Interplay of Recipient-Donor Matching for HLA, Race/Ethnicity and Gender on Long Term Outcomes in 365 Pediatric Recipients of Single 4/6 Matched Unrelated Cord Blood Transplantation (UCBT) after Myeloablative Therapy

BACKGROUND:The use of 4/6 matched cord blood units increases access to hematopoietic stem cell transplantation particularly for racial and ethnic minority patients. We conducted an analysis to identify factors that favor longer term survival in patients transplanted with single 4/6 matched cord blood (CB) grafts after myeloablative conditioning at a single center.

METHODS:We retrospectively reviewed all consecutive single CB transplants in patients ages <21 years using a myeloablative regimen from 08/1993-04/2012 at Duke using 4/6 matched (low-res HLA-A and B; high-res DRB1) unrelated donors. Prognostic factors were assessed in univariate KM analyses of overall survival (OS), disease free survival (DFS) and cumulative incidence (CInc) of neutrophil and platelet engraftment, acute grades III-IV graft-versus-host disease (GVHD) and chronic GVHD. Cox proportional hazards models were constructed using backward selection. P-values <0.05 were considered statistically significant in multivariate model. 

RESULTS:365 patients (68% Caucasian. 62.5% CMV+) with a median age of 6.28 years with malignant (MAL, n=208) and non-malignant (nMAL, n=157) diagnoses were identified with a median follow-up of 10.9 years (range, 1.4-19.9 years). Median cell dose was 6.3x10e7/kg overall and was higher in the nMAL group (8.47) which included younger children. The CInc of neutrophil engraftment was 77.9%, 80% and 75.2% and platelet engraftment was 54.2%, 51.2% and 58.2% for the total, MAL and nMAL cohorts, respectively. Graft failure or autologous recovery occurred in 24 (6.6%) and 12 (3.3%) patients. The probability of OS at 1, 5, 10 and 15 years was 57.3%, 47.6%, 46.2% and 46.2% in all patients and did not differ significantly for the MAL and nMAL cohorts. The probability of DFS at 1, 5, 10 and 15 years in the MAL cohort was 47.6%, 42.2%, 41.7% and 41.7%. The CInc of acute GVHD grades III-IV by 100 days was 14% and of chronic GVHD was 13.7% at 1 and 18.2% at 2 years. On multivariate analysis, OS in all patients and DFS in MAL cohort was favorably impacted by recipient CMV seronegativity and a cell dose of >2.5x10e7/kg measured on the pre-cryopreservation graft. In the MAL cohort, DFS was better in recipients of a gender mismatched graft and HLA matching. In the nMAL cohort, a cell dose >6.62x10e7/kg was associated with higher OS. Engraftment was better in recipients of higher cell dose grafts and in donor/recipient pairs matched at HLA-B. Acute GVHD was higher in black recipients overall, and higher when the donor/recipient pairs were not matched for race. 

CONCLUSIONS: 4/6 matched UCBT is an effective treatment for children with MAL and nMAL diseases leading to long term survival. Impact of cell dose, race, gender and differential HLA matching will improve donor selection. These outcomes are similar to those reported with better matched UCB grafts and support the use of 4/6 UCBT for patients lacking a closer matched donor.