Childhood Acute Lymphoblastic Leukemia in Remission, Childhood Acute Myeloid Leukemia in Remission, Childhood Myelodysplastic Syndrome, De Novo Myelodysplastic Syndrome, Leukemia, Myelodysplastic Syndromes, Previously Treated Myelodysplastic Syndrome, Recurrent Childhood Acute Myeloid Leukemia, Refractory Anemia, Refractory Anemia With Excess Blasts, Refractory Anemia With Excess Blasts in Transformation, Secondary Acute Myeloid Leukemia, Secondary Myelodysplastic Syndrome
Conditions
Keywords
MDS, AML
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
Interventions
BIOLOGICALfilgrastim
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.
DRUGbusulfan
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.
DRUGcyclosporine
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.
DRUGfludarabine phosphate
Administered 25 mg/m\^2 intravenous (IV) over 60 minutes on Days -4 through -2.
DRUGmelphalan
Administered 60 mg/m\^2 intravenous (IV) over 30 minutes on Days -4 through -2.
DRUGmycophenolate 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).
PROCEDUREumbilical cord blood transplantation
The product is infused via IV drip directly into the central line without a needle, pump or filter on Day 0.
Sponsors
Masonic Cancer Center, University of Minnesota
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 3 Years
Healthy volunteers
No
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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 Transplant-related Mortality (TRM) | at 6 months after transplant | defined as death due to transplant |
| Overall Survival | at 1 and 2 years after transplant | Alive after transplant. |
| Disease-free Survival | at 1 and 2 years after transplant | defined as patients who are alive and in hematological remission. |
| Incidence of Relapse | 1 and 2 years after transplant | defined using standard criteria (bone marrow blast count and cytogenetics). |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Double Unit UCB Transplantation Patients that receive 2 units of umbilical cord blood transplantation (UCBT). | 15 |
| 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). | 15 |
| BM Transplantation Blood and Marrow transplantation | 4 |
| Total | 34 |
Baseline characteristics
| Characteristic | Double Unit UCB Transplantation | Single Unit UCB Transplantation | BM Transplantation | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 15 Participants | 15 Participants | 4 Participants | 34 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 0 Participants | 0 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 12 Participants | 14 Participants | 4 Participants | 30 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 2 Participants | 0 Participants | 5 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 0 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 10 Participants | 13 Participants | 3 Participants | 26 Participants |
| Region of Enrollment United States | 15 participants | 15 participants | 4 participants | 34 participants |
| Sex: Female, Male Female | 8 Participants | 5 Participants | 4 Participants | 17 Participants |
| Sex: Female, Male Male | 7 Participants | 10 Participants | 0 Participants | 17 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 8 / 15 | 5 / 15 | 1 / 4 |
| other Total, other adverse events | 15 / 15 | 15 / 15 | 4 / 4 |
| serious Total, serious adverse events | 8 / 15 | 5 / 15 | 1 / 4 |
Outcome results
Primary
Incidence of Engraftment
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.
Time frame: Day 42 After Transplant
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Double Unit UCB Transplantation | Incidence of Engraftment | 100 Percentage of participants |
| Single Unit UCB Transplantation | Incidence of Engraftment | 93 Percentage of participants |
| BM Transplantation | Incidence of Engraftment | 100 Percentage of participants |
Secondary
Disease-free Survival
defined as patients who are alive and in hematological remission.
Time frame: at 1 and 2 years after transplant
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Double Unit UCB Transplantation | Disease-free Survival | 1 year | 0.13 Probability of survival |
| Double Unit UCB Transplantation | Disease-free Survival | 2 years | 0.13 Probability of survival |
| Single Unit UCB Transplantation | Disease-free Survival | 1 year | 0.2 Probability of survival |
| Single Unit UCB Transplantation | Disease-free Survival | 2 years | 0.20 Probability of survival |
| BM Transplantation | Disease-free Survival | 1 year | 0 Probability of survival |
| BM Transplantation | Disease-free Survival | 2 years | 0.33 Probability of survival |
Secondary
Incidence of Acute Graft-versus-host Disease (GVHD) Grade II-IV and Grade III-IV
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.
Time frame: Day 100 After Transplant
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Double Unit UCB Transplantation | Incidence of Acute Graft-versus-host Disease (GVHD) Grade II-IV and Grade III-IV | 40 Percentage of participants |
| Single Unit UCB Transplantation | Incidence of Acute Graft-versus-host Disease (GVHD) Grade II-IV and Grade III-IV | 33 Percentage of participants |
| BM Transplantation | Incidence of Acute Graft-versus-host Disease (GVHD) Grade II-IV and Grade III-IV | 0 Percentage of participants |
Secondary
Incidence of Chronic Graft-versus-host Disease (GVHD)
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.
Time frame: 1 Year After Transplant
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Double Unit UCB Transplantation | Incidence of Chronic Graft-versus-host Disease (GVHD) | 13 Percentage of participants |
| Single Unit UCB Transplantation | Incidence of Chronic Graft-versus-host Disease (GVHD) | 0 Percentage of participants |
| BM Transplantation | Incidence of Chronic Graft-versus-host Disease (GVHD) | 0 Percentage of participants |
Secondary
Incidence of Platelet Engraftment
defined as platelet count \> 50,000
Time frame: at 1 year after transplant
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Double Unit UCB Transplantation | Incidence of Platelet Engraftment | 80 Percentage of participants |
| Single Unit UCB Transplantation | Incidence of Platelet Engraftment | 100 Percentage of participants |
| BM Transplantation | Incidence of Platelet Engraftment | 100 Percentage of participants |
Secondary
Incidence of Relapse
defined using standard criteria (bone marrow blast count and cytogenetics).
Time frame: 1 and 2 years after transplant
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Double Unit UCB Transplantation | Incidence of Relapse | 1 year | 13 Percentage of participants |
| Double Unit UCB Transplantation | Incidence of Relapse | 2 years | 13 Percentage of participants |
| Single Unit UCB Transplantation | Incidence of Relapse | 1 year | 20 Percentage of participants |
| Single Unit UCB Transplantation | Incidence of Relapse | 2 years | 20 Percentage of participants |
| BM Transplantation | Incidence of Relapse | 1 year | 0 Percentage of participants |
| BM Transplantation | Incidence of Relapse | 2 years | 25 Percentage of participants |
Secondary
Incidence of Transplant-related Mortality (TRM)
defined as death due to transplant
Time frame: at 6 months after transplant
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Double Unit UCB Transplantation | Incidence of Transplant-related Mortality (TRM) | 33 Percentage of participants |
| Single Unit UCB Transplantation | Incidence of Transplant-related Mortality (TRM) | 13 Percentage of participants |
| BM Transplantation | Incidence of Transplant-related Mortality (TRM) | 0 Percentage of participants |
Secondary
Overall Survival
Alive after transplant.
Time frame: at 1 and 2 years after transplant
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Double Unit UCB Transplantation | Overall Survival | 1 year | 0.53 Probability of survival |
| Double Unit UCB Transplantation | Overall Survival | 2 years | 0.47 Probability of survival |
| Single Unit UCB Transplantation | Overall Survival | 1 year | 0.67 Probability of survival |
| Single Unit UCB Transplantation | Overall Survival | 2 years | 0.67 Probability of survival |
| BM Transplantation | Overall Survival | 1 year | 100 Probability of survival |
| BM Transplantation | Overall Survival | 2 years | 0.67 Probability of survival |