Double Unit Myeloablative Umbilical Cord Blood (UCB) Transplantation in Adults & Adolescents: High Incidence of Engraftment and Low Transplant-Related Mortality.

UCB cell dose is a critical determinant of hematopoietic recovery & survival after UCB transplantation (UCBT) & is the major barrier to adult UCBT. Therefore, we have investigated the combined transplantation of 2 partially HLA-matched UCB units to augment graft cell dose. Twenty-three patients with high-risk hematologic malignancy [median 24 yrs (range: 13–53)] received two UCB units [median infused dose 3.5 x 10⁷ NC/kg (range 1.1–6.3); larger unit 1.9 (0.6–3.6) & smaller unit 1.5 (0.5–2.7)]. Of the 46 units used, only 3 were 6/6, 16 were 5/6 & 27 were 4/6 HLA-A,B,DRB1 antigen matched unit to the recipient. All patients received myeloablative conditioning using cyclophosphamide 120 mg/kg (60 mg/kg days −7 & −6), & TBI 1320 cGy in 8 fractions with cyclosporine-A (CSA) from day -3 for at least 6 months. In addition, the first 2 patients received ATG 15 mg/kg every 12 hours days −3 to −1 & methylprednisone (MP) 1 mg/kg every 12 hours days 5–19. Subsequent patients (n = 21) received fludarabine 75 mg/m2 (25 mg/m2 days −8 to −6) & mycophenolate mofetil 1 gm twice daily from days −3 to +30 instead of ATG/MP. All evaluable patients (n = 21) engrafted at a median of 23 days (range 15–41). At day 21, engraftment was derived from both donors in 24% and a single donor in 76%, with one unit predominating in all patients (median chimerism in day 21 BM 100%). Notably, the predominating unit had a relatively low infused cell dose [median 1.8 x 10⁷ NC/kg (range 0.7–3.6); 1.5 x 10⁵ CD34+/kg (range 0.6–10.4)]. While neither NC, CD34+ & CFU-GM dose, nor HLA-A,B,DRB1 match, predicted which unit would predominate, the predominating unit had a significantly higher CD3+ dose (p < 0.01). However, the NC, CD34+ & CFU-GM doses of the predominating unit were significantly associated with the speed of neutrophil recovery. For example, the median day of neutrophil recovery for patients (n=11) with a predominating unit of 1.6–10.4 x 10⁵ CD34+/kg was day 19.5 (range 15–27) vs day 26 (range 15–41) in patients (n=10) with a predominating unit of 0.6–1.5 x 10⁵ CD34+/kg (p=0.01). Incidences of grade II–IV & III–IV acute GVHD were 65% (95%CI: 42–88) and 13% (95%CI: 0–26) at day 100, respectively, with 23% (95%CI: 6–40) having chronic GVHD at 1 year. Six month transplant-related mortality was 22% (95%CI: 5–39). With a median follow-up of 10 months (range: 3.5 months–2.5 yrs), disease-free survival (DFS) is 57% (95%CI: 35–79) at 1 year, with 72% (95%CI: 49–95) of patients alive at 1 year if transplanted in remission. These data clearly demonstrate the safety of double unit UCBT. Despite the low infused CD34+ cell dose of the predominating unit, all evaluable patients achieved sustained engraftment, with a low incidence of severe acute GVHD despite HLA-disparity. This has resulted in a low TRM, & DFS is high if patients are transplanted in remission. While the NC & CD34+ cell doses of each unit do not predict unit predominance, these parameters in the predominating unit determine the speed of neutrophil recovery. As a suitable double unit graft can be identified for the majority of adults, this approach represents a major extension of access to HSC transplantation.