Single Umbilical Cord Blood Transplantation Research Articles

Effects of Haplotype Matching on Outcomes after Adult Single-Cord Blood Transplantation.

It remains unclear whether the HLA haplotype of unrelated cord blood (UCB) should be matched to that of the patient in single UCB transplantation. Thus, using data from a Japanese registry, we analyzed the effect of haplotype matching on outcomes. Patients with hematologic diseases aged 16 years or older who had undergone their first transplant were included (N = 1347). The effects of haplotype matching and high-frequency HLA haplotype on outcomes were analyzed. Median patient age was 55 years. The cumulative incidences of neutrophil engraftment among groups with 0, 1, and 2 HLA haplotype matches were 79%, 82%, and 88%, respectively (P = .008). In a multivariate analysis, the group with 0 haplotype matches was marginally associated with worse neutrophil engraftment (P = .087) and significantly associated with platelet engraftment (P = .044) compared with the group with 1 haplotype match. Two-haplotype matches were associated with a higher risk of relapse. In the group with 1 haplotype match, the top 3 shared haplotypes were "A*24:02-B*52:01-C*12:02-DRB1*15:02" (HP-P1), "A*33:03-B*44:03-C*14:03-DRB1*13:02" (HP-P2), and "A*24:02-B*07:02-C*07:02-DRB1*01:01" (HP-P3). The presence of HP-P2 but not HP-P1 or HP-P3 was associated with a decreased risk of grades II to IV acute graft-versus-host disease (hazard ratio, .56; P = .001) but an increased risk of relapse (hazard ratio, 1.35; P = .045). HLA haplotype matching might be considered to improve engraftment. Two-haplotype matches should be avoided if the relapse risk is high. The haplotype itself may have an effect on the risk of acute graft-versus-host disease and relapse.

Effects of High Cytomegalovirus DNA Load on Immune Reconstitution and Clinical Outcomes after Single Unrelated Cord Blood Transplantation

To investigate the effects of cytomegalovirus (CMV) DNA load on immune reconstitution and clinical outcomes of patients after unrelated cord blood transplantation (UCBT). Eight-color flow cytometry was used to dynamically monitor the changes of peripheral blood lymphocyte subsets of 41 patients at one year after UCBT, and 10 healthy volunteers were enroled as controls. Patients were divided into two groups according to the DNA load of CMV (DNA copies <1000/ml and DNA copies ≥1000/ml). Comparative analyse of the effect of CMV DNA load on lymphocyte subsets and transplantation outcomes were carried out after transplantation. The high CMV DNA load group showed a faster and expanded T cell reconstitution, and the differences between the two groups were statistically significant at one and nine months after transplantation (0.38×109 /L vs 0.25×109 /L, P=0.015 and 2.53×109 /L vs 1.36×109 /L, P=0.006, respectively). Further analysis of T cell subsets suggested that CD8+ T cells presented a higher and faster recovery in the high DNA load group, and the differences between the two groups were statistically significant at one and nine months after transplantation (0.20×109 /L vs 0.10×109 /L, P=0.038 and 1.62×109 /L vs 0.68×109 /L, P=0.003, respectively). In addition, there were no significant differences in levels of B cells, regulatory B cells and NK cells between the two groups. Outcomes after one- and a-half-year transplantation showed that there were no significant difference in relapse, non-relapse mortality and overall survival between the high and the low DNA load groups (7.7% vs 7.5%) (P=0.900) (15.4% vs 21.4%) (P=0.686) and (76.9% vs 78.6%) (P=0.889) respectively. The high CMV DNA load induces a faster and long-lasting expansion of T cells, mainly as the expansion of CD8+ T cells after UCBT. Besides, under the current pre-emptive treatment of CMV, the high CMV DNA load does not affect the early survival of patients with acute myeloid leukemia after UCBT.

A New Conditioning Regimen Can Significantly Promote Post-Transplant Immune Reconstitution and Improve the Outcome of Umbilical Cord Blood Transplantation for Patients.

This study included data from 81 consecutively enrolled patients with hematological diseases who had been treated with unrelated umbilical cord blood transplantation (UCBT) between September 2014 and April 2019. All patients received intense conditioning regimens with combined fludarabine and high-dose cyclophosphamide (FC) before undergoing UCBT. Sixty-seven patients received a single UCBT, and 14 patients received a double UCBT. Fifty patients were pretreated with the fludarabine, busulfan, and cyclophosphamide (FBC) protocol, while 31 patients were treated with FC before transplantation. Graft-versus-host disease (GVHD) was prevented with cyclosporine A and mycophenolate mofetil administration. According to low-resolution, human leukocyte antigen (HLA) donor-recipient matching at six sites, 53 patients had 5-6 matches, while 28 patients had 4 matches. Seventy-eight patients (96.3%) achieved complete engraftment in this study. Thirty-six patients developed acute GVHD (aGVHD). The cumulative incidence of grade I-II aGVHD at day 100 posthematopoietic stem cell transplantation was 29.6%, and the cumulative incidence of grade III-IV aGVHD was 14.8%. At the end of the follow-up, 12 patients died due to treatment-related complications, and 4 died of disease relapse after transplantation. The transplant-related deaths were due to transplant-related infection (8 of 81), GVHD (2 of 81), and organ toxicity (2 of 81). The probability of overall survival (OS) was 80.2%. A higher dose of cyclophosphamide combined with fludarabine conditioning in UCBT was an effective curative method for treatment of hematologic disorders and could enhance the engraftment of umbilical cord blood stem cells, promote post-transplant immune reconstitution, and improve OS.

Prognostic factors for adult single cord blood transplantation among European and Japanese populations: the Eurocord/ALWP-EBMT and JSHCT/JDCHCT collaborative study.

Large differences in patient and transplant backgrounds make it difficult to identify consistent prognostic factors of unrelated cord blood transplantation (UCBT) among different populations. Thus, we performed a collaborative study between Eurocord/ALWP-EBMT and JSHCT/JDCHCT. Adults with acute leukaemia who underwent a single UCBT were eligible. In total, 3764 and 1027 patients of the JSHCT/JDCHCT and Eurocord/ALWP-EBMT registries, respectively, were included. The median ages of the Japanese and European cohorts were 51 and 38 years, respectively. Three or more HLA mismatches were more frequently observed in the Japanese cohort. The median total nucleated cell (TNC) counts were 2.58 and 3.51 × 107/kg in the Japanese and European cohorts, respectively. Anti-thymocyte globulin was used in only 2% of the Japanese cohort compared with 65% of the European cohort. The 3-year overall survival (OS) was 41% in JSHCT/JDCHCT and 33% in Eurocord/ALWP-EBMT. In the multivariate analysis, TNC dose and HLA matching had no significant effect on OS in either cohort, whereas year of transplantation, age, and refined disease risk index affected OS in both cohorts. Despite considerable differences in characteristics between the Japanese and European cohorts, we observed similar prognostic factors affecting UCBT outcomes in adult patients with acute leukaemia in both registries.

Efficacy Analysis of Unrelated Cord Blood Transplantation for High-Risk Refractory AML1-ETO Positive Myeloid Leukemia

To analyze the clinical outcomes of engraftment, graft-versus-host disease (GVHD) and survival in the patients with AML1-ETO positive acute myeloid leukemia (AML) treated with unrelated umbilical cord blood transplantation (UCBT). Forty-Five patients with high-risk refractory AML1-ETO positive AML were treated with a single UCBT in a single center from July 2010 to April 2018. All the patients underwent a myeloablative preconditioning regimen，and cyclosporine A (CSA) combined with mycophenolate mofetil (MMF) was used to prevent GVHD. The median value of total nucleated cells (TNC) in cord blood was 5.21 (1.96-12.68)×107/kg recipient body weight, and that of CD34+ cells was 5.61 (0.56-15.4)×105/kg recipient weight. The implantation rate of neutrophil at 42 d and that of platelet at 120 d were 95.6% and 86.7%, respectively. The median time of absolute neutrophil count (ANC)＞0.5×109/L and platelet 20×109/L were 16 (12-18) d and 37 (17-140) d after transplantation, respectively. The cumulative incidence of Ⅰ -Ⅳ grade acute GVHD (aGVHD) at 100 d after transplantation was 48.9% (95% CI 33.5%-62.6%), Ⅱ-Ⅳ grade aGVHD occurred in 12 cases (33.3%) (95% CI 20%-47.2%) , and Ⅲ-Ⅳ grade a GVHD in 8 cases (20%) (95% CI 9.8% -32.8%). In 5 cases of 40 patients survived over 100 days, the chronic GVHD (cGVHD) occurred after transplantation, among which 4 were localized, and 1 was extensive. 3 patients relapsed, and the 2-year cumulative relapse rate was 9.5% (95% CI 2.4%-22.8%). The median follow-up time was 23.5 (0.9-89.67) months, 10 patients died, 2-year disease-free survival rate (DFS) was 72.7%, and overall survival rate (OS) was 75.5%. Multivariate analysis showed that Ⅲ-Ⅳ. acute GVHD (aGVHD) affected overall survival. UCBT is an effective rescue treatment for patients with high-risk refractory AML1-ETO positive AML.

Safety and Efficacy of Donor Leukocyte Infusion for Single Unit Umbilical Cord Blood Transplantation to Accelerate Immune Reconstitution Prior to Thymopoiesis

Success of reduced intensity umbilical cord blood transplantation (UCBT) in chemotherapy naive patients is limited by an increased risk of mixed chimerism, infection, and delayed immune reconstitution (IR). In a prospective clinical trial, we utilized risk-adapted alemtuzumab dosing, tested the safety of donor leukocyte infusion (cDLI) from a fraction of the thawed graft and evaluated it's efficacy in impacting IR, viral infection, and/or donor chimerism. 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). Up to 5% of the graft was re-cryopreserved for potential cDLI and administered in cases of declining donor Tcell chimerism, viral infection, or delayed IR. Alemtuzumab levels were obtained on the day of UCBT. Chimerism and IR were measured at standard time points. 33 patients had cDLI stored and 18 patients received cDLI at a median of 65 days post-UCBT. Indications included mixed whole blood or CD3 chimerism, viral infection, or delayed IR. All patients engrafted with neutrophils at a median of 15 days post-UCBT, however, one patient experienced secondary graft failure at day +38, despite cDLI 28 days post-UCBT. Improvement in chimerism was seen in 5 of 9 patients, viral load and/or symptoms of infection in 5 of 9 patients and absolute CD3 count in 5 of 5 patients. 15 patients developed acute grade I-III GVHD at a median of 69 days post-UCBT. In those who received cDLI, 8 developed grade I-II skin GVHD at a median of 19 days post-cDLI. 2 patients with a history of GVHD received subsequent cDLI without GVHD flare. No patients who received cDLI developed grade III or IV acute 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% vs. 33%; p=0.81). The 3-year overall and event-free survival of all patients was 94% and 91% respectively, with treatment-related mortality (TRM) of 5% 1 year post-UCBT. We report outcomes on the largest prospective trial utilizing cord blood grafts for nonmalignant disease. cDLI is safe in patients undergoing single-unit UCBT as all engrafted. Greater than half of the patients had improvement in the primary indication for its use, without increased GVHD risk. Greatest benefit was seen in patients with delayed IR and TRM at 1 year was exceptionally low. In sum, cDLI may be a simple and effective way to address mixed chimerism, infection, and accelerate IR during the vulnerable time prior to the onset of thymopoiesis. Further characterization of the merits of cDLI should be explored in a larger clinical trial.

Use of Unlicensed Unrelated Umbilical Cord Blood Expands Access to Underserved Patients: Report of 2466 Transplants in a Racially/Ethnically Diverse Population

Background Umbilical Cord Blood (UCB) transplant (UCBT) is a curative procedure for patients with hematologic malignancies and genetic disorders, and expands transplant options for a racially/ethnically diverse population, who are often unable to find a fully matched unrelated donor. In 2011, the Food and Drug Administration (FDA) required that all unrelated UCBT use either licensed UCB or unlicensed UCB via an Investigational New Drug (IND). Methods To allow continued access to unlicensed UCB units, the National Marrow Donor Program® (NMDP) manages a prospective distribution protocol for unlicensed UCB units, under an IND, 10-Cord Blood Access. This is an interim report of outcomes of 2466 US patients receiving unlicensed UCB units from 2011-2016. Of note, only 6% of available UCB units were licensed by December 2016. Results 1509 adults and 957 children (564 malignant disease and 393 non-malignant disease) received single or double UCBT between October 2011 and December 2016. Median age was 31 years ( Conclusions Use of unlicensed UCB units is safe and effective, and provides an important graft source for a diverse population.

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.

Cord Blood Transplantation in Adolescents and Young Adults with Acute Leukemia: On Behalf of Eurocord, Ctiwp and PDWP of EBMT

▪Outcomes for adolescents and young adults (AYA) might be considerably different from children and older adults with acute leukemia (AL). Patients in this transitory period tend to be considered at higher risk for poorer outcomes. However, AYA is still underrepresented in most hematopoietic stem cell transplant (HSCT) studies. Recent evidence shows superior outcomes for AYA with acute lymphoblastic leukemia (ALL) using pediatric rather than adult first line chemotherapy regimens. The aim of this study is to analyze outcomes of umbilical cord blood transplant (UCBT) in AYA patients with ALL or acute myeloid leukemia (AML) after myeloablative conditioning regimen (MAC).Eligibility criteria included patients with AL aged 15-25 (median 19) years, transplanted between 2004 and 2016 in EBMT centers, with single or double UCBT as first allogenic transplantation after MAC regimen and reported to Eurocord. A total of 504 patients were included. Primary endpoint was overall survival (OS).Median follow-up for survivors was 38 months (1 month-11 years). Median time from diagnosis to UCBT was 11 months (1 month-17 years) (interquartile range 5-29 months). Diagnosis was ALL in 59% (n=297) and AML in 41% (n=207); 64% of patients were male. Disease status at UCBT were 42% in 1st complete remission (CR) (n=203), 2nd CR in 38% (n=183), and advanced disease in 20% (n=96).Fifty eight percent of patients (n=293) received single and 42% (n=211) double UCBT. Cyclophosphamide + TBI ± fludarabine (45%) was the most frequently used conditioning regimen. Anti-thymoglobulin (ATG) was used in 54% and GVHD prophylaxis was cyclosporine A + mycophenolate mofetil in 44% of patients. Median nucleated cell dose at collection was 3.63 (range 0.9-9.0) X107/Kg for single and 5.25 (range 2.3-10.6) X107/Kg for double UCBT.The 3-year OS was 45±2%; 3-year leukemia free survival (LFS) was 41±2% and refined GVHD free/relapse free survival (rGRFS) was 32±2%.OS was similar in ALL and AML (45±3% vs 45±4%, p-value=0.69). According to disease status at UCBT, 3-year OS was 54±4% for patients in CR1, 48±4% for CR2 and 20±4% for advanced disease (p-value<0.001).Cumulative incidence function (CIF) for neutrophil engraftment at day-60 was 88% [95% confidential interval (CI) 85-90] in a median time of 24 days. CIF of acute GVHD grade II-IV at day-100 was 28% (95%CI 24-32) and out of the 233 patients with aGVHD, 73 (21%) had grade III-IV.The 1-year CIF of chronic GVHD was also 28% (95%CI 24-33) and out of the 124 patients with cGVHD, 52 (42%) had the extensive form.The 3-year CIF of transplant related mortality (TRM) was 31% (95%CI 24-33). The 3-year CIF of relapse was 28% (95%CI 24-32), and according to disease status at UCBT, relapse was 28% (95%CI 21-34) for patients in CR1, 24% (95%CI 18-31) for those in CR2 and 37% (95%CI 27-47) for advanced disease.Main causes of death were relapse (41%) and TRM (57%, mainly infections and GVHD).In multivariate analysis, disease remission at UCBT (HR 0.46, 95%CI 0.32-0.66, p-value<0.001) and transplant performed in more recent years (HR 0.75, 95%CI 0.62-0.90, p-value=0.002) were independently associated with increased OS. A similar effect was observed for LFS (recent transplantation: HR 0.80, 95%CI 0.66-0.95, p-value =0.01 and disease remission: HR 0.51, 95%CI 0.36-0.72, p-value <0.001). On the other hand, negative CMV serology (HR 0.77, 95%CI 0.61-0.99, p-value =0.042), recent transplantation (HR 0.85, 95%CI 0.73-0.99, p-value=0.49) and disease remission (HR 0.61, 95%CI 0.44-0.84, p-value =0.002) were significantly associated with increased rGRFS. For grade II-VI aGVHD, ATG use (HR 0.52, 95%CI 0.32-0.82, p-value=0.005), single UCBT (HR 0.63, 95%CI 0.42-0.96, p-value=0.03), and recent transplant (HR 0.76, 95%CI 0.59-0.98, p-value=0.034) reduced the risk. However, no factor was associated to cGVHD.This large series of AYA patients with AL provides detailed information on UCBT for this particular cohort with results comparable with other sources of HSCT.Due to the lack of information on pre-transplant chemotherapy (pediatric versus adult protocols), we were unable to evaluate its effect on outcomes. Nevertheless, this study contributes to a better understanding of HSCT for an age group that is not thoroughly described in most publications. Demonstrating the feasibility of UCBT in AYA patients is important to facilitate the decision of stem cell source selection when a more standard donor is not available. DisclosuresHough:University College London Hospital's NHS Foundation Trust: Employment. Angelucci:Vertex Pharmaceuticals Incorporated (MA) and CRISPR CAS9 Therapeutics AG (CH): Other: Chair DMC; Celgene: Honoraria, Other: Chair DMC; Jazz Pharmaceuticals Italy: Other: Local ( national) advisory board; Novartis: Honoraria, Other: Chair Steering Comiittee TELESTO Protocol; Roche Italy: Other: Local (national) advisory board. Bader:Medac: Patents & Royalties, Research Funding; Neovii: Research Funding; Riemser: Research Funding; Cellgene: Consultancy; Novartis: Consultancy, Speakers Bureau.

A Novel Recombinant Human Thrombopoietin Therapy for Promoting Platelet Engraftment in Haematological Malignancies after Single Umbilical Cord Blood Transplantation: A Prospective Randomized Controlled Trial

▪Background: Umbilical cord blood transplantation (UCBT) is an alternative to matched-unrelated or mismatched-related peripheral blood (PB) or BMT and has emerged as a widely accepted treatment for a wide variety of hematologic malignancies. However, delayed platelet engraftment (DPE) and platelet engraftment failure still remain the common problems following UCBT. So far, no standard therapy has been recommended. A few studies have demonstrated that recombinant human thrombopoietin (rHuTPO) could play an effective role in advancing platelet recovery after allo-HSCT. Nevertheless, it remains unknown whether rHuTPO plays the same role while it is applied in UCBT. We designed this prospective randomized controlled trial with the purpose of determining whether rHuTPO improves platelet engraftment in patients undergoing single UCBT(sUCBT) and further evaluating the function of rHuTPO in sUCBT.Methods: We enrolled 120 patients with haematological malignancies between October 2016 and March 2018 undergoing sUCBT in Department of Hematology, the First Affiliated Hospital of University of Science and Technology of China. This study was supported by National Natural Science Foundation, China (81670165) and International Cooperation Projects of Anhui Province, China(1804b06020352). The trial was approved by the Medical Ethics Committee of the First Affiliated Hospital of University of Science and Technology of China, and registered on www.chictr.org.cn(ChiCTR-IPR-16009357). 60 patients were randomly assigned into the experimental group, in which they received rHuTPO on Day 14 after sUCBT with a dose of 300 U/kg once daily for a period of 14 days; the remaining 60 patients formed the no-treatment control group. Among 120 patients, 19 received total body irradiation (TBI) based conditioning and others received modified myeloablative conditioning without antithymocyte globulin (ATG) as myeloablative conditioning. All patients were given cyclosporin (CsA) and mycophenolate mofetil (MMF) preventing graft-versus-host disease (GVHD). Supportive care and other treatments, including infectious disease prophylaxis and the use of granulocyte colony-stimulating factor, were provided following our center's protocols.Results: With a median follow-up of 336 days (ranging between 96-618) for the surviving patients, the cumulative incidence of PLT engraftment in the rHuTPO group (89.7%, 95% confidence interval [CI], 77-95.5) was significantly higher than that in the control group (78.9%, 95%CI, 65.3-87.6) (p=0.0294); the median time of PLT engraftment was 35 and 40days (ranging between 18-144 and 19-170 respectively, P=0.155). The median time of PLT recovery in the rHuTPO group was 43days(ranging between 25-171days), which was significantly shorter than that in the control group(53days, ranging between 28-195, P=0.034). The rHuTPO group also showed an advantage over the control group in infused PLT units (6 vs 8, p=0.0294). The cumulative incidence of ANC engraftment was 98.3% (95% CI, 75.2-99.9) and 94.9% (95% CI, 83.8-98.5) (p=0.111) respectively in two groups.Multivariate analysis confirmed the significance of differences in platelet engraftment between two groups. The cumulative incidences of grade II-IV and III-IV acute graft-versus-host disease (GVHD),relapse,non-relapse mortality (NRM) and cytomegalovirus viremia and the probabilities of overall survival(OS) and leukemia free survival (LFS) did not differ between the two groups. No severe adverse effects were observed in all patients.Conclusions: Our results demonstrate that rHuTPO could noticeably improve platelet engraftment and promote platelet recovery in patients with haematological malignancies receiving sUCBT; in the meantime, it could also reduce the requirement for platelet transfusion. This study indicated that rHuTPO could be a good option for promoting platelet engraftment and recovery in haematological malignancies after sUCBT. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

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.

Intrabone transplant provides full stemness of cord blood stem cells with fast hematopoietic recovery and low GVHD rate: results from a prospective study

Umbilical Cord Blood (UCB) represents a valid option for patients with hematopoietic malignancies lacking an HLA matched donor. To overcome the limitation of the low stem cell dose of UCB, the intrabone (IB) route has been proposed. We report the results of a prospective study on a poor-prognosis cohort of 23 patients receiving intrabone single UCB transplant (Clinicaltrials.gov NCT00886522). Cumulative incidence of hematological recovery at day 90 was 82 ± 9% (ANC > 0.5 × 109/L) and 70 ± 10% (platelet > 50 × 109/L) and correlated with CD34 + cells in the graft. NRM was 20 ± 9%. No severe aGVHD and only one extensive cGVHD occurred, with fast immune reconstitution. To test the hypothesis that the direct IB injection could affect the expression of stem cells regulatory pathways, CD34 + cells from BM aspirates at day + 10, + 20, + 30, processed in hypoxic conditions mimicking the BM-microenvironment (7%pO2), were studied for the expression of c-Mpl, Notch1 and CXCR4. We found that the expression of c-Mpl in CD34 + cells at day + 10 significantly correlated with hematological recovery. In conclusion, IB-UCB transplant success is associated with low incidence of GVHD and high-speed platelet recovery; intrabone route may preserve full hematopoietic stemness by direct delivery of UCB stem cells into the hypoxic HSC niche.

Haploidentical transplantation is associated with better overall survival when compared to single cord blood transplantation: an EBMT-Eurocord study of acute leukemia patients conditioned with thiotepa, busulfan, and fludarabine

BackgroundThiotepa-busulfan-fludarabine (TBF) is a widely used conditioning regimen in single umbilical cord blood transplantation (SUCBT). More recently, it was introduced in the setting of non-T cell depleted haploidentical stem cell transplantation (NTD-Haplo). Whether TBF based conditioning provides additional benefit in transplantation from a particular alternative donor type remains to be established.MethodsThis was a retrospective study based on an international European registry. We compared outcomes of de-novo acute myeloid leukemia patients in complete remission receiving NTD-Haplo (n = 186) vs. SUCBT (n = 147) following myeloablative conditioning (MAC) with TBF. Median follow-up was 23 months. Treatment groups resembled in baseline characteristics.ResultsSUCBT was associated with delayed engraftment and higher graft failure. In multivariate analysis no statistically significant differences were observed between the two groups in terms of acute or chronic graft-versus-host disease (GvHD) (HR = 1.03, p = 0.92 or HR = 1.86, p = 0.21) and relapse incidence (HR = 0.8, p = 0.65). Non-relapse mortality (NRM) was significantly higher in SUCBT as compared to NTD-Haplo (HR = 2.63, p = 0.001); moreover, SUCBT did worse in terms of overall survival (HR = 2.18, p = 0.002), leukemia-free survival (HR = 1.94, p = 0.007), and GvHD relapse-free survival (HR = 2.38, p = 0.0002).ConclusionsOur results suggest that TBF-MAC might allow for a potent graft-versus-leukemia, regardless of the alternative donor type. Furthermore, in patients receiving TBF-MAC, survival with NTD-Haplo may be better compared to SUCBT due to decreased NRM.

Outcomes of Graft Failures after Umbilical Cord Blood Transplantation in Acute Leukemia: A Study from Eurocord and the Acute Leukemia Working Party of the EBMT

▪Backround & Methods. Approximately 12% of adult patients (pts) receiving umbilical cord blood transplantation (UCBT) as treatment for acute myeloid (AML) or lymphoblastic (ALL) leukemia are reported to experience graft failure (Baron et al., J Hematol Oncol 2015 ; 8 :107). No systematic large study has assessed their outcome thus far. Therefore the acute leukemia working party of the EBMT and EUROCORD performed a multicenter retrospective registry study on adult patients with AML or ALL receiving a first single or double UCBT between 2005 and 2016.Results. The study included 1836 pts. 215 of them (11.7%) had graft failure; 160 with AML and 55 with ALL. Their median age was 43 (range, 18-68) years. 115 pts were male and 100 female. Median year of transplantation was 2010. 67% of the patients were in complete remission (CR) at transplantation, while 33% had advanced disease. Conditioning regimen was myeloablative in 128 pts (60%) and RIC in 87(40%) pts, respectively. ATG was administered in 101 pts. 126 pts received a single UCBT and 49 a double UCBT. Among the 215 pts with graft failure 54 underwent a second allogeneic (n=53) or autologous (n=1) transplantation 16 to 700 (median 62) days after the first UCBT (the 1-year cumulative incidence of second transplantation was 24%). 100-day and 1 year OS in pts not undergoing a second transplantation were 21.9 % (95% CI: 16.3-29.3) and 10.6 % (95% CI: 6.7-16.8), respectively. Among the 53 pts who underwent a second allogeneic transplantation, the second donor was either an unrelated donor (n=34), an HLA-haploidentical (n=17), or an HLA-identical sibling (n=2). Stem cell source consisted of single (n=13) or double (n=13) UCB, PBSC (n=17), BM (n=7), PBSC + UCB (n=3) or PBSC + BM (n=1). Conditioning regimen for the second transplantation was a RIC in 87% of pts. Sustained engraftment was achieved by 33 pts (61%) after the second transplantation. One- and 3-year incidences of relapse, nonrelapse mortality, OS and LFS from second transplantation were 21% and 28%, 47% and 52%, 40% and 23%, and 33% and 21%, respectively. Main causes of death following second transplantation (n=39) included infection (n=14) and leukemia relapse/progression (n=12). In the 17 patients receiving an haploidentical transplantation as second graft 1- and 3-year OS were 51.8 % (95% CI: 32.4-82.7) and 41.4 % (95% CI: 21.8-78.6), respectively. In a multivariate Cox model assessing factors predicting OS in UCBT patients with graft failure, transplantation for advanced disease (HR=2.3; 95% CI : 1.6-3.3, P<0.0001) as well as graft failure after the salvage transplantation (HR=2.8; 95% CI : 1.6-5.0, P=0.0005) were predictive of poor OS while use of RIC conditioning for the first transplantation was associated with a better OS.Conclusions. In this large cohort of adult pts given UCBT as treatment for AML or ALL the incidence graft failure was 12%. A second transplantation could be performed only to a minority (24%) of patients with high, about 50%, TRM but led to a 3-year OS of 23%, rescuing about quater of the pts with graft failure post UCBT. Results were more encouraging in the 17 patients who received a salvage HLA-haploidentical transplantation (3-year OS of 41%). Future attempts should be focused on reducing the high TRM associated with the second transplant while recent progresses in cord blood engineering will likely dramatically decrease the incidence of graft rejction after UCBT. DisclosuresMohty:Sanofi: Honoraria, Speakers Bureau.

Occurrence of graft-versus-host disease increases mortality after umbilical cord blood transplantation for acute myeloid leukaemia: a report from Eurocord and the ALWP of the EBMT.

The efficacy of umbilical cord blood transplantation (UCBT) as treatment for acute myeloid leukaemia (AML) relies on immune-mediated graft-versus-leukaemia effects. Previous studies have suggested a strong association between graft-versus-host disease (GVHD) occurrence and graft-versus-leukaemia effects after allogeneic hematopoietic cell transplantation. Here, we evaluated the kinetics of relapse rate in correlation with GVHD occurrence after UCBT. The kinetics of relapse rate over time in correlation to GVHD occurrence were assessed by calculating the relapse rate per patient-year within sequential 90-day intervals. The impact of GVHD on relapse and mortality was further studied in multivariate Cox models handling GVHD as a time-dependent covariate. The study included data from 1068 patients given single (n=567) or double (n=501) UCBT. The proportion of patients with grade II, III and IV acute GVHD was 20%, 7% and 4%, respectively. At 2years, the cumulative incidence of chronic GVHD was 42%, the cumulative incidence of relapse was 32%, and overall survival was 32% as well. Relapse rates declined gradually over time during the first 30months after transplantation. There was a possible suggestion that grade II-IV acute (HR=0.8, P=0.1) and chronic (HR=0.65, P=0.1) GVHD decreased relapse risk. However, grade II-IV acute GVHD significantly increased early (the first 18months after UCBT) mortality (HR=1.3, P=0.02), whilst chronic GVHD increased each early (HR=2.7, P<0.001) and late (HR=4.9, P<0.001) mortality after UCBT. The occurrence of grade II-IV acute or chronic GVHD each increases overall mortality after UCBT for AML mitigating the possible graft-versus-leukemia effect of GVHD.

European Group for Blood and Marrow Transplantation Risk Score Predicts the Outcome of Patients with Acute Leukemia Receiving Single Umbilical Cord Blood Transplantation

The European Group for Blood and Marrow Transplantation (EBMT) risk score has been implemented as an important tool to predict patient outcomes after allogeneic hematopoietic stem cell transplantation. However, to our knowledge, this score has never been applied in cases of single umbilical cord blood transplantation (sUCBT). We retrospectively analyzed 207 consecutive patients with acute leukemia who received sUCBT at our center between February 2011 and December 2015. The probabilities of 3-year overall survival (OS) and leukemia-free survival (LFS) of the entire cohort were 65.0% and 59.8%, respectively, whereas the cumulative incidences of 3-year nonrelapse mortality (NRM) and relapse rate were 19.5% and 20.3%, respectively. In the univariate analysis, a higher EBMT risk score was associated with worse OS and LFS and higher NRM and relapse rate, ranging from 81.7%, 75.9%, 7.3%, and 15.3%, respectively, for patients with a score of 1 to 43.8%, 44.3%, 31.7%, and 23.9%, respectively, for patients with scores of 4 to 6. Hazard ratios of OS, LFS, and NRM all steadily increased for each additional score point. Importantly, the prognostic value of the EBMT risk score on OS, LFS, NRM, and relapse was maintained in the multivariate analysis. Moreover, considering the univariate analysis results of donor–recipient gender and mismatched allele-level HLA-A, -B, -C, and -DRB1 loci on patient outcomes and the fairly strong interaction between time from diagnosis to sUCBT and disease status, we developed a modified sUCBT-EBMT risk score by using degrees of 8-allele HLA match instead of donor type, donor–recipient gender combination, and time from diagnosis to sUCBT, and found that the modified score could also be used as a predictor for patient outcomes after sUCBT. The EBMT risk score is a good predictor of outcomes of patients with leukemia after sUCBT. The modified sUCBT-EBMT risk score can also be used as a pretransplant risk assessment, but this metric still requires further evaluation with a larger cohort.

Patients Lacking a KIR-Ligand of HLA Group C1 or C2 Have a Better Outcome after Umbilical Cord Blood Transplantation.

Donor natural killer (NK) cells can destroy residual leukemic cells after allogeneic hematopoietic stem cell transplantation. This effect is based on the interaction of killer-cell immunoglobulin-like receptors (KIR) of donor NK cells with ligands of the major histocompatibility complex found on the surface of the target cells. HLA-C1 subtypes provide the ligand for KIR2DL2 and KIR2DL3 and the HLA-C2 subtypes for KIR2DL1. We have studied the probability of relapse (PR) after single-unit unrelated cord blood transplantation (UCBT) in relation to the potential graft-vs.-leukemia effect mediated by NK cells present in the umbilical cord blood (UCB) by analyzing KIR-ligand and HLA-C typing of the receptor. Data from 33 consecutive patients given a single unit UCBT were included. We have considered two groups of patients based on the absence or the presence of one of the C-ligands for inhibitory KIR and the incompatibility HLA-C1/2 between UCB and patients. Group 1 (n = 21): the patient lacks a C-ligand for inhibitory KIR present in UCB NK cells, i.e., patients homozygous C1/C1 or C2/C2. Group 2 (n = 12): patients heterozygous C1/C2 in which KIR-mediated graft-vs.-leukemia effect is not expected (presence of both C ligands for inhibitory KIR in the receptor). With a median follow-up post-UCBT of 93 months, patients with absence of a C-ligand for inhibitory KIRs (Group 1) showed a lower actuarial PR than patients with both C-ligands (group 2): 21 ± 10 vs. 68 ± 18% at 2 year and 36 ± 13 vs. 84 ± 14% at 5 years (p = 0.025), respectively. In patients with acute lymphoblastic leukemia, the 2-year PR was 36 ± 21% for group 1 and 66 ± 26% for 2 (p = 0.038). Furthermore, group 1 had a lower incidence of grades II–IV acute graft-vs.-host disease (p = 0.04). In the setting of UCBT, the absence of a C-ligand (C1 or C2) of inhibitory KIR in the patient is associated with lower PR, which is probably due to the graft-vs.-host leukemia effect caused by UCB NK cells that lack a ligand for the inhibitory KIR 2DL1/2DL2/2DL3.

Durable Chimerism and Long-Term Survival after Unrelated Umbilical Cord Blood Transplantation for Pediatric Hemophagocytic Lymphohistiocytosis: A Single-Center Experience

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disorder of immune dysregulation characterized by fever, hepatosplenomegaly, cytopenias, central nervous system disease, increased inflammatory markers, and hemophagocytosis. Currently, allogeneic hematopoietic stem cell transplantation is the only curative approach for patients with HLH, with reported survival ranging from 50% to 70% with myeloablative conditioning (MAC) regimens. However, donor availability and transplantation-related mortality associated with conventional MAC are major barriers to success. Unrelated umbilical cord blood transplantation (UCBT) provides a readily available alternative donor source for patients lacking matched related donors. Accordingly, we report the results of UCBT in 14 children treated between 1998 and 2016. All children received standard HLH chemotherapy before UCBT. The median age at diagnosis was 2.7 months (range, .8 to 10.4) and at transplantation was 7.5 months (range, 3.8 to 17). Ten patients received MAC with busulfan/cyclophosphamide/etoposide /antithymocyte globulin (ATG) (n = 5), busulfan/cyclophosphamide /ATG (n = 4), or busulfan /melphalan/ATG (n = 1). Four patients received reduced-toxicity conditioning (RTC) with alemtuzumab/fludarabine/melphalan/hydroxyurea ± thiotepa. Cord blood units were mismatched at either 1 (n = 9) or 2 (n = 5) loci and delivered a median total nucleated cell dose of 11.9 × 107/kg (range, 4.6 to 27.9) and CD34+ dose of 3.1 × 105/kg (range, 1.1 to 6.8). The cumulative incidence of neutrophil engraftment by day 42 was 78.6% (95% confidence interval [CI], 42.9% to 93.4%) with a median of 19 days (range, 13 to 27), and that for platelet (50,000) engraftment by day 100 was 64.3% (95% CI, 28.2% to 85.7%) with a median of 51 days (range, 31 to 94). Six patients developed either grade II (n = 5) or grade IV (n = 1) acute graft-versus-host disease (GVHD); no extensive chronic GVHD was seen. Ten patients (71.4%) are alive and well at a median of 11.2 years after transplantation (range, .85 to 18.25), 9 of whom maintain sustained full donor chimerism after a single UCBT, whereas 1 patient with autologous recovery after first UCBT with RTC has achieved full donor chimerism after a second UCBT with MAC. This series demonstrates that, in combination with standard HLH therapy, UCBT after MAC or RTC conditioning can provide long-term survival with durable complete donor chimerism comparable to that of conventional donors. UCBT should be considered for patients with HLH lacking a fully matched related or unrelated adult donor.

134 - A Pilot Trial of Unrelated Donor Human Placenta-Derived Stem Cells (HPDSC) in Conjunction with Single Unrelated Cord Blood Transplantation (UCBT) in Children with Malignant and Non-Malignant Disease (IND 14949)

134 - A Pilot Trial of Unrelated Donor Human Placenta-Derived Stem Cells (HPDSC) in Conjunction with Single Unrelated Cord Blood Transplantation (UCBT) in Children with Malignant and Non-Malignant Disease (IND 14949)

Impact of Delayed Infusion Time in Umbilical Cord Blood Transplantation

In umbilical cord blood (UCB) transplantation, UCB units are typically thawed, washed, and infused into the patient as rapidly as possible. In some instances there is a delay in the time from the unit thaw and wash procedure to infusion into the patient. Therefore, we examined the effect of thaw duration time on engraftment outcomes in 567 patients undergoing UCB transplantation. With a range of 32 to 523 minutes, a prolonged thaw duration had no obvious effect on the incidence of neutrophil engraftment or time to recovery. This was true for recipients of single UCB transplantation (incidence: 97% versus 93%, P = .13; time to neutrophil recovery: 21 days versus 21 days, P = .32; and platelet recovery: 79% versus 78%, P = .48), and similar results were observed in double UCB transplantation (time to neutrophil engraftment: 20 days versus 19 days, P = .71). However, there was a trend toward better platelet recovery in recipients of double UCB transplants with prolonged thaw duration (HR, 1.28; P = .06). In conclusion, this study demonstrates prolonged thaw duration has no detrimental effect on engraftment after single or double UCB transplantation.