Non-Myeloablative (NMA) Umbilical Cord Blood Transplantation (UCBT): Promising Disease-Free Survival in 95 Consecutive Patients.

Abstract

Conventional allogeneic hematopoietic stem cell transplantation (HSCT) is limited by lack of rapidly available HLA-matched donors and excess transplant-related mortality (TRM). Therefore, we investigated the use of unrelated UCBT after NMA conditioning in patients (pts) with high-risk hematologic malignancy. From 10/01 to 06/05, 95 consecutive adults [median age 50 yrs (range 18-69), median weight 78 kg (range 50-134)] received a NMA prior to UCBT. Pts were eligible if aged >45 yrs (n=70; 74%), or had extensive prior therapy (n=25; 26% with 17 having had a prior autologous HSCT). Therapy consisted of cyclophosphamide (50 mg/kg), fludarabine (200 mg/m2) and TBI (200 cGy), with cyclosporine A and mycophenolate mofetil immune prophylaxis. Thirty pts (32%) without prior autologous transplant or chemotherapy in the last 3 months also received anti-thymocyte globulin (ATG). Pts received one (n=17) or two (n=78) 4–6/6 HLA A,B, and DRB1 matched UCB units (109 units were 4/6, 53 were 5/6, and 11 were 6/6 HLA matched with the pt) with a median infused cell dose of 3.6 x 107 NC/kg (range 1.1–6.8). Units were 4–5/6 HLA matched to each other in instances of double UCBT. Four pts died prior to day 28. Median follow-up is 14 mos. (range 3.3–42.7). Median time to neutrophil recovery after UCBT was 12 days (range 0–32) with an incidence of sustained donor engraftment of 87% (95%CI: 80–94). Complete chimerism was achieved by day 100 in 96% of pts. Graft failure occurred in 11 (6 primary, 5 secondary), with autologous recovery in 8. In univariate analysis neither the number of donor units, age, disease risk, ATG in the preparative regimen, CMV serostatus, HLA matching, in the 3 months prior to transplant, CD34 cell dose, diagnosis, and prior autologous transplant were independent predictors of sustained donor engraftment. Multivariate analysis identified no independent predictors of sustained engraftment. Incidence of grade II-IV & III-IV acute GVHD at day 100 and chronic GVHD at 1 yr were 61% (95%CI: 49–73), 25% (95%CI: 14–36) and 25% (95%CI: 15–35), respectively. Incidence of acute GVHD was lower among recipients receiving of ATG, but the difference was not statistically significant (II-IV=46% vs. 68%, p=.19; III-IV=13% vs. 27%, p=.24). Incidence of treatment related mortality (TRM) at day 180 and relapse/disease progression at 2 years was 18% (95%CI: 10–26) and 32% (95%CI: 22–42), respectively. In multivariate analysis, only age > 45 yrs (RR 0.3; 95%CI: 0.1–0.9, p=.03) and no chemotherapy within the 3 months prior to transplant were independent predictors of lower TRM (RR 0.36; 95%CI: 0.13–1.0, p=.05). Overall and progression-free survival were 52% (95%CI: 39–65) and 46% (95%CI: 35–57) at 1 yr, and 44% (95%CI: 30–58) and 43% (95%CI: 31–55) at 2 yrs, respectively. In Cox regression, age >45 yrs (RR of death 0.5; 95%CI: 0.2–0.9, p=.02) and chemotherapy in the 3 months prior to transplant was associated with improved survival (RR of death 0.53; 95%CI: 0.28–1.0, p=.05). In summary, with our graft selection strategy, a NMA UCBT is readily available for >90% of patients. NMA UCBT is associated with low TRM, and prompt neutrophil recovery, with progression free survival rates comparable to reported studies with HLA matched unrelated marrow HSCT. In the largest US series to date, these data suggest that age is not a limitation to allogeneic HSCT using UCB, in particular if it is the only reason for the patient to undergo a NMA transplant.