Single Cord Research Articles

Effect of posture and body weight loading on spinal posterior root reflex responses.

The posterior root muscle response (PRM) is a monosynaptic reflex that is evoked by single pulse transcutaneous spinal cord stimulation (tSCS). The main aim of this work was to analyse how body weight loading influences PRM reflex threshold measured from several lower limb muscles in healthy participants. PRM reflex responses were evoked with 1-ms rectangular monophasic pulses applied at an interval of 6s via a self-adhesive electrode (9 × 5 cm) at the T11-T12 vertebral level. Surface electromyographic activity of lower limb muscles was recorded during four different conditions, one in decubitus supine (DS) and the other three involving standing at 100%, 50%, and 0% body weight loading (BW). PRM threshold intensity, peak-to-peak amplitude, and latency for each muscle were analysed in different conditions study. PRM reflex threshold increased with body weight unloading compared with DS, and the largest change was observed between DS and 0% BW for the proximal muscles and between DS and 50% BW for distal muscles. Peak-to-peak amplitude analysis showed only a significant mean decrease of 34.6% (SD 10.4, p = 0.028) in TA and 53.6% (SD 15.1, p = 0.019) in GM muscles between DS and 50% BW. No significant differences were observed for PRM latency. This study has shown that sensorimotor networks can be activated with tSCS in various conditions of body weight unloading. Higher stimulus intensities are necessary to evoke reflex response during standing at 50% body weight loading. These results have practical implications for gait rehabilitation training programmes that include body weight support.

Bond characteristics between concrete and near-surface mounted carbon fiber reinforced polymer cords

ABSTRACT Previous studies showed that near-surface mounting (NSM) strengthening technique with rigid CFRP materials has potential advantages over the externally bonded reinforcing (EBR), therefore, it becomes efficient methodology for concrete strengthening. However, rigid NSM-CFRP cannot be wrapped around a deteriorated structural element; the need for the existence of flexible material has appeared. Therefore, in this study the flexible NSM-CFRP (cord) is investigated as strengthening technique instead of rigid NSM-CFRP. The aim of this study is to recognize the parameters affecting the bond performance of carbon fiber-reinforced concrete (CFRP) cord and concrete. These parameters are cords’ bonded length, the ratio between cord’s width and depth, concrete compressive strength, number of CFRP cords used and the distance separating cords in multi-cord specimens. Fifty-four concrete prisms were cast from 25 MPa and 50 MPa concrete compressive strengths. Thirtyeight prisms reinforced by a single cord with various cord sizes were prepared. Twelve and four specimens were reinforced with two and three cords, respectively. In the case of multi-cord specimens, a unified bond length and cord’s aspect ratio were carried out. The main parameter to be studied in this case is the cords’ separating spacing. The test results indicated that increasing (NSMCFRP) cords bonded length, concrete compressive strength, number of applied CFRP cords, the spacing between cords and reducing cords’ aspect ratio (width/depth ratio) cause an increment in the pull-out force, and then a better strengthening is achieved. Rupture was the predominant failure mode for specimens with the same bond and equal cord dimension, while debonding of the CFRP cords is the most frequent failure mode for multi-cords specimens with greater spacing.

Enhanced self-renewal of human long-term hematopoietic stem cells by a sulfamoyl benzoate derivative targeting p18INK4C

AbstractThe use of umbilical cord blood transplant has been substantially limited by the finite number of hematopoietic stem and progenitor cells in a single umbilical cord blood unit. Small molecules that not only quantitatively but also qualitatively stimulate enhancement of hematopoietic stem cell (HSC) self-renewal ex vivo should facilitate the clinical use of HSC transplantation and gene therapy. Recent evidence has suggested that the cyclin-dependent kinase inhibitor, p18INK4C (p18), is a critical regulator of mice HSC self-renewal. The role of p18 in human HSCs and the effect of p18 inhibitor on human HSC expansion ex vivo need further studies. Here we report that knockdown of p18 allowed for an increase in long-term colony-forming cells in vitro. We then identified an optimized small molecule inhibitor of p18, 005A, to induce ex vivo expansion of HSCs that was capable of reconstituting human hematopoiesis for at least 4 months in immunocompromised mice, and hence, similarly reconstituted secondary recipients for at least 4 more months, indicating that cells exposed to 005A were still competent in secondary recipients. Mechanistic studies showed that 005A might delay cell division and activate both the Notch signaling pathway and expression of transcription factor HoxB4, leading to enhancement of the self-renewal of long-term engrafting HSCs and the pool of progenitor cells. Taken together, these observations support a role for p18 in human HSC maintenance and that the p18 inhibitor 005A can enhance the self-renewal of long-term HSCs.

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.

PD-0773 Update of the results of single vocal cord irradiation for early-stage glottic cancer

PD-0773 Update of the results of single vocal cord irradiation for early-stage glottic cancer

Optimal umbilical cord blood collection, processing and cryopreservation methods for sustained public cord blood banking

Background aimsUmbilical cord blood is an established source of stem cells in patients with hematologic malignancies who do not have HLA-compatible matched related or unrelated donors. The success of an umbilical cord blood transplant depends on the dose of total nucleated and CD34+ cells infused. Therefore, collecting, banking and listing high-quality cord blood units with high total nucleated and CD34+ cell dose are essential. MethodsHere the authors describe their cord blood bank's novel collection technique, which involves both in utero and ex utero collection of a single cord blood unit. The authors also evaluated maternal, neonatal and collection parameters that may impact the cell dose. ResultsMaternal gestational age and race, and neonatal weight and sex correlated with the total nucleated cell dose. ConclusionsThe optimized collection of umbilical cord blood is critical for its use as a source of stem cells for transplantation.

Unrelated cord blood stem cell transplantation for high-risk/refractory childhood acute myeloid leukemia: a clinical analysis of 160 cases

目的探讨单份非血缘脐血干细胞移植（UCBT）治疗高危/难治儿童急性髓系白血病（AML）的疗效。方法对2008年6月至2018年12月期间接受UCBT的160例高危/难治AML（不含急性早幼粒细胞白血病）患儿进行回顾性分析。全部病例均采用清髓性预处理方案，应用环孢素A（CsA）联合短程霉酚酸酯（MMF）预防移植物抗宿主病（GVHD）。结果160例AML患儿中男103例、女57例，中位年龄7（1～14）岁，中位体重23（8～77）kg。移植后42 d中性粒细胞累积植入率为95.0％（95％CI 90.0％～97.5％），移植后120 d血小板累积植入率为85.5％（95％CI 83.3％～93.4％），中性粒细胞、血小板植入中位时间分别为移植后16（11～38）d、35（13～158）d。Ⅱ～Ⅳ、Ⅲ～Ⅳ度急性GVHD发生率分别为37.3％（95％CI 29.3％～45.2％）、27.3％（95％CI 20.0％～35.0％），慢性GVHD发生率为22.4％（95％CI 15.5％～28.7％）。可评估的移植后360 d移植相关死亡率（TRM）为13.1％（95％CI 8.4％～18.9％）。移植后5年累积复发率为13.8％（95％CI 8.5％～20.3％），无病生存（DFS）率为71.7％（95％CI 62.7％～77.8％）、总生存（OS）率为72.2％（95％CI 64.1％～78.7％），无GVHD无复发生存（GRFS）率为56.1％（95％CI 46.1％～64.9％）。移植前处于第1次完全缓解（CR1）期（95例）、第2次完全缓解（CR2）期（28例）、未缓解患者（37例）的移植后5年累积复发率分别为5.3％（95％CI 1.9％～11.1％）、19.9％（95％CI 6.9％～37.7％）、30.9％（95％CI 14.3％～49.2％）（P＝0.001），移植后5年OS率分别为79.9％（95％CI 70.3％～86.7％）、71.1％（95％CI 50.4％～84.4％）、52.9％（95％CI 33.0％～69.3％）（χ2＝7.552，P＝0.020）。结论UCBT是治愈高危/难治儿童AML安全、有效的治疗方法。第1次完全缓解期进行UCBT有利于改善预后。

Single-cell chromatin accessibility landscape of human umbilical cord blood in trisomy 18 syndrome

BackgroundTrisomy 18 syndrome (Edwards syndrome, ES) is a type of aneuploidy caused by the presence of an extra chromosome 18. Aneuploidy is the leading cause of early pregnancy loss, intellectual disability, and multiple congenital anomalies. The research of trisomy 18 is progressing slowly, and the molecular characteristics of the disease mechanism and phenotype are still largely unclear.ResultsIn this study, we used the commercial Chromium platform (10× Genomics) to perform sc-ATAC-seq to measure chromatin accessibility in 11,611 single umbilical cord blood cells derived from one trisomy 18 syndrome patient and one healthy donor. We obtained 13 distinct major clusters of cells and identified them as 6 human umbilical cord blood mononuclear cell types using analysis tool. Compared with the NC group, the ES group had a lower ratio of T cells to NK cells, the ratio of monocytes/DC cell population did not change significantly, and the ratio of B cell nuclear progenitor and megakaryocyte erythroid cells was higher. The differential genes of ME-0 are enriched in Human T cell leukemia virus 1 infection pathway, and the differential peak genes of ME-1 are enriched in apopotosis pathway. We found that CCNB2 and MCM3 may be vital to the development of trisomy 18. CCNB2 and MCM3, which have been reported to be essential components of the cell cycle and chromatin.ConclusionsWe have identified 6 cell populations in cord blood. Disorder in megakaryocyte erythroid cells implicates trisomy 18 in perturbing fetal hematopoiesis. We identified a pathway in which the master differential regulatory pathway in the ME-0 cell population involves human T cell leukemia virus 1 infection, a pathway that is dysregulated in patients with trisomy 18 and which may increase the risk of leukemia in patients with trisomy 18. CCNB2 and MCM3 in progenitor may be vital to the development of trisomy 18. CCNB2 and MCM3, which have been reported to be essential components of the cell cycle and chromatin, may be related to chromosomal abnormalities in trisomy 18.

Umbilical Cord Mesenchymal Stem Cells for Inhibiting the Fibrosis and Autoimmune Development in HOCl-Induced Systemic Scleroderma Mouse Model.

Background and ObjectivesSystemic scleroderma (SSc) is a rare and serious connective tissue disease, an autoimmune disease, and a rare refractory disease. In this study, preventive effect of single systemic human umbilical cord mesenchymal stem cells (UC-MSCs) transfusion on SSc was preliminarily explored.Methods and ResultsSSc mouse model was established by daily intradermal injection of Hypochlorite (HOCl). SSc mice were treated by single transfusion of UC-MSCs at 0.625×105, 2.5×105 and 1×106 respectively. At the 42nd day of intradermal injection of HOCl, the symptoms showed up by skin and alveolar wall thickening, lymphocytic infiltration, increased collagen in skin/lung, and the increased proportion of CD3＋CD4＋CD25＋FoxP3＋ cells (a Treg subset) in spleen. After UC-MSCs transfusion, the degree of skin thickening, alveolar wall thickening and lymphocyte infiltration were decreased, the collagen sedimentation in skin/lung was decreased, and the proportion of CD3＋CD4＋CD25＋FoxP3＋ cells was decreased.ConclusionsUC-MSC can achieve a preventive effect in SSc mice by fibrosis attenuation and immunoregulation.

Momentum of neutrophil recovery using an exponential growth model predicts the prognosis of single cord blood transplantation.

After the first appearance of peripheral blood neutrophils, recipients from adult donor sources have a rapid increase in neutrophil recovery, whereas cord blood transplantation (CBT) recipients have a slow increase. However, the momentum of neutrophil recovery after CBT varies widely among individuals, but optimal methods to evaluate the momentum of neutrophil recovery and their clinical impacts are yet to be clarified. We retrospectively examined the prognostic effect of the momentum of neutrophil recovery in the last 7days until neutrophil engraftment, which was calculated by an exponential growth model, after single CBT following myeloablative conditioning for 207 adults. Among patients who achieved each hematopoietic lineage recovery by day 100, the momentum of neutrophil recovery, which was represented as a growth constant, was associated with the day of neutrophil engraftment (P<.0001), red blood cell engraftment (P<.0001), and platelet engraftment (P<.0001) using the Spearman's rank correlation coefficient test. More importantly, overall survival was superior with a higher growth constant compared with a lower growth constant (P<.001). In the multivariate analysis, a higher growth constant showed a lower overall mortality compared with a lower growth constant (hazard ratio: 0.48, P=.014). Our data demonstrated that the momentum of neutrophil recovery during the last 7days before neutrophil engraftment, which was measured using an exponential growth model, was associated not only with hematopoietic recovery but also with a better prognosis after single CBT.

Low-Dose ATG Combined with Facybu Conditioning Regimen Followed By Single Unrelated Cord Blood Transplantation in Hematological Malignancies

Objective: This study aims to evaluate the efficacy and safety of low-dose ATG combined with FACyBu conditioning regimen for single unrelated cord blood transplantation in hematological malignanciesMethod: From Jul 2013 to Feb 2017, 30 patients of hematological malignancies (15 patients with ALL,11 patients with AML,3 patients with NHL,1 patient with CML ) who underwent unrelated cord blood transplantation were followed up. The median age was 24(3.16-46)years. Seventeen patients were in complete remission(CR) while 13 patients were in progressive stage. All the patients were pretreated with low dose ATG(Fresenius) (24patients 10.0mg/kg/d, 6 patients 5.0mg/kg/d;d-5,d-4) plus FACyBu(a myeloablative FA-BUCY protocol of 25 mg/m2/day Fludarabine and high-dose 2 g/m2/day Cytarabine for 5 consecutive days from day −13 to day −9, 1.8g/m2/day CY from day −8 to day −7, 3.2mg/kg/day BU from day −6 to day −4 and MCCNU 250mg /m2 d-3). Cyclosporine and mycophenolate were applied for Graft-versus-host disease (GVHD) prophylaxis. The GVHD, RFS, nonrelapse mortality, relapse mortality, OS, DFS and graft-versus-host disease-free/relapse-free survival (GRFS) probabilities were investigated. The side effects of the regimens were also evaluated.Result: The median CD34+ cell infusion quantity was 0.17 (0.07-1.26)*106/Kg. the median neutrophil engraftment time was 18(10-27)days and the median platelet engraftment time was 33(15-49)days. The cumulative incidence of grades II-IV acute GVHD was 23.5%. It's interesting that no grade III-IV acute GVHD was observed. The cumulative incidence of limited chronic GVHD and extensive chronic GVHD was 5.0% , 9.1% respectively. The median follow-up time was 10.8(2.6-46.1) months. The nonrelapse mortality, relapse mortality, OS, DFS and GRFS were 27.6%,10.9%,64.5%,64.4% and 61.4%, respectively. For the CR patients, the OS, DFS and GRFS were 85.9%, 85.9%, 80.2%, respectively. While for the nonremission patients, the OS, DFS and GRFS were 38.5%,28.5%, 38.5%Conclusion: The clinical efficacy of low-dose ATG combined with FACyBu conditioning regimen followed by single unrelated cord blood transplantation in hematological malignancies patients is similar to that of alternative allogeneic bone marrow transplantation as reported. The incidence of GVHD was low .The patients who were treated with this regimen experience good quality of life. DisclosuresNo relevant conflicts of interest to declare.

Pediatric Acute GVHD Grade, Risk Prediction and Response to Upfront Steroids in 370 Children Treated at the University of Minnesota

To better understand the nature of acute GVHD in children, their response to upfront steroid therapy, and to test whether our MN acute GVHD risk score which was developed primarily in adult patients (BBMT , 2015;21:761) demarcates risk in children, we examined the acute GVHD clinical stage, grade and response to prednisone 60 mg/m2 of 370 pediatric patients (median age 7 years, range 0.2-17.95 years) treated at the University of Minnesota (MN) from 1990 to 2016. Underlying diseases included malignancies (53%), inborn errors of metabolism (25%), and other non-malignant diseases (22%). Graft sources included HLA-identical sibling bone marrow or peripheral blood (BM/PB) (n=61), mismatched related BM/PB (n=8), matched unrelated BM/PB (n=104), mismatched unrelated BM/PB (n=65) single umbilical cord blood (UCB; n=97) or double UCB (n=35). The majority (95%) received myeloablative conditioning regimens.Initial GVHD organ involvement was skin only (n=250; 68%), upper and/or lower GI only (n=67;18%), liver only (n=3;1%) or multi-organ (n=50;14%) The maximum initial GVHD stage at the onset of prednisone therapy is shown in the Table. Initially, 307 (83%) patients had grade I-II GVHD, 63 (17%) had severe grade III-IV GVHD, 328 (89%) had MN standard risk GVHD and 42 (11%) had MN high risk GVHD.Overall response (CR+PR) at day 28 was observed in 65% patients with CR in 52% and PR in 13%. Initial GVHD grade did not predict overall response at day 28 (68% for grade I, 67% for grade II, 59% for grade III, and 43% for grade IV, p=0.21). However, as shown in the Figure, MN risk score significantly demarcated day 28 response with 68% standard risk patients achieving CR/PR at day 28 compared to only 48% high risk patients (p<0.01).In multiple regression analysis, the odds of day 28 CR/PR was lower in patients with MN high risk GVHD (Odds ratio [OR] 0.4, 95% CI 0.2-0.8, p=0.01) and in recipients of HLA mismatched unrelated donor grafts (OR 0.3, 95% CI 0.2-0.7, p=0.01). Patients without CR/PR at day 28 had higher transplant related mortality (TRM) at 2 years (56%, 95% CI 46-66%) than patients with CR (25%, 95% CI, 19-32%) or PR at day 28 (23%, 95% CI, 11-35%, p<0.01). Patients with MN high risk GVHD had a 1.6-fold increased risk of TRM (cumulative incidence 47%: (hazard ratio 1.6, 95% CI, 1.0-2.7, p=0.05) compared to MN standard risk acute GVHD (35% 2 year TRM). Risks of TRM were also significantly higher in older patients, recipients of HLA-partial and mismatched adult volunteer URD grafts (but not umbilical cord blood), and in those with non-malignant diseases.When compared to our previously published series of predominantly adult patients, these data demonstrate that pediatric patients with acute GVHD more often have isolated skin involvement, less liver involvement and less multi-organ involvement than adults, yet a similar proportion have MN standard versus high risk GVHD. Importantly, pediatric patients respond to upfront steroid GVHD therapy at a similar frequency as adult patients. It is imperative that children be included in future trials to investigate less toxic therapies for standard risk patients and novel approaches for those with high risk GVHD. As in the adult population, compared to initial GVHD grade, the MN GVHD risk score better demarcates risk of steroid failure and TRM in pediatric patients and should be used for risk stratification in future clinical GVHD trials. [Display omitted] DisclosuresMacMillan:Magenta Therapeutics: Research Funding. Holtan:Incyte: Other: One-time advisory board member.

Outcomes of Unrelated Cord Blood Transplantation for 18 Patients with Severe Aplastic Anemia

Objective To evaluate the outcomes of unrelated cord blood transplantation (UCBT) for severe aplastic anemia (SAA).Methods The clinical data of 18 SAA patients, including 9 very severe aplastic anemia (vSAA), received UCBT from Sep 2009 to Feb 2017 were analyzed retrospectively. Three patients received a single unrelated cord blood unit, fifteen patients received double unrelated cord blood units. One patient was 4/6 HLA match, nine patients were 5/6 HLA match, eight patients were 6/6 HLA match. The conditioning regimens were as follow: 1 patient received modified BU/CY- based regimen, 1 patient received fludarabine (Flu) + antithymocyte globulin (ATG) + cyclophosphamide (CY) + total body irradiation (TBI) regimen, 16 patients received fludarabine (Flu) + antithymocyte globulin (ATG) + cyclophosphamide (CY) regimens. Prophylaxis for graft-versus host disease (GVHD): cyclosporine (CsA) plus short-term methotrexate (MTX).Results There was1 patient early death on day +2, 6 patients experienced primary graft rejection, but 5 of them acquired autologous myeloid recovery, 11 patients were engrafted successfully. The median days of neutrophils(ANC)above 0.5 × 109/L and platelets (PLT) more than 20 × 109/L were 18.5(9~29)days and 26.5(20~48)days, respectively. Six patients (54.5%) developed acute GVHD (aGVHD), 1 for grade I aGVHD, 3 for grade Ⅱ aGVHD, 2 for grade Ⅳ aGVHD. Of 9 patients, 2 occurred chronic GVHD (cGVHD), 1 for mild cGVHD, 1 for severe cGVHD. After a median follow-up of 56(4 ∼ 72)months, 9 patients (50.0%) died, out of which one died of severe aGVHD, the reasons of death were GVHD, severe infection, posttransplant lymphoproliferative disorders (PTLD) and transplant-associated thrombotic microangiopathy (TMA). The 5-year estimated overall survival was 46.9% ± 12.3%. No patient relapsed.Conclusion UCBT is an effective therapy for SAA patients who lack an appropriate matched related donor. DisclosuresNo relevant conflicts of interest to declare.

Impact of Donor Type in Patients with Acute Myeloid Leukemia Given Allogeneic Hematopoietic Cell Transplantation after Low-Dose TBI Based Regimen: A Study from the Acute Leukemia Working Party of the EBMT and Eurocord

Backround. Low-dose total body irradiation (TBI)-based nonmyeloablative conditioning regimens are widely used in acute myeloid leukemia (AML) patients in first or second complete remission (CR) at the time of transplantation. With these regimens the burden for tumor eradication relies mostly on immune-mediated graft-versus-leukemia (GVL) effects that can be impacted by donor type. Here we assessed the impact of donor type in a large cohort of AML patients transplanted in CR after low-dose TBI-based nonmyeloablative conditioning regimens.Methods. Inclusion criteria included >= 18 years of age, de novo or secondary AML in CR1 or CR2, transplantation between 2004 and 2015, conditioning with fludarabine + 2 Gy TBI with or without pre- or post-transplant cyclophosphamide, no in vitro or in vivo T cell depletion of the graft (besides post-transplant cyclophosphamide), and either an HLA-matched sibling donor (MSD), a 10/10 HLA-matched unrelated donor (MUD), an HLA-haplo-identical donor (Haplo) or a single or double umbilical cord blood (CBT).Results. Data from 1357 patients receiving grafts from MSD (n=594), MUD (n=442), Haplo (n=77) or given single or double CBT (n=244) were included. The proportion of patients transplanted in CR1 was 87%, 80%, 66% and 60% in MSD, MUD, Haplo and CBT groups, respectively (P<0.001) while median patient age at transplantation was 58, 63, 57 and 55 years, respectively (P<0.001). The proportion of patients with secondary AML was 16%, 22%, 21% and 20% in MSD, MUD, Haplo and CBT groups (P=0.04). Median follow-up was 49, 25, 17 and 48 months, respectively (P<0.001). Graft rejection occurred in 2% of each MSD and MUD recipients, 7% of haplo patients and 8% of CBT recipients (P<0.001). Grade III-IV acute GVHD was more frequent in CBT (16%) than in MUD (9%), haplo (8%) or MSD (7%) recipients (P<0.001). In contrast, chronic GVHD was less frequent in CBT (27%) and in haplo (30%) patients than in MSD (50%) and MUD (52%) recipients (P<0.001). Two-year OS and GRFS were 60% and 30% in MSD patients, 56% and 41% in CBT recipients, 54% and 24% in MUD recipients, and 42% and 35% in haplo patients, respectively (P=0.02 for OS and P=0.03 for GRFS ; Figure 1). Two-year incidences of relapse and nonrelapse mortality (NRM) were 33% and 12% in MSD patients, 29% and 20% in MUD recipients, 34% and 17% in CBT recipients, and 37% and 21% in haplo patients, respectively (P=0.7 for relapse and P<0.001 for NRM). In multivariate analyses, in comparison to MSD patients, each other donor type was associated with a significantly higher NRM. Interestingly, CBT was associated with a higher incidence of grade III-IV acute GVHD (HR 2.9, P=0.001) but a lower incidence of chronic GVHD (HR=0.4, P<0.001) than MSD resulting in a significantly worse GVHD-free relapse free survival (GRFS) the first 100 days (HR=1.5, P=0.02) but significantly better GRFS beyond day 100 (HR=0.6, P=0.001). Finally, there was a suggestion for lower OS in haplo patients (HR 1.5, P=0.08). Factors associated with worse OS included intermediate and adverse-risk cytogenetics and secondary AML. AML relapse, GVHD and infections were the primary causes of death of 24%, 6% and 4% of MSD recipients, 21%, 7% and 7% of MUD recipients, 22%, 5% and 14% of haplo recipients, and 25%, 8% and 5% of CBT recipients, respectively.Conclusions. In this large cohort of AML patients transplanted in CR following low-dose TBI-based nonmyeloablative conditioning regimen there were no significant differences in OS and LFS between MSD, MUD and UCB while there was a suggestion for lower LFS and OS with haplo due to a higher incidence of death from infection. Since this regimen relies nearly exclusively on GVL effects for tumor eradication, our data suggest that the intensity of GVL effects is comparable with these four donor types. Further studies including more haplo patients are needed to confirm these results. [Display omitted] DisclosuresSavani:Jazz Pharmaceuticals: Speakers Bureau. Mohty:Sanofi: Honoraria, Speakers Bureau.

Kidney Dysfunction Post-Allogeneic Transplant: High Incidence of TMA and Kidney GvHD

Introduction:Kidney dysfunction is an important problem in adult recipients of allogeneic stem cell transplantation (HSCT) and independently predicts overall survival and non-relapse mortality. Kidney dysfunction occurs in ~50% of transplant recipients. More than 20% of all survivors of HSCT in long-term follow up develop chronic kidney disease. However, there is currently limited data on the cause and consequences of kidney dysfunction in adult recipients after allogeneic HSCT.Common causes of kidney dysfunction after HSCT include chemotherapy or radiation toxicity, infections, sepsis, hepatic sinusoidal obstruction, drug toxicities due to immunosuppressive medications, thrombotic microangiopathy, as well as acute or graft versus host disease (GvHD). Kidney biopsies are seldom obtained and hence the tissue diagnosis in these patients often remains speculative. Early identification of the causes of kidney dysfunction may help define preventive and therapeutic strategies and improve outcome.Hence, in August 2016, we designed a prospective study at our center to systematically evaluate kidney dysfunction in adult recipients of allogeneic HSCT. Herein we present our initial report of 8 kidney biopsies.Methods:All adult HSCT recipients with kidney dysfunction were evaluated by Nephrologists to determine the need for kidney biopsy. Kidney dysfunction was defined as either (i) acute kidney failure or (ii) proteinuria. Acute kidney failure was defined by the ‘ Kidney Disease: Improving Global Outcomes (KDIGO)‘ criteria. Proteinuria was defined as (i) spot urine albumin to creatinine ratio of ≥1 (equivalent to ≥1 g in 24 hours). Kidney biopsies were done under ultrasound guidance and the tissue specimens were interrogated by light, immunofluorescence and electron microscopy.Results:A total of 8 HSCT recipients (including one patient who had a biopsy prior to Aug 2016) underwent kidney biopsies. The patient and transplant characteristics are summarized in Table 1.Seven of the 8 pts had AML. One patient had NHL in CR2. Four patients received a MUD transplant. Two received MRD transplants. Two received combined haploidentical and single unit cord blood transplant (haplo-cord). Six of the 8 patients received conditioning with fludarabine and melphalan. One patient received additional 400 Gy TBI. One patient received additional azacytidine.Median time to neutrophil engraftment was 13.5 days (range 9-20). Median time to platelet engraftment was 19 days (range 14-76). There were no cases of graft failure. All patients also demonstrated either acute or chronic GvHD of other organs - most commonly skin.All kidney biopsies were performed without complications. Kidney biopsies were done at median 254 days after transplantation (range 126-680). Baseline serum creatinine (mg/dL) prior to transplant was 0.95 (median, range 0.65-1.1, reference range: 0.64-1.27 mg/dL). Creatinine at time of biopsy: 3.0 (median, range 1.53-5.07). Urine albumin/creatinine ratio: 832 (median, range 55-2864, reference range: <30).The kidney biopsy findings are summarized in Table 2. All patients had evidence of endothelial cell injury, either acute or chronic. Three patients had features suggestive of GvHD of the kidney while one patient had BK virus nephropathy.Four of the 8 recipients died; 80 days (median, range 39-124) from the biopsy, 346 days (median, range 178-804) from transplantation. The clinical outcome is summarized in Table 3.Conclusions:Kidney biopsies post-transplant are an important diagnostic tool that should be considered for prolonged kidney dysfunction or proteinuria, particularly in the setting of other post-transplant complications. Our single-center biopsy results highlight the under-recognition of kidney dysfunction complications and complexities observed post-transplant. All kidney biopsies performed were instrumental in treatment planning. Further investigation is needed to define criteria for diagnosis and to understand the pathophysiology. This requires multi-disciplinary engagement as well as a proactive approach for obtaining kidney biopsies. With appropriate transfusion support, percutaneous kidney biopsies were performed safely without complication. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Omidubicel vs standard myeloablative umbilical cord blood transplantation: results of a phase 3 randomized study

AbstractOmidubicel is an ex vivo expanded hematopoietic progenitor cell and nonexpanded myeloid and lymphoid cell product derived from a single umbilical cord blood unit. We report results of a phase 3 trial to evaluate the efficacy of omidubicel compared with standard umbilical cord blood transplantation (UCBT). Between January 2017 and January 2020, 125 patients age 13 to 65 years with hematologic malignancies were randomly assigned to omidubicel vs standard UCBT. Patients received myeloablative conditioning and prophylaxis with a calcineurin inhibitor and mycophenolate mofetil for graft-versus-host disease (GVHD). The primary end point was time to neutrophil engraftment. The treatment arms were well balanced and racially diverse. Median time to neutrophil engraftment was 12 days (95% confidence interval [CI], 10-14 days) for the omidubicel arm and 22 days (95% CI, 19-25 days) for the control arm (P < .001). The cumulative incidence of neutrophil engraftment was 96% for patients receiving omidubicel and 89% for patients receiving control transplants. The omidubicel arm had faster platelet recovery (55% vs 35% recovery by 42 days; P = .028), had a lower incidence of first grade 2 to 3 bacterial or invasive fungal infection (37% vs 57%; P = .027), and spent more time out of hospital during the first 100 days after transplant (median, 61 vs 48 days; P = .005) than controls. Differences in GVHD and survival between the 2 arms were not statistically significant. Transplantation with omidubicel results in faster hematopoietic recovery and reduces early transplant-related complications compared with standard UCBT. The results suggest that omidubicel may be considered as a new standard of care for adult patients eligible for UCBT. The trial was registered at www.clinicaltrials.gov as #NCT02730299.

Incidence and risk factors of late-onset hemorrhagic cystitis after single umbilical cord blood transplantation with myeloablative conditioning regimen.

To explore the incidence and risk factors of late-onset hemorrhagic cystitis (LOHC) in patients undergoing single umbilical cord blood transplantation for hematological malignancies. Clinical data from 234 patients who consecutively underwent single UCBT using a myeloablative conditioning regimen without antithymocyte globulin in our center were retrospectively analyzed. In total, 64 (27.4%) patients developed LOHC with a median onset time of 40.5 (range 8-154) days, and 15 (6.4%) patients gradually developed grade III-IV LOHC. The incidence of LOHC was marginally higher in adults (31.0%) than in children (23.7%) (p = 0.248). HLA matching ≤ 6/8 (HR = 2.624, 95% CI 1.112-6.191, p = 0.028) was an independent risk factor for LOHC. The overall survival of LOHC patients (59.8%, 95% CI 61.7-85.5%) was significantly lower than that of patients without LOHC (86.8%, 95% CI 79.6-91.6%) at 130days post transplantation (p = 0.036). Patients with less well-matched grafts have a higher incidence of LOHC. Inherent deficiencies in immunity in the context of HLA disparity and more intense pharmacologic immunosuppression after severe acute graft-versus-host disease may contribute to viral activation. Prevention and treatment of LOHC have the potential to prolong long-term survival.

Cytokine combinations for human blood stem cell expansion induce cell-type– and cytokine-specific signaling dynamics

AbstractHow hematopoietic stem cells (HSCs) integrate signals from their environment to make fate decisions remains incompletely understood. Current knowledge is based on either averages of heterogeneous populations or snapshot analyses, both missing important information about the dynamics of intracellular signaling activity. By combining fluorescent biosensors with time-lapse imaging and microfluidics, we measured the activity of the extracellular-signal–regulated kinase (ERK) pathway over time (ie, dynamics) in live single human umbilical cord blood HSCs and multipotent progenitor cells (MPPs). In single cells, ERK signaling dynamics were highly heterogeneous and depended on the cytokines, their combinations, and cell types. ERK signaling was activated by stem cell factor (SCF) and FMS-like tyrosine kinase 3 ligand in HSCs but SCF, interleukin 3, and granulocyte colony-stimulating factor in MPPs. Different cytokines and their combinations led to distinct ERK signaling dynamics frequencies, and ERK dynamics in HSCs were more transient than those in MPPs. A combination of 5 cytokines recently shown to maintain HSCs in long-term culture, had a more-than-additive effect in eliciting sustained ERK dynamics in HSCs. ERK signaling dynamics also predicted future cell fates. For example, CD45RA expression increased more in HSC daughters with intermediate than with transient or sustained ERK signaling. We demonstrate heterogeneous cytokine- and cell-type–specific ERK signaling dynamics, illustrating their relevance in regulating hematopoietic stem and progenitor (HSPC) cell fates.

Feasibility of an intensified myeloablative conditioning regimen consisting of busulfan, fludarabine, cytarabine, and total body irradiation before single cord blood transplantation in elderly patients.

The optimal conditioning regimen for stem cell transplantation in elderly patients remains to be established. We developed a novel preparative regimen using fludarabine 180mg/m2, intravenous busulfan 12.8mg/m2, cytarabine 8g/m2, and 4-Gy total body irradiation before cord blood transplantation (CBT) in patients older than 55years with various hematological malignancies. All but one patient received graft-versus-host disease (GVHD) prophylaxis consisting of cyclosporine (CsA) and short-term methotrexate (sMTX). Thirty-three patients were included in this study, with a median age of 64years (range 56-70). The disease risk index was high or very high in 67% of patients, and 73% had a disease status other than complete remission. The probabilities of overall survival and disease-free survival at 3years were 60 and 57%, respectively. The cumulative incidences of relapse and non-relapse mortality at 3years were 18 and 25%, respectively. Regimen-related toxicities were generally tolerable. Disease-free survivors (n = 20) stopped immunosuppressants at a median of 7.4months (range 2.6-25.0), in all cases by the time of the last follow-up. In conclusion, this highly myeloablative conditioning regimen resulted in a high probability of disease-free, GVHD-free, immunosuppressant-free survival after single CBT.(190 words).

Favorable Outcomes after Single Cord Blood Transplantation for Patients with High-Risk Hematologic Diseases: A Single-Institute Retrospective Analysis

The donor selection algorithm for cord blood (CB) with regards to matched related and unrelated donors has not been fully investigated. To assess the potential of CB transplantation (CBT) in patients with hematologic malignancies, especially for high-risk patients, we performed a single-institute retrospective analysis and compared the clinical outcomes of CBT with those of HLA-matched sibling and unrelated donor transplantation. We included 394 patients aged 16 years and older with hematologic diseases who received their first allogeneic hematopoietic cell transplantation between 1990 and 2018 at Kyoto University Hospital. These included 394 recipients of single unrelated cord blood units (UCB, n=108), HLA-matched sibling donors (MSDs, n=143), or HLA-matched unrelated donors (MUDs, n=143). There was no significant difference in relapse-free survival (RFS) between UCB, MSD, and MUD recipients (P=.975). However, we found a significant interaction between transplant year and CBT outcomes (P=.010), with significantly better outcomes observed in the more recent years. Furthermore, we found that CBT showed better RFS than matched donor transplantation (hazard ratio [HR], 0.50; 95% confidence interval [CI], 0.30 to 0.84). This impact was more prominent in high-risk patients (HR, 0.35; 95% CI, 0.16 to 0.77), with lower relapse rates (HR, 0.25; 95% CI, 0.11 to 0.54), and comparable non-relapse mortality (NRM) compared to matched donor transplantation. Extensive chronic graft-versus-host disease was less frequently observed in CBT (HR, 0.58; 95% CI, 0.26 to 1.28). CBT associated with favorable outcomes, particularly in high-risk patients, with good RFS and low relapse rates without an increase in NRM in the single-institute study. Although the findings should be externally validated, CBT might serve as a reasonable donor choice, particularly in high-risk patients.