Hematopoietic Stem Cell Transplantation in the Treatment of Infant Leukemia

OBJECTIVES:

Primary

- Determine the incidence of engraftment, defined as achieving donor-derived neutrophil
count > 500/mm³ by day 42, in infants with high-risk acute myeloid leukemia, acute
lymphoblastic leukemia, or myelodysplastic syndromes treated with a non-irradiation
containing myeloablative conditioning regimen comprising busulfan, fludarabine, and
melphalan followed by double umbilical cord blood transplantation (UCBT) with two
partially HLA-matched units.

Secondary Objectives

- Determine the incidence of transplant-related mortality (TRM) at 6 months after UCBT

- Evaluate pattern of chimerism after double UCBT

- Determine the incidence of platelet engraftment at 1 year after UCBT

- Determine the incidence of acute graft-versus-host disease (GVHD) grade II-IV and grade
III-IV at day 100 after UCBT

- Evaluate the developmental outcome after UCBT

Transplant Related Objectives

- Determine the incidence of chronic GVHD at 1 year after UCBT

- Determine the survival and disease free survival at 1 and 2 years after UCBT

- Determine the incidence relapse at 1 and 2 years after UCBT

Inclusion Criteria:

- Matched sibling donor (HLA 8/8), if available, or a unrelated partially HLA matched
single unit based on the following priority:

- 1st priority: 4/6 matched unit, cell dose >5 x 10-7 nucleated cells/kg

- 2nd priority: 5/6 matched unit, cell dose > 4 x 10-7 nucleated cells/kg

- 3rd priority: 6/6 matched unit, cell dose > 3 x 10-7 nucleated cells/kg

- Patients aged ≤ 3 years at diagnosis (not age of transplant) with hematological
malignancy as detailed below:

- 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 complete response (CR); CR2 or higher; Preceding myelodysplastic
syndrome (MDS); All patients must be in CR or early relapse (i.e., <15%
blasts in BM).

- Acute lymphocytic leukemia: high risk CR1 as evidenced by: High-risk
cytogenetic: 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.

- Persistent or rising minimal residual disease (MRD) after standard chemotherapy
regimens: Patients with evidence of minimal residual disease at the completion of
therapy or evidence of rising MRD while on therapy. MRD will be defined by either
flow cytometry (>0.1% residual cells in the blast gate with immune phenotype of
original leukemic clone), by molecular techniques (PCR or FISH) or conventional
cytogenetics (g-banding).

- New Leukemia Subtypes: A major effort in the field of pediatric hematology is to
identify patients who are of high risk for treatment failure so that patients can
be appropriately stratified to either more (or less) intensive therapy. This
effort is continually ongoing and retrospective studies identify new disease
features or characteristics that are associated with treatment outcomes.
Therefore, if new high risk features are identified after the writing of this
protocol, patients can be enrolled with the approval of two members of the study
committee.

- Recipients must have a Lansky score ≥ 50% and have acceptable organ function defined
as:

- Renal: glomerial filtration rate > 60ml/min/1.73m^2

- Hepatic: bilirubin, AST/ALT, ALP < 5 x upper limit of normal,

- Pulmonary function: oxygen saturation >92%

- Cardiac: left ventricular ejection fraction > 45%.

- Voluntary written informed consent before performance of any study-related procedure
not part of normal medical care.

Exclusion Criteria:

- Active infection at time of transplantation (including active infection with
Aspergillus or other mold within 30 days).

- History of HIV infection or known positive serology

- Myeloablative transplant within the last 6 months.

- Evidence of active extramedullary disease (including central nervous system leukemia).