or known active hepatitis B or C infection with detectable viral load by polymerase chain reaction (PCR)
• PATIENTS: Chronic myeloid leukemia (CML) blast crisis
• PATIENTS: Active central nervous system malignancy