Double Umbilical Cord Blood Transplantation Research Articles

Single vs double umbilical cord blood transplantation in acute leukemia: Systematic review and meta-analysis

Background and aimsUmbilical cord blood transplantation (UCBT) has emerged as a promising treatment option for patients with acute leukemia needing hematopoietic stem cell transplantation. Both single (sUCBT) and double cord blood units (dUCBT) demonstrate potential benefits, but studies comparing their effectiveness have shown mixed results. This meta-analysis aimed to determine the comparative safety and efficacy of sUCBT versus dUCBT in acute leukemia patients. MethodsElectronic databases were systematically examined to identify relevant studies comparing single vs double UCBT published until November 2023. Nine studies involving 3864 acute leukemia patients undergoing UCBT were included. Outcomes analyzed were acute graft-versus-host disease (GVHD), chronic GVHD, relapse, non-relapse mortality, leukemia-free survival and overall survival. Pooled risk ratios (RR) with 95% confidence intervals (CI) were calculated using a random effects model. ResultsThe risk of Grade II-IV acute GVHD (RR 1.55, 95% CI 1.19–2.03) and Grade III-IV acute GVHD (RR 1.25, 95% CI 1.07–1.46) were significantly higher with dUCBT. Relapse risk was lower with dUCBT (RR 0.57, 95% CI 0.38–0.88) while overall survival favored sUCBT (RR 1.25, 95% CI 1.06–1.46). No significant differences were observed for chronic GVHD, non-relapse mortality or leukemia-free survival. ConclusionBoth single and double UCBT have potential as effective treatments for acute leukemia. The choice of treatment should consider various factors, including the risk of GVHD, relapse, and mortality. More research, especially randomized trials, is needed to provide definitive guidance on the optimal use of single and double unit UCBT in patients with acute leukemia.

Mismatched Unrelated Donor Transplantation with Ptcy-Based Gvhd Prophylaxis Is Associated with Better Survival Than Double Unit Umbilical Cord Blood Transplantation in Patients with AML in First CR: A Study from the ALWP of the EBMT

Background: The best donor option for acute myeloid leukemia (AML) patients lacking an HLA-matched donor has remained unknown. The recently reported BNT CTN 1101 trial observed higher non-relapse mortality (NRM) and lower overall survival (OS) in patients randomized to double-unit unrelated umbilical cord blood transplantation (dCBT) in comparison to those randomized to HLA-haploidentical bone marrow transplantation with post-transplant cyclophosphamide (PTCy)-based graft-versus-host disease (GVHD) prophylaxis 1. In addition, recent registry studies observed at least as good transplantation outcomes in AML patients given grafts from 9/10 HLA-matched unrelated donor (UD 9/10) with PTCy-based GVHD prophylaxis as those given grafts from HLA-haploidentical donors 2,3. These observations prompted us to perform a retrospective registry study comparing hematopoietic cell transplantation (HCT) outcomes between UD 9/10 and dCBT. Methods: Inclusion criteria consisted of adult patient, AML in CR1 at transplantation, either peripheral blood stem cells (PBSC) from UD 9/10 with PTCy as GVHD prophylaxis or dCBT, transplantation between 2013 and 2021, and no in vivo T-cell depletion. Results: A total of 208 dCBT patients and 270 UD 9/10 allo-HCT were included. The 180-day cumulative incidence of grade II-IV acute GVHD was 29% in UD 9/10 versus 44% in dCBT recipients (P=0.001). The 2-year cumulative incidences of relapse and of NRM were 23.5% and 12.5%, respectively, in UD 9/10 recipients versus 27% (P=0.39) and 18% (P=0.07), respectively in dCBT recipients. Two-year OS and LFS were 70% and 64%, respectively, in UD 9/10 recipients versus 60% (P=0.016) and 55% (P=0.028), respectively in dCBT recipients. In multivariate analyses, in comparison with UD 9/10 recipients, dCBT patients had a higher non-relapse mortality (HR=2.35, 95% CI: 1.23-4.48; P=0.01), comparable relapse incidence (HR=1.12, 95% CI: 0.67-1.86; P=0.66), lower leukemia-free survival (HR=1.5, 95% CI: 1.01-2.23; P=0.047), and lower overall survival (HR=1.66, 95% CI: 1.08-2.55; P=0.02). Conclusions: In summary, our results suggest that transplantation outcomes are better with UD 9/10 with PTCy-based GVHD prophylaxis than with dCBT for AML patients in CR1. These data might support the use of UD 9/10 with PTCy-based GVHD prophylaxis in AML patients lacking an HLA-matched donor. References Fuchs, E. J. et al. Double unrelated umbilical cord blood vs HLA-haploidentical bone marrow transplantation: the BMT CTN 1101 trial. Blood 137, 420-428 (2021).Baron, F. et al. Comparison of HLA-mismatched unrelated donor transplantation with post-transplant cyclophosphamide versus HLA-haploidentical transplantation in patients with active acute myeloid leukemia. Bone Marrow Transplant. 57, 1657-1663 (2022).Battipaglia, G. et al. Post-transplant cyclophosphamide in one-antigen mismatched unrelated donor transplantation versus haploidentical transplantation in acute myeloid leukemia: a study from the Acute Leukemia Working Party of the EBMT. Bone Marrow Transplant. 57, 562-571 (2022).

Emergence of human CMV-induced NKG2C+ NK cells is associated with CD8+ T-cell recovery after allogeneic HCT

AbstractCytomegalovirus (CMV) infection is associated with the expansion of a mature NKG2C+FcεR1γ− natural killer (NK) cell population. The exact mechanism underlying the emergence of NKG2C+ NK cells, however, remains unknown. Allogeneic hematopoietic cell transplantation (HCT) provides an opportunity to longitudinally study lymphocyte recovery in the setting of CMV reactivation, particularly in patients receiving T-cell−depleted (TCD) allografts. We analyzed peripheral blood lymphocytes from 119 patients at serial time points after infusion of their TCD allograft and compared immune recovery with that in samples obtained from recipients of T-cell−replete (T-replete) (n = 96) or double umbilical cord blood (DUCB) (n = 52) allografts. NKG2C+ NK cells were detected in 92% (45 of 49) of recipients of TCD HCT who experienced CMV reactivation. Although NKG2A+ cells were routinely identifiable early after HCT, NKG2C+ NK cells were identified only after T cells could be detected. T-cell reconstitution occurred at variable times after HCT among patients and predominantly comprised CD8+ T cells. In patients with CMV reactivation, recipients of TCD HCT expressed significantly higher frequencies of NKG2C+ and CD56neg NK cells compared with patients who received T-replete HCT or DUCB transplantation. NKG2C+ NK cells after TCD HCT were CD57+FcεR1γ+ and degranulated significantly more in response to target cells compared with the adaptive the NKG2C+CD57+FcεR1γ− NK cell population. We conclude that the presence of circulating T cells is associated with the expansion of a CMV-induced NKG2C+ NK cell population, a potentially novel example of developmental cooperation between lymphocyte populations in response to viral infection.

Cost-Effectiveness of Unrelated Umbilical Cord Blood Transplantation versus HLA-Haploidentical Related Bone Marrow Transplantation: Evidence from BMT CTN 1101

BMT CTN 1101 was a Phase III randomized controlled trial comparing reduced-intensity conditioning followed by double unrelated umbilical cord blood transplantation (UCBT) versus HLA-haploidentical related donor bone marrow transplantation (haplo-BMT) for patients with high-risk hematologic malignancies. Here we report the results of a parallel cost-effectiveness analysis of these 2 hematopoietic stem cell transplantation (HCT) techniques. In this study, 368 patients were randomized to unrelated UCBT (n=186) or haplo-BMT (n=182). We estimated healthcare utilization and costs using propensity score-matched haplo-BMT recipients from the OptumLabs Data Warehouse for trial participants age <65 years and Medicare claims for participants age ≥65 years. Weibull models were used to estimate 20-year survival. EQ-5D surveys by trial participants were used to estimate quality-adjusted life-years (QALYs). At a 5-year follow-up, survival was 42% for haplo-BMT recipients versus 36% for UCBT recipients (P=.06). Over a 20-year time horizon, haplo-BMT is expected to be more effective (+.63 QALY) and more costly (+$118,953) for persons age <65 years. For those age ≥65 years, haplo-BMT is expected to be more effective and less costly. In one-way uncertainty analyses, for persons age <65, the cost per QALY result was most sensitive to life-years and health state utilities, whereas for those age ≥65, life- years were more influential than costs and health state utilities. Compared to UCBT, haplo-BMT was moderately more cost-effective for patients age <65 years and less costly and more effective for persons age ≥65 years. Haplo-BMT is a fair value choice for commercially insured patients with high-risk leukemia and lymphoma who require HCT. For Medicare enrollees, haplo-BMT is a preferred choice when considering costs and outcomes.

Health-Related Quality of Life in Double Umbilical Cord Blood versus Haploidentical Marrow Transplantation: A Quality of Life Analysis Report of BMT CTN 1101

The Blood and Marrow Transplant Clinical Trials Network study 1101 (BMT CTN 1101; ClinicaTrials.gov identifier NCT01597778) was a multicenter phase III randomized trial comparing the clinical outcomes and quality of life (QoL) of patients with hematologic malignancies undergoing double umbilical cord blood transplantation (dUCBT) or HLA-haploidentical bone marrow transplantation (haplo-BMT) after reduced-intensity conditioning. At a 5-year follow-up, there were no significant differences in progression- free survival (PFS) or overall survival (OS) between the 2 cohorts. The impact of alternative donor source on QoL is unknown, however. English- and Spanish-speaking patients completed the Functional Assessment of Cancer Therapy-General (FACT-G), Short Form 36 (SF-36), EuroQoL-5 Dimensions EQ-5D, and Global QoL patient-reported outcome (PRO) assessments pretransplantation and at 12 and 24 months post-transplantation. We compared longitudinal QoL measures between the dUCBT and haplo-BMT cohorts and investigated the association of QoL and clinical outcomes using an inverse probability weighted-independent estimating equations method, accounting for missingness and baseline variables. We found no significant differences between the 2 cohorts in any of the QoL scores pretransplantation and at 12 and 24 months post-transplantation. Pretransplantation scores were the only significant predictors of post-transplantation QoL scores. Relapse and grade III-IV acute graft-versus-host disease (GVHD) were associated with significant declines in mean FACT-BMT and SF-36 Physical Component scores, and chronic GVHD was associated with a decline in mean EQ-5D utility scores. There were no significant associations between pretransplantation QoL scores and OS or PFS. Donor type did not impact post-transplantation QoL. Pretransplantation QoL scores and clinical events of GVHD and relapse were the only predictors of post-transplantation QoL. QoL was not associated with survival in either treatment arm. PROs may be valuable tools in pretransplantation risk assessment strategies to improve QoL outcomes.

Quality of Life in Patients Undergoing Double Umbilical Cord Blood Vs. Haploidentical Marrow Transplantation: A QOL Analysis Report of BMT CTN 1101

Introduction BMT CTN 1101 was a multicenter phase III randomized trial comparing the clinical outcomes and quality of life (QOL) of patients with hematological malignancies receiving double umbilical cord blood transplants (dUCBT) or haploidentical bone marrow transplants (haplo) with post-transplant cyclophosphamide after reduced intensity conditioning. Extended follow-up at 5 years showed that there were no significant differences in progression free survival (PFS) or overall survival (OS) between the two cohorts. However, the hazard ratio for NRM was 2.69 in favor of haplo transplants with all of the difference seen in the first 18 months post-transplant. The impact of donor source on QOL, however, is unknown. Thus, the objectives of this analysis are to compare longitudinal QOL between dUCBT and haplo and to investigate the association of QOL and clinical outcomes. Methods Enrollment occurred from 6/2012-6/2018, and included 368 patients (n=186 dUCBT, n=182 haplo), age 18-70 with 2 year follow up. QOL assessments included the FACT-BMT measure; the MOS Short Form 36 Physical Component Score (PCS) and Mental Component Score (MCS); the EQ-5D; and the Global QOL Scale. These were completed pre-transplant and at 12 and 24 months post-transplant. To account for missing assessments, scores were compared between arms using an inverse probability weighted-independent estimating equations (IPW-IEE) method that models scores in surviving patients while accounting for baseline variables (age, race/ethnicity, primary disease, disease risk, performance status, and HCT-CI) and follow-up outcomes that impact the likelihood of missingness. Cox models evaluated potential associations of pre-transplant QOL scores with OS and PFS while adjusting for these baseline variables. Analyses were performed using intention-to-treat (ITT) patient assignment from the time of randomization. A threshold of 1% was used to determine statistical significance for all analyses. Results No significant differences were observed between treatment arms in baseline patient, disease, and transplant characteristics (previously described) among patients who participated in at least one QOL assessment. In the UCB arm, PRO response rates were 145/186 (78%) pre-transplant, 67/105 (64%) at 12 months, and 47/85 (55%) at 24 months. In the haplo arm, PRO response rates were 134/182 (74%) pre-transplant, 79/115 (69%) at 12 months, and 50/102 (49%) at 24 months. HCT-CI >3 pre-transplant and relapse at 12 and 24 months were the most consistent factors significantly associated with lower completion of QOL questionnaires at respective time points. We found no significant difference in any of the QOL scores at pre-transplant, 12, and 24 months between the treatment arms (Figure 1). In multivariable IPW-IEE models, pre-transplant FACT-BMT total score, SF-36 PCS, and EQ-5D scores were the only significant predictors of post-transplant QOL scores. There was no significant association of treatment arm or baseline clinical variables with FACT-BMT or SF-36 PCS scores post-transplant. Age >60 was associated with higher mean EQ-5D (0.08, 99% CI 0.025-0.131, p=0.0002) and SF-36 MCS scores (4.45, 99% CI 0.288-8.622, p=0.0059) on post-transplant assessments. There was no significant impact of treatment arm on Global QOL score or subscale scores post-transplant. We evaluated the association of post-transplant clinical events with primary QOL endpoints (Table 1). Relapse and Grade III-IV aGVHD were associated with significant declines in mean FACT-BMT and SF-36 PCS scores. cGVHD was associated with a decline in mean EQ-5D utility scores. We found no significant association between pre-transplant QOL scores and OS or PFS (p>0.10 for all models). There were no significant interactions between treatment groups and baseline characteristics on QOL measures. Conclusions This longitudinal QOL analysis of BMT CTN 1101 showed that donor type did not impact post-transplant QOL. Pre-transplant QOL scores were the only predictor of post-transplant 12 and 24 month scores which, however, were not associated with OS or PFS in either treatment arm. Clinical events of GVHD and relapse were associated with declines in QOL scores. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Long-Term Persistence of Mixed Full Donor Chimerism after Double Cord Blood Transplantation. Example of Tolerance in Allogeneic Hematopoietic Cell Transplantation Setting

Background Double umbilical cord blood transplantation (UCBT) is recognized as an alternative source of hematopoietic donor cells for allogeneic haematopoietic cell transplantation (HCT), particularly in adult setting. Because of important infectious complications, UCBT are rarely utilized and more and more replaced by haplo-identical cell transplantation for adult patients. Nevertheless, some very good results were observed with a long-term follow-up. In most cases, after several weeks, one unit turns immuno-dominant and thus, the second one is no longer detected. Patients and Methods We reported three cases of long-term mixed full donor chimerism associated to documented complete remission of haematological malignancies after double UCBT. The indications of UCBT were acute myeloid leukaemia for 2 patients [1 AML MRC (female of 65 years) and 1 transformation of Fanconi disease (female of 20 years)] and acute lymphoid leukaemia for 1 patient (female of 22 years). AML received a reduced intensity and ALL a standard conditioning. The general characteristics of recipients and UCB are presented in Table 1. The chimerism follow-up were performed by STR and qPCR techniques with a sensitivity of 5 and 0.2% respectively. Early after transplantation, patient 1 developed a grade I graft-versus-host disease (GVHD), patient 3 a grade II GVHD treated by extracorporeal photopheresis, and patient 2 did not develop any GVHD. The follow-up of these patients were 14, 13 and 8 years respectively after UCBT without any episodes of relapse and at the last follow-up still a total donor mixed chimerism. Results Results of STR and qPCR after transplantation early revealed the presence of the two transplant units with a total donor chimerism (Table 1). Patient 1 presented a perfectly balanced chimerism with 54 % of the majority unit. The other two patients showed an imbalance in the proportions of their two UCB with 83% and 72% of their majority units respectively but a long-term persistence of 17% and 28% of their second UCB. The study of total blood chimerism during their follow-up revealed a stabilization of the proportions of the two units during the first year (Figure 1). A more in-depth study of circulating cell subsets (CD3+, CD15+ and CD19+) chimerism of patient 1 revealed a very strong initial imbalance of the two units, which ended up being balanced at two years after transplantation. In the other two patients, the respective study of CD3+ and CD33+ cells showed a stabilization of the two unit percentage around six months after transplantation. At five years after transplantation, patient 1 had an in-depth study of circulating cells sub-populations (CD4+ T lymphocytes, CD8+ T lymphocytes, B-lymphocytes, natural killer cells, regulatory T cells, monocytes, naive CD4+ and CD8+ T lymphocytes) by flow cytometry, after separation of the two units cells by specific monoclonal antibody directed against HLA mismatching antigen (HLA-A2). This analysis revealed an imbalance in the percentage of NK and monocytes. The immune-dominant unit had three times more NK cells than the other one and this imbalance ratio increased by twenty-two for monocytes. A co-culture study of the CD4+ lymphocytes demonstrated a lack of reactivity of both unit against the other one but a normal ability to react against an allogeneic third-part cell. Conclusions This expected tolerance, highlighted in co-culture experience, showed rare cases of naturally induced graft tolerance. A study of tolerance markers and underlying mechanisms in these special cases of persistent mixed full donor chimerism is necessary to acquire better knowledge and to define more investigations ways for the induction of tolerance in patients receiving hematopoietic cell transplantation or organ transplantations. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Does Race/Ethnicity Impact Umbilical Cord Blood Transplant Outcomes in a Contemporary Era?

Background: Studying the impact of race/ethnicity on stem cell transplant outcomes helps us improve health care disparities and access to transplant. The use of umbilical cord blood (UCBT) was designed to allow mismatched UCB units and improve access to transplant for patients lacking a fully matched donor. Previous CIBMTR studies (Ballen et al, BBMT, 2012) showed that Black patients had a lower overall survival (OS) than White patients following single UCBT; however, outcomes were similar when UCB units of comparable cell dose and HLA match were used. The current study draws on a larger, more modern cohort and compares outcomes among non-Hispanic White (White), non-Hispanic Black (Black), Hispanic/Latinx (Latinx) and Asian patients. Methods: CIBMTR data from 2007 to 2017 were used. Patients were between ages 1 and 80; 983 received single and 1259 double UCBT, following either a myeloablative (N=1752) or reduced intensity conditioning (N=759). The primary outcome was OS at 2 years, which was estimated using the Kaplan-Meier method with the log-rank test used for univariate comparisons. Secondary outcomes included disease free survival, transplant related mortality (TRM), acute and chronic graft vs host disease (GVHD), and GVHD free, relapse free survival (GRFS). Multivariate analysis was performed to determine factors associated with outcomes and whether race/ethnicity influences these outcomes. Results: A total of 1705 adults and 807 children were included. For adults, in univariate analysis, 2-year OS was 41.5% (99% CI, 37.6-45.3) for Whites, 36.1% (99% CI, 28.2-44.5) for Latinx, 45.8% (99% CI, 36.7-55.1) for Blacks, and 44.5% (99% CI, 33.6-55.6) for Asians. In multivariate analysis of adults, Latinx patients had inferior OS compared to other racial/ethnic groups (p=0.005) (Figure 1). OS improved over time across all racial/ethnic groups (p=0.009; 2016-2017 vs. 2007-2009 HR 0.68, 99% CI 0.51-0.91). Relapse and TRM rates were higher in Latinx compared to other groups but did not reach statistical significance. GVHD rates were comparable among the different racial/ethnic groups. There was no survival advantage to receiving a UCB unit from a donor of similar race/ethnicity, for any racial/ethnic groups In children, the 2-year OS in univariate analysis was 66.1% (99% CI, 59.7-72.2) for Whites, 57.1% (99%CI, 49-64.9) for Latinx, 46.8% (99%CI, 35.3-58.4) for Blacks, and 53.8% (99%CI, 32.7-74.2) for Asians. In multivariate analysis of children, no difference in OS was observed among racial/ethnic groups (p = 0.05) (Figure 2). Similarly, there was no difference in relapse (p=0.40) and TRM rates (p=0.14). Grade 3-4 Acute GVHD was higher in Blacks compared with Whites (p= 0.0016, HR 2.25, 99% CI 1.36-3.74). There was no survival advantage to receiving a UCB unit from a donor of similar race/ethnicity, for any racial/ethnic groups. Conclusion: 1. UCBT provides a donor for diverse patients. 2. In adults, OS has improved over time for all racial/ethnic groups. 3. In adults, OS is comparable among Whites, Blacks, and Asians and lower for Latinx patients. 4. In children, OS is comparable among Whites, Blacks, Latinx, and Asians. 5. In children, Grade 3 and 4 acute GVHD was higher in Black patients. 6.There was no survival benefit to matching UCB unit and patient by race/ethnicity for adults and children, although the numbers were small in the non-White cohorts. As our study reveals race/ethnicity matching has minimal to no impact on outcomes post UCB transplant it may be advantageous for UCB banks to target collection of larger units over race/ethnicity quotas. Future studies will study biologic or socioeconomic explanations for the lower OS in adult Latinx patients and the higher acute GVHD in pediatric black patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Retinopathy associated with severe thrombocytopenia

In January, 2019, a 37-year-old, White man presented to Saint-Etienne University Hospital (France) with relapsed Hodgkin lymphoma. A PET-CT scan showed hypermetabolic adenomegaly above and below the diaphragm, without visceral or bone involvement. Two cycles of intravenous chemotherapy (gemcitabine 800 mg/m2, vinorelbine 15 mg/m2, and pegylated liposomal doxorubicin 10 mg/m2 on days 1 and 8 every 21 days) resulted in a complete metabolic response in March, 2019. Consolidation consisted of double umbilical cord blood transplantation (dUCBT; total nucleated cells 15·4 × 107 cells per kg and 19·1 × 107 cells per kg for each cord, CD34+ cells 6·5 × 105 cells per kg and 7·9 × 105 cells per kg) after an intravenous conditioning regimen (thiotepa 5·0 mg/kg, busulfan 3·2 mg/kg, fludarabine 40 mg/m2, thymoglobulin 5·0 mg/kg).

Hospitalization and Healthcare Resource Use of Omidubicel Vs Cord Blood Transplantation for Hematological Malignancies in a Global Randomized Phase III Clinical Trial

IntroductionUmbilical cord blood (UCB) remains an important source of hematopoietic stem cells for patients, where no matched donor is available and for racial minorities. However, cord blood transplants have been associated with delayed hematopoietic recovery, prolonged hospitalization, and higher costs of transplant compared with other donor sources. Omidubicel is an advanced cell therapy that preserves stem cell function to optimize cell homing, engraftment, differentiation, and self-renewal and is manufactured from an appropriately HLA-matched single UCB unit for each patient. A recent phase III clinical trial (NCT02730299) reported that patients who received omidubicel experienced faster time to neutrophil engraftment, faster platelet recovery, reduced rates of infections and shorter hospitalization time than patients who received standard single (33%) or double (67%) UCB transplantation [Horwitz et al, Blood, 2021]. We report on an analysis of resource utilization including hospital length of stay, hospital care setting, visits by provider type, rates of transfusions and readmissions from the Phase III trial.MethodsThe Phase III clinical trial included patients aged 12-65 with hematological malignancies and eligible for an allogeneic transplant. The primary endpoint was time to neutrophil engraftment, with secondary endpoints of time to platelet engraftment, first grade 2/3 bacterial or fungal infections and days alive and out of hospital in the first 100 days. 125 patients were randomized in the study. We analyzed resource utilization data for patients treated with omidubicel (n=52) or UCB (n=56) (“as-treated population”) focusing on resource utilization within the first 100 days of transplantation. Summary statistics were compared between treatment arms, means and medians used to draw comparison and significance testing was performed.ResultsIn the Phase III clinical trial, omidubicel met its primary endpoint and secondary endpoints with statistical significance. The demographics and patient characteristics were overall well-balanced with slightly more males (52% vs 63%) and a lower median age (40 vs 36) in the UCB arm. The study population was diverse with 17.6% Black, 14.8% Asian, 14% Hispanic or Latino and 12% other/unknown. Most patients had AML (45%) or ALL (34.3%), with MDS, CML and lymphomas making up the rest of the study population. The disease risk index was high/very high in 35% of the patients and 24% of the patients had a Karnofsky/Lansky performance score of <90. The rapid hematopoietic recovery was supported by a reduced rate of infections. The rates of acute and chronic GVHD in the two arms were comparable.Within the first 100 days after transplant, omidubicel patients experienced shorter average total length of hospital stay than UCB recipients (mean 41.2 vs 50.8 days; p = 0.027) and more days alive and out of the hospital (mean 55.8 vs 43.7 days; p=0.023). 12% of patients on omidubicel arm died vs 16% on UCB arm before day 100. During the primary hospitalization (transplant to discharge), fewer omidubicel patients required intensive care unit (ICU) stay (9.6% vs 23.2%) and spent fewer days in the ICU (mean 0.4 vs 4.7 days; p =0.028) and the transplant unit (mean 25.3 vs 32.9 days; p =0.022) compared to UCB recipients. Omidubicel patients required fewer outpatient consultant visits and fewer outpatient non-consultant visits (X-rays, scans, biopsies etc.) and required fewer platelet or other transfusions (RBC, albumin, plasma, and factor product) within 100 days from transplant (Table 1).ConclusionsThis analysis shows that more rapid hematopoietic recovery in patients transplanted with omidubicel was associated with significantly shorter hospital length of stay and reduced healthcare resource use compared to UCB in the clinical trial. Although economic data were not collected as part of the clinical trial, the costs of providing transplantation care during the first 100 days are likely lower with omidubicel compared to UCB in the real-world setting, as hospital stay, outpatient visits, and blood product transfusions are among the major drivers of costs during this time period. [Display omitted] DisclosuresMajhail: Incyte Corporation: Consultancy; Anthem, Inc: Consultancy. Manghani: Gamida Cell, Inc.: Current Employment; Tricida, Inc.: Ended employment in the past 24 months. Sivaraman: Incyte Corporation: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Gamida Cell, Inc.: Current Employment. Galamidi-Cohen: Gamida Cell, Ltd: Current Employment. Maziarz: Bristol-Myers, Squibb/Celgene, Intellia, Kite: Honoraria; CRISPR Therapeutics: Consultancy; Artiva Therapeutics: Consultancy; Intellia: Honoraria; Omeros: Research Funding; Athersys: Other: Data and Safety Monitoring Board, Patents & Royalties; Incyte Corporation: Consultancy, Honoraria; Novartis: Consultancy, Other: Data and Safety Monitoring board, Research Funding; Allovir: Consultancy, Research Funding; Vor Pharma: Other: Data and Safety Monitoring Board.

NOTCH-mediated exvivo expansion of human hematopoietic stem and progenitor cells by culture under hypoxia.

SummaryActivation of NOTCH signaling in human hematopoietic stem/progenitor cells (HSPCs) by treatment with an engineered Delta-like ligand (DELTA1ext-IgG [DXI]) has enabled ex vivo expansion of short-term HSPCs, but the effect on long-term repopulating hematopoietic stem cells (LTR-HSCs) remains uncertain. Here, we demonstrate that ex vivo culture of human adult HSPCs with DXI under low oxygen tension limits ER stress in LTR-HSCs and lineage-committed progenitors compared with normoxic cultures. A distinct HSC gene signature was upregulated in cells cultured with DXI in hypoxia and, after 21 days of culture, the frequency of LTR-HSCs increased 4.9-fold relative to uncultured cells and 4.2-fold compared with the normoxia + DXI group. NOTCH and hypoxia pathways intersected to maintain undifferentiated phenotypes in cultured HSPCs. Our work underscores the importance of mitigating ER stress perturbations to preserve functional LTR-HSCs in extended cultures and offers a clinically feasible platform for the expansion of human HSPCs.

First Application Of The EBMT Risk Score In Double Umbilical Cord Blood Transplantation For Hematological Malignancies: Significant Impact On Different Outcomes

The European Group for Blood and Marrow Transplantation (EBMT) risk score provides a simple tool to assess chances and risks of hematopoietic stem cell transplantation (HSCT) for an individual patient from related and unrelated donors. To our knowledge, this score has never been applied in double umbilical cord blood transplantation (dUCBT). We recently published results of 136 patients who underwent dUCBT reported to the SFGM-TC registry from 23 centers between 2005 and 2007 (Labussiere et al., Exp. Hem. 2013). After having recorded the full data on CB units including HLA and sex, we decided to test the validity of the EBMT risk score and check its application in dUCBT. There were 88 males and 48 females with a median age of 41 years (range: 18 – 66), 76 patients with acute leukemias (42 AML, 27 ALL, 5 secondary AL and 2 Biphenotypic AL), 8 with chronic leukemias (5 lymphoid and 3 myeloid), 10 with myelodysplasic syndormes, 24 with Hodgkin and non Hodgkin lymphomas, 13 with multiple myelomas and 5 with other myeloproliferative diseases. Median interval between diagnosis and transplantation was 20.5 months (range: 3-385). At time of allogeneic transplantation, 41 patients were in first complete remission (CR1), 40 in ≥CR2 and 55 less than CR. Forty-six patients received myeloablative and 90 reduced intensity conditioning regimens. The EBMT risk score uses the 5 pre-transplant factors: age of the patient, disease status, time from diagnosis to transplant, kind of donor (related/unrelated), and donor-recipient sex combination with 0 to 1 or 2 points (pts) for each factor. Age was categorized as <20 years (0 pt; n= 6), 20 to 40 years (1 pt; n= 59) and >40 years (2 pts; n=71). For disease status we distinguished patients in CR1 at transplantation, (0 pt; n=41) from patients in CR >1 (1 pt; n=40) and patients not in CR (2 pts; n=55). Time from diagnosis to transplant was categorized into ≤12 months (0 pt; n=26) and >12 months (1pt; n=110). The adaptation of the new risk score concerned HLA and sex matching. Complete information concerning HLA typing was obtained from the database of the national network of cord blood banks on behalf of Eurocord. HLA typing was evaluated across 3 loci: HLA-A, -B and -DRB1; it was based on antigenic level for HLA-A and HLA-B, and on allelic level for HLA-DRB1. HLA matching showed patients with at least 4/6 HLA matching on HLA-A, -B and DRB1 without any mismatch on DRB1 alleles between the recipient and each UCB unit and the 2 units together (0 pt; n=77); patients with at least 4/6 HLA matching on HLA-A and -B between the recipient and each unit but without complete matching on DRB1 or with less than 4/6 HLA matching between the 2 units (1 pt; n=51), and finally patients with more than 2 mismatches on the three loci (2 pts; n=8). Donor-recipient sex combination separated all others (0 pt; n=73) from the male recipient with one female and one male cord blood unit (1pt; n=45) and male recipient with two female cord blood units (2 pts; n=18). Hence, we found 5 patients (4%) in score 1, 12 (9%) in score 2, 23 (17%) in score 3, 26 (19%) in score 4, 30 (22%) in score 5, 26 (19%) in score 6, 11 (8%) in score 7 and 3 (2%) in score 8. We pooled patients with scores 1-2; 3-4 and 5-8 as their outcomes were found to be similar. After a median follow-up of 49.5 months, the 3 years probabilities of overall and progression-free survivals for the whole population were 41% and 35% respectively. with a two-year cumulative relapse incidence of 28% (24.0 – 31.8). Interestingly patients with score 1-2 showed better overall survival rates than those with score 3-4 and 5-8 with a 3 years probability of 77%, 42% and 32% respectively (p=0.002); this was associated with a 3 years relapse incidence of 19%, 35% and 55% respectively (p=0.021), while the 3 years transplant related mortality (TRM) was 6%, 39% and 36% respectively (score 1-2 versus all others, p=0.02), Figure 1. [Display omitted] In conclusion, we found that the EBMT risk score can perfectly be applied to double UBCT with a significant impact on different outcomes; its use enables a better selection of patients who will benefit the more from this treatment strategy. Disclosures:No relevant conflicts of interest to declare.

Outcomes of Cord Blood Transplantation for Adult Patients with Hodgkin Lymphoma, a Eurocord and EBMT Lymphoma Working Party Study

Allogeneic stem cell transplantation represents an alternative for relapsed or refractory patients (pts) with Hodgkin Lymphoma (HL). In this setting, only limited data on unrelated umbilical cord blood transplantation (UCBT) are available. We analyzed 133 adult pts with HL who underwent UCBT in EBMT centers. Histological subtype was nodular sclerosis in 65% of the pts. Median age at UCBT was 29 (18-65) years. Median follow-up was 37 (2-119) months and median year of UCBT was 2010 (2003-2015). Ninety pts had received a previous autologous transplantation (ASCT), while 19 had received 2 ASCT before UCBT; median time from ASCT to UCBT was 15 (2-281) months. Disease status at UCBT was complete remission (CR) in 45%, partial remission (PR) in 28% and relapse or refractory disease in 27% of the pts. Sixty percent of pts were male and 54% had a positive cytomegalovirus serology. Fifty-one percent (n=68) received a single UCBT and 49% (n=65) a double UCBT; 58% of pts received a graft with 2 or more HLA mismatch. The majority of the pts (n=104, 77%) underwent a reduced intensity conditioning regimen, the most frequent conditioning regimen (n=69) being Cyclophosphamide + Fludarabine + Total Body Irradiation (TBI) (2 Gy). Forty percent (n=46) of pts received anti-thymocyte globulin and Cyclosporine A + mycophenolate mofetil prophylaxis was given to 60% (n=80) of the pts. Median total nucleated cell (TNC) dose at cryopreservation was 3.99 (1.5-12.2) x107/Kg.The cumulative incidence (CI) of neutrophil engraftment at 60 days was 87% (81%-93%). The 100-day CI of acute grade II-IV GVHD was 26% (19%-35%). At 3 years, chronic GVHD was 30% (21%-41%). Relapse incidence (RI) and non-relapse mortality (NRM) were 40% (32%-50%) and 30% (23%-40%) at 3 years, respectively. The overall survival (OS) was 48% (39%-57%) and progression free survival (PFS) was 28% (21%-37%) at 3 years. Sixty-nine patients died: 27 of relapse and 39 of transplant related causes (infections, n=13, GVHD, n=7, idiopathic pneumonia syndrome n=6, EBV-PTLD n=2, VOD n=2 and others causes, n=9). According to disease status at UCBT, OS at 3 years was 68% (55%-79%) for pts in CR, 31% (18%-50%) for pts in PR and 26% (14%-44%) for pts in relapsed or refractory disease.In multivariate analysis, adjusted for median year of UCBT, Cyclophosphamide + Fludarabine + low dose TBI conditioning regimen, disease status at UCBT, conditioning intensity and type of UCBT, none of these factors were found to be associated with acute or chronic GVHD. 3-year RI and NRM were higher for pts in relapse or refractory disease at UCBT compared to pts in CR (HR=2.62, 95%CI 1.12-6.11, p=0.03 and HR=3.66, 95%CI 1.52-8.80, p=0.004, respectively). The use of Cyclophosphamide + Fludarabine + low dose TBI conditioning regimen was associated with a lower risk of NRM (HR=0.38, 95%CI 0.15-0.95, p=0.04) and also with a better OS (HR=0.37, 95%CI 0.18-0.76, p=0.006). OS was significantly worse for pts who underwent UCBT in PR (HR=1.97, 95%CI 1.02-3.80, p=0.04) and for those in relapse or refractory disease at transplant (HR=2.86, 95%CI 1.41-5.81, p=0.004). Pts transplanted in relapse or refractory disease have also a lower PFS (HR=3.12, 95%CI 1.71-5.71, p<0.001).In conclusion, UCBT is feasible in heavily pretreated pts with HL, if there are no other alternative donors. Conditioning with Cyclophosphamide + Fludarabine + low dose TBI is associated with a better OS and NRM. However, outcomes are poor for patients not in CR at the time of UCBT and one might consider the use of new therapeutic agents earlier before UCBT in this setting. DisclosuresZuckerman:BioSight Ltd.: Consultancy. Snowden:Sanofi: Honoraria. Robinson:Gilead: Honoraria, Other: Travel Grants; Takeda: Consultancy, Honoraria, Other: Travel Grants; Roche: Honoraria, Other: Travel Grants; Riemser: Consultancy.

Phase I Dose-Finding, Safety, and Tolerability Trial of Romiplostim to Improve Platelet Recovery After UCB Transplantation

Platelet recovery is delayed after umbilical cord blood transplant (UCBT). Romiplostim is a thrombopoietin receptor agonist that has the potential to improve platelet engraftment after UCBT. The purpose of this study was to determine the safety profile and maximum tolerated dose (MTD) of romiplostim and to investigate whether romiplostim accelerates platelet recovery post-UCBT. It was a single-center, dose-finding, safety and tolerability phase I trial of weekly romiplostim in 20 adult patients who failed to achieve an un-transfused platelet count of 20×109/L by day +28 post-UCBT. Romiplostim was administered at the assigned dose as 6 weekly injections beginning by day +42 post-UCBT. Four dose levels (4, 6, 8, and 10 µg/kg per dose) were evaluated. The MTD of romiplostim was determined by the continual reassessment method, with a goal to identify a dose level with desired toxicity rate of ≤20%. Median age of the patients was 59.5 years, and 60% were female. Eleven patients received nonmyeloablative (NMA) double UCBT, seven patients received myeloablative single UCBT, and two patients received NMA single UCBT. Two patients received 4 µg/kg per dose, two received 6 µg/kg per dose, four received 8 µg/kg per dose, and the remaining 12 received 10 µg/kg per dose. Only five patients completed the full six doses of treatment. Of the 15 patients who received fewer than six doses, 12 were due to a platelet count of >100×109/L, two were due to platelet count of >400×109/L, and one was due to right upper extremity edema without thrombosis. All romiplostim-treated patients achieved platelet engraftment to 20×109/L at a median of 45 days post-UCBT compared to 90% of controls at a median of 45 days (P=.08). Similarly, 90% of romiplostim-treated patients achieved platelet engraftment to 50×109/L at a median of 48 days compared to 75% of controls at a median of 52 days (P=.09). All dose levels were effective with low toxicity; therefore, the MTD of romiplostim was 10 µg/kg per dose, and romiplostim is a safe and potentially effective therapy to counter delayed platelet recovery post-UCBT.

Double Umbilical Cord Blood Transplantation in a Pediatric Patient: A First for Nebraska

Double Umbilical Cord Blood Transplantation in a Pediatric Patient: A First for Nebraska

Unlicensed Umbilical Cord Blood Units Provide a Safe and Effective Graft Source for a Diverse Population: A Study of 2456 Umbilical Cord Blood Recipients.

Umbilical cord blood (UCB) transplantation (UCBT) is a curative procedure for patients with hematologic malignancies and genetic disorders and expands access to transplantation for non-Caucasian patients unable to find a fully matched unrelated donor. In 2011, the US Food and Drug Administration required that unrelated UCBT be performed using either licensed UCB or unlicensed UCB under the Investigational New Drug (IND) program. The National Marrow Donor Program manages an IND under which 2456 patients (1499 adults and 957 children, 564 with malignant diseases and 393 with nonmalignant diseases) underwent single or double UCBT between October 2011 and December 2016. The median patient age was 31 years (range, <1 to 81 years), and 50% of children and 36% of adults were non-Caucasian. The median time to neutrophil engraftment (ie, absolute neutrophil count ≥500/mm3) was 22 days for adults, 20 days for pediatric patients with malignant diseases, and 19 days for pediatric patients with nonmalignant diseases, with corresponding rates of engraftment at 42 days of 89%, 88%, and 90%. In these 3 groups of patients, the incidence of acute graft-versus-host disease (GVHD) grade II-IV was 35%, 32%, and 24%; the incidence of chronic GVHD was 24%, 26%, and 24%; and 1-year overall survival (OS) was 57%, 71%, and 79%, respectively. In multivariate analysis, younger age, lower Hematopoietic Cell Transplantation-Specific Comorbidity Index, early-stage chemotherapy-sensitive disease, and higher performance score were predictive of improved OS for adults. In a subset analysis of children with malignancies undergoing single UCBT, the use of either licensed UCB (n=48) or unlicensed UCB (n=382) was associated with similar engraftment and survival. The use of unlicensed UCB units is safe and effective and provides an important graft source for a diverse population.

No Engraftment Advantage after Single or Double Umbilical Cord Blood Transplant (CBT) with the Addition of a Non-HLA Matched Off-the-Shelf Expanded Cord Blood Unit Compared to Conventional CBT: Results of a Randomized Trial

Background: Based on pilot study data demonstrating safety and excellent survival [Blood 2014 124:46] in acute leukemia patients undergoing myeloablative cord blood transplant (CBT) plus infusion of an off-the-shelf non-HLA matched expanded CB unit (OTS) for bridging hematopoiesis, a randomized trial was conducted to determine whether myeloablative CBT with or without an OTS would confer more rapid neutrophil (ANC) engraftment and therefore a survival advantage. Methods: We conducted a multi-center, randomized controlled phase II trial (RCT) with a primary endpoint of ANC engraftment defined as the first of 2 consecutive days in which neutrophil count ≥ 500 cells/μL. Secondary endpoints included platelet engraftment, overall survival (OS), disease free-survival (DFS), acute/chronic graft-versus-host disease (GVHD), non-relapse mortality (NRM), and relapse. 160 patients were enrolled between February 2013 and June 2018. Patients were randomized to receive either a conventional single or double CBT (SOC group) (n=78) or SOC + OTS (OTS group) (n=82). Unmanipulated CB units had to be at least 4/6 HLA-matched to the patient (intermediate resolution for HLA-A, -B and allele-level for HLA-DRB1) with no HLA matching required for the OTS. Patient disease (AML=68, ALL=77, MDS=7, CML/other=8), disease risk, gender, age, race, ethnicity, CMV serology, performance score and HLA-match were balanced between the two study groups. Patients received conditioning with either FLU 75mg/m2, TBI 13.2 Gy, CY120 mg/kg or with FLU 150mg/m2, TBI 4Gy, CY 50 mg/kg and Thiotepa 10 mg/kg. Cyclosporin and MMF were used for GVHD prophylaxis in all patients (Table 1). Results: The median follow-up of surviving patients was 15 months. Approximately 30% of patients enrolled were &amp;lt;18 years and most patients received the high dose TBI (13.2Gy) regimen (85% in OTS group and 91% in SOC group). The median pre-cryopreserved total nucleated cell dose was 5.4 × 107/kg for both groups while the median pre-cryopreserved CD34 cell dose was 0.30 and 0.28 × 106/kg for the OTS and SOC group, respectively. Patients in the OTS group received an additional median CD34+ cell dose of 10.5x106/kg. Median time to ANC engraftment was similar between the 2 groups, at 20 days (range 7-46) in the OTS group and 19 days (13-51) in the SOC group. Five patients experienced graft failure, 2 in the OTS group and 3 in the SOC group. Similarly, no difference was seen for median time to platelet engraftment [38 days (35-43) vs. 40 days (30-42) for the OTS and the SOC group]. Peripheral blood chimerisms performed weekly (day 7-28) revealed that the initial circulating myelomonocytes present in the peripheral blood of OTS patients at day 7 were nearly all generated from the OTS product. Contribution to engraftment of the OTS graft was transient, and generally undetectable after day 21. All outcomes were similar between the two groups. OS and DFS at 2 years were 70% and 60% vs 61% and 55% for the OTS and the SOC groups, respectively. Cumulative incidence of relapse and NRM at 2 years were 18% and 21% in the OTS group and 21% and 22% in the SOC group. Grade III-IV aGVHD was 16% and 14% for the and the SOC group, respectively. The OTS product was well tolerated, and serious adverse events rates similar between the 2 groups. Patients continue to be followed through 2 years to assess cGVHD, and graft-relapse-free-survival. Conclusion: In this multi-center RCT, no significant difference was observed in the primary or secondary endpoints. Importantly, while the median time to ANC recovery in the OTS group was unchanged (20 days) from our pilot study, the observed time to neutrophil recovery in the SOC group was 7 days quicker than expected based on previously observed outcomes following myeloablative CBT (median 26 days). During the 5 years that this study was open to accrual, the criteria for CB donor selection have improved, now regularly utilizing CD34+ cell content and high-resolution HLA-typing where available, as has the quality of the CB inventory. This RCT highlights that delayed engraftment should no longer be a barrier in the consideration of SOC CBT for patients with hematological malignancies. As expected, and observed consistently following CBT, both groups demonstrated low incidence of severe acute GVHD and relapse at 2 years. Interventions in CBT should focus on improving immune reconstitution and reducing the risk of NRM but must be easily adopted into SOC in order to be adopted clinically. Disclosures Milano: ExCellThera: Research Funding; Amgen: Research Funding. Rezvani:Kaleido: Membership on an entity's Board of Directors or advisory committees, Other: one-time compensation from advisory boards; Nohla Therapeutics: Membership on an entity's Board of Directors or advisory committees, Other: one-time compensation from advisory boards; AbbVie: Other: Principal investigator ; U.S. Department of Justice: Other: Expert medical witness; Johnson &amp; Johnson: Employment, Other: Brother is employed. Delaney:Nohla Therapeutics: Employment, Equity Ownership; Biolife Solutions: Membership on an entity's Board of Directors or advisory committees.

Romiplostim Improves Platelet Recovery after UCB Transplant

Background: Prolonged thrombocytopenia after hematopoietic stem cell transplant is a relatively common complication associated with intricate mechanisms including impaired thrombopoiesis and increased platelet turnover. Platelet recovery is particularly delayed after umbilical cord blood transplant (UCBT). Romiplostim is a thrombopoietin receptor agonist that is FDA approved for the treatment of chronic ITP. Although an increasing number of studies recently show promising results on the use of romiplostim in chemotherapy induced thrombocytopenia, the effect of romiplostim on platelet recovery in patients with persistent thrombocytopenia after UCBT remains unknown. Objectives: The primary objective of the study was to determine the maximum tolerated dose (MTD) of romiplostim in patients who failed to achieve platelet recovery by day +28 after UCBT. Secondary objectives were to determine if romiplostim influences the speed of platelet recovery, decreases the risk of thrombocytopenia related complications or affects the incidence of bone marrow (BM) fibrosis or relapse. Methods: This was a single center dose escalation trial of weekly romiplostim in patients &gt;18 years who failed to achieve an untransfused platelet count (PLT) of 20 x 109/L by day +28 after myeloablative (MA) or nonmyeloablative (NMA) UCBT. A total of 21 patients were enrolled from April 2015 to December 2018. One patient withdrew and was replaced so 20 patients are included in the analysis. Romiplostim was administered at the assigned dose as 6 weekly injections beginning by day +42 post UCBT with an end date by day +100. Four dose levels (4, 6, 8, and 10 mcg/kg/dose) were evaluated. There was no intra-patient dose escalation. The MTD of romiplostim was determined by the Continual Reassessment Method, with a goal to identify a dose level which corresponds to the desired toxicity rate of £ 20%. Toxicities of interest included thrombosis, PLT&gt;400x109/L and any grade 4-5 adverse event (AE) attributed to romiplostim. The comparison group were historical controls selected from our prospectively collected database based on age, gender, underlying disease, conditioning intensity and transplant type (1:1 matching). Results: Median (range) age of the patients was 59.5 (18-68) years and 60% were female. Ten patients had AML, 5 ALL, 3 MDS, 1 NHL and 1 MM. Of those, 11 received NMA double UCBT, 7 MA single UCBT and 2 received NMA single UCBT. Two patients received 4 mcg/kg/dose, two 6 mcg/kg/dose, four 8 mcg/kg/dose and the remaining 12 received 10 mcg/kg/dose. Only 5 patients completed the full 6 doses of treatment. Of the 15 patients who received less than 6 doses, 12 were due to a PLT&gt;100×109/L, 2 due to PLT&gt;400×109/L, and 1 was due to physician choice after the subject developed right upper extremity edema (without thrombosis). As shown in figure 1, 100% of romiplostim treated patients achieved platelet engraftment to 20 x 10^9/L at a median of 45 days post UCBT compared to 85% of controls who achieved platelet engraftment at a median of 49 days (p=0.07). Similarly, 90% of romiplostim treated patients achieved platelet engraftment to 50 x 10^9/L at a median of 48 days compared to 70% of historical controls who achieved platelet engraftment at a median of 52 days (p=0.04). The most common AEs were insomnia (30%), arthralgia (25%), myalgia (20%), headache (20%), dizziness and abdominal pain (15%). Only three patients experienced serious AEs requiring discontinuation of the drug: two had a PLT&gt;400x109 /L (without complications) and one developed right upper extremity edema. Bleeding episodes improved with the use of the drug as well as need of transfusions (patients vs controls, p&lt;0.05). All dose levels appear to be effective with overall low toxicity. Therefore, the MTD of romiplostim was 10mcg/kg/dose. All study patients were evaluated for BM fibrosis and relapse at regular intervals. There were no BM findings suggestive of increased fibrosis or relapse by day +100, and peripheral blood morphology was normal (no significant dacryocytosis, normal platelet morphology). Conclusion: Our study showed that romiplostim was well tolerated and accelerates platelet engraftment in patients undergoing UCBT, with the MTD being 10mcg/kg/dose. These results indicate that romiplostim is safe and potentially effective therapy to improve platelet recovery after UCBT. Further studies in larger numbers of patients are needed to confirm these observations. Disclosures Wagner: BlueRock: Research Funding; Rocket Pharmaceuticals: Consultancy; Novartis: Research Funding; Magenta: Consultancy, Research Funding; Gadeta: Membership on an entity's Board of Directors or advisory committees. Brunstein:Gamida: Research Funding; Magenta: Research Funding; Astex: Research Funding. Bejanyan:Kiadis Pharma: Other: advisory board. Smith:Amgen: Research Funding; Jazz Pharmaceuticals: Research Funding. OffLabel Disclosure: Romiplostim (Nplate) is an FDA approved drug for chronic ITP. In this study (phase I trial) we aimed to evaluate the safety and effectiveness of romiplostim on platelet recovery following 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.

Current status of umbilical cord blood transplantation in children

The first umbilical cord blood (UCB) transplantation was performed 30years ago. UCB transplantation (UCBT) is now widely used in children with malignant and non-malignant disorders who lack a matched family donor. UCBT affords a lower incidence of graft-versus-host disease compared to alternative stem cell sources, but also presents a slower immune recovery and a high risk of infections if serotherapy is not omitted or targeted within the conditioning regimen. The selection of UCB units with high cell content and good human leucocyte antigen match is essential to improve the outcome. Techniques, such as double UCBT, ex vivo stem cell expansion and intra-bone injection of UCB, have improved cord blood engraftment, but clinical benefit remains to be demonstrated. Cell therapies derived from UCB are under evaluation as potential novel strategies to reduce relapse and viral infections following transplantation. In recent years, improvements within haploidentical transplantation have reduced the overall use of UCBT as an alternative stem cell source; however, each may have its relative merits and disadvantages and tailored use of these alternative stem cell sources may be the optimal approach.