Naive T Cell Depletion for Preventing Chronic Graft-versus-Host Disease in Children and Young Adults With Blood Cancers Undergoing Donor Stem Cell Transplant

Participants are randomized to 1 of 2 arms. All participants receive 1 of 3 conditioning
regimens.

CONDITIONING REGIMEN A: Participants undergo total body irradiation (TBI) twice daily (BID)
on days -10 to -7, then receive thiotepa intravenously (IV) over 4 hours once daily (QD) on
days -6 and -5, and fludarabine IV over 30 minutes once daily on days -6 to -2.

CONDITIONING REGIMEN B: Participants undergo TBI BID on days -8 to -5, then receive
fludarabine IV over 30 minutes QD on days -4 to -2, and cyclophosphamide IV over 1 hour QD on
days -3 and -2.

CONDITIONING REGIMEN C: Participants receive fludarabine IV over 30 minutes QD on days -6 to
-2, busulfan IV over 180 minutes QD on days -5 to -2, and undergo total body irradiation BID
on day -1.

ARM I: Participants receive naive T-cell depleted PBSCs on day 0.

ARM II: Participants receive unmanipulated T cell-replete BM on day 0.

GVHD PROPHYLAXIS: All participants receive tacrolimus IV beginning on day -1 and methotrexate
IV on days 1, 3, 6, and 11.

After completion of study treatment, participants are followed up periodically.

Inclusion Criteria:

- The patient must have one of the following diagnoses and be considered to be an
appropriate candidate for allogeneic HCT by the study site Principal Investigator
(PI):

- Acute lymphoblastic leukemia (ALL) with < 5% marrow blasts.

- Acute myeloid leukemia (AML) with < 25% marrow blasts.

- Other acute leukemia (OAL) including but not limited to acute biphenotypic
leukemia (ABL), ambiguous lineage (ALAL), mixed phenotype acute leukemia (MPAL),
blastic plasmacytoid dendritic cell neoplasm (BPDCN), and acute undifferentiated
leukemia (AUL) with < 5% marrow blasts.

- Myelodysplastic syndrome (MDS) with excess blasts (EB-1 and EB-2) and has
received cytotoxic induction chemotherapy (excluding small molecule inhibitors
and de-methylating agents).

- Matched related donor (MRD) or matched unrelated donor (MUD) (defined as 8/8 match for
human leukocyte antigen [HLA]-A, -B, -C, -DRB1).

- Planned product type for infusion is PBSC or BM (i.e. not cord blood):

- For feasibility phase, planned product type for infusion must be PBSC.

- For RCT, planned product type must be PBSC or BM.

- Karnofsky or Lansky score >= 60%.

- Left ventricular ejection fraction (LVEF) at rest >= 40%.

- Diffusing capacity of the lungs for carbon monoxide (DLCO) (corrected for hemoglobin)
>= 60% predicted by pulmonary function tests (PFTs)

* Patients who are unable to perform PFTs (age < 6 years or considered developmentally
incapable of PFTs): oxygen saturation (by oximetry) must be >= 92% on room air.

- Total bilirubin =< 2 x upper limit of normal (ULN) (unless value[s] > 2 x ULN are
disease- or medication-related).

* If value(s) are > 2 x ULN and not disease- or medication related, patient must be
evaluated by a gastrointestinal (GI) physician. If GI physician considers protocol
treatment to be contraindicated for the patient, the patient will not be eligible for
the study.

- Alanine aminotransferase (ALT), aspartate aminotransferase (AST) =< 2 x ULN (unless
value[s] > 2 x ULN are disease- or medication-related).

* If value(s) are > 2 x ULN and not disease- or medication related, patient must be
evaluated by a gastrointestinal (GI) physician. If GI physician considers protocol
treatment to be contraindicated for the patient, the patient will not be eligible for
the study.

- Serum creatinine (SCr) within normal range for age. If SCr is outside normal range for
age, creatinine clearance (CrCl) > 40 mL/min/1.73m^2 must be obtained (measured by
24-hour [hr] urine specimen or nuclear glomerular filtration rate [GFR]).

- Age (Years): Maximum SCr (mg/dL)

- =< 5: 0.8

- 6-10: 1

- 11-15: 1.2

- > 15: 1.5

- Recipient informed consent/assent/legal guardian permission documentation must be
obtained.

- DONOR: May be related (MRD) or unrelated (MUD) to the subject.

- DONOR: Must be matched to the subject at 8/8 HLA alleles (HLA-A, -B, -C, and -DRB1)

- DONOR: Be >=18 years of age.

- DONOR: Must be available to donate in the United States of America (USA) (i.e.
excludes international donors).

- DONOR: Must agree to donate BM or PBSC (i.e. agree to donate whichever product type is
requested) (applicable only to the RCT phase of this study)).

- DONOR: MUDs:

- Must give informed consent according to applicable National Marrow Donor Program
(NMDP) donor regulatory requirements.

- Must meet eligibility criteria as defined by the NMDP or be ineligible with
statement of urgent medical need.

- Tests must be performed using Food and Drug Administration (FDA) licensed,
cleared, and approved test kits in a Clinical Laboratory Improvement
Amendments (CLIA)-certified laboratory.

- DONOR: MRDs:

- Must give informed consent using the Related Donor Informed Consent to
Participate in a Research Study form

- Must be negative for human immunodeficiency virus (HIV)-1, HIV-2, human
T-lymphotropic virus (HTLV)-1, HTLV-2, hepatitis B, hepatitis

- (serological and/or nucleic acid testing (NAT) and/or other approved testing)

- Must meet institutional donor eligibility criteria, or be ineligible with
statement that the donor is a first or second degree relative

- Tests must be performed using FDA licensed, cleared, and approved test kits
in a CLIA-certified laboratory.

Exclusion Criteria:

- Active central nervous system (CNS) disease. A patient may have a history of CNS
disease; however, any CNS disease must be cleared by the end of the pre-conditioning
evaluation time frame. If CNS disease is identified on the first cerebrospinal fluid
(CSF) evaluation within 30 days of the start of the preparative regimen a repeat
lumbar puncture (LP) with CSF evaluation must be performed and show no evidence of
disease in order for the patient to be eligible for the protocol.

- Patients on other experimental protocols for the prevention of GVHD.

- Patient body weight:

- Matched related donor (MRD): > 100 kg are ineligible

- Matched unrelated donor (MUD): > 75 kg must be discussed with the protocol PI
prior to enrollment.

- HIV-positive.

- Uncontrolled infections must be evaluated by an infectious disease physician and
considered suitable to undergo HCT by the study site PI, infectious disease physician
and protocol PI. Upper respiratory tract infection (URI) does not constitute an
uncontrolled infection in this context.

- Life expectancy < 3 months from disease other than acute leukemia or myelodysplastic
syndrome (MDS).

- Significant medical condition that would make recipient unsuitable for HCT.

- Prior allogeneic or autologous HCT.

- Females who are pregnant or breastfeeding.

- Patients of child bearing age who are presumed to be fertile and are unwilling to use
an effective birth control method or refrain from sexual intercourse during study
treatment and for 12 months following HCT.

- Known hypersensitivity to tacrolimus, fludarabine, or methotrexate (MTX).