Phase II Trial of Myeloablative Conditioning & Transplantation of Partially HLA-mismatched Marrow With Post-transplant Cyclophosphamide for Peds Pts w/ Hematologic Malignancies

This is a phase II prospective study designed to evaluate the incidence of 6 month non-
relapse mortality, safety, and feasibility of haploidentical bone marrow transplantation
(BMT) after myeloablative conditioning with post-transplant Cy. Conditioning regimens include
a total body irradiation-based prep for lymphoid leukemias and a chemotherapy based prep for
myeloid leukemias.

To estimate the incidence of non-relapse mortality at 180 days following myeloablative
haploidentical BMT for children and young adults with high risk hematologic malignancies.

Inclusion Criteria:

- Patient age 0.5-25years

- Patients must have a first-degree related donor or half-sibling who is at minimum HLA
haploidentical. The donor and recipient must be identical at at least one allele of
each of the following genetic loci: HLA-A, HLA-B, HLA-Cw, HLA-DRB1, and HLA-DQB1. A
minimum match of 5/10 is therefore required, and will be considered sufficient
evidence that the donor and recipient share one HLA haplotype.

- An unrelated donor search is not required for a patient to be eligible for this
protocol, or a donor search and donor mobilization may be abandoned if the clinical
situation dictates an urgent transplant. Clinical urgency is defined as 6-8 weeks from
referral to transplant or a low-likelihood of finding a matched, unrelated donor.
Patients with an eligible HLA-matched RELATED should not be enrolled on this trial.

- Patients must have at least one of the following high-risk conditions listed below
(criteria are meant to complement existing criteria within COG protocols):

- Acute lymphocytic leukemia (ALL) in CR1* as defined by at least one of the following:

hypodiploidy, induction failure, MRD after consolidation

- Acute myeloid leukemia (AML) in CR1 with high risk features defined as: High allelic
ratio FLT3/ITD+, Monosomy 7, Del (5q), Standard risk cytogenetics with positive minimal
residual disease at the end of Induction I chemotherapy (for patients being treated on or
according to COG AAML1031 who have had MRD studies sent to Seattle or performed at their
local institution where the flow assay is sensitive enough to detect > 0.1% blasts)

- Acute Leukemias in 2nd or subsequent CR (CR>2)

- Mixed phenotype/Undifferentiated Leukemias in 1st or subsequent CR*

- Secondary or therapy related leukemias in CR > 1

- NK cell lymphoblastic leukemia CR > 1

- Myelodysplastic syndrome (MDS)

- JMML (patients are eligible if they are not eligible for COG1221)

- Prior transplant eligible if < 18yo, >6 months has elapsed since BMT, and patient is
off immunosuppression for > 3 months with no GVHD

- No known active CNS involvement or extramedullary involvement by malignancy. Such
disease treated into remission is permitted.

- Acute Leukemia - Remission is defined as morphology with < 5% blasts with no
morphological characteristics of acute leukemia (e.g., Auer Rods) in a bone marrow
with > 20% cellularity.

Exclusion Criteria:

- Patients will not be excluded on the basis of sex, racial or ethnic background.

- Poor cardiac function: left ventricular ejection fraction <45% as determined by MUGA
or ECHO. For pediatric patients LVEF <45% or a shortening fraction below normal limits
for age.

- Symptomatic pulmonary disease. Poor pulmonary function: FEV1, FVC, and DLCO <50%
predicted (corrected for hemoglobin) for patients who have not received thoracic or
mantle irradiation. For patients who have received thoracic or mantle irradiation,
FEV1 and FVC <70% predicted or DLCO < 50 of predicted. For children unable to perform
PFTs because of developmental stage pulse oximetry < 92% on RA.

- Poor liver function: bilirubin >2 mg/dl (not due to hemolysis, Gilbert's or primary
malignancy). ALT or AST > 3 x laboratory upper normal limits.

- Poor renal function: Creatinine >2.0mg/dl or creatinine clearance (calculated
creatinine clearance is permitted) < 60 mL/min based on Traditional Cockcroft-Gault
formula: 140 - age (yrs) x Smaller of Actual Weight vs. Ideal Body Weight (kg) / 72 x
Serum creatinine (mg/dl) Multiply by another factor of 0.85 if female Intended for
ages 18-110, serum creatinine 0.6-7 mg/dl For patients <18 years: CrCl will be
estimated by the Schwartz formula. A measured CrCl or a GFR may be substituted to
determine the subject's CrCl.

- Schwartz equation: CrCl (ml/min/1.73m2)=[length (cm) x k] /serum creatinine K = 0.45
for infants 1 to 52 weeks old k = 0.55 for children 1 to 13 years old k = 0.55 for
adolescent females 13-18 years old k = 0.7 for adolescent males 13-18 years old

- HIV-positive

- Positive leukocytotoxic crossmatch Specifically, complement dependent cytotoxicity and
flow cytometric crossmatch assays must be negative, and the mean fluorescence
intensity (MFI) of any anti-donor HLA antibody by solid phase immunoassay should be
<3000. Consult with PI for the clinical significance of any anti-donor antibody.

- Women of childbearing potential who currently are pregnant (HCG+) or who are not
practicing adequate contraception or who are breastfeeding

- Uncontrolled viral, bacterial, or fungal infections (currently taking medication and
have progression of clinical symptoms)

- Patients with symptoms consistent with RSV, influenza A, B, or parainfluenza at the
time of enrollment will be assayed for the above viruses and if positive are not
eligible for the trial until they are no longer symptomatic (patients may have
continued assay positivity for a period of time post resolution of symptoms secondary
to the nature of the assay