Single or Double Umbilical Cord Blood Unit Transplantation Followed by GVHD Prophylaxis With FK506 and MMF

• 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 ]
  

Procedure: Umbilical Cord Blood Transplant
Day - -6 Fludarabine 40 mg/m2 IV Day- -6 Cyclophosphamide 50 mg/kg IV Day- -5 Fludarabine 40 mg/m2 IV Day- -4 Fludarabine 40 mg/m2 IV Day- -3 Fludarabine 40 mg/m2 IV Day- -2 Fludarabine 40 mg/m2 IV Day- -1 TBI 200 cGy X 1 Day 0 Cord blood transplant Cyclophosphamide will be dosed on adjusted ideal body weight if actual body weight is greater than the ideal body weight. If the ideal body weight is greater than or equal to the actual body weight then the actual body weight will be used for dosing. Fludarabine will be dosed on actual body weight Patients will receive standard mesna prophylaxis to prevent hemorrhagic cystitis.
Drug: GVHD prophylaxis with Tacrolimus and Mycophenolate Mofetil

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.

Other Names:
• FK 506
• MMF
• cellcept

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)