Reduced-intensity conditioning (RIC) with conventional adult donor allogeneic graft sources is increasingly utilized for patients deemed unable to tolerate fully myeloablative conditioning due to advanced age and/or comorbidity; with the advantages of lower early treatment-related mortality and faster hematopoietic recovery. 1 Use of unrelated allogeneic umbilical cord blood (UCB) grafts in the reduced-intensity setting, however, has been limited due to concerns of possible higher rates of primary graft failure. 2, 3 Limited cell dose in a single UCB graft provides sound rationale for consideration of multiple UCB unit transplantation in adult patients. Early experience with two unit UCB infusions has included specified requirements for human leukocyte antigens (HLA) matching between UCB units as well as to the patient. 4–6 In UCB multiunit studies to date, there has been no unit characteristic (cell dose, degree of HLA matching and so on) that predicts donor engraftment of one UCB unit over another. This exploratory phase I prospective clinical trial was designed to determine if a minimum nucleated cell dose (X5Â 107 per kg) provided by infusion of multiple (3–5) unrelated donor UCB units would improve rates and kinetics of allogeneic donor engraftment for adult recipients treated with RIC. This strategy was based on a review of UCB engraftment after myeloablative conditioning7 indicating 100% probability of allogeneic donor engraftment in pediatric recipients receiving single UCB graft cell doses exceeding 5 Â107 cells per kg. The clinical objectives of the study were to determine the safety of this approach in adults with advanced hematologic malignancies, and to determine the rates and kinetics of UCB donor-derived engraftment. Correlative laboratory studies included measurement of host-vs–graft (HvG) T-and natural killer (NK)-cell reactivity in mixed lymphocyte cultures and their relation to clinical observations of donor engraftment. A total of seven patients were consecutively enrolled and treated during March 2002 to March 2003 (Table 1). The median age of enrolled study patients was 56 years (range 20–69), and median weight was 77 kg (range 71–99). Four study patients had received intensive chemotherapy within 3 months prior to multi UCB unit transplantation. The UCB graft characteristics are summarized in Tables 2a and b. Graft units (3–5) were at least an HLA 4/6 match to the patient and no matching was required between the cord blood units. UCB grafts and patient HLA typing was performed using standard molecular analyses including antigen level for HLA-A and-B loci, and allele level for HLA-DR loci. To determine overall degree of HLA matching, the total number of HLA matched loci of all grafts was divided by all HLA loci. The median overall proportion of HLA matching for the entire patient cohort was 72%(range 67–83, Table 2a). HLA matching between individual UCB units was not required. Patients received a combined median nucleated cell dose of 5.4 Â107 cells per kg (range 4.2–8.9 Â107 cells per kg), which provided a median CD34þ cell dose of 2.3 Â105 cells per kg (range 1.7–6.2 Â105 cells per kg). A median CD3þ T-cell dose of 11.5 Â 106 cells per kg (range 8.8–23.7 Â106 cells per kg) was infused. Additionally, a median NK and NK/T-cell dose of 1.2 Â106 (range 0.4–9.8 Â106 cells per kg) and 5.3 Â106 cells per kg (range 4.5–12.3 Â106 cells per kg) was infused (Table 2b). Individual unit total nucleated cell doses pre-freeze included a median of 1.2 Â107 cells per kg (range 0.6–3.6 Â107 cells per kg). It is noteworthy that 2 of the 24 individual UCB units contained> 2.5 Â107 nucleated cells per kg and 11 of 24 …