Clinical Trial: Fludarabine-based Conditioning for Severe Aplastic Anemia (BMT CTN 0301)

Study Status: Completed
Recruit Status: Completed
Study Type: Interventional

Official Title: Fludarabine-based Conditioning for Allogeneic Marrow Transplantation From HLA-compatible Unrelated Donors in Severe Aplastic Anemia (BMT CTN #0301)

Brief Summary: The purpose of the current study is to continue to optimize conditioning regimens in high-risk patients with severe aplastic anemia transplanted with marrow from HLA-compatible unrelated donors. Specifically, the study will determine whether the addition of fludarabine to the conditioning regimen previously described by Deeg et al. will permit a reduction in the CY dose, to a point where sustained hematopoietic engraftment and survival are maintained (or improved), while the frequency of major regimen-related toxicity (RRT) and early deaths is reduced.

Detailed Summary:

BACKGROUND:

Aplastic anemia (AA) remains a life-threatening illness. Treatment options include supportive care (transfusions, growth factors, etc.), immunosuppression therapy and stem cell transplantation. Only the latter two have favorably impacted the natural history of the disease. The prognosis of AA patients, particularly severe aplastic anemia (SAA), as defined by Camitta et al., who fail to respond to immunosuppressive therapy (IS) or who relapse after an initial response to IS is poor. Although many of these patients can be supported in the short term with growth factors, transfusions and possibly rechallenged successfully with IS, the cumulative morbidity and mortality from infection, hemorrhage or transfusion-related complications is substantial.

While allogeneic bone marrow transplantation is potentially curative in AA, no more than 25% of patients have a human leukocyte antigen (HLA)-identical sibling donor. Cyclophosphamide (CY)-antithymocyte globulin (ATG) has been recommended as the preparative regimen of choice in sibling donor transplants. Results of bone marrow transplantation from alternative donors, such as matched unrelated donors and mismatched related donors in AA patients who have failed IS, have largely been unsatisfactory. The cyclophosphamide-ATG conditioning regimen has proved inadequate in ensuring engraftment in allogeneic transplants from matched, unrelated donors for AA. This was the major reason why total body radiation (TBI) has been added to the conditioning regimen.

Graft failure is a very serious and frequently life-threatening or fatal event following matched unrelated donor (MUD) allografts in aplastic anemia. It is an immunologically mediated event. Risk factors for graft failure include the use of HLA nonidentical or unrelated donors
Sponsor: Medical College of Wisconsin

Current Primary Outcome: Disease-free Survival (DFS) [ Time Frame: Day 100 ]

DFS includes graft failure, regimen-related toxicity (RRT), and early death. Graft Failure is defined by lack of neutrophil engraftment (ANC less than 0.5 x 10^9/L for 3 consecutive days on different days). Major RRT is defined as severity of grade 4 in any organ system or grade 3 for pulmonary, cardiac, renal, oral mucosal or hepatic. Early death is defined as death prior to Day 100 post-transplant.


Original Primary Outcome:

  • Primary Graft Failure - defined by lack of neutrophil engraftment (ANC < 0.5 x 109/L for 3 consecutive days on different days) by 42 days post-transplant
  • Regimen-related Toxicity (RRT) - scored according to the Bearman scale
  • Early Death - defined as death prior to Day 42 post-transplant


Current Secondary Outcome:

  • Cumulative Incidence of Graft Failure [ Time Frame: Day 365 ]
    Primary and secondary graft failure are included, secondary graft failure is defined by initial neutrophil engraftment followed by subsequent decline in the ANC to less than 0.5 x 10^9/L for three consecutive measurements on different days, unresponsive to growth factor.
  • Acute Graft vs Host Disease (GVHD) [ Time Frame: Day 100 ]
    All GVHD grades 2-4 will be graded according to the BMT CTN Manual of Procedures (MOP)
  • Chronic GVHD [ Time Frame: Day 365 ]
    Chronic GVHD is scored according to the BMT CTN MOP. The first day of chronic GVHD onset will be used to calculate cumulative incidence curves.
  • Overall Survival (OS) [ Time Frame: Day 365 ]
    OS is defined as alive at 1 year, the event is death from any cause. Patients alive at the time of last observation, for statistical purposes, will have a survival time which is censored.


Original Secondary Outcome:

  • Secondary Graft Failure - defined (in patients surviving at least 42 days) by initial neutrophil engraftment followed by subsequent decline in the ANC to < 0.5 x 109/L for three consecutive measurements on different days, unresponsive to growth factor
  • Acute GVHD of Grades 2-4 and 3-4 - graded according to the BMT CTN Manual of Procedures (measured through 100 days)
  • Chronic GVHD - Chronic GVHD is scored according to the BMT CTN MOP. The first day of chronic GVHD onset will be used to calculate cumulative incidence curves.


Information By: Medical College of Wisconsin

Dates:
Date Received: May 12, 2006
Date Started: January 2006
Date Completion:
Last Updated: October 3, 2016
Last Verified: August 2016