The influence of cell dose and human leukocyte antigen (HLA) match on doubleunit cord blood (CB) engraftment is not established. Therefore, we analyzed the impact of cell dose and high-resolution HLA match on neutrophil engraftment in 84 double-unit CB transplant recipients. The 94% sustained engraftment rate was accounted for by 1 unit in nearly all patients. Higher CD3 ؉ cell doses (P ‫؍‬ .04) and percentage of CD34 ؉ cell viability (P ‫؍‬ .008) were associated with unit dominance. After myeloablative conditioning, higher dominant unit total nucleated cell (TNC), CD34 ؉ cell, and colony-forming unit doses were associated with higher sustained engraftment and faster neutrophil recovery (P ‫؍‬ .07, P ‫؍‬ .0008, and P < .0001, respectively). Total infused TNC (P ‫؍‬ .0007) and CD3 ؉ cell doses (P ‫؍‬ .001) also significantly influenced engraftment. At high-resolution extensive donor-recipient HLA disparity was frequent, but had no influence on engraftment (P ‫؍‬ .66), or unit dominance (P ‫؍‬ .13). Although the unit-unit HLA match also did not affect sustained engraftment (P ‫؍‬ 1.0), recipients of units closely (7-10 to 10-10) HLA-matched to each other were more likely to demonstrate initial engraftment of both units (P < .0001). Our findings have important implications for unit selection and provide further insight into double-unit biology. (Blood. 2011;117(12): 3277-3285)

Factors contributing to infection risk following cord blood transplantation (CBT) include the use of anti-thymocyte globulin (ATG), prolonged neutropenia, and failure to transfer immunity. To potentially reduce the infection risk we have investigated double unit CBT without ATG, and have evaluated the nature of serious infections in the first year after CBT using this approach. Seventy-two predominantly adult patients were transplanted for hematologic malignancies; 52 patients received myeloablative and 20 had non-myeloablative conditioning. The peak incidence of bacterial infections, fungal infections, or bacterial/ fungal pneumonias was in the first 30 days post-transplant and affected 32%, 14%, and 10% of patients, respectively. Three such infections contributed to early mortality. The peak incidence of viral infections was 31-60 days post-transplant affecting 30% of patients. Cytomegalovirus (CMV) was the most common viral infection. CMV infections prior to day 120 (n = 23) had no relationship with graft-versus-host disease (GVHD), whereas CMV infections after day 120 (n = 5), and all Epstein-Barr virus viremia (EBV, n = 5) and adeno-viral enteritis (n = 2) occurred exclusively in the context of GVHD therapy or corticosteroid use for another indication. Viral infections had the highest lethality: 2 were a direct cause of death and 3 contributed to death. Patients exhibited steady immune recovery achieving a median CD3+4+ T-cell count > 200 cells/microL by day 120, and after day 120 there were no infection-related deaths. Our results suggest that double unit CBT without ATG is associated with prompt T-cell recovery, and unlike CBT incorporating ATG, infection is rarely a primary cause of death. However, CBT without ATG is associated with a significant risk of GVHD and serious infections remain a burden, especially in the setting of GVHD. New strategies are required to further reduce infectious complications after CBT and will require earlier neutrophil recovery and more effective prevention of GVHD, ideally without the profound T-cell depletion associated with ATG.

• Dominant unit infused viable CD34 1 cell dose determines engraftment after double-unit CBT.• Postthaw CD341 cell recovery and viability are strongly associated with differences in CB banking practices.We investigated the unit characteristics associated with engraftment after double-unit cord blood (CB) transplantation (dCBT) and whether these could be reliably identified during unit selection. Cumulative incidence of neutrophil engraftment in 129 myeloablative dCBT recipients was 95% (95% confidence interval: 90-98%). When precryopreservation characteristics were analyzed, the dominant unit CD34 1 cell dose was the only characteristic independently associated with engraftment (hazard ratio,

Key Points• ST2 is independently associated with aGVHD after day 28 in cord blood transplantation recipients.• High ST2 levels predict for increased TRM in cord blood transplantation recipients.While cord blood transplantation (CBT) is an effective therapy for hematologic malignancies, acute graft-versus-host disease (aGVHD) is a leading cause of transplant-related mortality (TRM). We investigated if biomarkers could predict aGVHD and TRM after day 28 in CBT recipients. Day 28 samples from 113 CBT patients were analyzed. Suppressor of tumorigenicity 2 (ST2) was the only biomarker associated with grades II-IV and III-IV aGVHD and TRM. Day 180 grade III-IV aGVHD in patients with high ST2 levels was 30% (95% confidence interval [CI], 18-43) vs 13% (95% CI, 5-23) in patients with low levels (P 5 .024). The adverse effect of elevated ST2 was independent of HLA match. Moreover, high day 28 ST2 levels were associated with increased TRM with day 180 estimates of 23% (95% CI, 13-35) vs 5% (95% CI, 1-13) if levels were low (P 5 .001). GVHD was the most common cause of death in high ST2 patients. High concentrations of tumor necrosis factor receptor-1, interleukin-8, and regenerating isletderived protein 3-a were also associated with TRM. Our results are consistent with those of adult donor allografts and warrant further prospective evaluation to facilitate future therapeutic intervention to ameliorate severe aGVHD and further improve survival after CBT. (Blood. 2015;125(1):199-205)

Cord blood transplantation (CB-T) is increasingly used as a treatment alternative for hematologic malignancies. However, how CB-T compares to related (RD-T) and unrelated donor transplantation (URD-T) is not established. We compared survival of 75 double unit CB-T, 108 RD-T, and 184 URD-T recipients transplanted over the same period for the treatment of hematologic malignancies. Patients had similar ages and disease-risk, and a similar percentage had acute leukemia. The incidence of day 180 transplant-related mortality (TRM) of 21% (95%CI:12-31) after CB-T was higher than that of RD-T recipients. However, this was compensated for by a low risk of TRM after day 180, and a relatively low incidence of relapse. Hence, the 2 year progression-free survival (PFS) of 55% (95%CI:45-68) after CB-T was similar to that after RD-T or URD-T (p = 0.573). In multivariate analysis, donor source had no influence on PFS, with the only significant factors being recipient age and disease-risk. In a sub-analysis of 201 patients with acute leukemia, CB-T, RD-T and URD-T recipients also had similar 2 year disease-free survival (p = 0.482). These data provide strong support for the further investigation of double unit CB grafts as an alternative hematopoietic stem cell source.