Creation of a double chimera by transplantation of two unrelated donor umbilical cord blood units

Despite promising outcomes in 0-3 HLA-mismatched unrelated donor umbilical cord blood (UCB) transplant recipients, low UCB cell dose adversely affects hematopoielic recovery and survival. Therefore, we are investigating whether transplant with 2 UCB units combined will improve outcomes in larger recipients. Adults with: 1 ) advanced leukemia, 2) no HLA-matched bone marrow (BM) donor, and 3) no single 4-6 HLAmatched UCB unit with a cell dose of 2.5 x 107 nucleated cells/kilogram (nuc/kg) are eligible. A 53-year-old female patient with accelerated chronic myelogenous leukemia meeting these criteria was transplanted with 2 male UCB units. Each unit was HLA-A and B matched but double HLA-DRB1 mismatched to the patient, and were mismatched to each other at a single HLA-DRB1 locus. Infused cell doses were 0.7 x l O7 (UCB l ) and 0.9 x 107 (UCB 2) nuc/kg, respectively. The conditioning of cyclophosphamide 120 mg/kg. 1320 cGy total body irradiation and anti-thymocyte globulin 15 mg/kg (6 doses) was followed by granulocyte-colony-stimulating factor 5 Hg/kg daily from day 0 until neutrophil engraftment. GVHD prophylaxis consisted of cyclosporine and methylprednisone 2 mg/kg/day (days +5-19). The early clinical course was uneventful. Neutrophil recovery occurred on day+ 25. BM on day+21 was< 5% cellular with 97% donor chimerism, and on day +55 was 25% cellular with trilineage hematopoiesis, 98% donor chimerism and 20/20 male metaphases. Contribution of each UCB to hematopoiesis is shown below: Recipient UCB 1 UCB 2 D+21 BM 3% 76% 21% D+31Blood:Unseparated 1% 63% 36% D+55 BM 2% 71% 27% D+60 Blood:Mononudear 3% 68% 29% D+60 Blood:Ncuttophil 3% 76% 21% These data support the principle that two immunologically distinct UCB units might support hematopoiesis early after transplant potentially reducing a prolonged period of neutropenia associated with low UCB cell dose.