Clinical trial NCT00357565: Hematopoietic Stem Cell Transplantation in the Treatment of Infant Leukemia
Official title: Hematopoietic Cell Transplantation in the Treatment of Infant Leukemia and Myelodysplastic Syndrome
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: 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
Keywords: MDS
AML
Lead sponsor: Masonic Cancer Center, University of Minnesota
Sponsor class: OTHER
First posted: 2006-07-27
Enrollment: 33
Sex: ALL
Maximum age (years): 3
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Eligibility criteria: 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).

Primary outcomes:
measure: Incidence of Engraftment
timeFrame: Day 42 After Transplant
Secondary outcomes:
measure: Incidence of transplant-related mortality (TRM)
timeFrame: at 6 months after transplant
measure: Incidence of platelet engraftment
timeFrame: at 1 year after transplant
measure: Incidence of acute graft-versus-host disease (GVHD) grade II-IV and grade III-IV
timeFrame: Day 100 After Transplant
measure: Incidence of chronic graft-versus-host disease (GVHD)
timeFrame: 1 Year After Transplant
measure: Incidence of relapse
timeFrame: 1 and 2 years after transplant
measure: Overall survival
timeFrame: at 1 and 2 years after transplant
measure: Developmental Outcomes
timeFrame: at 1 and 2 after transplant
measure: Disease-free survival
timeFrame: at 1 and 2 years after transplant
Other outcomes:
Locations:
city: Minneapolis
country: United States
facility: Masonic Cancer Center, University of Minnesota
state: Minnesota
Study officials:
affiliation: Masonic Cancer Center, University of Minnesota
name: Christen Ebens, MD
role: PRINCIPAL_INVESTIGATOR
References: