Hematopoietic Stem Cell Transplantation in the Treatment of Infant Leukemia

Sponsor

Masonic Cancer Center, University of Minnesota (Other)

Overall Status

Recruiting

CT.gov ID

NCT00357565

Collaborator

(none)

Enrollment

Location

Arms

205

Anticipated Duration (Months)

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

RATIONALE: Giving chemotherapy, such as busulfan, fludarabine, and melphalan, before a donor umbilical cord blood stem cell transplant helps stop the growth of abnormal or cancer cells and prepares the patient's bone marrow for the stem cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Giving cyclosporine and mycophenolate mofetil may stop this from happening.

PURPOSE: This phase II trial is studying how well combination chemotherapy followed by a donor umbilical cord blood transplant works in treating infants with high-risk acute leukemia or myelodysplastic syndromes.

Condition or Disease	Intervention/Treatment	Phase
Leukemia Myelodysplastic Syndromes Childhood Acute Myeloid Leukemia in Remission Recurrent Childhood Acute Myeloid Leukemia Secondary Acute Myeloid Leukemia Childhood Acute Lymphoblastic Leukemia in Remission Previously Treated Myelodysplastic Syndrome Secondary Myelodysplastic Syndrome Refractory Anemia With Excess Blasts in Transformation Refractory Anemia With Excess Blasts Refractory Anemia De Novo Myelodysplastic Syndrome Childhood Myelodysplastic Syndrome	Biological: filgrastim Drug: busulfan Drug: cyclosporine Drug: fludarabine phosphate Drug: melphalan Drug: mycophenolate mofetil Procedure: umbilical cord blood transplantation	Phase 2

Detailed Description

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

Study Design

Study Type:

Interventional

Anticipated Enrollment :

20 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Hematopoietic Cell Transplantation in the Treatment of Infant Leukemia and Myelodysplastic Syndrome

Actual Study Start Date :

Nov 1, 2005

Anticipated Primary Completion Date :

Dec 1, 2022

Anticipated Study Completion Date :

Dec 1, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Double Unit UCB Transplantation Patients that receive 2 units of umbilical cord blood transplantation (UCBT).	Biological: filgrastim All patients will receive G-CSF 5 mcg/kg/day intravenous (IV) (dose rounded to vial size) based on the actual body weight IV beginning on day +1 after umbilical cord blood (UCB) infusion. G-CSF will be administered daily until the absolute neutrophil count (ANC) exceeds 2.5 x 10^9/L for three consecutive days and then discontinued. If the ANC decreases to <1.0 x 10^9/L, G-CSF will be reinstituted. Other Names: G-CSF Drug: busulfan Administered 1.1 mg/kg if <12 kg intravenous (IV) every 6 hours (0.8 mg/kg if >12 kg IV every 6 hours on Days -8 through -5. Other Names: Busulfex Drug: cyclosporine Patients will receive cyclosporine (CSA) therapy beginning on day -3 maintaining a level of >200 ng/mL. For children < 40 kg the initial dose will be 2.5 mg/kg intravenous (IV) over 2 hours every 8 hours. Other Names: CSA Drug: fludarabine phosphate Administered 25 mg/m^2 intravenous (IV) over 60 minutes on Days -4 through -2. Other Names: Fludara Drug: melphalan Administered 60 mg/m^2 intravenous (IV) over 30 minutes on Days -4 through -2. Other Names: Alkeran Drug: mycophenolate mofetil All patients will begin mycophenolate mofetil (MMF) on day -3. Patients <45 kilograms will receive MMF at the dose of 15 mg/kg/dose every 8 hours (max dose 1gm/dose) orally or intravenously (PO or IV). Other Names: MMF Procedure: umbilical cord blood transplantation The product is infused via IV drip directly into the central line without a needle, pump or filter on Day 0.
Experimental: Single Unit UCB Transplantation Patients that receive one unit of umbilical cord blood transplantation (only if 2 adequate size and matched units are not available).	Biological: filgrastim All patients will receive G-CSF 5 mcg/kg/day intravenous (IV) (dose rounded to vial size) based on the actual body weight IV beginning on day +1 after umbilical cord blood (UCB) infusion. G-CSF will be administered daily until the absolute neutrophil count (ANC) exceeds 2.5 x 10^9/L for three consecutive days and then discontinued. If the ANC decreases to <1.0 x 10^9/L, G-CSF will be reinstituted. Other Names: G-CSF Drug: busulfan Administered 1.1 mg/kg if <12 kg intravenous (IV) every 6 hours (0.8 mg/kg if >12 kg IV every 6 hours on Days -8 through -5. Other Names: Busulfex Drug: cyclosporine Patients will receive cyclosporine (CSA) therapy beginning on day -3 maintaining a level of >200 ng/mL. For children < 40 kg the initial dose will be 2.5 mg/kg intravenous (IV) over 2 hours every 8 hours. Other Names: CSA Drug: fludarabine phosphate Administered 25 mg/m^2 intravenous (IV) over 60 minutes on Days -4 through -2. Other Names: Fludara Drug: melphalan Administered 60 mg/m^2 intravenous (IV) over 30 minutes on Days -4 through -2. Other Names: Alkeran Drug: mycophenolate mofetil All patients will begin mycophenolate mofetil (MMF) on day -3. Patients <45 kilograms will receive MMF at the dose of 15 mg/kg/dose every 8 hours (max dose 1gm/dose) orally or intravenously (PO or IV). Other Names: MMF Procedure: umbilical cord blood transplantation The product is infused via IV drip directly into the central line without a needle, pump or filter on Day 0.

Arm

Intervention/Treatment

Experimental: Double Unit UCB Transplantation

Patients that receive 2 units of umbilical cord blood transplantation (UCBT).

Biological: filgrastim

All patients will receive G-CSF 5 mcg/kg/day intravenous (IV) (dose rounded to vial size) based on the actual body weight IV beginning on day +1 after umbilical cord blood (UCB) infusion. G-CSF will be administered daily until the absolute neutrophil count (ANC) exceeds 2.5 x 10^9/L for three consecutive days and then discontinued. If the ANC decreases to <1.0 x 10^9/L, G-CSF will be reinstituted.

Other Names:

G-CSF

Drug: busulfan

Administered 1.1 mg/kg if <12 kg intravenous (IV) every 6 hours (0.8 mg/kg if >12 kg IV every 6 hours on Days -8 through -5.

Other Names:

Busulfex

Drug: cyclosporine

Patients will receive cyclosporine (CSA) therapy beginning on day -3 maintaining a level of >200 ng/mL. For children < 40 kg the initial dose will be 2.5 mg/kg intravenous (IV) over 2 hours every 8 hours.

Other Names:

CSA

Drug: fludarabine phosphate

Administered 25 mg/m^2 intravenous (IV) over 60 minutes on Days -4 through -2.

Other Names:

Fludara

Drug: melphalan

Administered 60 mg/m^2 intravenous (IV) over 30 minutes on Days -4 through -2.

Other Names:

Alkeran

Drug: mycophenolate mofetil

All patients will begin mycophenolate mofetil (MMF) on day -3. Patients <45 kilograms will receive MMF at the dose of 15 mg/kg/dose every 8 hours (max dose 1gm/dose) orally or intravenously (PO or IV).

Other Names:

MMF

Procedure: umbilical cord blood transplantation

The product is infused via IV drip directly into the central line without a needle, pump or filter on Day 0.

Experimental: Single Unit UCB Transplantation

Patients that receive one unit of umbilical cord blood transplantation (only if 2 adequate size and matched units are not available).

Biological: filgrastim

Other Names:

G-CSF

Drug: busulfan

Administered 1.1 mg/kg if <12 kg intravenous (IV) every 6 hours (0.8 mg/kg if >12 kg IV every 6 hours on Days -8 through -5.

Other Names:

Busulfex

Drug: cyclosporine

Other Names:

CSA

Drug: fludarabine phosphate

Administered 25 mg/m^2 intravenous (IV) over 60 minutes on Days -4 through -2.

Other Names:

Fludara

Drug: melphalan

Administered 60 mg/m^2 intravenous (IV) over 30 minutes on Days -4 through -2.

Other Names:

Alkeran

Drug: mycophenolate mofetil

Other Names:

MMF

Procedure: umbilical cord blood transplantation

The product is infused via IV drip directly into the central line without a needle, pump or filter on Day 0.

Outcome Measures

Primary Outcome Measures

Incidence of Engraftment [Day 42 After Transplant]
Defined as achieving donor derived neutrophil count >500/uL by day 42 in young children with leukemia or myelodysplastic syndrome undergoing a partially matched single unit umbilical cord blood transplant (UCBT) after a myeloablative preparative regimen consisting of busulfan, melphalan and fludarabine.

Secondary Outcome Measures

Incidence of transplant-related mortality (TRM) [at 6 months after transplant]
defined as death due to transplant
Incidence of platelet engraftment [at 1 year after transplant]
defined as platelet count > 50,000
Incidence of acute graft-versus-host disease (GVHD) grade II-IV and grade III-IV [Day 100 After Transplant]
Graft-versus-host disease (GVHD) is a common complication of allogeneic bone marrow transplantation in which functional immune cells in the transplanted marrow recognize the recipient as "foreign" and mount an immunologic attack.
Incidence of chronic graft-versus-host disease (GVHD) [1 Year After Transplant]
Graft-versus-host disease (GVHD) is a common complication of allogeneic bone marrow transplantation in which functional immune cells in the transplanted marrow recognize the recipient as "foreign" and mount an immunologic attack.
Incidence of relapse [1 and 2 years after transplant]
defined using standard criteria (bone marrow blast count and cytogenetics).
Overall survival [at 1 and 2 years after transplant]
Alive after transplant.
Developmental Outcomes [at 1, 2, and 5 years after transplant]
Neuropsychological evaluation to assess baseline neurocognitive, adaptive, and behavioral functioning and presence of developmental delays
Disease-free survival [at 1 and 2 years after transplant]
defined as patients who are alive and in hematological remission.

Eligibility Criteria

Criteria

Ages Eligible for Study:

N/A to 3 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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).