Transplantation of Umbilical Cord Blood in Patients With Hematological Malignancies Using a Reduced-Intensity Preparative Regimen (A Multi-Center Trial Coordinated by the FHCRC)
Overview
- Phase
- Phase 2
- Intervention
- Allogeneic Hematopoietic Stem Cell Transplantation
- Conditions
- Acute Lymphoblastic Leukemia
- Sponsor
- Fred Hutchinson Cancer Center
- Enrollment
- 73
- Locations
- 6
- Primary Endpoint
- Overall Survival
- Status
- Completed
- Last Updated
- 6 years ago
Overview
Brief Summary
This phase II trial is studying how well umbilical cord blood transplant from a donor works in treating patients with hematological cancer. Giving chemotherapy and total-body irradiation (TBI) before a donor umbilical cord blood transplant helps stop the growth of cancer and abnormal cells and helps stop the patient's immune system from rejecting the donor's stem cells. When the healthy stem cells from an unrelated donor, that do not exactly match the patient's blood, 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 (called graft-versus-host disease). Giving cyclosporine and mycophenolate mofetil before and after transplant may stop this from happening.
Detailed Description
PRIMARY OBJECTIVES: I. Estimate probability of one year survival. II. Demonstrate equivalent or improved engraftment rates with a non-anti-thymocyte globulin (ATG) based conditioning regimen. Patients will be considered graft failure/rejections provided they meet any of the criteria listed below: * Absence of 3 consecutive days with neutrophils \>= 500/ul combined with host cluster of differentiation (CD)3 peripheral blood chimerism \>= 50% at day 42 * Absence of 3 consecutive days with neutrophils \>= 500/ul under any circumstances at day 55 * Death after day 28 with neutrophil count \< 100/ul without any evidence of engraftment (\< 5% donor CD3) * Primary autologous count recovery with \< 5% donor CD3 peripheral blood chimerism at count recovery and without relapse SECONDARY OBJECTIVES: I. Six month non-relapse mortality. II. Overall incidence of graft failure/rejection. Patients will be considered graft failure/rejections provided they meet any of the criteria listed below: * Absence of 3 consecutive days with neutrophils \>= 500/ul combined with host CD3 peripheral blood chimerism \>= 50% at day 42 * Absence of 3 consecutive days with neutrophils \>= 500/ul under any circumstances at day 55 * Death after day 28 with neutrophil count \< 100/ul without any evidence of engraftment (\< 5% donor CD3) * Primary autologous count recovery with \< 5% donor CD3 peripheral blood chimerism at count recovery and without relapse III. Kinetics of chimeric reconstitution. IV. Incidence of neutrophil engraftment by day 42. V. Incidence of platelet engraftment by six months. VI. Incidence of grade II-IV and III-IV acute graft-versus-host disease (GvHD) at day 100. VII. Incidence of one year chronic GvHD. VIII. Incidence of clinically significant infections at 6 months, 1 year, 2 years. IX. Probability of one and two year survival. X. Incidence of one and two year relapse or disease progression. XI. Fred Hutchinson Cancer Research Center (FHCRC) patients: Kinetics of immune reconstitution, with both functional and quantitative assays. XII. FHCRC patients: Examination of possible immunologic factors leading to emergence of a dominant unit. OUTLINE: CONDITIONING REGIMEN: Patients receive fludarabine phosphate intravenously (IV) over 1 hour on days -6 to -2 and cyclophosphamide IV over 1-2 hours on day -6. Patients undergo a lower dose of total-body irradiation (TBI) on day -1. UMBILICAL CORD BLOOD TRANSPLANT: Patients undergo donor umbilical cord blood infusion on day 0. IMMUNOSUPRESSIVE THERAPIES: Patients receive cyclosporine IV over 1 hour every 8-12 hours on days -3 to +180 and mycophenolate mofetil IV or orally (PO) every 8 hours on days 0 to +96. After completion of study treatment, patients are followed periodically for up to 2 years.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Patients \> 70 may be considered if performance status \> 80% or Eastern Cooperative Oncology Group (ECOG) =\< 1 and comorbidity score \< 3; these patients must be discussed with the principal investigator (PI), Rachel Salit prior to enrollment
- •Adequate cardiac function defined as absence of decompensated congestive heart failure, or uncontrolled arrhythmia and:
- •Left ventricular ejection fraction \>= 35% or
- •Fractional shortening \> 22%
- •Adequate pulmonary function defined as diffusion capacity of carbon monoxide (DLCO) \> 30% predicted, and absence of oxygen (O2) requirements
- •Adequate hepatic function; patients with clinical or laboratory evidence of liver disease will be evaluated for the cause of liver disease, its clinical severity in terms of liver function, histology, and the degree of portal hypertension; patients with fulminant liver failure, cirrhosis with evidence of portal hypertension or bridging fibrosis, alcoholic hepatitis, esophageal varices, a history of bleeding esophageal varices, hepatic encephalopathy, or correctable hepatic synthetic dysfunction evidenced by prolongation of the prothrombin time, ascites related to portal hypertension, bacterial or fungal abscess, biliary obstruction, chronic viral hepatitis with total serum bilirubin \> 3 mg/dL, and symptomatic biliary disease will be excluded
- •Adequate renal function defined as creatinine =\< 2.0 mg/dl (adults) or creatinine clearance \> 40 ml/min (pediatrics)
- •All adults with a creatinine \> 1.2 or a history of renal dysfunction must have estimated creatinine clearance \> 40 ml/min
- •Performance status score: Karnofsky (for adults) \>= 60 or ECOG 0-2; Lansky (for children) score \>= 50
- •If recent mold infection, e.g., Aspergillus, must be cleared by infectious disease
Exclusion Criteria
- •Patients with an available 5-6/6 HLA-A, B, DRB1 matched sibling donor
- •Pregnancy or breastfeeding
- •Evidence of human immunodeficiency virus (HIV) infection or known HIV positive serology
- •Uncontrolled viral or bacterial infection at the time of study enrollment
- •Active or recent (prior 6 month) invasive fungal infection without infectious disease (ID) consult and approval
- •Active central nervous system malignancy
- •Patients who have received \>= 2 cycles of multiagent chemotherapy within the 3 months previous to UCBT; patients who have had previous autologous transplant within 12 months of UCBT are excluded regardless of history of recent treatment
- •DONOR: Any cord blood units with \< 1.5 x 10\^7 total nucleated cells per kilogram recipient weight
- •DONOR: Any cord blood units without the full maternal testing and negative results for hepatitis A, B, C, HIV, and human T-lymphotropic virus (HTLV-1) viruses; any additional available virology results on the unit itself will be reviewed but are not mandated, complete or always available; cord blood units are presumed to be cytomegalovirus (CMV) negative regardless of serologic testing due to passive transmission of maternal CMV antibodies
Arms & Interventions
Treatment (chemotherapy, transplant)
CONDITIONING REGIMEN: Patients receive fludarabine phosphate IV over 1 hour on days -6 to -2 and cyclophosphamide IV over 1-2 hours on day -6. Patients undergo a lower dose of TBI on day -1. UMBILICAL CORD BLOOD TRANSPLANT: Patients undergo donor umbilical cord blood infusion on day 0. IMMUNOSUPRESSIVE THERAPIES: Patients receive cyclosporine IV over 1 hour every 8-12 hours on days 0 to +180 and mycophenolate mofetil IV or PO every 8 hours on days -3 to +96.
Intervention: Allogeneic Hematopoietic Stem Cell Transplantation
Treatment (chemotherapy, transplant)
CONDITIONING REGIMEN: Patients receive fludarabine phosphate IV over 1 hour on days -6 to -2 and cyclophosphamide IV over 1-2 hours on day -6. Patients undergo a lower dose of TBI on day -1. UMBILICAL CORD BLOOD TRANSPLANT: Patients undergo donor umbilical cord blood infusion on day 0. IMMUNOSUPRESSIVE THERAPIES: Patients receive cyclosporine IV over 1 hour every 8-12 hours on days 0 to +180 and mycophenolate mofetil IV or PO every 8 hours on days -3 to +96.
Intervention: Cyclophosphamide
Treatment (chemotherapy, transplant)
CONDITIONING REGIMEN: Patients receive fludarabine phosphate IV over 1 hour on days -6 to -2 and cyclophosphamide IV over 1-2 hours on day -6. Patients undergo a lower dose of TBI on day -1. UMBILICAL CORD BLOOD TRANSPLANT: Patients undergo donor umbilical cord blood infusion on day 0. IMMUNOSUPRESSIVE THERAPIES: Patients receive cyclosporine IV over 1 hour every 8-12 hours on days 0 to +180 and mycophenolate mofetil IV or PO every 8 hours on days -3 to +96.
Intervention: Cyclosporine
Treatment (chemotherapy, transplant)
CONDITIONING REGIMEN: Patients receive fludarabine phosphate IV over 1 hour on days -6 to -2 and cyclophosphamide IV over 1-2 hours on day -6. Patients undergo a lower dose of TBI on day -1. UMBILICAL CORD BLOOD TRANSPLANT: Patients undergo donor umbilical cord blood infusion on day 0. IMMUNOSUPRESSIVE THERAPIES: Patients receive cyclosporine IV over 1 hour every 8-12 hours on days 0 to +180 and mycophenolate mofetil IV or PO every 8 hours on days -3 to +96.
Intervention: Fludarabine Phosphate
Treatment (chemotherapy, transplant)
CONDITIONING REGIMEN: Patients receive fludarabine phosphate IV over 1 hour on days -6 to -2 and cyclophosphamide IV over 1-2 hours on day -6. Patients undergo a lower dose of TBI on day -1. UMBILICAL CORD BLOOD TRANSPLANT: Patients undergo donor umbilical cord blood infusion on day 0. IMMUNOSUPRESSIVE THERAPIES: Patients receive cyclosporine IV over 1 hour every 8-12 hours on days 0 to +180 and mycophenolate mofetil IV or PO every 8 hours on days -3 to +96.
Intervention: Laboratory Biomarker Analysis
Treatment (chemotherapy, transplant)
CONDITIONING REGIMEN: Patients receive fludarabine phosphate IV over 1 hour on days -6 to -2 and cyclophosphamide IV over 1-2 hours on day -6. Patients undergo a lower dose of TBI on day -1. UMBILICAL CORD BLOOD TRANSPLANT: Patients undergo donor umbilical cord blood infusion on day 0. IMMUNOSUPRESSIVE THERAPIES: Patients receive cyclosporine IV over 1 hour every 8-12 hours on days 0 to +180 and mycophenolate mofetil IV or PO every 8 hours on days -3 to +96.
Intervention: Mycophenolate Mofetil
Treatment (chemotherapy, transplant)
CONDITIONING REGIMEN: Patients receive fludarabine phosphate IV over 1 hour on days -6 to -2 and cyclophosphamide IV over 1-2 hours on day -6. Patients undergo a lower dose of TBI on day -1. UMBILICAL CORD BLOOD TRANSPLANT: Patients undergo donor umbilical cord blood infusion on day 0. IMMUNOSUPRESSIVE THERAPIES: Patients receive cyclosporine IV over 1 hour every 8-12 hours on days 0 to +180 and mycophenolate mofetil IV or PO every 8 hours on days -3 to +96.
Intervention: Total-Body Irradiation
Treatment (chemotherapy, transplant)
CONDITIONING REGIMEN: Patients receive fludarabine phosphate IV over 1 hour on days -6 to -2 and cyclophosphamide IV over 1-2 hours on day -6. Patients undergo a lower dose of TBI on day -1. UMBILICAL CORD BLOOD TRANSPLANT: Patients undergo donor umbilical cord blood infusion on day 0. IMMUNOSUPRESSIVE THERAPIES: Patients receive cyclosporine IV over 1 hour every 8-12 hours on days 0 to +180 and mycophenolate mofetil IV or PO every 8 hours on days -3 to +96.
Intervention: Umbilical Cord Blood Transplantation
Outcomes
Primary Outcomes
Overall Survival
Time Frame: At 1 year
Kaplan-Meier and cumulative incidence estimates will be used.
Secondary Outcomes
- Time to Platelet Engraftment of > 20,000 Cells Per mm3(By 6 months)
- Percent of Patients With Non-relapse Mortality(1 year)
- Median Time to ANC > 500(By day 55)
- Number of Participants With Graft Failure/Rejection(By day 55)
- Percent of Patients With Grade II-IV Acute Graft Versus Host Disease(By day 100)
- Percent of Patients With Acute GVHD Grades III-IV(100 days)
- Percent of Patients With Chronic GVHD(At 2 years)