Non-Myeloablative Umbilical Cord Blood Transplantation (UCBT): Low Transplant-Related Mortality in 59 High-Risk Adults.

Conventional allogeneic HSC transplantation is limited by lack of rapidly available, HLA-matched donors & excess transplant-related mortality (TRM) in high-risk adults. Therefore, we investigated the combined use of unrelated donor UCB, utilizing 2 units to augment graft cell dose, with non-myeloablative (NMA) conditioning in adults with advanced or high-risk hematologic malignancy. From 10/01 to 3/04, 59 consecutive adults [median age 49 years (range 19–60), median weight 78 kg (range 53–114)] received NMA UCB UCBT. Patients were eligible if: age >45 years (n=43; 73%); &/or extensive prior therapy (n=25; 42%, inc. 14 prior transplants); &/or serious co-morbidity (n=18; 31%). Patients received cyclophosphamide 50 mg/kg (day-6), fludarabine 200 mg/m² (40 mg/m² days−6 to −2), & 200 cGy TBI (day-1), with cyclosporine-A to at least day 100 & mycophenolate mofetil to day 30. Twelve patients without recent chemotherapy also received ATG during conditioning. Patients received either single (n=14) or double (n=45) UCB units with a median total infused cell dose of 3.4 x 10⁷ NC/kg (range 1.1–5.7). Of the 104 units used, 61 were 4/6, 35 were 5/6 & 8 were 6/6 HLA-A,B,DRB1-antigen matched with the recipient. Of 58 evaluable patients, neutrophil recovery to >0.5 x 10⁹/l occurred at a median of 8 days (range 5–32) with a cumulative incidence of sustained donor engraftment of 89% (95%CI: 81–97). In patients with sustained donor engraftment the median BM chimerism was 85% (range 8–100) at day 21, 100% (range 72–100) at day 100, & 100% (range 87–100) at 1 year after transplant. Four patients had primary graft failure & 2 had secondary graft rejection. Of the 44 patients with a prior autograft or chemotherapy within 3 months prior to UCBT, 43 (98%) achieved sustained engraftment as compared to 9/14 (64%) patients who had no chemotherapy or whose chemotherapy was at least 4 months prior to UCBT. The cumulative incidences of grade II–IV & III–IV acute GVHD were 63% (95%CI: 49–77) & 25% (95%CI: 14–36) at day 100, & chronic GVHD was 28% (95%CI: 16–40) at 1 year. TRM was 19% (95%CI: 9–29) at day 180, & relapse/progression was 33% (95%CI: 20–46) at both 1 & 2 years. Regression of relapsed or persistent disease has been seen in patients with MDS (n=2), CML (n=1), intermediate and low grade NHL/CLL (n=11), Hodgkins disease (n=1) & myeloma (n=1). With a median follow-up of 16 months (range 4–30), the probability of overall & progression-free survival was 52% (95%CI: 39–65) & 37% (95%CI: 24–50) at 1 year, & 44% (95%CI: 30–58) & 37% (95%CI: 24–50) at 2 years, with no difference in outcome between single & double unit recipients. Notably, day 180 TRM in patients aged >45 years was 14% (95%CI: 4–24), & in those with extensive prior therapy was 24% (95%CI: 8–40). Serious co-morbidity, however, was associated with a higher day 180 TRM of 44% (95%CI: 20–68)(p<0.01). Despite HLA disparity & NMA conditioning, NMA UCBT is associated with prompt neutrophil recovery, a high incidence of sustained engraftment & relatively low TRM in older or extensively pre-treated adults. Further, a graft-vs-malignancy effect is suggested in both myeloid & lymphoid malignancies. Extended follow-up confirms that the progression-free survival is reasonable given the high-risk nature of this patient population. This approach allows transplantation to be offered to many adults who would otherwise be ineligible based on lack of donor &/or inability to tolerate conventional conditioning.