Cord Blood Grafts Research Articles

Efficacy Analysis of Unrelated Umbilical Cord Blood Transplantation for the Treatment of Wiskott-Aldrich Syndrome

To explore the clinical efficacy and safety of unrelated umbilical cord blood transplantation (UCBT) for the treatment of Wiskott-Aldrich syndrome(WAS). Five pediatric patients with WAS received single UCBT were retrospectively analyzed. The median age of these male patients was 268 days (range, 3 days -695 days). Among them, 2 patients were transplanted with a 6/6 matched cord blood graft，the other 3 patients received a 5/6 matched cord blood graft. Myeloablative conditioning regimen was applied, and all patients received a combination of cyclosporine and mycophenolate mofetil for the prophylaxis of graft versus host disease (GVHD). The recovery time of neutrophils and platelets as well as chimerism after transplantation were taken as the evidence of hematopoietic reconstruction. All the five pediatric patients had hematopoietic recovery. A median time of neutrophil cells after transplantation was at 15.8 days (range,11 days -25 days), and platelet recovery was at a median of 20.4 days(range,12 days-30 days). Chimerism data were available for 5 patients at 30 days after UCBT, 4 out of the 5 patients had full donor chimerism and only one patient had mixed chimerism. There were 2 cases with pre-engraftment syndrome, 3 cases with acute GVHD gradeⅠ-Ⅲ, 4 cases with pulmonary infection and cytomegalovirus infection, but chronic GVHD was not observed in 5 cases. Four patients were alive with a median follow-up of 12.3 months (range, 5 months-17 months), and one patient had died at 22 days after UCBT. Unrelated umbilical cord blood transplantation is a safe and effective treatment method for Wiskott-Aldrich syndrome.

Pre-Transplant and Peri-d100 Gastrointestinal Dysbiosis Is Associated with the Subsequent Development of Chronic Graft-Versus-Host Disease

IntroductionChronic graft-versus-host disease (cGVHD) affects up to 50% of the long-term survivors of allogeneic hematopoietic stem cell transplantation (HCT), and is the leading cause of mortality in patients who survive to two years post-transplant. Unlike acute GVHD (aGVHD), the primary pathology in cGVHD is fibrotic, affecting the skin, and lacrimal and salivary glands, and shares many features with the autoimmune conditions Sjogrens syndrome and systemic sclerosis. Certain gastrointestinal microbiota compositions have been associated with these autoimmune conditions, and we thus hypothesized that the configuration of microbial communities would also be associated with cGVHD, and may then serve as predictive biomarkers or offer mechanistic insights into cGVHD pathogenesis.MethodsWe identified a cohort of 55 patients with cGVHD as confirmed by a formal clinical consensus process applying NIH criteria, transplanted at MSKCC between January 2013 and August 2017. 47% of patients underwent transplantation for acute leukemia, with the remainder for non-hodgkin lymphoma (25%), myelodysplastic syndrome (13%), chronic leukemia (6%), myeloma and myeloproliferative disorder (each 2%). The majority received unmodified peripheral blood stem cell grafts (60%) with the remainder receiving CD34- selected grafts (20%), and marrow or cord blood grafts (20%). 55% of the cohort developed acute GVHD prior to day 100.532 stool samples were available from 55 cGVHD cases, and were compared with 1462 samples from 165 control patients (matched for graft-source from the MSK allo-HCT Fecal Biobank). The median day of cGVHD onset in the cases was d194. The patient characteristics in the cases and controls were equivalent, including the rate of aGVHD prior to day 100 (55% vs 46%; p = 0.27). In addition, we compared the cGVHD cases with a separate cohort of patients with grade 3-4 aGVHD who were selected from the database on the basis of aGVHD diagnosis and a failure to develop cGVHD (n = 71 patients, contributing 835 samples), and an additional control group (matched for graft-source, n = 213 patients, 1786 samples) who did not develop any GVHD. All stool samples underwent 16S-targeted sequencing (V4-V5 region) on the Illumina platform.ResultsNo differences in a-diversity as a function of time peri-HCT were observed, nor did we observe clustering of community characteristics in tSNE-space, or differences using the linear discriminant effect size (LEfSE) pipeline when we specifically examined samples collected pre-transplant, peri-engraftment, or peri-d100. Targeted analysis of genera reported to be enriched in intestinal communities of patients with autoimmune diseases however, revealed higher relative abundance in Prevotella prior to BMT in patients who went on to develop chronic GVHD (cGVHD case vs source-matched control p < 0.0001; cGVHD case vs cGVHD case vs no-GVHD control p <0.0001; Fig 1A). When we analyzed the relative abundance of genera known to be relevant in GVHD, we found increased relative abundance of Akkermansia and Streptococcus at day 100 in the cGVHD cases compared to controls (p =0.017; Fig 1B).ConclusionHere, we report for the first time, genus-level intestinal microbial signatures that are associated with cGVHD, identifiable at pre-transplant (Prevotella) and peri-d100 (Akkermansia, Streptococcus) time points, prior to cGVHD onset. Interestingly, at species level, Prevotella copri abundance has been mechanistically associated with new-onset rheumatoid arthritis, and we have previously associated Akkermansia muciniphilia, a commensal bacteria with known mucus-degrading capacity, with aGVHD in pre-clinical studies. Thus, the cGVHD-associated dysbiosis we have identified may have value as both a biomarker for cGVHD risk and mechanistic relevance. [Display omitted] DisclosuresPerales:Merck: Other: Personal fees; Takeda: Other: Personal fees; Novartis: Other: Personal fees; Abbvie: Other: Personal fees; Incyte: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees and Clinical trial support. Peled:Seres Therapeutics: Research Funding.

Burden and Outcomes of Mucosal Barrier Injury-Laboratory Confirmed Bloodstream Infections (MBI-LCBI) in the First 100 Days after Allogeneic Stem Cell Transplant: A CIBMTR Analysis

Background: Patients undergoing stem cell transplant (SCT) are at risk of bloodstream infections (BSI). BSI led to prolonged hospitalization, intensive care admissions, prolonged antibiotic treatment and increased mortality. Recently, the Centers for Disease Control and Prevention developed a modification of the Central line associated bloodstream infection (CLABSI) definition, termed “mucosal barrier injury laboratory-confirmed bloodstream infection” (MBI-LCBI) to differentiate BSI likely related to mucosal barrier injury. BSI are identified as an MBI-LCBI if: (1) it resulted from 1 or more of a group of selected organisms known to be commensals of the oral cavity or gastrointestinal tract and (2) occurred in a patient with signs or symptoms compatible with the presence of mucosal barrier injury such as gastrointestinal graft-versus-host disease and/or neutropenia. We utilized the CIBMTR database to determine the incidence and timing of MBI-LCBI, risk factors for development of MBI-LCBI, and compare transplant outcomes by 1 year after SCT.Methods: We identified 16,875 pediatric and adult patients receiving first allogeneic transplant from 2009-2016. Patients were classified into 4 categories based on the occurrence of BSI in first 100 days: MBI-LCBI (n=1434; 8.5%), MBI-LCBI +other BSI (n=700; 4.1%), BSI only (n=3016; 17.8%), and control (n=11725; 69.5%) (Figure 1). Demographics and outcomes, including overall survival (OS), chronic GVHD, and transplant-related mortality (TRM, for malignant disease patients only), were compared between groups.Results: The cumulative incidence of MBI-LCBI was 13% (99% CI: 12-13%) by day 100 whereas the probability for another BSI not meeting MBI-LCBI criteria was 22% (99% CI: 21-23%) by day 100. The median time from transplant to first MBI-LCBI was 8 days (<1-98), MBI-LCBI + other BSI 10 days (<1-99), and other BSI was 38 days (<1-100). Karnofsky/Lansky performance status <90 [RR 1.21 (99% CI: 1.06 - 1.38)], myeloablative conditioning [RR 1.45 (99% CI: 1.27-1.69)], post-transplant cyclophosphamide as GVHD prophylaxis [RR 1.83 (99% CI: 1.40 - 2.39)], and receipt of cord blood [RR 2.89 (99% CI: 2.06 - 4.06)] were associated with a significant increase in the risk of MBI-LCBI (Table 1). The 1 year OS was inferior for patients with MBI-LCBI only [59% (99% CI: 56 - 61%); RR 1.86 (99% CI: 1.65 - 2.09)], Other BSI only [60% (99% CI: 58 - 63%); RR 1.86 (99% CI: 1.70 - 2.04)], and MBI-LCBI + Other BSI [46% (99% CI: 41 - 50%); RR 2.79 (99% CI: 2.42 - 3.23)] compared to controls [72% (71 - 73); p <0.0001] (Table 2). There was no impact of MBI-LCBI only, Other BSI only, or MBI-LCBI + Other BSI compared to controls on development of chronic GVHD. As expected 1 year TRM in patients with malignant disease was increased with any BSI but was similar for patients with MBI-LCBI only [30% (99% CI: 27 - 34%); RR 2.41 (99% CI: 2.05-2.82] or Other BSI [25% (99% CI: 23 - 27%); RR 2.20 (1.94 - 2.51)] and further worsened for patients with both MBI-LCBI + Other BSI [45% (99% CI: 39 - 50%); RR 4.23 (3.53 - 5.07)] compared to controls [16% (99% CI:15 - 17%)]. Finally, infection as a cause of mortality was higher in patients with MBI-LCBI (19%), BSI only (17%), and MBI-LCBI + BSI (21%) then controls (12%).Discussion: Our data demonstrate approximately 13% of all patients develop at least one MBI-LCBI and an additional 22% of patients develop another BSI in the first 100 days post SCT. Multivariable analysis revealed increased risk of MBI-LCBI with poor performance status, cord blood grafts, myeloablative conditioning, and post-transplant cyclophosphamide GVHD prophylaxis. BSI, whether or not MBI-LCBI, significantly decreases overall survival, primarily related to an increased TRM. The combination of MBI-LCBI and other BSI worsens both TRM and OS, but the respective impact of MBI-LCBI only was similar to Other BSI only. BSI, both MBI-LCBIs and other BSI, lead to significant morbidity and mortality and healthcare resource utilization. Reduction in frequency of BSI should be a major public health and scientific priority. [Display omitted] DisclosuresPerales:Novartis: Other: Personal fees; Incyte: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees and Clinical trial support; Abbvie: Other: Personal fees; Takeda: Other: Personal fees; Merck: Other: Personal fees.

Donor NKG2C Copy Number: An Independent Predictor for CMV Reactivation after Double Cord Blood Transplantation

Cytomegalovirus (CMV) is a member of the herpesviridae family and remains latent in the host cells after primary infection. The virus reactivates in the immunosuppressed host and is a leading cause of morbidity following allogeneic hematopoietic stem cell transplant (allo-HSCT). Natural killer (NK) cells provide the first-line defence against viruses and a subset of NK cells expressing NKG2C have been shown to play a role in the immune surveillance of human CMV. Deletion of the NKG2C gene has been reported as a risk factor for viral infections including CMV and HIV, but current data on the influence of NKG2C gene-copy number variations in the donor graft on the risk of CMV reactivation after allo-HSCT is limited. Following cord blood transplantation (CBT), where the T-cell compartment is functionally naïve, the NKG2C genotype may have an even more pronounced impact on the risk of CMV reactivation. Therefore, we studied NKG2C copy number in the donor graft and the risk of CMV reactivation after double umbilical cord blood transplantation (DUCBT) in 100 CMV seropositive DUCBT recipients and their corresponding cord blood grafts (n=200). The gene encoding NKG2C is present at different copy numbers in the genomes of different individuals, with possible genotypes including 2 copies (wt/wt), 1 copy due to heterozygous deletion (wt/del) or 0 copies due to homozygous deletion (del/del). Among the donor CB units, approximately 2/3 had both copies of the gene (wt/wt), 1/3 had only one copy (wt/del) and only a minority of units had 0 copies with both alleles deleted (del/del). In the setting of DUCBT, the combined graft may contain 0 to 4 functional copies of NKG2C gene. In our cohort, patients whose combined grafts contained only 1 or 2 NKG2C gene copies had a significantly higher probability of CMV reactivation than patients whose combined grafts had 3 or 4 NKG2C copies. The 6-month cumulative incidence of CMV reactivation for the 4 groups was 100%, 92.9%, 60.5% and 55.9% respectively (p=0.005). No patient received a graft with zero gene copies. For the rest of the analysis we divided the patients into two groups, namely the 84 patients who received a combined graft with 3 or 4 NKG2C copies and the 16 patients who received two units with 1 or 2 NKG2C copies. The 6-month cumulative incidence of CMV reactivation for the two groups was 58.4% and 93.7% respectively (p=0.0003). In a multivariate analysis, receiving a combined graft with low NKG2C copy number (1 or 2 copies) (HR=2.72, CI=1.59-4.64; p<0.0001) and reduced intensity conditioning (RIC) (HR=0.59, CI=0.35-0.99, p=0.046) were the only independent predictors for CMV reactivation. Interestingly, the NKG2C copy number of the dominant cord was not predictive for CMV reactivation, suggesting that both cord blood units contribute to the antiviral response early post-DUCBT. Our study points to an important role for donor NKG2C in protection against CMV reactivation after DUCBT. If confirmed in larger numbers of CBT recipients, NKG2C genotyping of the CB graft may be a useful biomarker for predicting the risk of CMV infection after CBT, thus guiding the intensity of CMV prophylaxis for individual patients. Moreover these novel findings may provide a compelling rationale for considering NKG2C genotype as a criterion in the algorithm of CB selection for DUCBT. DisclosuresOran:ASTEX: Research Funding; AROG pharmaceuticals: Research Funding; Celgene: Consultancy, Research Funding. Champlin:Sanofi: Research Funding; Otsuka: Research Funding. Shpall:Affirmed GmbH: Research Funding.

The Optimal Alternative Donor Transplant for Pediatric Patients with Acute Leukemia: A Comparison between Alfa-Beta T-Cell and B-Cell Depleted Haplo-SCT and UCBT

▪Children with acute leukemia (AL) in need of an allograft and lacking an HLA-identical sibling and an HLA-matched unrelated donor, could benefit either from unrelated cord blood transplantation (UCBT) or T-cell depleted haploidentical (haplo) stem cell transplantation (SCT).Different techniques of T-cell depletion have been developed for improving immune reconstitution and for enhancing the graft-versus-leukemia (GvL) effect. Locatelli et al. (Blood 2017) reported remarkable results for children with AL given haplo-SCT after a novel method of graft manipulation based on selective, negative depletion of alfa-beta T and B cells.On behalf of Eurocord, CTIWP, and PDWP of EBMT, we compared outcomes of patients < 18 years with AL undergoing either single-UCBT (n=444) or haplo-SCT after alfa-beta T-cell and B-cell-depletion (n=99) from 2012 to 2016 using a myeloablative conditioning regimen (MAC).Median age at SCT was 6 (range 0.3-18) and 8 (range 0.6-18) years, and median follow-up was 36 and 14 months (p<0.05) for UCBT and haplo-SCT recipients, respectively. Compared to UCBT, haplo-SCT were performed more recently (median year 2016 vs 2012, p<0.05). Acute lymphoblastic leukemia (ALL) was the most frequent diagnosis (62% versus 55%), while 38% and 45% of patients had acute myeloid leukemia (AML) in the UCBT and haplo-SCT group, respectively. Cytogenetics was mainly at intermediate risk for UCBT (54%) and haplo-SCT (73%, p<0.05); 49% and 54% of patients were in CR1 at time of the allograft in UCBT and haplo-SCT group, respectively (p=0.45). In vivo T-cell depletion with ATG was more frequently adopted in haplo-SCT recipients (90% versus 81%, p=0.05). For UCBT recipients, HLA compatibility was 6/6 matched for 19% of patients, 5/6 for 58% and 4/6 for 23%. Cord blood graft contained a median TNC count at cryopreservation of 7.02x10e7/Kg (range 2.63-43) and at infusion of 5.3x10e7/Kg (range 0.3-39).Conditioning regimen varied according to the type of transplant: for haplo-SCT recipients Fludarabine+TBI (28%) and Thiotepa+Busulfan+fludarabine (TBF) (24%) were the most frequent MAC. In UCBT, Busulfan+Cyclophosphamide (Cy), or Cy+Fludarabine+TBI or TBF were used in 19%, 15% and 13% of patients, respectively.Haplo-SCT recipients did not receive any additional pharmacological post-transplant graft-versus-host disease (GvHD) prophylaxis, while CyclosporineA (CSA)+ steroids and CSA+mycophenolate mofetil were used in 38% and 32% of UCBT recipients.The 60-day probability of neutrophil engraftment was 91% vs 93% (p<0.05) for UCBT and haplo-SCT. The cumulative incidence (CI) of grade II-IV and grade III-IV acute (a) GvHD was 38% vs 12% (p<0.05) and 17% vs 4% (p<0.05) in UCBT and haplo-SCT recipients, respectively. The 2-year CI of relapse (RI) was similar following from UCBT and haplo-SCT (22% vs 25%, p=0.75), as well as non-relapse mortality (NRM) (18% vs 10%, p=0.07), respectively. Disease recurrence was the most common causes of death in both groups, with infections and GvHD being the most frequent transplant-related fatalities.According to donor type, no differences were found in overall survival (OS) (65% vs 68%, p=0.17) and leukemia-free survival (LFS) (61% vs 65%, p=0.24), while a lower GvHD-free, relapse-free survival (GRFS) was observed in UCBT compared to haplo-SCT (49% vs 60%, p<0.05). OS was 67% and 58% for patients with AML and ALL respectively, p=0.11.In multivariate analysis, UCBT was associated with higher risk of NRM (HR 2.36, p<0.05), while RI was not associated with type of allograft. Higher risk of grade II-IV aGVHD was observed in UCBT (HR 2.81, p<0.05), with no difference for cGVHD among the two groups (HR 0.68, p=0.31). OS (HR 1.52, p=0.10) and LFS (HR 1.28, p=0.28) were comparable between UCBT and haplo-SCT, while GRFS resulted lower for UCBT (HR 1.58, p<0.05). No others factors were associated with outcomes.Our results showed that RI, LFS, OS and cGVHD were comparable between UCBT and haplo-SCT recipients, while better NRM, aGVHD and GRFS were observed in patients transplanted from a family donor. These data confirm that alfa-beta T-cell and B-cell depleted haplo-SCT is a valid alternative for patients in need of an urgent allograft. Costs of manipulation in the haplo-SCT setting and costs of cord blood procurement should be further investigated. Technical expertise with this refined approach of graft manipulation and center experience are important to optimize patient's outcome. DisclosuresLocatelli:Miltenyi: Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees; bluebird bio: Consultancy; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Zecca:Chimerix: Honoraria. Bader:Medac: Patents & Royalties, Research Funding; Cellgene: Consultancy; Neovii: Research Funding; Riemser: Research Funding; Novartis: Consultancy, Speakers Bureau.

HLA Class I Alloimmunization and Platelet Transfusion Support in HLA-Identical Bone Marrow Transplant for Sickle Cell Disease: A Sickle Transplant Alliance for Research Study

Introduction: HLA alloimmunziation has been described in patients, including pediatric patients with sickle cell disease (SCD), who received only leukocyte-reduced red blood cell (RBC) transfusions. While HLA alloimmunization has significant implications in bone marrow transplant (BMT) with an HLA-disparate donor (donor-specific HLA antibodies increase the risk of graft rejection), the clinical significance of this alloimmunization in HLA-identical BMT is unclear. In particular, it is unknown whether HLA class I alloimmunization affects platelet transfusion support during BMT. Platelet transfusions are especially important in BMT for SCD because of the historic high incidence of intracranial bleeding and the subsequent adoption of a relatively high platelet transfusion threshold.Methods: We tested for HLA class I alloimmunization using pre-BMT serum or plasma from 32 pediatric patients with SCD undergoing BMT with an HLA-identical sibling donor. HLA class I alloimmunization was evaluated using the FlowPRA® (panel reactive antibody) screening test which detects IgG antibodies to the majority of HLA class I antigens. Pre-BMT, patients had received leukocyte-reduced RBC transfusions. All patients undergoing BMT received leukocyte-reduced, irradiated, apheresis platelet transfusions to maintain a platelet count greater than 50 x 109/L. The number of platelet transfusions received in the first 45 days post-BMT was compared between those with a positive PRA versus those with a negative PRA using a two-sample t-test.Results: Among the 32 patients studied, the mean age at BMT was 9.4 years (range 1-21 years). Pre-BMT, 40% had received greater than 10 RBC transfusions and 32% of the entire cohort was receiving chronic RBC transfusions. BMT conditioning regimens included: traditional myeloablative busulfan, cyclophosphamide, antithymocyte globulin (BU-CY-ATG) (n=10); dose-reduced BU-CY-ATG + fludarabine (flu) (n=16); reduced intensity conditioning (RIC) alemtuzumab, flu, melphalan +/- thiotepa (n=5); and RIC BU-flu-ATG (n=1). All patients received HLA-identical sibling donor bone marrow, with 3 patients receiving a combined bone marrow and cord blood graft. All patients engrafted with 100% survival at day +45. Six patients developed acute graft-versus-host disease (GVHD): 1 grade I, 3 grade II, 1 grade 3, 1 grade 4. No patient had an intracranial bleed or other serious bleeding.From testing of the pre-BMT sample, 11/32 (34%) of patients had a positive HLA class I antibody screen. HLA class I alloimmunized patients received significantly more platelet transfusions than non-alloimmunized patients: mean 19.2 (SD 13.9) vs. 11.2 (SD 8.0) transfusions, p=0.049 (Figure). On univariate analysis, age, sex, conditioning regimen, and GVHD were each not significantly associated with the number of platelet transfusions (p>0.1). Only two patients developed hepatic sinusoidal obstruction syndrome (one HLA alloimmunized patient, one non-alloimmunized patient). Mean day of platelet engraftment was not significantly different between alloimmunized compared to non-alloimmunized patients: day +34.6 (SD 10.6) vs. day +30.2 (SD 11.3), p=0.28. Among HLA class I alloimmunized patients, the mean positive PRA was 19.7% (range 4-55%); there was no association with this PRA value and the number of platelet transfusions (r2=0.0064, p=0.81).Conclusion: In pediatric HLA-identical sibling BMT for SCD, pre-BMT HLA class I alloimmunization (but not the absolute PRA value) appears to be associated with more platelet transfusions. It is unclear if this increased platelet transfusion requirement is due directly to HLA antibody immune-mediated clearance of transfused platelets or other inherent differences of HLA class I alloimmunized patients. [Display omitted] DisclosuresQayed:Novartis: Consultancy.

Donor Leukocyte Infusion for Single Unit Umbilical Cord Blood Transplantation: 5% of Thawed Single Cord Blood Unit Refrozen on Day of Transplant Is Safe with Signals of Efficacy in Improving Donor Derived Immunity

Introduction:Success of umbilical cord blood transplantation (UCBT) is limited by an increased risk of graft rejection, mixed chimerism, infection, and delayed immune reconstitution. Additionally, strategies such as donor lymphocyte infusion (DLI) to improve declining donor chimerism or augment immune reconstitution are extremely limited in UCBT. We hypothesized that removing and storing a portion of the thawed cord blood graft for future use as a cord DLI (cDLI) could be used to improve mixed chimerism or augment immunity without adverse impact on engraftment or graft versus host disease (GVHD).Methods:Patients with inborn errors of metabolism, immunity, or hematopoiesis underwent a single unit UCBT following a reduced-intensity conditioning regimen of alemtuzumab, hydroxyurea, fludarabine, melphalan, and thiotepa (ClinicalTrials.gov: NCT00744692) with a thaw and dilute (no wash) methodology. Up to 5% of the cord blood graft was removed from the thawed graft and re-cryopreserved for potential cDLI. The cDLI was infused at the discretion of the treating physician in discussion with the study PI (P.S.) in cases of mixed or declining donor chimerism, viral infection, or delayed immune reconstitution.Results:A total of 33 patients had cells cryopreserved prior to UCBT for potential cDLI. The characteristics of these patients are shown in Table 1. A total of 18 patients received cDLI at a median of 65 days (range 14-124) post-UCBT. The median cell dose of the cDLI was 8.46e+05 CD3/kg and 1.53e+04 CD34/kg. The indication for cDLI was mixed whole blood or CD3 chimerism (n=9), viral infection (n=9), and delayed immune reconstitution (n=5); 5 patients had more than one indication for cDLI, most commonly infection with delayed immune reconstitution (n=4).All patients engrafted with neutrophils at a median of 15 days post-transplant (range: 10-31 days); however, one patient experienced secondary graft failure at day 38 post-transplant despite cDLI at day 28 post-transplant. Improvement in chimerism was seen in 5 of 9 patients, viral load and/or clinical symptoms of viral infection in 5 of 9 patients (including gastroenteritis due to rotavirus (n=1) or adenovirus (n=1)), and absolute CD3 count in 5 of 5 patients (Figure).A total of 15 patients (45%) developed acute grade I-III GVHD at a median of 69 days (range: 13-95 days) post-UCBT. In the group of patients who received cDLI, 8 developed grade I-II skin GVHD at a median of 19 days (range 4-81 days) post-cDLI. In addition, 2 patients with a history of GVHD received subsequent cDLI without GVHD flare post-cDLI and were analyzed for progression post-cDLI. No patients who received cDLI developed grade III or IV acute GVHD or extensive chronic GVHD, while 4 patients who did not receive cDLI developed grade III GVHD affecting skin and/or the gastrointestinal tract. There was no difference in the cumulative incidence of acute GVHD between those who received cDLI and those who did not (44% and 33%, respectively; p=0.81; Figure). The 3-year overall and event-free survival of the entire group was 94% and 91% respectively (Figure), with treatment-related mortality of 6% at 1 year post-transplant.Conclusions:The use of cDLI is safe in patients undergoing single-unit UCBT. Despite the removal of a small portion of the cord blood graft for cDLI, all patients engrafted with neutrophils and no increased morbidity was seen. In addition, although the sample size is small, over half of the patients who received cDLI had improvement in the primary indication (chimerism, viral infection, or immune reconstitution) for cDLI, with the most benefit seen in patients receiving cDLI for delayed immune reconstitution, as evidenced by both clinical improvement in infectious symptoms and increases in absolute CD3 count. This suggests that cDLI may be an effective way to address mixed chimerism, infection, and particularly, delayed immune reconstitution and should be explored in a larger clinical trial. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Double-Unit Cord Blood (CB) Transplantation with Haplo-Identical CD34+ Cells (haplo-dCBT) May Speed Neutrophil Recovery Although Successful Bridging Is Contingent on Close Haplo-Winning CB Unit HLA-Match

Background: While dCBT is associated with high rates of sustained donor engraftment, delayed neutrophil recovery in adults is frequent and can contribute to extended hospitalization and early transplant-related mortality.Methods: We investigated engraftment after myeloablative dCBT supplemented with CD34+ selected haploidentical PBSC (haploCD34+) in patients (pts) with high risk hematologic malignancies or aplastic anemia in a phase II clinical trial. The aim was to abrogate neutropenia (ANC >/= 500 within 14 days) with a haplo myeloid bridge prior to CB engraftment. Pts did not receive ATG due to the increased mortality risk reported in adult CBT. Double unit CB grafts allowed comparison to dCBT controls without haploidentical graft supplementation.Results: 78 adult pts [median age 48.5 years (range 21-68), median weight 82 kgs (range 48-138), 44 (56%) CMV+, 3 with prior allografts] underwent haplo-dCBT between 9/2012-12/2017. Diagnoses included 54 (69%) acute leukemias, 10 (13%) MDS/ MPN (all ≤ 10% blasts at work-up), 10 (17%) NHL/ HD and 1 aplastic anemia. Conditioning was myeloablative (1 Cy 120/ Flu 75/ TBI 1375, 77 intermediate intensity Cy 50/ Flu 150/ Thio 5-10/ TBI 400) with CSA/ MMF. CB units had a median infused TNC of 2.3 (range 1-5.7) x 107/kg/unit & median infused viable CD34+ cell dose of 1.1 (range 0.1-3.1) x 105/kg/unit with a median 5/8 (range 2-7) unit-recipient HLA-allele match. Haplo CD34+ grafts [procured from children (46%), siblings (31%), parents (13%) or extended family (10%)] had a median infused CD34+ dose of 5.2 x 106/kg (range 1.1-16.8) and a median infused CD3+ dose of 1.6 x 103/kg (range 0.3-13.7). Sixty-one (78%) haplos were 4/8 and 17 (22%) were 5-7/8 HLA-matched to the pt. In 77 evaluable pts (1 pt died on day 14), 4 engraftment patterns were observed (Table 1). All but 2 pts had sustained CB engraftment with either an optimal haplo-bridge (Gp. 1, 34/77, 44%), a transient bridge with a second nadir preceding CB engraftment (Gp. 2, 20/77, 26%), or no bridge (Gp. 3, 21/77, 27%). The 2 remaining pts had CB/ haplo graft failure (Gp. 4, 2/77, 3%); both were successfully re-transplanted with single CB units. While there was no difference in the day 100 TRM in the 34 optimal bridge pts vs pts with transient or no bridge [9% (95%CI 2-21) vs 15% (95%CI 6-27), p = 0.388], optimal bridge pts had faster platelet recovery [19 (range 14-41) vs 44.5 days (range 14-67)] and earlier hospital discharge [28.5 (range 20-60) vs 36 days (range 28-98)]. Similar to dCBT alone, chimerism analysis revealed sustained engraftment in haplo-dCBT is mediated by a “winning” CB unit. This was heralded by winning unit-derived T-cells seen as early as day +28. Although universal, the speed of haplo rejection varied, and a high haplo chimerism percentage early post-transplant did not guarantee successful bridging. Analysis of factors potentially predicting an optimal bridge is shown in Table 2. The median winning CB unit-haplo 8-allele HLA-match was 3/8 (range 1-7/8). In univariate analysis, higher haplo CD34+ dose/kg, > 4/8 haplo-recipient HLA-match and ≥ 3/8 winning unit-haplo HLA-match were associated with a higher likelihood of bridging. Haplo CD34+ dose and winning unit-haplo HLA-match remained significant in multivariate analysis.Conclusions: While haplo-dCBT can be associated with enhanced neutrophil recovery, this platform does not guarantee a successful myeloid bridge due to early haplo rejection by the winning CB unit. This universal haplo rejection highlights the importance of the CB graft dose and quality with this ATG-free strategy as the CB will mediate sustained engraftment. Our findings have significance for strategies that combine unmanipulated CB with any third-party or ex vivo expanded T-cell depleted product given higher product CD34+ cell dose and better HLA-match to the unmanipulated CB unit could improve the likelihood of successful myeloid bridging. The data also support alternative approaches to improve myeloid recovery after CBT such as optimized unit selection and vivo expansion. [Display omitted] DisclosuresO'Reilly:Atara Biotherapeutics: Consultancy, Patents & Royalties, Research Funding. Perales:Takeda: Other: Personal fees; Novartis: Other: Personal fees; Incyte: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees and Clinical trial support; Merck: Other: Personal fees; Abbvie: Other: Personal fees. Sauter:Juno Therapeutics: Consultancy, Research Funding; Sanofi-Genzyme: Consultancy, Research Funding; Spectrum Pharmaceuticals: Consultancy; Novartis: Consultancy; Precision Biosciences: Consultancy; Kite: Consultancy. Shah:Janssen: Research Funding; Amgen: Research Funding.

A High Degree of Engrafting Unit-Recipient HLA-Allele Mismatch Is Not Associated with an Increased Risk of Transplant-Related Mortality (TRM) or Inferior Progression-Free Survival (PFS) after Double Unit Cord Blood (CB) Transplantation (dCBT) in Adults with Hematologic Malignancies

Background: While incorporation of HLA-allele matching has highlighted high degrees of CB unit-recipient HLA-disparity, the less stringent HLA-match requirements extends allograft access to many patients without matched adult donors. The extent to which HLA-mismatch can adversely affect CBT outcomes, & the maximum permitted degree of HLA-mismatch, however, are not established.Methods: We analyzed TRM, relapse & PFS after intermediate intensity myeloablative cyclophosphamide 50 mg/kg, fludarabine 150 mg/m2, thiotepa 5-10 mg/kg, 400 cGy TBI double unit CBT in adults transplanted for hematologic malignancies. Eligible patients (pts) were first allograft recipients ≤ 65 years transplanted for acute leukemia/ MDS/ MPD (≤ 10% blasts pre-CBT), B-cell or T-cell lymphomas between 1/2014 - 12/2017. TNC & CD34+ dose were typically given priority over HLA-match in unit selection.Results: 102 pts [51 (50%) non-European, 59 (58%) CMV seropositive, median age 50 years (range 21-65), median weight 80 kg (range 36-137)] were transplanted. Diagnoses included 71 acute leukemias, 17 CML/ MPD/ MDS, 14 B- or T-cell NHLs. All received double unit grafts comprised of 2 (1%) 6/6 units, 21 (10%) 5/6, 181 (89%) 4/6 HLA-match, median unit-recipient 8-allele HLA-match 5/8 (range 3-7), & median infused viable CD34+ dose 1.3 x 105/kg/unit (range 0.2-8.6). Forty-eight (47%) CB grafts were supplemented with haplo-identical CD34+ cells as a myeloid bridge. The cumulative incidence of sustained CB engraftment was 97% (95%CI 90-99) with 2 pts having graft failure. A dominant (engrafting) unit was identified in all pts but 1 who died on day +14. Day 180 incidences of grades II-IV & III-IV aGVHD were 89% (95%CI 81-94) & 23% (95%CI 15-31), respectively. 1-yr cGVHD was 4% (95%CI 1-9). Cumulative incidence of TRM was 9% (95%CI 4-15) at day 180 & 14% (95%CI 8-22) at 2 yrs. 11% (95%CI 6-19) of pts relapsed by 2 yrs. With a median survivor follow-up of 2 yrs 3 months (range 6 - 51), the 2-yr overall survival is 82% (95%CI 75-90) & PFS is 74% (95%CI 66-84). Causes of death were transplant-related in 16 pts [6 aGVHD, 4 infection (2 viral, 1 bacterial, 1 fungal), 4 organ failure, 1 graft failure, 1 unknown] & due to relapse in 4 pts. By 2-yrs post-CBT, engrafting unit-recipient HLA-allele match had no association with TRM or PFS (Figure). Univariate analysis of the association between recipient variables [age, age adjusted hematopoietic cell transplant-comorbidity index (aaHCT-CI), revised disease risk index (rDRI)] & graft variables [engrafting unit-recipient HLA-allele match & infused CD34+ cell dose] & TRM, relapse & PFS are shown (Table). Age & aaHCT-CI were associated with 2-yr TRM with the 50 younger pts (< 50 years), & the 66 pts with aaHCT-CI 0-3, having especially low 2-yr TRM of 5% & 10%, respectively. Neither engrafting unit-recipient HLA-match nor CD34+ dose were associated with TRM. No pt or graft variable was associated with relapse. The only significant variable associated with 2-yr PFS was aaHCT-CI. The 66 pts with a lower aaHCT-CI score of 0-3 had a higher 2-year PFS [82% (95%CI 73-92)] than the 36 high score 4-9 pts [60% (95%CI 46-79)]. rDRI, engrafting unit-recipient 8-allele HLA-match & CD34+ cell dose had no effect. Multivariate analysis of TRM was precluded by too few events. Multivariate analysis of PFS including aaHCT-CI, rDRI & engrafting unit-recipient HLA-match showed high aaHCT-CI was associated with worse PFS [HR 2.82 (1.28-6.25) if score 4-9 vs 0-3, p = 0.01]; neither rDRI [HR 1.21 (0.54-2.69) if high-very high vs low-intermediate, p = 0.64] nor engrafting unit-recipient HLA-match [HR 2.06 (0.89-4.74) if 5-7/8 vs 3-4/8 matched (p = 0.09] were significant.Conclusions: Our finding that a high level of HLA-allele mismatch of the engrafting unit was not significantly associated with TRM or PFS in adult dCBT for hematologic malignancies has multiple implications. It supports the use of units with a relatively high degree of HLA-mismatch in the dCBT setting if needed in these pts. This facilitates extension of allograft access to the majority of pts including minorities. Moreover, the high PFS supports our centers unit selection strategy that gives unit quality & cell dose a priority in adults with malignancies to optimize engraftment. Finally, this data support CBT in many high-risk or urgent pts even if a well-matched CB graft cannot be identified. This is especially true in younger pts or those with a low 0-3 aaHCT-CI who had high 2-yr PFS. [Display omitted] DisclosuresPerales:Incyte: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees and Clinical trial support; Novartis: Other: Personal fees; Abbvie: Other: Personal fees; Merck: Other: Personal fees; Takeda: Other: Personal fees. Sauter:Juno Therapeutics: Consultancy, Research Funding; Sanofi-Genzyme: Consultancy, Research Funding; Spectrum Pharmaceuticals: Consultancy; Novartis: Consultancy; Precision Biosciences: Consultancy; Kite: Consultancy. Shah:Janssen: Research Funding; Amgen: Research Funding.

Intrabone Delivery of CD34+ Cells Using an Optimized Delivery System Does Not Enhance Engraftment in a Rhesus Macaque Model of Hematopoietic Stem Cell Transplantation

Introduction: Umbilical cord blood (UCB) grafts are the only option for a significant minority of patients who require hematopoietic stem cell transplantation (HSCT) but lack a suitable related or unrelated donor. While UCB can serve as a suitable ‘off the shelf’ graft for many patients, units with the best HLA match often contain low and sometimes insufficient numbers of CD34+ cells for use in transplantation, particularly for adult patients. Furthermore, UCB grafts contain lower CD34+ cells number compared to BM or PBSC grafts, which leads to longer engraftment times and a higher risk of graft failure. BM and PBSC grafts are usually injected intravenously, homing to the bone marrow after several hours in the circulation. During this time, CD34+ cells are lost in the lungs, liver and spleen with typically < 20% making it to the bone marrow.1 Investigators have sought to overcome the limitation of low cell dose in UCB grafts and loss of CD34+ cells in the circulation by injecting CD34+ cells directly into the bone marrow space. However, we have recently shown that conventional intrabone delivery methods used in investigational trials to transplant UCB, result in low-level retention of hematopoietic progenitor cells in the intrabone space. Recently, we developed an optimized intrabone (OIB) transplant method using computer controlled low pressure and low volume injection (controlled infusion rate <0.2ml/min, total volume <5ml) under CT guidance. Utilizing porcine and rhesus macaque models, we have shown that OIB delivery of CD34+ cells improves intrabone retention, preventing circulation of CD34+ cells through the lungs, which is observed with conventional non-optimized intrabone methods.2 Here we conducted experiments using an autologous myeloablative transplant model in rhesus macaques comparing engraftment of gene-marked CD34+ cells transplanted intravenously, with cells transplanted using OIB delivery.Methods: Rhesus macaques received GCSF and plerixafor mobilization prior to apheresis. Products were CD34+ selected using Miltenyi beads. CD34+ cells were split equally for transduction with lentiviral vectors encoding the reporters GFP and YFP. After myeloablative conditioning with 10Gy total body irradiation, half the graft was injected directly intra-bone using the OIB method, with the other half of the autograft simultaneously being injected intravenously via slow iv push. Peripheral blood samples were measured daily by flow cytometry to assess the proportion of engrafting cells deriving from each source. To address whether OIB transplantation could allow engraftment of low CD34+ cell numbers, as found in UCB units, the cell doses transplanted in one rhesus macaque recipient were reduced to only 0.5 x 106CD34+ cells/kg.Results: CD34+ cells injected intrabone utilizing the OIB method engrafted in all 3 animals. However, flow cytometric analysis gating on GFP vs YFP positive neutrophils showed CD34+ cells injected utilizing OIB delivery did not engraft quicker than IV transplanted cells. Sequential monitoring of neutrophils over 30 days showed the contribution to hematopoiesis of OIB delivered cells was significantly lower than the cells injected IV (Table 1.)Conclusions: We developed a novel intrabone delivery system that optimizes the retention of CD34+ cells into the bone marrow space. Although autologous CD34+ cells injected using this OIB transplant method were capable of engrafting in rhesus macaques that had undergone myeloablative conditioning, they did not engraft faster and contributed less to hematopoiesis than CD34+ cells simultaneously transplanted using conventional IV infusion. These data raise questions over whether intrabone delivery, even when using techniques to optimize intrabone retention, has utility in improving CD34+ cell engraftment.

Risk Factors of Clostridium Difficile Infection in Hematopoietic Stem Cell Transplant Recipients: A Systemic Review and Meta-Analysis

Introduction:C. difficile infection (CDI) is a common nosocomial infection. Immune suppression is thought to be a major risk factor for CDI. Hematopoietic stem cell transplant (HSCT) recipients represent a major subgroup of immunologically vulnerable patients. It is unclear if these patients have novel risk factors for CDI development. We, therefore, performed a systematic review and meta-analysis to evaluate the predictors of CDI in HSCT recipients.Methods:A systematic search of Medline, Embase, and Web of Science was performed from January 2000 up to June 2018. All studies that assessed risk factors associated with CDI development in HSCT recipients were eligible for inclusion. Data on clinical characteristics and risk factors associated with CDI development were collected. Study quality was assessed using the Newcastle-Ottawa scale. Meta-analyses were performed using random effects models and pooled odds ratios with 95% confidence interval (CI) for risk factors reported in ≥ 2 studies were calculated.Results:Overall, 17 studies, including 6328 HSCT patients were included. Of those 874 patients developed CDI. The rate of CDI development in these patients was 13.81% with a follow up ranging from 1- 36 months. A total of 34 different risk factors were studied, of which 20 were identified in ≥ 2 studies. Our analysis showed that cephalosporin use (Odds ratio [OR] 2.21, 95% confidence interval [CI] 1.26-3.87), cord blood transplant (OR 1.36, 95% CI 1.01-1.83), graft versus host disease (GVHD) (OR 1.63, 95% CI 1.07-2.48) & prior hospitalization within 90 days of HSCT (OR 1.85, 95% CI 1.21-2.83) were associated with statistically significant increased risk of CDI in HSCT patients (Figure 1). On the other hand, many characteristics of HSCT patients including age, diabetes, lung disease, fluoroquinolones, proton pump inhibitors, rituximab, mucositis, myeloablative therapy, melphalan use before BMT, total body irradiation, growth factor use during admission, neutropenia, autologous vs allogenic transplant and use of matched related donor were not associated with increased risk of CDI.Conclusion:HSCT recipients are at an increased risk of CDI compared to general population. In addition to the common risk factors like cephalosporin use and prior hospitalization, these patients have novel characteristics including presence of GVHD and cord blood transplant that puts them at a higher risk of CDI. HSCT patients with these risk factors may warrant a closer surveillance for early detection and treatment of CDI. DisclosuresNo relevant conflicts of interest to declare.

Extracorporeal Photopheresis for First Line Treatment of Acute Graft Versus Host Disease

Background. Extracorporeal photopheresis (ECP) is increasingly used in the treatment of acute and chronic graft versus host disease (aGVHD). It is recognized as an immunomodulatory therapy that can decrease inflammation and allow for immune tolerance. Interesting results have obtained using ECP as salvage therapy in patients with steroid-refractory GVHD after failure of one or more lines of immunosuppressive therapy. With this background, we hypothesized that incorporation of ECP as part of first line treatment for aGVHD may improve response rate and avoid the development of steroid-refractory or steroid-dependent aGVHD, mainly in cases of aGVHD with predominant skin involvement.Patients and methods. Forty consecutive patients who received ECP as part of their first line treatment of aGVHD with skin involvement between 2013 and 2016 were included in this single center analysis. 36 patients (90%) received granulocyte-colony stimulating factor mobilized PBSC as grafts, 3 patients (7.5%) received a bone marrow graft and one patient (2.5%) received an umbilical cord blood graft. Donor was a matched related one for 10 patients, haploidentical for 8 patients, matched unrelated for 16 patients and mismatched unrelated for 6 patients. 4 patients received a reduced intensity conditioning regimen and 36 a myeloablative reduced toxicity conditioning regimen. All patients received a combination of cyclosporine A (CsA) and mycophenolate mofetil for GVHD prophylaxis, except for patients with a matched related donor who received cyclosporine A alone. Patients transplanted with a haploidentical donor, received post-transplant cyclophosphamide (PTCy; 50mg/kg/d at d+3/d+5). ECP was initiated as soon as possible after the diagnosis of aGVHD with predominant skin involvement. The primary endpoint was to determine the best response achieved through the use of ECP for first line treatment of aGVHD.Results. Median age was 57 (range, 22-66) years, with 28 male patients (49%). Diagnoses were myeloid (n=32) or lymphoid malignancies (n=8) and disease status at transplant was complete remission in 23 patients, partial remission in 8 patients, relapse/progression in 8 patients and untreated in 2 patients. Patients developed aGVHD at a median of 31 days after alloHCT (range, 11-129). 5 patients had late onset aGVHD and two patients developed aGVHD after DLI. None of them had an overlap syndrome. aGVHD grade was I in 13 patients, II in 18 patients and III-IV in 9 patients. All patients had skin involvement and 10 patients had gut (n=8) and/or liver (n=5) involvement. All patients, but one, were still receiving CsA at time of aGVHD diagnosis. Systemic corticosteroids were initiated in 29 patients, while 11 patients received only topical dermo-corticoids. ECP was initiated at a median of 9 days (range, 0-83) after the diagnosis of aGVHD. ECP was performed weekly for 26 patients and twice weekly for 14 patients. Overall response rate (ORR) was 80% after a median of 3 (range, 1-9) weeks of treatment, including 24 complete responses (CR, 60%), 6 very good partial responses (VGPR, 15%) and 2 partial responses (PR, 5%). According to aGVHD grade, in patients with grade I aGVHD, the ORR was 92%, including 11 CR and 1 VGPR. In patients with grade II aGVHD, the ORR was 83%, including 8 CR and 7 VGPR/PR. In patients with grade III-IV aGVHD, ORR was 55%, all of them being in CR. In responding patients, 1 patient presented a recurrence of aGVHD and 15 developed chronic GVHD, including 4 overlap syndromes. Median follow-up was 32 months (range, 22-58) among surviving patients. At 24 months after transplant, the OS and PFS rates were respectively 78% (95% CI, 61%-88%) and 56% (range, 39%-70%). The 2-years cumulative incidence of relapse was 33% (95% CI, 19%-49%) and the 2-years cumulative incidence of non-relapse mortality was 10% (95% CI, 3%-22%).Conclusion. ECP is an effective and well-tolerated option for treatment of acute GVHD with predominant skin involvement with a 2 years cumulative incidence of NRM of 10% and an ORR of 80%. Best responses were seen in patients with grade I-II aGVHD, suggesting that ECP should be started as early as possible after the diagnosis of aGVHD. Incorporation of ECP as part of first line treatment for aGVHD may improve response rate and avoid the development of steroid-refractory aGVHD. Prospective randomized trial are warranted to evaluate ECP as adjuvant treatment for first line treatment of skin aGVHD. DisclosuresMohty:Celgene: Consultancy, Honoraria; Takeda: Honoraria, Speakers Bureau; Janssen: Honoraria, Research Funding, Speakers Bureau; Jazz Pharmaceuticals: Honoraria, Research Funding, Speakers Bureau; MaaT Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Myers: Consultancy, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau; Molmed: Consultancy; Servier: Consultancy; Amgen: Consultancy, Honoraria.

Successful Umbilical Cord Blood Transplantation in Relapsed B-Cell Acute Lymphoblastic Leukemia after Chimeric Antigen Receptors Therapy

Chimeric antigen receptors (CARs) therapy targeting CD19, a cell surface molecule found in most B-cell leukemias and lymphomas, has been the most successful therapeutic T-cell engineering to treat refractory or relapsed B-cell acute lymphoblastic leukemia. After achieving a second complete remission (CR) by CARs therapy, patients then have opportunities for allogeneic hematopoietic cell transplantation (allo-HCT) to be cured. However, in many patients, especially children and adolescent, a HLA-matched sibling or unrelated donor is often unavailable in China. Umbilical cord blood grafts require less strict genetic matching and are more readily available, has been identified as an alternative donor source for transplantation. However, umbilical cord blood transplantation (UCBT) following CARs therapy in relapsed B-cell Acute Lymphoblastic Leukemia (ALL) has rarely been reported before. What is the efficacy and safety by this type of transplantation? Here, we performed a successful UCBT following CARs therapy in a 9-year-old relapsed and chemo-refractory B-ALL girl.The girl was diagnosed as common B-ALL in July 2015 and suffered bone marrow relapse in August 2017. She was refractory to reinduction chemotherapy and got CR2 after CARs therapy. Unfortunately, her minimal residual disease (MRD) became positive again after 1month of CARs therapy. Stem cell transplantation is emergent. The girl didn't have matched related or unrelated donors, so a suitable umbilical cord blood graft was found with a matching of 4/6 alleles. Pretransplantation conditioning consisted of fludarabine 30 mg/m2 daily from days − 8 to − 5, busulfan 4 mg/kg daily from days − 7 to − 4, cyclophosphamide 60 mg/kg daily from days − 3 to - 2. Prophylaxis for acute graft versus host disease (GVHD) included cyclosporine A (CsA) and mycophenolate mofetil. She received one UCB unit on January 4, 2018. The infused cell doses of total nuclear cells (TNCs) and CD34+cells were 6.6 × 107/kg and 0.8 × 105/kg, respectively. Granulocyte colony-stimulating factor was given intravenously at a dose of 5 μg/kg on day 6 after transplantation and on each day thereafter until the WBC remained above 2.0 × 109/L for three consecutive days. The last follow up time was July 15, 2018.During the period of granulocytopenia, the patient didn't suffer obvious infections. The neutrophil count increased to over 0.5 × 109/L on day +15 and exceeded 1.0 × 109/L on day +16. The self- sustained platelet count exceeded 20 × 109/L on day +39. Hematopoietic chimerism was determined by quantitative PCR based on the amplification of short tandem repeat (STR) markers. Peripheral blood samples were obtained from the donor and the recipient before UCBT and from the recipient at 7 d, 14 d, 1 month, 2 months, 3 months and 6 months post-transplant. A complete donor chimera (100% donor DNA) was detected at 14 d, 1 month, 2 months, 3 months and 6 months following transplantation. Only grade I acute GVHD but no chronic GVHD occurred. Her MRD detected by flow cytometry kept negative since 2 months after transplantation.Thus, UCB transplantation following CARs therapy in relapsed and chemo-refractory B-ALL also appears to be an alternative donor source with successful engraftment, excellent graft versus leukemia (GVL) effect associated with no to mild GVHD. Unrelated UCB is an excellent alternative stem cell source for these patients especially for children. DisclosuresNo relevant conflicts of interest to declare.

Prognostic Performance of the Augmented Hematopoietic Cell Transplantation-Specific Comorbidity/Age Index in Recipients of Allogeneic Hematopoietic Stem Cell Transplantation from Alternative Graft Sources.

The Hematopoietic Cell Transplantation-Specific Comorbidity Index (HCT-CI) was developed and validated to weigh the burden of pretransplantation comorbidities and estimate their impact on post-transplantation risks of nonrelapse mortality (NRM). Recently, the HCT-CI was augmented by the addition of both age and the values of 3 markers: ferritin, albumin, and platelet count. So far, research involving The HCT-CI has been limited almost exclusively to recipients of allogeneic hematopoietic cell transplantation (HCT) from HLA-matched grafts. To this end, we sought to investigate the discriminative capacity of an augmented comorbidity/age index among 724 recipients of allogeneic HCT from HLA-mismatched (n = 345), haploidentical (n = 117), and umbilical cord blood (UCB; n = 262) grafts between 2000 and 2013. In the overall cohort, the augmented comorbidity/age index had a higher c-statistic estimate for prediction of NRM compared with the original HCT-CI (.63 versus .59). Findings were similar for recipients of HLA-mismatched (.62 versus .59), haploidentical (.60 versus .54), or UCB grafts (.65 versus .61). Compared with patients with an HCT-CI score ≥4, those with a score <4 had a higher survival rate among recipients of HLA-mismatched (55% versus 39%; P < .0008), HLA-haploidentical (58% versus 38%; P = .01), or UCB (67% versus 48%; P = .004) grafts. Our results demonstrate the utility of the augmented comorbidity/age index as a valid prognostic tool among recipients of allogeneic HCT from alternative graft sources.

Donor NKG2C Copy Number: An Independent Predictor for CMV Reactivation After Double Cord Blood Transplantation.

Cytomegalovirus (CMV) remains a major cause of morbidity following allogeneic hematopoietic stem cell transplant. Natural killer cells expressing NKG2C have been shown to play a role in the immune surveillance of human CMV. We studied NKG2C copy number in the donor graft and the risk of CMV reactivation after double umbilical cord blood transplantation (DUCBT) in 100 CMV seropositive DUCBT recipients and their corresponding cord blood (CB) grafts (n = 200). In the setting of DUCBT, the combined graft may contain 0–4 functional copies of NKG2C gene. Sixteen patients received a combined graft with 1 or 2 NKG2C copies and 84 patients were recipients of a combined graft with 3 or 4 NKG2C copies. The 6-month cumulative incidence of CMV reactivation for the two groups was 93.7 and 58.4%, respectively (p = 0.0003). In multivariate analysis, low NKG2C copies in the graft was an independent predictor of CMV reactivation (HR = 2.72, CI = 1.59–4.64; p < 0.0001). Our study points to an important role for donor NKG2C for protection against CMV reactivation after DUCBT. These novel findings may help identify patients at a higher risk of CMV reactivation after DUCBT. Donor NKG2C genotype may be used as a potential criterion in the algorithm for graft selection for DUCBT.

Aldehyde dehydrogenase activity in cryopreserved cord blood cells for quality assessment prior to transplantation.

In umbilical cord blood transplantation (UCBT), the number of cluster of differentiation (CD)34+ cells and colony‑forming units (CFUs) in the cord blood (CB) graft positively correlate with patient survival. Therefore, these parameters are currently used for quality assessment of the cryopreserved CB cells in the attached segment that is considered representative of the CB in the main bag prior to UCBT. Since aldehyde dehydrogenase (ALDH) activity is high in hematopoietic stem cells, the number of ALDH‑bright (ALDHbr) cells was examined in comparison with the number of CD34+ cells and CFUs for the quality assessment of CB units. In the cryopreserved main bag, the number of ALDHbr cells in the CB unit exhibited positive correlation with the number of CD34+ cells, and with CFU‑granulocytes/macrophages and total CFU counts. Furthermore, the concentration of ALDHbr cells in the cryopreserved attached segment was not significantly different compared to that of the main bag, suggesting that the attached segment is representative of the main bag. In conclusion, the present study suggested that ALDHbr cell counts in the cryopreserved attached segments may serve as a quality assessment indicator for CB units prior to UCBT.

Transplant Outcomes in Beta-Thalassemia Major Patients Receiving Combined Granulocyte Colony-Stimulating Factor-Primed Bone Marrow and Cord Blood Graft Compared to Granulocyte Colony-Stimulating Factor-Primed Bone Marrow Alone

Background: Hematopoietic stem cell transplantation (HSCT) is currently the only curative treatment for thalassemia major^TM. Graft rejection (GR) and graft-versus-host disease (GVHD) are the primary obstacles to a successful outcome. Methods: We conducted a retrospective study of HSCT in 29 children (median age at transplantation: 6 years) with Beta-thalassemia (β-TM) after the combined infusion of granulocyte colony-stimulating factor-primed bone marrow (G-BM) and cord blood (CB) from the human leukocyte antigen (HLA)-identical sibling donors. We also compared the outcomes of the co-transplanted children with those of children with β-TM who received G-BM alone from an HLA-identical sibling donor (n = 26). Results: Compared to the G-BM transplant (G-BMT) recipients, those who received a co-transplant had a lower incidence of grade ≥II acute (17.24 vs. 30.7%, p = 0.047) and limited chronic (0 vs.15.4%, p = 0.022) GVHD as well as a lower incidence of GR (0 vs. 7.7%, p = 0.132). Neutrophil recovery time was faster in the co-transplant group (18.5 vs. 21 days, p = 0.04). All the patients were monitored until December 31, 2016; the median follow-up time was 74 months<unterline>,</unterline> and the 5-year thalassemia-free survival rate was 89.7% in the co-transplant group and 84.6% in the G-BMT-alone group (p = 0.590). Conclusions: A combined CB and G-BM graft from an HLA-identical sibling donor is an effective treatment option for TM in children, with less acute and chronic GVHD.

213 - Sepax-Processed Umbilical Cord Blood Grafts are Associated with Excellent Clinical Outcomes

213 - Sepax-Processed Umbilical Cord Blood Grafts are Associated with Excellent Clinical Outcomes

Hematopoietic stem cell transplantation for acute myeloid leukemia.

Although allogeneic hematopoietic stem cell transplantation (allo-HSCT) yields a high rate of curability for acute myeloid leukemia (AML), it is also associated with transplant-related morbidity and mortality (TRM). The risk and severity of TRM increase with the use of an alternative donor graft in the absence of an HLA-matched sibling donor (MSD). With the declining birthrate and aging of the population, the numbers of patients with an MSD are decreasing, and alternative donor transplants, including the post-transplant cyclophosphamide method using haplo-identical donors, are increasing. Autologous (auto)-HSCT, which enables the intensification of chemotherapy, has the advantage of high availability of a transplant graft, and is associated with a lower TRM, but these benefits may be offset by a higher rate of relapse due to the lack of a graft-versus-leukemia (GVL) effect. Although allo-HSCT remains the first-line treatment for poor and very-poor-risk patients, auto-HSCT is again gaining increased attention. It has also recently been suggested that cord blood grafts may induce a stronger GVL effect than other grafts; as such, the positioning of cord blood transplantation should also be reconsidered for AML patients.

Reduced-Intensity Allogeneic Transplant for Acute Myeloid Leukemia and Myelodysplastic Syndrome Using Combined CD34-Selected Haploidentical Graft and a Single Umbilical Cord Unit Compared with Matched Unrelated Donor Stem Cells in Older Adults

Haplo/cord transplantation combines an umbilical cord blood (UCB) graft with CD34-selected haploidentical cells and results in rapid hematopoietic recovery followed by durable UCB engraftment. We compared outcomes of transplants in older patients with acute myeloid leukemia (AML) or high-risk myelodysplastic syndromes (MDS) who received either HLA-matched unrelated donor (MUD) cells or haplo/cord grafts. Between 2007 and 2013, 109 adults ages 50 and older underwent similar reduced-intensity conditioning with fludarabine and melphalan and antibody-mediated T cell depletion for AML (n = 83) or high-risk MDS (n = 26) followed by either a MUD (n = 68) or haplo/cord (n = 41) graft. Patient characteristics were similar for each graft source except for more minority patients receiving a haplo/cord transplant (P = .01). One half of the AML patients were not in remission. Two-year progression-free survival (PFS), overall survival (OS), and graft-versus-host disease–free relapse-free survival were 38%, 48%, and 32.1% for MUD and 33%, 48%, and 33.8% for haplo/cord transplants (P = .62 for PFS; P = .97 for OS; P = .84), respectively. Acute grades II to IV and chronic graft-versus-host-disease rates did not differ at 19.5% and 4.9% in haplo/cord compared with 25% and 7.4% after MUD (P = .53 and P = .62, respectively). Multivariate analysis confirmed no significant differences in transplant outcomes by donor type. Haplo/cord reduced-intensity transplantation achieves similar outcomes relative to MUD in older AML and MDS patients, making this a promising option for those without matched donors.