Single or Double Umbilical Cord Blood Unit Transplantation Followed by GVHD Prophylaxis With FK506 and MMF
Recruitment status was Active, not recruiting
Allogeneic stem cell transplant (SCT) is a potentially curative treatment for a variety of hematological malignancies. Only about 30% of patients have a suitable matched related donor (MRD) identifiable. Unrelated donors are available to 70% of Caucasians, but the percentage of minorities who can find a matched unrelated donor (MUD) is much less. Adult unrelated donors need to be either completely matched or with minimal mismatch, because the rate of severe fatal graft-versus-host disease (GVHD) increases as the rate of mismatch also increases. Umbilical cord blood (UCB) SCT has the potential advantages of increased accessibility to the stem cells, and a decreased incidence of severe GVHD despite being HLA mismatched. The widespread applicability of UCB SCT has been limited by the small number of stem cells in each unit. Recent advances in the field of UCB SCT have shown the potential feasibility of double UCB SCT to increase the cell dose and facilitate earlier engraftment. The incidence, severity, and optimal prevention of GVHD after such transplants are not known. We propose to study single or double UCB SCT in high risk patients to address some of these issues.
Cord Blood Stem Cell Transplantation
Procedure: Umbilical Cord Blood Transplant
Drug: GVHD prophylaxis with Tacrolimus and Mycophenolate Mofetil
|Study Design:||Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||The Treatment of Hematologic Malignancies With Single or Double Umbilical Cord Blood Unit Transplantation Followed by Graft-Versus-Host Disease Prophylaxis With Tacrolimus and Mycophenolate Mofetil|
- To determine the safety (as assessed by the day 100 non-relapse mortality) and feasibility of single or double UCB SCT in patients with hematological malignancies receiving GVHD prophylaxis with tacrolimus and mycophenolate mofetil (MMF). [ Time Frame: +100 days ] [ Designated as safety issue: Yes ]
- sustained donor engraftment [ Time Frame: 42 days ] [ Designated as safety issue: Yes ]
- neutrophil recovery [ Time Frame: 3 consecutive days with an ANC above 500/mm3 ] [ Designated as safety issue: Yes ]
- platelet recovery [ Time Frame: 7 days where the platelet count remains above 20,000/mm3 without transfusion support. ] [ Designated as safety issue: Yes ]
- incidence and severity of acute GVHD [ Time Frame: develops within the first three months after transplantation ] [ Designated as safety issue: Yes ]
- incidence and severity of chronic GVHD [ Time Frame: does not occur until two-three months after transplantation. ] [ Designated as safety issue: Yes ]
- relapse rate [ Time Frame: followed at least on a monthly basis until 1 year post transplant and then every 2-4 months ] [ Designated as safety issue: Yes ]
- 100 day all cause mortality [ Time Frame: 100 days ] [ Designated as safety issue: Yes ]
- overall survival [ Time Frame: until death ] [ Designated as safety issue: Yes ]
- immune reconstitution after single or double UCB SCT in patients with hematologic malignancies receiving GVHD prophylaxis with tacrolimus and MMF. [ Time Frame: +730 (+/-10) day after transplant ] [ Designated as safety issue: Yes ]
|Study Start Date:||September 2005|
|Estimated Study Completion Date:||September 2009|
|Estimated Primary Completion Date:||September 2009 (Final data collection date for primary outcome measure)|
Procedure: Umbilical Cord Blood Transplant
- FK 506
Adult and pediatric patients will receive tacrolimus(FK 506)and mycophenolate mofetil (MMF, cellcept)
Adult(age greater than or equal to 18 years but less than or equal to 40 years) MMF will be dosed at 15 mg/kg IV or PO bid, with doses rounded to the nearest 250 mg (capsules are 250 mg). For adult patients, MMF is administered on days 0 through 100.
Pediatric (defined as less than 18 years)
MMF will be dosed at 15 mg/kg IV or PO Q8, with doses rounded to the nearest 250 mg (capsules are 250 mg). For all patients, MMF is administered on days 0 through 100.
Tacrolimus will be given orally at 0.12 mg/kg/day in 2, divided doses (or intravenously at 0.03 mg/kg/day by continuous infusion if the patient is unable to tolerate PO medication) day -2 through day +180.
At day +180 ifno evidence of GVHD, tacrolimus tapered at approximately 10% every 5-7 days until finishing or development of GVHD.
Patients unable to tolerate FK switched to Cyclosporine and continued on study.
An increasing number of patients with fatal malignant and nonmalignant diseases are being treated with SCT. Unfortunately only about 30% of patients who could benefit from this procedure have a HLA-matched related donor (MRD), and only an additional 20% can find a suitable HLA-matched unrelated donor (MUD) 1. This problem is magnified in patients of minority groups who are often underrepresented in the donor pool. In an attempt to expand the number of patients who could be helped by transplantation alternative donor sources has been explored including UCB. Transplantation using UCB has numerous advantages including: ease of procurement, lack of donor attrition, absence of risk to mothers and donors, potential reduced risk of GVHD, and less stringent criteria for HLA matching 2. However these benefits are limited by the delayed engraftment, extended post-transplant neutropenia and thrombocytopenia, increased infection rate, and relative decreased cell dose of the graft.
Pediatric Experience in UCB SCT (Related and Unrelated Donors) Related UCB SCT
By November 1996, 74 patients had been treated with a related UCB SCT and the data had been reported to the International Cord Blood Transplant Registry (ICBTR) 3. Twenty patients received HLA 1-3 antigen mismatched grafts. Pretransplant conditioning therapy, post-transplant use of hematopoietic growth factors and prophylaxis for acute GVHD varied between institutions.
For recipients of HLA-matched or HLA-1 antigen mismatched UCB grafts, the actuarial probability of hematopoietic recovery at 60 days after transplantation was 91% ± 8%. Median times to neutrophil recovery (defined as time to achieve an absolute neutrophil count [ANC] > 0.5 x 109/L) and platelet recovery (defined as platelet count >50 x 109/L untransfused for 7 days) were 22 days (range, 9 to 46) and 51 days (range, 15 to 117) after transplantation, respectively. Four patients never had signs of hematopoietic recovery and one patient had early recovery but cells were entirely host in origin. Of the 5 patients without donor cell engraftment, 4 had undergone UCB SCT for the treatment of a bone marrow failure syndrome and one for the treatment of Hunter's syndrome.
Acute GVHD has occurred very infrequently in recipients of HLA-matched and HLA-1 antigen mismatched UCB SCT. The actuarial probability of grade II-IV GVHD at 100 days after transplantation was 3%. Notably, only one patient has been reported to have grade III-IV aGVHD.
Of the 15 recipients of 2 and 3 antigen disparate haploidentical transplants, 12 were evaluable for GVHD (3 died of graft failure). Moderate to severe GVHD occurred in 3 patients. As shown in Table 1, donor-recipient pairs mismatched at the maternal allele appeared to be much less likely to develop grade II-IV GVHD than donor-recipient pairs mismatched at the paternal allele. This observation supports the hypothesis that partial tolerance may develop to the non-inherited maternal allele (NIMA) during gestation as opposed to the non-inherited paternal allele (NIPA)
|United States, Tennessee|
|Vanderbilt University Medical Center|
|Nashville, Tennessee, United States, 37232-5505|
|Principal Investigator:||Brian G. Engelhardt, M.D.||Vanderbilt University|