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Individual comorbidities have distinct contributions to non-relapse mortality (NRM) following allogeneic hematopoietic cell transplantation (allo-HCT). We studied the impact of comorbidities both individually and in combination in a single-center cohort of 573 adult patients who underwent CD34-selected allo-HCT following myeloablative conditioning. Pulmonary disease, moderate to severe hepatic comorbidity, cardiac disease of any type, and renal dysfunction were associated with increased NRM in multivariable Cox regression models. A Simplified Comorbidity Index (SCI) composed of the four comorbidities predictive of NRM,as well as age> 60 years, stratified patients into five groups with a stepwise increase inNRM. NRM rates ranged from 11.4% to 49.9% by stratum, with adjustedhazard ratios of 1.84, 2.59, 3.57, and 5.38. The SCI was also applicable in an external cohort of 230 patientswho underwent allo-HCT with unmanipulated grafts following intermediate-intensity conditioning. The areaunder the ROC curve (AUC)of the SCI for 1-year NRM was 70.3 and 72.0 over the development and external-validation cohorts, respectively; corresponding AUCs of the Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI) were 61.7 and 65.7. In summary, a small setof comorbidities, aggregated into the Simplified Comorbidity Index, are highly predictive of NRM. The new index stratifies patients into distinct risk groups, was validated in an external cohort, and provides higher discrimination than the HCT-CI.

No relevant conflicts of interest to declare.

No relevant conflicts of interest to declare.

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INTRODUCTION:T-cell depleted allogeneic peripheral blood stem cell transplant (TCD PBSCT) using CD34 selection achieves relapse rates comparable to those of unmodified grafts (Pasquini et al., JCO 2012), but disease-related predictors of outcome have not been fully characterized in the TCD setting. We evaluated the prognostic utility of the refined Disease Risk Index (DRI; Armand et al., Blood 2014) in TCD PBSCT.

Perales: National Marrow Donor Program: Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria; Amgen: Honoraria; Incyte: Honoraria; Seattle Genetics: Honoraria. Giralt:TAKEDA: Consultancy, Honoraria, Research Funding; JAZZ: Consultancy, Honoraria, Research Funding, Speakers Bureau; AMGEN: Consultancy, Research Funding; SANOFI: Consultancy, Honoraria, Research Funding; CELGENE: Consultancy, Honoraria, Research Funding. Scaradavou:National Cord Blood Program- New York Blood Center: Employment.

Peled: Merck: Research Funding. Giralt:SANOFI: Consultancy, Honoraria, Research Funding; TAKEDA: Consultancy, Honoraria, Research Funding; AMGEN: Consultancy, Research Funding; JAZZ: Consultancy, Honoraria, Research Funding, Speakers Bureau; CELGENE: Consultancy, Honoraria, Research Funding. Perales:Merck: Honoraria; Takeda: Honoraria; Amgen: Honoraria; Astellas: Honoraria; NMDP: Membership on an entity's Board of Directors or advisory committees. van den Brink:Boehringer Ingelheim: Consultancy, Other: Advisory board attendee; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Tobira Therapeutics: Other: Advisory board attendee; Regeneron: Honoraria; Merck: Honoraria.

Perales: NMDP: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Astellas: Honoraria; Merck: Honoraria; Takeda: Honoraria.

Perales: BeTheMatch/ National Marrow Donor Program: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; Astellas: Honoraria; Merck: Honoraria; Amgen: Honoraria. Giralt:TAKEDA: Consultancy, Honoraria, Research Funding; JAZZ: Consultancy, Honoraria, Research Funding, Speakers Bureau; AMGEN: Consultancy, Research Funding; SANOFI: Consultancy, Honoraria, Research Funding; CELGENE: Consultancy, Honoraria, Research Funding. Straus:Millenium Pharmaceuticals: Research Funding. Moskowitz:GSK: Research Funding; Merck: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding.

Prockop: Atara Biotherapeutics: Other: I have no financial disclosures, but Atara Biotherapeutics has exercised a licensing agreement with Memorial Sloan Kettering Cancer Center and MSKCC and some investigators at MSKCC have a financial interest in Atara.. Hasan:Atara Biotherapeutics: Research Funding. O'Reilly:Atara Biotherapeutics: Research Funding.

Giralt: JAZZ: Consultancy, Honoraria, Research Funding, Speakers Bureau; TAKEDA: Consultancy, Honoraria, Research Funding; CELGENE: Consultancy, Honoraria, Research Funding; AMGEN: Consultancy, Research Funding; SANOFI: Consultancy, Honoraria, Research Funding. Scaradavou:National Cord Blood Program- New York Blood Center: Employment.

Background:Hepatic SOS is a serious complication after allogeneic HSCT. It has been reported elsewhere that in the period between 1979-2007, the overall mean incidence of hepatic SOS was 13.7% (95%CI:13-15). While prophylactic procedures are widely used, there is no uniform consensus on the optimal strategy for the prevention of this disease. Low dose UFH have been used but its benefit in the prevention of SOS and the potential associated risk of serious bleeding complications have not been fully established.

No relevant conflicts of interest to declare.

Boulad: Genzyme Sanofi: Trials partially funded by Genzyme Sanofi Other.

Boulad: Genzyme Sanofi: Trials partially funded by Genzyme Sanofi Other.

No relevant conflicts of interest to declare.

Moskowitz: Merck: Research Funding; Genentech: Research Funding; Seattle Genetics, Inc.: Consultancy, Research Funding.

No relevant conflicts of interest to declare.

No relevant conflicts of interest to declare.

No relevant conflicts of interest to declare.

No relevant conflicts of interest to declare.

No relevant conflicts of interest to declare.

No relevant conflicts of interest to declare.

Allogeneic-HCT is recommended for AML patients (pts) in CR2, in CR1 with poor-risk cytogenetics, and should be considered for those in CR1 with intermediate-risk. Non-relapse mortality (NRM) and GVHD remain major causes of treatment failure. Ex vivo TCD can prevent GvHD but large case series have not been published.A retrospective chart review was conducted to evaluate 178 pts with AML in CR1 and CR2 undergoing TCD-HCT between 2001 and 2011. All pts received myeloablative-conditioning. The majority received ATG for graft rejection prophylaxis. Acute (A) and chronic(c) GVHD were assessed by standard criteria. No GVHD prophylaxis was administered post-transplant. Soybean agglutination+sheepRBC rosetting (sRBCR) was used for BM TCD. CD34+ selection +/- sRBCR was used for PBSC TCD. Pt characteristics were compared using Pearson's chi-squared and Fisher's exact tests. Prognostic factors relating to overall survival (OS) and DFS, including age, gender, leukemia etiology, cytogenetic-risk group, donor-type, TCD-method, conditioning-regimen, HLA match grade, HCT-specific comorbidity index and immune reconstitution were evaluated using log-rank test statistics. Differences in cumulative incidence (CI) rates were evaluated using Gray's test. Cox proportional-hazards regression was used to further adjust for pt risk factors for OS and DFS.Pt characteristics and outcomes are summarized in Tables 1 and 2. Median follow-up of survivors is 52 mo (12-134). 177 pts engrafted. One died pre-engraftment, 7 developed late graft-failure (GF), and 3 are alive after a 2nd HCT. One yr incidence of aGVHD was low (grade 2-4 13%, 3-4 3%). Only 1 pt developed cGVHD by NIH consensus criteria. Univariate association between CR status (1 vs 2), OS and DFS was not statistically significant (p=0.17 and 0.16, respectively). After adjusting for HLA status, age, sex, cytogenetic risk, and regimen, CR2 pts had an increased risk of death (HR: 1.90 (1.14-3.16), p= 0.014). In CR1 pts, cytogenetics was associated with relapse incidence (p=0.003) and was highest in patients with adverse cytogenetics (31%, 95%CI 16-48) and <10% in intermediate I-II risk pts. Overall CI relapse at 1 and 2 yrs was 13% and 16%, respectively. Causes of death were: relapse (n=29), infection (n=25), GVHD (n=7), organ toxicities (n=5), GF (n=2) and other (n=7).Female gender was significantly associated with decreased OS and DFS (p<0.002 and 0.003, respectively). Two yr estimates of OS and DFS in females vs males was 51% vs. 71% and 49% vs. 69%, respectively. These differences were due to a higher NRM in females receiving the chemotherapy based regimen (p<0.001). Gender difference was not observed in pts receiving TBI-based regimens (p=0.599). This difference persisted after adjusting for other common prognostic factors in a multivariate model. For the entire group, 2yr OS and DFS was 67% and 62%, respectively. For CR1 pts, 2 yr OS and DFS was 70% and 64%, respectively (Fig.1).These results support the use of TCD HCT in AML pts in CR. Durable DFS and long-term OS can be achieved with low rates of GVHD without compromising the graft-vs-leukemia effect.No relevant conflicts of interest to declare.

Mycophenolate mofetil (MMF) is frequently combined with cyclosporine-A (CSA) as immunosuppression in unrelated donor CBT. Recent evidence suggests that therapeutic drug monitoring of mycophenolic acid (MPA), the active metabolite of MMF, is advisable based on intra- and inter-patient variability of MMF pharmacokinetics. Moreover, an increased incidence of acute graft-versus-host disease (aGVHD) has been associated with low unbound MPA AUCs in hematopoietic stem cell transplantation. This is highly relevant in cord blood transplantation (CBT) as aGVHD is a leading cause of transplant-related morbidity and mortality. However, as AUCs are cumbersome, a limited pharmacokinetic parameter such as MPA troughs would be ideal. Additionally, the toxicity associated with MPA trough levels is not established and is of concern in CBT especially due to the theoretical risk of myelosuppression from high MPA levels.We evaluated the association between serial (weeks 1-6) total MPA serum trough levels and transplant outcomes in pediatric and adult recipients of double-unit CB grafts. Patients were transplanted between 8/2009 and 11/2012 for hematologic malignancies with 4-6/6 HLA-A,-B antigen, -DRB1 allele donor-recipient matched units and intravenous CSA/MMF was commenced on day -3. To evaluate the association between trough levels and outcomes, the trough levels were dichotomized into < 2 mcg/mL and ≥ 2 mcg/mL for toxicity (neutrophil and platelet engraftment, gastro-intestinal toxicity as measured by TPN duration, and CMV infection) at each time point. For the efficacy (aGVHD prevention) analysis, mean week 1 and 2 trough levels were split at < 0.5 versus ≥ 0.5 mcg/mL.Eighty-three patients (median age 44 years, range 1-71) had MPA serum trough levels drawn weekly for the first 6 weeks after CBT. Sixty-nine (83%) received myeloablative (MA) conditioning and 45 (54%) were CMV seropositive. Diagnoses included acute leukemia (n = 51), myeloproliferative disorders/MDS (n = 7), or lymphoma (n = 25). Median trough levels by week were 0.9, 0.9, 0.6, 0.6, 0.9 and 1.3 mcg/mL. The increase in trough levels over time reached significance (p = 0.03). Recipients of MA conditioning had lower MPA troughs than those who received non-myeloablative conditioning (p = 0.02). Younger age (0-15 years old) was associated with lower trough levels (p = 0.002). By time dependent Cox regression analysis, there was no association between trough levels and toxicity as measured by speed and success of neutrophil engraftment, duration of TPN in myeloablative CBT recipients, or time to CMV viremia in seropositive patients. However, MA CBT recipients with a MPA trough ≥ 2 mcg/mL had enhanced platelet recovery (p = 0.005). In a competing risk 2-week landmark efficacy analysis, there were no differences in rates of grade II-IV aGVHD (61% vs 57%, p = 0.52) according to trough level. However, patients with a low MPA trough early post-CBT had nearly triple the incidence of severe (grade III-IV) aGVHD (27.8% vs 9.5%, p = 0.06, Figure 1).This analysis suggests that higher total MPA serum trough levels are safe from the standpoint of toxicity and may protect against severe aGVHD. The beneficial effect on platelet engraftment was unexpected but may be explained by a lower incidence of severe aGVHD. Prospective investigation of the utility of MPA trough measurements, and ultimately intervention based on drug monitoring in a larger CBT series is warranted. No relevant conflicts of interest to declare.

Acute graft-versus-host disease (aGVHD) is common after double-unit cord blood transplantation (CBT) with an incidence of grade II-IV aGVHD as high as 55% by day 180 in patients transplanted without ATG. aGVHD is associated with increased morbidity and transplant-related mortality (TRM). Mycophenolate mofetil (MMF) combined with a calcineurin-inhibitor is commonly used to prevent GVHD after CBT. However, unlike the 1 gram (gm) every 8 hours dosing that is now standard in adult donor allografts, MMF dosing in CBT has traditionally been every 12 hours. Our center has increased MMF dose from 1 gm every 12 (q12) to 1 gm every 8 (q8) hours in an effort to reduce severe aGVHD after double-unit CBT. However, the efficacy of this intervention is not established and a theoretical concern is that intensified MMF dosing could result in an increased risk of delayed engraftment or graft failure.We evaluated 171 double-unit CBT recipients (median age 39 years, range 0.9-71) transplanted with either myeloablative (MA, n = 133) or non-myeloablative (NMA, n = 38) conditioning for high-risk hematologic malignancies between 10/2005 and 4/2013. CB units were 4-6/6 HLA-A, -B antigen, -DRB1 allele matched to the recipient (16 6/6, 171 5/6, 155 4/6). All patients received GVHD prophylaxis with intravenous calcineurin-inhibitor (predominantly CSA) and MMF from day -3 without ATG. Prior to 9/2009, 80 patients (47%) received MMF 1 gm IV q12 (and those <12 years received 15 mg/kg/dose). From 9/2009, 91 patients (53%) received MMF at 1 gm IV q8 for patients both >12 years and ≥50 kg (or 15 mg/kg/dose if >12 years but <50 kg, or 20 mg/kg/dose if <12 years). The Gray's test compared the incidence of GVHD across the q12 and q8 dosing while the log-rank test was used to compare progression-free survival (PFS).Patient characteristics and infused viable CD34+ cell doses were similar in the q12 and q8 MMF groups. A comparison of transplant outcomes by MMF dosing is shown (Table). There were no differences in the time to neutrophil or platelet engraftment and the median time to count recovery was also similar. The incidences of grade II-IV aGVHD at day 100 were similar in the groups (46% vs 52%). However, there was a suggestion of decreased grade III-IV aGVHD at day 100 in the q8 MMF group (12%) versus the q12 group (21%), although this comparison did not reach significance. With a median follow-up of 41 months (range 3-94), the PFS in each dosing group was not significantly different.We demonstrated that intensified q8 MMF dosing is safe from the standpoint of engraftment and toxicity. There was a suggestion of decreased severe grade III-IV aGVHD in recipients of 1 gm IV every 8 hours. While a larger analysis is needed to further investigate these findings, the results are encouraging. They suggest that, as with adult donor allografts, intensified q8 hour MMF dosing should be the dose investigated for the prevention of aGVHD in CBT recipients transplanted with CSA/ MMF prophylaxis without ATG. Finally, aGVHD prophylaxis could be further optimized in CSA/ MMF-based CBT by mycophenolic acid trough level drug monitoring, early post-transplant biomarker measurements such as ST2, and delayed taper post-transplant.No relevant conflicts of interest to declare.

The selection of CB units with a high engraftment potential is key to the success of single and double-unit CB transplantation (CBT). However, the best predictors of engraftment potential at the time of unit selection and prior to infusion are not established.We analyzed determinants of engraftment in recipients of double-unit CBT at our transplant center (TC) who underwent myeloablative conditioning for hematological malignancies from 10/2005-5/2013. As infused viable CD34+ cell dose was critical to engraftment in this analysis, we then evaluated units thawed at our center for the two determinants of infused viable CD34+ cell dose: post-thaw CD34+ cell recovery and CD34+ cell viability. CD34+ cell recovery was calculated as TC CD34+ cell count/Bank CD34+ cell count. Post-thaw viability was evaluated by flow cytometry using modified ISHAGE gating and 7-AAD exclusion to assess the percentage of viable CD34+ cells (of total present).The cumulative incidence of neutrophil engraftment in the 128 myeloablative double-unit CBT recipients was 96% (95%CI: 93-100%). Reported Bank total nucleated cell (TNC) dose, Bank CD34+ cell dose, TC infused TNC dose, TC infused total CD34+ cell dose, TC infused viable CD34+ cell dose, and TC CFU dose were all significantly associated with neutrophil engraftment on univariate analysis. However, only the infused viable CD34+ cell dose was significant on multivariate analysis [HR=1.95 (1.33-2.86), p = 0.001, Figure]. Platelet engraftment was also strongly associated with infused viable CD34 cell dose (data not shown). To evaluate the reliability of CD34+ cell counts and determinants of viability, 402 units (302 domestic and 100 international) from 43 Banks thawed at our TC between 10/2005-5/2013 were then analyzed. For 7 selected Banks accounting for 135 (33%) units, there was strong correlation between Bank and TC CD34+ cell counts (r2 = 0.8, p < 0.001) with a median 92% CD34+ cell recovery at the TC (range 44-189%). However, for the remainder, there was greater variation in CD34+ cell recovery (range 12-1480%, median 107%) with a weaker (but still significant) correlation between CD34+ cell counts (r2 = 0.5, p < 0.001). In 40 (10%) units the recovery was less than 66%. Finally, while the median post-thaw CD34+ cell viability was 92%, it ranged 34-99%, and 33 units (8%) had <75% viable CD34+ cells. Unit characteristics significantly associated with CD34+ cell viability are shown in the Table. Bank location (domestic vs. international), shipping distance (New York vs. Australia), processing method (manual vs. automated or semi-automated) and unit hematocrit did not correlate with viability. In multivariate analysis, Bank FACT accreditation, year of cryopreservation, and cryovolume were associated with viability.Infused viable CD34+ cell dose was the critical determinant of neutrophil and platelet engraftment. Although correlation between Bank and TC CD34+ cell counts was excellent for some banks and post-thaw CD34+ cell viability was satisfactory for the majority of units, 17% of units had <66% CD34+ cell recovery and/or <75% CD34+ cell viability post-thaw. The variability in CD34+ cell recovery and viability was not random but linked to known differences in banking practice and at least one independent measure of Bank quality (FACT accreditation). These findings have significant implications to CB banking and transplantation. Although units can be selected based on CD34+ cell dose, TC must be able to react to lower than expected post-thaw CD34+ cell counts and/or low CD34+ cell viability. Thus, methods to measure the infused viable CD34+ cell dose on transplant day (or other rapidly available measures of potency) should be employed to ensure the delivery of a graft with optimal engraftment potential and a back-up strategy in case of a compromised unit. This is even more important in single-unit CBT in which, unlike double-unit CBT, engraftment is solely dependent on a single unit. No relevant conflicts of interest to declare.

Ex vivo TCD Allogeneic-HCT results in long-term relapse-free (RFS) and overall survival (OS) in patients with AML in CR or MDS, with a low incidence of acute and chronic graft-versus-host disease (GVHD). The HCT-CI predicts non-relapse mortality (NRM) and 1-year survival in recipients of conventional grafts. We investigated whether HCT-CI also predicted outcomes in ex vivo TCD-HCT in order to improve patient selection.A retrospective chart review was conducted to evaluate 218 pts (median age 50.4) with AML in CR (n=155) or MDS (n=63) undergoing TCD-HCT between 1997-2008. All pts received myeloablative conditioning. The majority received ATG for graft rejection prophylaxis. No GVHD prophylaxis was administered post-transplant. TCD of BM utilized soybean agglutination+sheepRBC rosetting (sRBCR). CD34+ selection +/- sRBCR was used for PBSC TCD. HCT-CI was determined according to Sorror et al. (Blood 2005). Prognostic factors relating to OS and RFS, including age, conditioning-regimen (TBI vs. chemo), HLA match (identical vs. other), and HCT-CI were evaluated using log-rank test statistics. Univariate and multivariate Cox proportional-hazards regression were performed for OS & RFS.The median HCT-CI score was 2 (range 0-9). HCT-CI score was 0 (low) in 25% patients, 1-2 (intermediate) in 36% and =3 (high) in 39%. Median follow-up of survivors is 70 months (range 6.1-182.6). Outcomes of the univariate and multivariate analysis are summarized in Table 1. Age and HCT-CI score were significantly associated with OS and RFS by univariate and multivariate analysis. In addition, in the multivariate analysis, HLA-match was associated with OS and RFS, while regimen was only associated with RFS. Patients with a high HCT-CI had significantly lower OS and RFS than those with a low or intermediate HCT-CI (Figure 1). Furthermore, while the cumulative incidence of relapse did not differ based on HCT-CI, patients with a high HCT-CI had a significantly higher incidence of NRM compared to patients with low or intermediate HCT-CI (not shown).These results support the use of the HCT-CI to stratify patients with AML and MDS who are eligible for myeloablative TCD-HCT and identify patients who are candidates for other approaches. Interestingly, unlike conventional grafts, we do not see worse outcomes (OS/RFS/NRM) in patients with intermediate vs. low HCT-CI, suggesting that patients with intermediate HCT-CI may better tolerate a TCD-HCT than a conventional HCT. A planned prospective three arm randomized Phase III, comparing two calcineurin inhibitor-free strategies for GVHD prophylaxis (CD34-selection and post-HCT Cy) to standard tacrolimus and methotrexate (BMT-CTN 1301) will further address these questions.No relevant conflicts of interest to declare.

Cord blood transplantation (CBT) is a proven therapy for high-risk hematologic malignancies. However, severe grade III-IV acute graft-versus-host disease (aGVHD) has emerged as a significant source of morbidity and mortality and most commonly targets the gastrointestinal (GI) tract after CBT. Plasma biomarkers have been found to predict aGVHD onset, aGVHD therapy response, and transplant-related mortality (TRM) after adult donor hematopoietic stem cell transplantation. However, whether plasma biomarkers are informative in CBT recipients has not been investigated.Plasma biomarkers were measured 28 days after unrelated donor double-unit CBT in 113 consenting patients (median age 41 years, range 1.7-69) transplanted at a single center between 5/2006 and 5/2012 for the treatment of high-risk hematologic malignancies. Conditioning was myeloablative (n = 37), reduced intensity (n = 47), or non-myeloablative (n = 29), and CB units were 4-6/6 HLA-A, -B antigen, -DRB1 allele matched to the recipient. The median follow-up was 44 months (range 14-84). Batched samples blinded to transplant outcomes were analyzed by enzyme-linked immunosorbent assay for levels of suppressor of tumorigenicity 2 (ST2), IL-2 receptor-a (IL-2Ra), tumor necrosis factor receptor-1 (TNFR1), hepatocyte growth factor (HGF), IL-8, elafin, and regenerating islet-derived protein 3-a (REG3a). Patients were grouped according to being above or below the median day 28 value for each biomarker. The cumulative incidence of aGVHD and TRM from day 28 landmark was estimated for each biomarker and significance was assessed using Gray's test. Patients who had aGVHD onset prior to day 28 (n = 7) were excluded from aGVHD evaluation.We found significant associations between day 28 plasma biomarkers and grade II-IV aGVHD and/or 6-month TRM, which are shown in Table. IL2Ra, elafin, and HGF were not significant for either outcome (data not shown). ST2 was the only biomarker associated with day 100 grade II-IV aGVHD with high ST2 patients having a median aGVHD onset of 42 days (range 28-93). Notably, patients with high day 28 ST2 had significantly increased day 100 grade III-IV aGVHD of 27% (95%CI:16-40) versus 11% (95%CI:4-20) in patients with low ST2 levels, p = 0.025. High ST2 was also associated with substantially increased 6-month TRM, and GVHD was the most common cause of transplant-related death [11/19 (58%) of deaths] with a median time to GVHD death of 170 days (range 70-400). High concentrations of TNFR1, IL-8, and REG3a were also significantly associated with 6-month TRM. Notably, aGVHD and organ failure due to lung toxicity were the most common causes of TRM in patients with high TNFR1, IL8, and REG3a levels.This is the first biomarker analysis conducted in CBT recipients. We demonstrate that a high day 28 ST2 level is associated with a subsequent increased risk of grade II-IV and III-IV aGVHD, as well as 6-month TRM. These findings are consistent with those recently reported in adult unmodified (T-replete) allograft recipients (Vander Lugt et al, NEJM, 2013). GVHD is the predominant mechanism of death in high ST2 patients and the day of onset is after day 28 in the majority which would permit time for therapeutic intervention. Thus, our findings have significant practical implications. Whether the other biomarkers offer additional prognostic information remains to be determined. They were not associated with the overall grade II-IV aGVHD incidence, but where associated with mortality from GVHD and organ failure. Overall, our promising results warrant further prospective evaluation in a large patient cohort with the ultimate aim of future interventions to ameliorate severe aGVHD and improve survival after CBT.No relevant conflicts of interest to declare.

Availability of suitably HLA-matched adult donors is a major barrier to allogeneic transplantation. Cord blood (CB) extends transplant access to many patients including minorities. However, some patients have no suitable unrelated donors (URDs) or CB grafts. Moreover, HLA-match is a critical determinant of URD & CB transplantation (CBT) outcome, & some patients will only have access to mismatched URDs &/or highly HLA-mismatched CB units. We evaluated if URD/ CB access has improved with increased size of URD registries & global CB inventories.We prospectively collected ancestry data on patients undergoing searches between 10/2005-6/2013, & analyzed the availability of 9-10/10 HLA-matched URDs or 4-6/6 HLA-A,-B antigen, -DRB1 allele matched CB units by recipient ancestry in patients with hematologic malignancies. 10 HLA-allele matched URDs were given priority if available; otherwise HLA-mismatched URDs or double-unit CB grafts were chosen. Given our minimum CB total nucleated cell (TNC) dose criteria was increased from 1.5 to 2.0 x 107/kg/unit in 2010, this analysis was restricted to units with a cryo. TNC dose = 2.0. Also, as high-resolution typing was performed in all CB units & considered in unit selection since 2012, availability of CB units by 10-allele match was evaluated. Finally, given the global public CB inventory reached 500,000 units in 2011, URD/CB availability was compared between early (10/2005-12/2010) & recent (1/2011-6/2013) periods.708 patients were evaluated including 223 (31%) of non-European origins. 511 (72%) patients received an URD transplant, 159 (22%) received a CBT, & 38 (5%) had no graft. URD recipients were predominantly of European ancestry (n = 400, 78%) whereas only 77 (48%) of CBT recipients had European origins. 30/38 (79%) patients without any graft were non-European with over half (n = 20) being of African ancestry. “No graft” patients had a higher weight (median 93 kg, range 50-151) than CBT recipients (median 68 kg, range 8-133), p < 0.001. The availability of grafts for Europeans & non-Europeans during the early versus recent time periods is shown (Table). Patient ancestry distribution was equal during the periods. The majority of Europeans received a 10/10 URD transplant in both periods & very few had no graft (< 1% recently). However, only approximately half of non-Europeans undergoing URD transplant received a 10/10 match. Moreover, of non-Europeans overall, only 29/129 (22%) had a 10/10 URD in the early period, & this has not improved recently [28/94 (30%), p = 0.28]. The percentage of non-Europeans receiving CB units with a = 5/6 donor-recipient HLA-match has not improved (data not shown). However, while only 28% of non-Europeans received a CB graft consisting of = 6/10 HLA-matched units in the early period, this donor-recipient HLA-match rate improved to 69% recently (p < 0.001), a rate similar to that of European patients. The percentage of non-Europeans with no graft has decreased from 17% to 8.5% (p = 0.08). Furthermore, while African patients were the largest group among no graft patients (68% in early period & 63% recently), of African patients without an URD, 16/31 (52%) had a CB graft in the early period versus 15/20 (75%) recently, p = 0.14.Very few Europeans do not have an URD &/or CB graft. However, URDs are a poor donor source for patients with non-European ancestry. By contrast, CB is a critically important stem cell source for minorities, & transplantation of units with higher rates of 10 HLA-allele match is now frequently possible likely due to a bigger inventory & the use of high-resolution matching. Our analysis suggests CB availability in non-Europeans has improved. However, additional measures are required to extend graft access for African ancestry patients.No relevant conflicts of interest to declare.

Double-unit CB transplantation (DCBT) has provided high rates of sustained donor engraftment in patients with hematologic malignancies. However, delayed engraftment is frequent with a median neutrophil & platelet recovery of 25 & 48 days, respectively, in adult DCBT recipients at our center. This delay is associated with increased transplant-related mortality (TRM). It is also associated with prolonged hospitalization with a median discharge time of +42 days (range 25-76) in recent adult myeloablative DCBT recipients.We investigated the combined transplantation of a 4-6/6 HLA-A,-B antigen, -DRB1 allele matched double-unit CB allograft (infused on day 0) with peripheral blood stem cell derived Miltenyi column selected haplo-identical CD34+ cells (haplo-CD34+, infused on day 0 or +1) to speed myeloid recovery. We used DCB grafts to facilitate comparison with historic/concurrent DCB controls transplanted without haplo-CD34+.Of 23 protocol eligible patients, 6/23 (26%) underwent DCBT only due to the lack of any suitable haplo-identical donor. Thus, 17 patients [median 39 years (range 16-69), median 78 kg (range 63-133)] were transplanted 9/2012-6/2013 with DCB plus haplo-CD34+ cells for high-risk hematologic malignancies. Diagnoses included 12 acute leukemias & 5 lymphomas. Conditioning was myeloablative with CSA/MMF immune suppression & no ATG. Median infused CB TNC x 107/kg was 2.29 (larger unit, range 1.73-2.95) & 1.82 (smaller unit, range 1.26-2.48). Haplo-identical donors (median 37 years, range 19-71) had a median donor-recipient HLA-match of 5/10 (range 5-7). 15 patients received the targeted infused haplo-CD34+ cell dose of 3 x 106/kg whereas 2 each received haplo-CD34+ cell doses of 1 x 106/kg. The median infused haplo-CD3+ dose was 0.6 x 103/kg (range 0.3-1.6). One patient died on day 14. Of 16 remaining evaluable patients, all (100%) engrafted with a median neutrophil recovery of 13.5 days (range 11-31) in 14 patients who received 3 x 106/kg haplo-CD34+ cells, and 26 and 18 days in the 2 patients who received 1 x 106/kg haplo-CD34+ cells. Platelet recovery ≥ 20 × 109/l has occurred in 12/15 patients (median 27 days, range 18-46) to date. Serial chimerism results demonstrating the contribution of haplo-CD34+ cells & each CB unit to date is shown (Table). While myeloid recovery on day 14 was predominantly haplo-CD34+ cell mediated, one CB unit dominated by day 28 in both neutrophil & T-cell subsets. The median total donor chimerism was 100% the dominant CB unit by day 100. With a median follow-up of survivors of 5 months (range 1-10), to date 9 of 15 evaluable patients have developed grade II-IV aGVHD by day 100 (7 grade II, 1 grade III, 1 grade IV). One patient with refractory leukemia transplanted with disease has relapsed, & 4 have died of TRM (2 organ failure, 1 grade IV aGVHD, 1 CMV infection). Excluding early deaths, of patients who were discharged in the first 100 days (n = 13), the median day of discharge was day +33 (range 21-60).Double-unit CBT supplemented by haplo-CD34+ cells is safe. The incidence of neutrophil engraftment is high & the speed of neutrophil recovery is enhanced compared with recent DCBT controls. A shorter time of initial hospitalization (9 days) has offset the cost of the addition of haplo-CD34+ cells. It is intriguing that the dominant CB unit can rapidly reject the haplo-identical donor. This may be facilitated by omission of ATG, and the determinants of the speed of haplo-donor rejection are under investigation. Whether the same results could be achieved with a single CB unit plus haplo-CD34+ cells requires investigation. Addition of haplo-CD34+ cells is also an alternative to expansion, although expansion remains an important strategy to augmenting myeloid recovery given some patients do not have any suitable haplo-identical donors.No relevant conflicts of interest to declare.

DCB transplantation (DCBT) appears to enhance engraftment despite sustained hematopoiesis usually being derived from a single unit. Therefore, to further investigate DCB biology we established in vitroand in vivoDCB models using samples from patient DCB grafts.