Double Umbilical Cord Blood Transplantation with Reduced Intensity Conditioning and Sirolimus-Based GVHD Prophylaxis.

Umbilical cord blood (UCB) is an alternative stem cell source for patients without related or unrelated donors. Single-unit UCB transplantation in adults is associated with high transplant-related mortality, largely due to delayed engraftment and infection. While double umbilical cord blood transplantation (DUCBT) is associated with faster engraftment, it is also associated with high rates of acute GVHD. We studied DUCBT using sirolimus and tacrolimus as GVHD prophylaxis to improve GVHD outcomes. Methods: Reduced-intensity conditioning consisted of fludarabine (30mg/m2×6 days), melphalan (100mg/m2× 1day), and rabbit ATG (1.5 mg/kg × 4 days). Cord blood units were ≥4/6 HLA-A, B, DR allele-matched with each other and the recipient, and contained a minimum combined dose of 3.7× 107 TNC/kg (pre-cryopreservation). GVHD prophylaxis consisted of tacrolimus (serum conc. 5–10 ng/ml) and sirolimus (serum conc. 3–12 ng/ml). Filgrastim was used routinely after transplantation, and subjects received prophylactic anti-fungal antibiotics as part of routine supportive care. Results: 27 patients (median age 49 years, range 19–67) with >100 day follow-up are reported. Diagnoses include AML(8), NHL(7), HD(4), MDS(3), CLL/PLL(2), ALL(1), MPD (1) and CML(1). The median total cell doses prior to cryopreservation were 5.25 ×107 TNC/kg (range 3.74–7.58 ×107) and 12.57 ×106 CD34+ cells (range 1.45–29.0 ×106). Neutrophil engraftment occurred at a median of 21 days (range 13–70) and platelet engraftment to 20 000/μL occurred at a median of 42 days (range 25–162) after DUCBT. Three subjects did not attain platelet transfusion independence by day 100 and there were 2 late graft failures. 3 patients developed Gr II–IV acute GVHD (2 Gr. II and 1 Gr. III). The rate of acute GVHD was lower when compared with a prior cohort that received the identical conditioning regimen, but with cyclosporine and MMF as GVHD prophylaxis (11.1% vs. 37.7%, p=0.05). 2 patients developed chronic GVHD at a median of 203 days from transplantation. The median follow up is 12 months (15 months among survivors, range 4–20 months). 100-day treatment-related mortality was 11.1%. There was no VOD or TMA. Relapse-free and overall survival at 1 year are 54.4% and 72.9% respectively. Causes of death include sepsis(4), relapse(2), and EBV-associated PTLD(2). Chimerism analysis at day 100 (n=22) revealed complete single cord chimerism in 13 subjects with mixed cord chimerism in 9. The first infused unit was the predominant unit at day 100 in 14/22 subjects. There was no correlation between cord dominance and HLA match, TNC/kg or CD34+ cell count prior to cryopreservation. Conclusions: This study demonstrates excellent engraftment after DUCBT in adult recipients after a reduced-intensity conditioning regimen. The risk of acute and chronic GVHD is low when sirolimus and tacrolimus are used as GVHD prophylaxis when compared with our prior experience with cyclosporine and MMF, and survival is comparable to historical unrelated donor cohorts.