Unmanipulated Bone Marrow As Third Party Donor for Unrelated Cord Blood Transplant Decreases 100-Day Mortality in Children

• UCBT has high early transplant-related mortality. We explored the feasibility of using related, mismatched, and unmanipulated bone marrow as third party donor graft with the addition of post-transplant cyclophosphamide (PtCy) for unrelated single unit UCBT (dual transplants). Our aim was to decrease UCBT early mortality without increasing aGvHD. We compared 16 cases of dual transplant (09/2012-08/14, center 1) with two single UCBT historical groups; One with PtCy (20 cases, 07/2010-08/12, center 1 & 2), and a 2nd without PtCy (31 cases, 03/2010-07/12, center 2). We did not include Fanconi and diskeratosis congenita patients. The main features of this dual platform were; 1. Pre-transplant rATG (7 mg/kg/total dose) with Rituximab (100 mg/m2/total dose), 2. Related bone marrow graft stimulated with 3 days G-CSF and 3. PtCy on days +3 and +4 (100 mg/kg/total dose). We used this core for both myeloablative (59%) and RIC UCBT. In the first 11 cases, CSA and MMF were started at day +5. In the other 6 patients, we used sirolimus before transplant (day -6) and MMF (day +5). To estimate adjusted hazards rates (HR) by transplant group we carried-out Cox’s multivariate regression models clustered by transplant year. Covariates included in the models were: age, sex, RIC, HLA match, CMV receptor status, pre-freezing total nucleated cells (TNC), CD34, female:male receptor:donor mismatch. Receptors in the dual group were older (median age (yrs) 12.1 vs 6.0 vs 6.7; P<0.01). Median CB TNC and CD34 cells infused for dual, with and without PtCy were 5.7 vs 6.7 vs 5.4x10⁷/kg (P=0.08), and 2.2 vs 2.7 vs 2.7x10⁵/kg (P=0.45), respectively. Dual, PtCy, and non-PtCy groups median time to neutrophil and platelet engraftment was 18.5 vs 25 vs 17 days (P=0.07), and 19 vs 40.5 vs 33 (P=0.01), respectively. Grades II-IV aGvHD for each group was 47%, 31%, and 56% (P=0.30). There were no cases of grade IV aGvHD in the dual or the PtCy group. Acute leukemia 12 months cumulative relapse was 6% for dual compared with the other 2 groups (32% and 33%, P=0.12). Cumulative 100-day mortality was 7% for dual compared with 23% and 28% for the other two cohorts (P=0.1). Using the non-PtCy cohort as referent, 100-day mortality HR was 0.2 (95%CI: 0.1, 0.6) for dual and 0.9 (95%CI: 0.2, 5.2) for the PtCy group. One-year HR was 0.6 (95% CI: 0.3, 1.5) for dual, and 0.9 (95%CI: 0.3, 2.9) for the PtCy group. Overall, PtCy-dual transplant approach decreases 100-day mortality, compared with PtCy and non-PtCy UCBT. This effect was independent of other relevant variables. The shorter time to neutrophil and platelet engraftment and no increase of aGVHD could explain the decrease in early mortality. The impact of this approach over cGvHD and long-term mortality in uncertain at this moment, nevertheless, we have not evidence of increased relapse in acute leukemia. Although further studies are necessary, dual-PtCy could be an alternative for patients without matched sibling donor.