Single vs Double Umbilical Cord Blood Transplants in Children With High Risk Leukemia and Myelodysplasia (BMT CTN 0501)

BACKGROUND:

In nearly every large single center or registry analysis of outcomes after UCB
transplantation, cell dose is identified as an important factor influencing the incidence and
rate of hematopoietic recovery, risk of transplant-related mortality, and probability of
survival. Pilot data suggest that infusion of two partially human leukocyte antigen
(HLA)-matched UCB units, which always augments the graft cell dose, is safe and may improve
neutrophil recovery and survival. To determine whether the infusion of two UCB units enhances
survival, a multi-center, open-label, randomized trial is proposed. As adequate single UCB
units can be identified for more than 80% of pediatric recipients (in contrast to less than
30% for adults), this study will be open only to pediatric patients. The population will be
restricted to patients with high-risk hematologic malignancy, the most common indication of
UCB transplantation in children.

DESIGN NARRATIVE:

Participants will include patients 1 to 21 years of age with a diagnosis of hematological
malignancy and with two partially HLA-matched UCB units. Units must be HLA-matched at 3 of 6
HLA-A and B (intermediate resolution molecular typing) and DRB1 (high resolution molecular
typing) with each other and 4 of 6 with the recipient. Two appropriately HLA-matched units
must be available such that one unit delivers a pre-cryopreserved, nucleated cell dose of at
least 2.5 x 10^7 per kilogram and the second unit delivers at least 1.5 x 10^7 per kilogram.

Patients will be randomized no more than 14 days prior to initiation of conditioning. UCB
units will be shipped prior to initiation of conditioning.

The preparative regimen will consist of the following:

- Fludarabine: 25 mg/m2/day IV on Days -10, -9, and -8.

- Total Body Irradiation (TBI): 165 cGy twice daily on Days -7, -6, -5, and -4.

- Cyclophosphamide: 60 mg/kg/day x 2 on Days -3 and -2.

- Day 0 will be the day of the UCB transplant. The Graft-vs-Host-Disease (GVHD)
prophylaxis regimen will be mycophenolate mofetil (MMF) 15 mg/kg IV BID on Day -3 to Day
+ 45 and cyclosporine A (CSA) to maintain level 200-400 ng/mL beginning on Day -3.

Patients will be followed for at least 24 months post-transplant.

Inclusion Criteria:

- Two partially HLA-matched UCB units. Units must be HLA-matched minimally at 4 of 6
HLA-A and B (at intermediate resolution by molecular typing) and DRB1 (at high
resolution by molecular typing) loci with the patient, and the units must be
HLA-matched at 3 of 6 HLA- A, B, DRB1 loci with each other (using same resolution of
molecular typing as indicated above). Two appropriately HLA-matched units must be
available such that one unit delivers a pre-cryopreserved nucleated cell dose of at
least 2.5 x 10^7 per kilogram and the second unit at least 1.5 x 10^7 per kilogram.

- Acute myelogenous leukemia (AML) at the following stages:

1. High risk first complete remission (CR1), defined as the following:

- Having preceding myelodysplasia (MDS)

- High risk cytogenetics (high risk cytogenetics: del (5q) -5, -7, abn (3q), t
(6;9) complex karyotype [at least 5 abnormalities],)the presence of a high
FLT3 ITD-AR (> 0.4)

- Requiring more than 1 cycle of chemotherapy to obtain complete remission
(CR);

- FAB M6

2. Second or greater CR

3. First relapse with less than 25% blasts in bone marrow

4. Morphologic complete remission with incomplete blood count recovery

- Therapy-related AML for which prior malignancy has been in remission for at least 12
months

- Acute lymphocytic leukemia (ALL) at the following stages:

1. High risk first remission, defined as one of the following conditions:

- Philadelphia chromosome-positive adult lymphoblastic leukemia (Ph+ ALL)

- Mixed lineage leukemia (MLL) rearrangement with slow early response (defined
as having M2 [5-25% blasts] or M3 [more than 25% blasts on bone marrow
examination on Day 14 of induction therapy])

- Hypodiploidy (less than 44 chromosomes or DNA index less than 0.81)

- End of induction M3 bone marrow

- End of induction M2 with M2-3 at Day 42

- Evidence of minimal residual disease (MRD). If a patient's only high risk
criterion is MRD, approval by a protocol chair or protocol officer is
required for enrollment. For COG centers, this will only be for MRD greater
than 1 percent by flow MRD at the end of extended induction.

2. High risk second remission, defined as one of the following conditions:

- Philadelphia chromosome-positive adult lymphoblastic leukemia (Ph+ ALL)

- Bone marrow relapse less than 36 months from induction

- T-lineage relapse at any time

- Very early isolated central nervous system (CNS) relapse (6 months from
diagnosis)

- Slow reinduction (M2-3 at Day 28) after relapse at any time

- Evidence of minimal residual disease (MRD). If a patient's only high risk
criterion is MRD, approval by a protocol chair or protocol officer is
required for enrollment. For COG centers, this will only be for MRD greater
than 1 percent by flow MRD at the end of extended induction.

3. Any third or subsequent CR

- NK cell lymphoblastic leukemia in any CR

- Biphenotypic or undifferentiated leukemia in any CR or if in first relapse must have
less than 25% blasts in bone marrow (BM)

- Myelodysplastic syndrome (MDS) at any stage

- Chronic myelogenous leukemia (CML) in chronic or accelerated phase

- All patients with evidence of CNS leukemia must be treated and be in CNS CR to be
eligible for study.

- Patients 16 years old or older must have a Karnofsky score of at least 70% and
patients younger than 16 years old must have a Lansky score of at least 70%.

- Patients with adequate physical function as measured by:

1. Cardiac: Left ventricular ejection fraction greater than 40% or shortening
fraction greater than 26%

2. Hepatic: Bilirubin no more than 2.5 mg/dL; alanine aminotransferase (ALT),
aspartate aminotransferase (AST), and alkaline phosphatase (ALP) no more than 5
times the upper limit of normal (ULN)

3. Renal: Serum creatinine within normal range for age, or if serum creatinine is
outside normal range for age, then renal function (creatinine clearance or GFR)
greater than 70 mL/min/1.73 m^2

4. Pulmonary: Diffusing capacity of the lung for carbon monoxide (DLCO), forced
expiratory volume in one second (FEV1), or forced vital capacity (FVC) greater
than 50% of predicted value (corrected for hemoglobin); if unable to perform
pulmonary function tests, then O2 saturation greater than 92% of room air

Exclusion Criteria:

- Pregnant (β-positive human chorionic gonadotropin [HCG]) or breastfeeding

- Evidence of HIV infection or HIV positive serology

- Current uncontrolled bacterial, viral, or fungal infection (currently taking
medication and progression of clinical symptoms)

- Autologous transplant less than 12 months prior to enrollment

- Prior autologous transplant for the disease for which the UCB transplant will be
performed

- Prior allogeneic hematopoietic stem cell transplant

- Active malignancy other than the one for which the UCB transplant is being performed
within 12 months of enrollment

- Inability to receive TBI

- Requirement of supplemental oxygen

- HLA-matched related donor able to donate