Nonmyeloablative Allogeneic Hematopoietic Cell Transplantation From HLA Matched Unrelated Donors for Treatment of Patients With High Risk Acute Lymphocytic Leukemia in Complete Remission - A Multicenter Trial
Overview
- Phase
- Phase 2
- Intervention
- nonmyeloablative allogeneic hematopoietic stem cell transplantation
- Conditions
- Adult Acute Lymphoblastic Leukemia in Remission
- Sponsor
- Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
- Enrollment
- 30
- Locations
- 3
- Primary Endpoint
- Leukemia-free survival
- Status
- Completed
- Last Updated
- 13 years ago
Overview
Brief Summary
The reason for doing this study is to determine whether a new method of blood stem cell transplant (also known as bone marrow transplant) is able to treat acute lymphocytic leukemia. Blood stem cells are the "seed cells" necessary to make all blood cells. This new method of transplant uses a combination of low dose radiation and chemotherapy that may be less toxic and cause less harm than a conventional transplant. This lower dose transplant is called a "nonmyeloablative transplant". Researchers want to see if using less radiation and less chemotherapy combined with new immune suppressing drugs after the transplant will help a stem cell transplant to work. Researchers hope that this treatment will cure acute lymphocytic leukemia with fewer side effects. Researchers are hoping to see a mixture of recipient and donor blood cells after transplant. This mixture of donor and recipient blood cells is called "mixed chimerism". Researchers hope that donor cells will attack and eliminate the leukemia. This is called the "graft-versus-leukemia" effect. In addition, after the transplant, white blood cells from the donor may be given to enhance or "boost" the graft-versus-leukemia effect, and hopefully remove all remaining cancer cells. This study is being done because at the present time blood stem cell transplantation (or bone marrow transplantation) is the only known curative therapy for acute lymphocytic leukemia. Because of age or underlying health status acute lymphocytic leukemia patients have a higher likelihood of experiencing severe harm from a conventional blood stem cell transplant. Researchers are doing this study to see if this new nonmyeloablative method of low dose radiation and low dose chemotherapy given before transplant and immune suppressive drugs after transplant will help make the transplant safer and also cure acute lymphocytic leukemia
Detailed Description
PRIMARY OBJECTIVES: I. To determine if a one-year disease-free survival (DFS) of \> 25% can be achieved among adult patients with high risk acute lymphocytic leukemia (ALL) in complete remission (CR) who undergo nonmyeloablative allografting. II. To determine if a one-year DFS of \>= 40% can be achieved among pediatric patients with high risk ALL in CR who undergo nonmyeloablative allografting. SECONDARY OBJECTIVES: I. To determine if a day +200 transplant-related mortality (TRM) of \< 25% can be achieved among patients with high risk ALL in CR who undergo nonmyeloablative allografting. II. To evaluate the efficacy and toxicity of donor lymphocyte infusion (DLI) in the treatment of minimal residue disease (MRD) after nonmyeloablative allografting for patients with high risk ALL in CR. OUTLINE: NONMYELOALATIVE CONDITIONING REGIMEN: Patients receive fludarabine phosphate intravenously (IV) on days -4 to -2 and undergo total body irradiation (TBI) on day 0. TRANSPLANTATION: Patients undergo allogeneic peripheral blood stem cell transplantation (PBSCT) on day 0. Patients with minimal residual disease may receive donor lymphocyte infusion IV. IMMUNOSUPPRESSION: Patients receive cyclosporine orally (PO) every 12 hours on days -3 to 100 with taper to day 177 and mycophenolate mofetil PO very 8 hours on days 0 to 40 with taper to day 96. After completion of study treatment, patients are followed up at days 28, 56, 84, 120, 180, and 360; at 18 months; and annually for up to 5 years.
Investigators
Eligibility Criteria
Inclusion Criteria
- •ADULT PATIENTS:
- •Patients 50-75 years old with high risk ALL in first CR (CR1) or ALL in CR \>= second CR (CR2)
- •Patients \>= 18 years old and \< 50 years old with high risk ALL in CR1 who are not eligible for a conventional allogeneic transplantation based on general medical condition
- •Patients \>= 18 years old and \< 50 years old with high risk ALL in CR1 who refuse a conventional allogeneic transplant
- •Patients \>= 18 years old and \< 50 years old with ALL in CR \>= CR2 who are not eligible for a conventional allogeneic transplantation based on general medical condition
- •Patients \>= 18 years old and \< 50 years old with high risk ALL in CR \>= CR2 who refuse a conventional allogeneic transplant
- •CR is defined as \< 5% blasts by morphology on a bone marrow aspirate and the absence of peripheral blasts
- •High risk adult ALL in CR1 includes those patients with one or more of the following:
- •Age \>=30 years
- •Non T-cell phenotype
Exclusion Criteria
- •Active central nervous system (CNS) disease
- •Presence of circulating leukemic blasts (in the peripheral blood) detected by standard pathology
- •Fertile men or women unwilling to use contraceptive techniques during and for 12 months following treatment
- •Pregnancy or breastfeeding
- •Human immunodeficiency virus (HIV) seropositivity
- •ORGAN DYSFUNCTION, ADULT CRITERIA:
- •Requiring supplementary continuous oxygen OR diffusing capacity of the lung for carbon monoxide (DLCO) \< 40%
- •Cardiac ejection fraction \< 35%
- •Patients with clinical or laboratory evidence of liver disease would be evaluated for the cause of liver disease, its clinical severity in terms of liver function, and the degree of portal hypertension; patients will be excluded if they are found to have fulminant liver failure, cirrhosis of the liver with evidence of portal hypertension, alcoholic hepatitis, esophageal varices, a history of bleeding esophageal varices, hepatic encephalopathy, uncorrectable hepatic synthetic dysfunction evinced by prolongation of the prothrombin time, ascites related to portal hypertension, bridging fibrosis, bacterial or fungal liver abscess, biliary obstruction, chronic viral hepatitis with total serum bilirubin \> 3 mg/dL, and symptomatic biliary disease
- •Karnofsky performance score \< 50
Arms & Interventions
Treatment (nonmyeloablative allogeneic PBSCT)
NONMYELOALATIVE CONDITIONING REGIMEN: Patients receive fludarabine phosphate IV on days -4 to -2 and undergo TBI on day 0. TRANSPLANTATION: Patients undergo allogeneic PBSCT on day 0. Patients with minimal residual disease may receive donor lymphocyte infusion IV. IMMUNOSUPPRESSION: Patients receive cyclosporine PO every 12 hours on days -3 to 100 with taper to day 177 and mycophenolate mofetil PO very 8 hours on days 0 to 40 with taper to day 96.
Intervention: nonmyeloablative allogeneic hematopoietic stem cell transplantation
Treatment (nonmyeloablative allogeneic PBSCT)
NONMYELOALATIVE CONDITIONING REGIMEN: Patients receive fludarabine phosphate IV on days -4 to -2 and undergo TBI on day 0. TRANSPLANTATION: Patients undergo allogeneic PBSCT on day 0. Patients with minimal residual disease may receive donor lymphocyte infusion IV. IMMUNOSUPPRESSION: Patients receive cyclosporine PO every 12 hours on days -3 to 100 with taper to day 177 and mycophenolate mofetil PO very 8 hours on days 0 to 40 with taper to day 96.
Intervention: donor lymphocytes
Treatment (nonmyeloablative allogeneic PBSCT)
NONMYELOALATIVE CONDITIONING REGIMEN: Patients receive fludarabine phosphate IV on days -4 to -2 and undergo TBI on day 0. TRANSPLANTATION: Patients undergo allogeneic PBSCT on day 0. Patients with minimal residual disease may receive donor lymphocyte infusion IV. IMMUNOSUPPRESSION: Patients receive cyclosporine PO every 12 hours on days -3 to 100 with taper to day 177 and mycophenolate mofetil PO very 8 hours on days 0 to 40 with taper to day 96.
Intervention: cyclosporine
Treatment (nonmyeloablative allogeneic PBSCT)
NONMYELOALATIVE CONDITIONING REGIMEN: Patients receive fludarabine phosphate IV on days -4 to -2 and undergo TBI on day 0. TRANSPLANTATION: Patients undergo allogeneic PBSCT on day 0. Patients with minimal residual disease may receive donor lymphocyte infusion IV. IMMUNOSUPPRESSION: Patients receive cyclosporine PO every 12 hours on days -3 to 100 with taper to day 177 and mycophenolate mofetil PO very 8 hours on days 0 to 40 with taper to day 96.
Intervention: total-body irradiation
Treatment (nonmyeloablative allogeneic PBSCT)
NONMYELOALATIVE CONDITIONING REGIMEN: Patients receive fludarabine phosphate IV on days -4 to -2 and undergo TBI on day 0. TRANSPLANTATION: Patients undergo allogeneic PBSCT on day 0. Patients with minimal residual disease may receive donor lymphocyte infusion IV. IMMUNOSUPPRESSION: Patients receive cyclosporine PO every 12 hours on days -3 to 100 with taper to day 177 and mycophenolate mofetil PO very 8 hours on days 0 to 40 with taper to day 96.
Intervention: fludarabine phosphate
Treatment (nonmyeloablative allogeneic PBSCT)
NONMYELOALATIVE CONDITIONING REGIMEN: Patients receive fludarabine phosphate IV on days -4 to -2 and undergo TBI on day 0. TRANSPLANTATION: Patients undergo allogeneic PBSCT on day 0. Patients with minimal residual disease may receive donor lymphocyte infusion IV. IMMUNOSUPPRESSION: Patients receive cyclosporine PO every 12 hours on days -3 to 100 with taper to day 177 and mycophenolate mofetil PO very 8 hours on days 0 to 40 with taper to day 96.
Intervention: mycophenolate mofetil
Treatment (nonmyeloablative allogeneic PBSCT)
NONMYELOALATIVE CONDITIONING REGIMEN: Patients receive fludarabine phosphate IV on days -4 to -2 and undergo TBI on day 0. TRANSPLANTATION: Patients undergo allogeneic PBSCT on day 0. Patients with minimal residual disease may receive donor lymphocyte infusion IV. IMMUNOSUPPRESSION: Patients receive cyclosporine PO every 12 hours on days -3 to 100 with taper to day 177 and mycophenolate mofetil PO very 8 hours on days 0 to 40 with taper to day 96.
Intervention: laboratory biomarker analysis
Treatment (nonmyeloablative allogeneic PBSCT)
NONMYELOALATIVE CONDITIONING REGIMEN: Patients receive fludarabine phosphate IV on days -4 to -2 and undergo TBI on day 0. TRANSPLANTATION: Patients undergo allogeneic PBSCT on day 0. Patients with minimal residual disease may receive donor lymphocyte infusion IV. IMMUNOSUPPRESSION: Patients receive cyclosporine PO every 12 hours on days -3 to 100 with taper to day 177 and mycophenolate mofetil PO very 8 hours on days 0 to 40 with taper to day 96.
Intervention: peripheral blood stem cell transplantation
Outcomes
Primary Outcomes
Leukemia-free survival
Time Frame: 1 year
Incidence of survival without relapse. Kaplan-Meier estimates will be used to estimate one-year leukemia-free survival.
Secondary Outcomes
- Transplant-related mortality(1 year)
- Efficacy of DLI for the elimination of MRD(Up to day 120)
- Toxicity of DLT, graded using a modified version of the National Cancer Institute (NCI) Common Toxicity Criteria(Up to 5 years)
- Overall survival(1 year)
- Incidence of relapse(1 year)
- Incidence of rejection(1 year)
- Incidence of acute grade II-IV graft-versus-host disease (GVHD) and chronic GVHD, graded using a modified version of the National Cancer Institute (NCI) Common Toxicity Criteria(Up to 5 years)
- Karnofsky performance score and Lansky performance score(1 year)