Transplantation and Cellular Therapy最新文献

{"title":"Venous Thromboembolism Incidence and Risk Factors in Patients Undergoing Hematopoietic Stem Cell Transplantation","authors":"Miranda Benfield , Jiaxian He , Justin Arnall , Whitney Kaizen , Elizabeth Jandrisevits , Karine Eboli-Lopes , Brandy Dodd , Michael R. Grunwald , Belinda Avalos , Edward Copelan , Jai N. Patel","doi":"10.1016/j.jtct.2024.10.016","DOIUrl":"10.1016/j.jtct.2024.10.016","url":null,"abstract":"<div><div>Malignancy is a well-known risk factor for venous thromboembolism (VTE), and the Khorana risk score is effective for screening patients with solid tumors. However, there is a lack of validated screening tools and established risk factors for patients undergoing hematopoietic stem cell transplantation (HCT). Current literature reports a 2.5% to 8.5% incidence of VTE in HCT recipients. Anticoagulation is difficult to manage post-transplantation, given prolonged thrombocytopenia and the likelihood of bleeding. By identifying risk factors, a predictive model may be developed to prospectively test prophylaxis strategies in patients at the highest risk of a thromboembolic event (TE). This retrospective single-center study evaluated the cumulative incidence of TE at 6 months following allogeneic or autologous HCT in adult subjects undergoing transplantation between March 2014 and December 2019. The study also aimed to identify risk factors for developing a TE, evaluate the time from HCT to TE, and compare 1-year survival following HCT between patients with a TE and those without a TE. In evaluating the incidence of TE, ICD-9 and ICD-10 codes were used to determine cancer diagnosis, TE events occurring up 180 days after HCT, and comorbidities of interest. Each subject was reviewed for data accuracy by a manual retrospective chart review. Statistical tests including the cumulative incidence method with competing risks, Gray's test, and univariate and multivariate Cox proportional hazards models were used to analyze the time to first TE, evaluate risk factors, and assess 1-year survival post-HCT in relation to TEs occurring within 180 days of HCT. Variables examined included age, sex, body mass index, transplant type, hospital length of stay (LOS), history of TE prior to transplantation, active infections, graft-versus-host disease (GVHD), veno-occlusive disorder, cytomegalovirus serostatus, and other factors. The study included 636 evaluable patients; the majority were male (57.9%) and white (68.7%) and had undergone autologous HCT (68.4%). Twenty-nine patients (4.6%) experienced a TE within 180 days post-transplantation. TEs were more common in the allogeneic HCT recipients (n = 13/201; 6.5%) compared to the autologous HCT recipients (n = 16/435; 3.7%; <em>P</em> = .122). The cumulative incidence of TE was higher in patients who developed an active infection compared to those who did not (7.6% versus 3.1%; <em>P</em> = .011). Hospital LOS (hazard ratio [HR], 1.03; 95% confidence interval [CI], 1.0 to 1.06; <em>P</em> = .036) and active infection (HR, 2.34; 95% CI, 1.1 to 4.95; <em>P</em> = .027) were significantly associated with TE in univariate analysis but were not retained in the final multivariate model. There was no difference in 1-year survival between all patients who experienced a TE and those who did not; however, in the autologous HCT group, 1-year survival rate was significantly lower in patients with a TE compared to those without ","PeriodicalId":23283,"journal":{"name":"Transplantation and Cellular Therapy","volume":"31 2","pages":"Pages 111.e1-111.e10"},"PeriodicalIF":3.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142590789","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prophylactic Defibrotide in High-Risk Pediatric HSCT: Solution or New Set of Challenges?","authors":"Archana Ramgopal DO ,&nbsp;Breana K. Goscicki PharmD, BCPPS ,&nbsp;Shiva Sridar BS ,&nbsp;Li Wang ,&nbsp;Daniel Klein ,&nbsp;Tsuyoshi Fujita MD ,&nbsp;Ram Kalpatthi MD ,&nbsp;Jignesh Dalal MD","doi":"10.1016/j.jtct.2025.01.061","DOIUrl":"10.1016/j.jtct.2025.01.061","url":null,"abstract":"<div><h3>Introduction</h3><div>Sinusoidal obstructive syndrome (SOS) is a life-threatening complication that can arise after hematopoietic stem cell transplantation (HSCT), especially in high-risk pediatric patients. Despite some understanding of key risk factors, a detailed review of these high-risk groups in the U.S. is essential to better assess the contributing factors, healthcare implications, and patient outcomes associated with prophylactic defibrotide use. Previous studies, including one that was terminated early due to lack of efficacy, have not provided conclusive results on its effectiveness. However, its use persists, making it important to evaluate its real-world efficacy in preventing SOS and its effect on patient outcomes.</div></div><div><h3>Study Design</h3><div>A retrospective study was conducted on 10,250 patient encounters involving 8,200 unique pediatric patients. The study population was divided into high-risk (n=9,584) and very high-risk (n=666) groups based on the Harmony trial criteria. High-risk patients were defined by factors such as prior transplants, active infections, use of hepatotoxic medications, or advanced disease. Very high-risk patients had multiple risk factors or significant liver dysfunction. The patients were divided into three categories: those who received no defibrotide (n=9,606), prophylactic defibrotide (n=344), and treatment defibrotide (n=683). Data were analyzed for outcomes such as the development of SOS, duration of hospital stays, ICU admissions, mortality rates, and costs. The analysis used a mixed-effects regression model, with statistical significance set at p&lt;0.05.</div></div><div><h3>Findings</h3><div>In the high-risk group, SOS occurred in 1.4% of patients who did not receive defibrotide compared to 26.5% in those who did. For the very high-risk group, SOS occurred in 2.4% of patients without defibrotide and 31.0% in those with prophylactic use. Median hospital stays for high-risk patients were 32 days in the no defibrotide group vs. 40 days in the prophylactic group (p&lt;0.001). ICU admissions were significantly higher in the prophylactic group (50.7% vs. 30.4%, p&lt;0.001). Mortality was also higher for the prophylactic group (7.9% vs. 2.6%, p&lt;0.001), with increased costs for prophylactic defibrotide patients. Similarly, acute GVHD, infections, and sepsis rates were elevated in the prophylactic group.</div></div><div><h3>Conclusion</h3><div>Prophylactic defibrotide does not seem to lower the occurrence of SOS in high and very high-risk pediatric HSCT patients. Instead, it is linked to higher rates of ICU admissions, longer hospitalizations, increased mortality, and elevated costs. The findings suggest a need for alternative preventative approaches and additional studies to improve SOS prevention in this patient population.</div></div>","PeriodicalId":23283,"journal":{"name":"Transplantation and Cellular Therapy","volume":"31 2","pages":"Page S27"},"PeriodicalIF":3.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143487743","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Minor Histocompatibility Antigens Cross-Reactive Against Gut-Tropic Viral Epitopes Facilitate Acute GvHD of the Gut","authors":"Nicoletta Cieri MD, PhD ,&nbsp;Yiren Shao ,&nbsp;Kaila Powell ,&nbsp;Christof Smith MD, PhD ,&nbsp;Dr. Vincent T. Ho MD ,&nbsp;Meredith O. Kerrigan ,&nbsp;Jonathan Stevens ,&nbsp;William J. Lane ,&nbsp;Haesook T. Kim PhD ,&nbsp;Donna Neuberg ScD ,&nbsp;Chip Stewart ,&nbsp;Gad Getz ,&nbsp;Jerome Ritz MD ,&nbsp;Robert J. Soiffer MD ,&nbsp;Catherine J. Wu M.D.","doi":"10.1016/j.jtct.2025.01.057","DOIUrl":"10.1016/j.jtct.2025.01.057","url":null,"abstract":"&lt;div&gt;&lt;div&gt;Severe manifestations of acute gastrointestinal (GI) GvHD portend a poor prognosis after allo-HCT. Therefore, new tools to predict – and possibly mitigate – GI aGvHD risk are urgently needed. In HLA-matched allo-HCT, T cell alloreactivity is directed against minor histocompatibility antigens (mHAgs), for the identification of which we have previously developed an analytic framework based on polymorphism detection by whole exome sequencing (WES) of germline DNA from donor-recipient (D-R) pairs (Cieri, &lt;em&gt;Nat Biotechnol&lt;/em&gt; 2024). Building on the clinical observation that viral reactivations often coincide with the development of GvHD, we hypothesized that sequence homology of mHAgs with gut-tropic viral epitopes (ADV, CMV and EBV) may contribute to GI aGvHD pathophysiology.&lt;/div&gt;&lt;div&gt;To quantify the extent of cross-reactivity across the patient-specific mHAg landscape, complete viral proteomes for ADV, CMV and EBV were retrieved from UniProt to create &lt;em&gt;in silico&lt;/em&gt; all possible 8-11mers (&lt;em&gt;n&lt;/em&gt; = 1,108,265) that were then subjected to HLA class I epitope prediction, resulting in a catalog of 195,081 viral epitopes across 129 HLA class I alleles. Predicted mHAgs from WES analysis of 520 HLA-matched D-R pairs (220 MRD, 300 URD) were first filtered for expression in GI-resident non-hematopoietic cells, as identified by single cell RNASeq datasets of GI tissue from healthy and post-transplant individuals. Homology with predicted viral epitopes was defined by either: (&lt;em&gt;i&lt;/em&gt;) &lt;em&gt;sliding window&lt;/em&gt;, i.e., mHAg and viral antigen sharing ≥6 consecutive amino acids; or (&lt;em&gt;ii&lt;/em&gt;) &lt;em&gt;skipping window&lt;/em&gt;, i.e., Levenshtein distance between mHAg and viral antigen ≤2 amino acids, irrespective of position. Predicted mHAgs were considered cross-reactive only if displaying homology with viral epitopes presented on the same HLA restriction.&lt;/div&gt;&lt;div&gt;Across the MRD cohort, the median number of cross-reactive GI-specific mHAgs was 37 (range: 13 – 87). Patients who developed severe GI aGvHD (grade III-IV) had a higher load of cross-reactive GI-specific mHAgs than patients who did not (&lt;em&gt;P&lt;/em&gt; = 0.038). We considered the impact of diagnosis, prognostic risk score, status at transplant, conditioning regimen, graft source, donor age and CMV status against median cross-reactive mHAg load on risk for GI aGvHD. Only cross-reactive mHAg load &gt; median was associated with increased risk of developing severe GI aGvHD (HR = 4.96, 95% CI: 1.13 – 19.44, &lt;em&gt;P&lt;/em&gt; = 0.03). Preliminary analysis of an independent cohort of 300 HLA-matched URD D-R pairs confirmed the association of cross-reactive mHAg load with severe GI a GvHD (&lt;em&gt;P&lt;/em&gt; = 0.018).&lt;/div&gt;&lt;div&gt;Our findings reveal cross-reactivity against gut-tropic viruses as a key contributor to GI aGvHD pathophysiology. Molecular characterization of D-R pairs to quantify cross-reactivity provides a promising tool for pre-transplant prognostication that could facilitate the incorporation of pre","PeriodicalId":23283,"journal":{"name":"Transplantation and Cellular Therapy","volume":"31 2","pages":"Page S33"},"PeriodicalIF":3.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143487882","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reni-Cel, an Investigational AsCas12a Gene-Edited Cell Medicine, Led to Sustained Hemoglobin Normalization and Increased Fetal Hemoglobin in Patients with Severe Sickle Cell Disease Treated in the RUBY Trial","authors":"Mark Walters MD ,&nbsp;Haydar Frangoul MD, MS ,&nbsp;Christopher McKinney MD ,&nbsp;Luis Pineiro MD ,&nbsp;Markus Mapara MD, PhD ,&nbsp;Jignesh Dalal MD ,&nbsp;Hemalatha Rangarajan MD ,&nbsp;Harold Atkins MD ,&nbsp;Kai-Hsin Chang PhD ,&nbsp;Michael Jaskolka PhD ,&nbsp;Keunpyo Kim PhD ,&nbsp;Baisong Mei MD, PhD ,&nbsp;Olubunmi Afonja MD, MBA ,&nbsp;Rabi Hanna MD","doi":"10.1016/j.jtct.2025.01.039","DOIUrl":"10.1016/j.jtct.2025.01.039","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Introduction&lt;/h3&gt;&lt;div&gt;Sickle cell disease (SCD) complications, including vaso-occlusive events (VOEs), are reduced when fetal hemoglobin (HbF, α2γ2) is durably increased. Renizgamglogene autogedtemcel (reni-cel), an investigational gene-edited autologous hematopoietic stem cell therapy, is comprised of CD34&lt;sup&gt;+&lt;/sup&gt; cells edited at the γ-globin gene (&lt;em&gt;HBG1/2&lt;/em&gt;) promoters with a highly efficient and specific, proprietary gene-editing nuclease, AsCas12a. These edits mimic naturally occurring variants of hereditary persistence of HbF. In preclinical studies, editing CD34&lt;sup&gt;+&lt;/sup&gt; cells from patients with SCD at this genomic region led to robust HbF production and significantly reduced sickling in erythroid lineage cells. The ongoing RUBY trial (NCT04853576) is a Phase I/II/III, multicenter, open label, single arm study evaluating safety, tolerability, and efficacy of reni-cel in patients with severe SCD.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;Participants (pts) 12–50 years (yrs) of age who have severe SCD, defined as ≥2 severe VOEs/yr in the 2 yrs before consent, are eligible. Autologous CD34&lt;sup&gt;+&lt;/sup&gt; hematopoietic stem and progenitor cells are mobilized using plerixafor, collected, and edited at the &lt;em&gt;HBG1/2&lt;/em&gt; promoters. After myeloablative conditioning with busulfan, pts receive a single infusion of reni-cel (≥3 × 10&lt;sup&gt;6&lt;/sup&gt; CD34&lt;sup&gt;+&lt;/sup&gt; cells/kg) and are monitored for 24 months (mos).&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;As of June 28, 2024, 21 pts received reni-cel and were a median (range) of 8.0 (0.6–24.1) mos post-reni-cel infusion; 7 pts had &gt;1 yr follow-up. Median (range) days to neutrophil and platelet engraftment was 23.0 (15–29) and 24.5 (18–51) days, respectively (n=20). At Mo 6, mean (standard deviation [SD]) total hemoglobin (Hb) was 14.2 (2.0) g/dL (n=10) and HbF was 48.2% (3.4%; n=12). These levels were the same or higher through last follow-up. The % F-cell and mean HbF concentration/F-cell (MCH-F/F-cell) increased early. The MCH-F/F-cell ratio was &gt;10 pg/F-cell through last follow-up. Hemolysis markers improved or normalized by Mo 6 and were generally maintained over time. No pts experienced VOEs post-infusion compared with a mean (SD) of 4.9 (2.8) severe VOEs/yr in the 2 yrs before enrollment (n=21). There were high levels of allelic editing at Mo 12 (mean [SD]: in peripheral blood nucleated cells [n=4], 80.9% [5.9%]; in bone marrow-derived CD34&lt;sup&gt;+&lt;/sup&gt; cells [n=3], 86.9% [4.1%]). The safety profile reflected myeloablative conditioning with busulfan.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusions&lt;/h3&gt;&lt;div&gt;Results with reni-cel treatment were promising, including reliable and prompt engraftment, early Hb normalization, and durable increases in HbF. The data also demonstrate improvement in hemolysis markers, sustained high levels of editing, resolution of VOEs, and a safety profile consistent with myeloablative conditioning with busulfan. These findings build on clinical evidence supporting continued i","PeriodicalId":23283,"journal":{"name":"Transplantation and Cellular Therapy","volume":"31 2","pages":"Pages S21-S22"},"PeriodicalIF":3.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143488147","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Allogeneic Hematopoietic Stem Cell Transplantation in Puerto Rico","authors":"Cristian I Rodriguez-Arocho MD ,&nbsp;Andres E Juliá-Beltrán DrPH MPH ,&nbsp;Carlos R Bachier-Cintrón MD ,&nbsp;Mariola A Vazquez-Martinez MD ,&nbsp;Joel López-Figueroa MD ,&nbsp;Victor Gordo-González MD ,&nbsp;William D Marrero-León MD ,&nbsp;Dominic Sánchez-Paredes MD ,&nbsp;Alexis M Cruz-Chacon MD, FACP","doi":"10.1016/j.jtct.2025.01.027","DOIUrl":"10.1016/j.jtct.2025.01.027","url":null,"abstract":"&lt;div&gt;&lt;div&gt;The blood and marrow transplantation program at Hospital Auxilio Mutuo (HAM) in San Juan, Puerto Rico (PR) was founded on May 2015. On February 2017, the first allogeneic hematopoietic stem cell transplant (allo-HSCT) was done. Prior to this date the only option for patients from PR in need for allo-HSCT was to travel to a center in the United States (US). However, most patients faced multiple barriers to achieve this goal, including economic status, and socio-economic support. Most patient from PR had no access to allo-HSCT and faced life-threatening disease.&lt;/div&gt;&lt;div&gt;Data from patients undergoing allo-HSCT from February 2017 to December 2023 was collected and retrospective analysis done. A total 119 allo-HSCT were performed. The median age for allo-HSCT was 43 years, with youngest patient having 17 years and oldest having 70 years. Sex distribution was 54% females and 46% males. Most patients were part of public health system (47%).&lt;/div&gt;&lt;div&gt;The most frequent diagnosis among allo-HSCT was acute myelogenous leukemia (AML, 33%) followed by acute lymphoblastic leukemia (ALL, 18%), myelodysplastic syndrome (MDS, 16%), non-Hodgkin's lymphoma (NHL, 12%), severe aplastic anemia (SAA, 11%), and Hodgkin's lymphoma (7%).&lt;/div&gt;&lt;div&gt;Donor source was 42% match related, 57% haploidentical and 1% match unrelated. Conditioning regimen was reduced intensity (RIC) in 54% and myeloablative (MAC) in 46% of cases. The median age for MAC was 40 years and for RIC was 46 years. Most common diseases treated with RIC were SAA (20.3%), AML (20.3%), and NHL (18.3%). Most common diseases treated with MAC were AML (47.3%), ALL (29.1%) and MDS (16.4%). Overall survival (OS) at 30-days, 100-days and 1-year post-transplant was 91%, 83% and 65% respectively for allo-HSCT. Two-year OS by type of donor was 57.4% for matched related and 59.7% for haploidentical. Incidence of acute graft-versus-host disease in 2023 was 39.2%.&lt;/div&gt;&lt;div&gt;Existing literature suggests that studies on allo-HSCT are often not representative of the broader patient population, with a lack of diversity in terms of racial/ethnic background. This raises concerns about the applicability of research findings to diverse populations, such as the unique demographic and socio-economic profile of PR. Since February 2017, PR have access to allo-HSCT locally with the same standards and quality medical care of centers in US. The probability to find a MUD is lower for a patient from PR because of ethnical biodiversity. For this reason, haploidentical donors became a convenient and practical option for patients from PR in need of allo-HSCT. In 2023 HAM in collaboration with TCT Oncology started reporting data of allo-HSCT and autologous-HSCT performed in PR to the Center for International Blood &amp; Marrow Transplant Research (CIBMTR). Hispanic patients from PR are now represented in these database. This effort will help support research and improve patient outcomes. Our goal is obtaining FACT accreditation ","PeriodicalId":23283,"journal":{"name":"Transplantation and Cellular Therapy","volume":"31 2","pages":"Page S16"},"PeriodicalIF":3.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143488185","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Betibeglogene Autotemcel (Beti-cel) Gene Addition Therapy Results in Durable Hemoglobin A (HbA) Production with up to 10 Years of Follow-up in Participants with Transfusion-Dependent β-Thalassemia","authors":"Timothy S. Olson MD, PhD ,&nbsp;Alexis A. Thompson MD, MPH ,&nbsp;Janet L. Kwiatkowski MD, MSCE ,&nbsp;Jennifer Schneiderman MD, MS ,&nbsp;Isabelle Thuret MD ,&nbsp;Andreas E. Kulozik MD, PhD ,&nbsp;Evangelia Yannaki MD ,&nbsp;Marina Cavazzana MD, PhD ,&nbsp;Suradej Hongeng MD ,&nbsp;Martin G. Sauer MD ,&nbsp;Adrian J. Thrasher MBBS, PhD ,&nbsp;Ashutosh Lal MD ,&nbsp;John E.J. Rasko BSc (Med), MBBS (Hons), PhD, MAICD, FFSc (RCPA), FRCPA, FRACP, FAHMS ,&nbsp;Hancheng Jiang ,&nbsp;Ge Tao PhD ,&nbsp;Himal L. Thakar MD ,&nbsp;Niki Witthuhn ,&nbsp;Mark C. Walters MD ,&nbsp;Franco Locatelli MD, PhD","doi":"10.1016/j.jtct.2025.01.037","DOIUrl":"10.1016/j.jtct.2025.01.037","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Introduction&lt;/h3&gt;&lt;div&gt;Beti-cel gene addition therapy is a one-time treatment for transfusion-dependent β-thalassemia (TDT) that adds functional copies of the β-globin gene (β&lt;sup&gt;T87Q&lt;/sup&gt;) to address the underlying cause of disease. Here, we report long-term outcomes of participants treated with beti-cel.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;After completion of a 2-year phase 1/2 (HGB-204 [NCT01745120]; HGB-205 [NCT02151526]) or phase 3 (HGB-207 [NCT02906202]; HGB-212 [NCT03207009]) beti-cel study, participants were eligible for the long-term, 13-year follow-up study, LTF-303 (NCT02633943). Clinical efficacy, iron homeostasis, health-related quality of life, and safety are reported through last follow-up.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;As of Feb 2024, 63 participants (median [range] age: 17 [4-35] y) received beti-cel and subsequently enrolled in LTF-303 (median [range] follow-up: 71.2 [34.5-121.4] mo); 2 participants had 10 y of follow-up, 51 (81.0%) had at least 5 y, and 1 withdrew consent after 39 mo for personal reasons. Peripheral blood vector copy number and HbA&lt;sup&gt;T87Q&lt;/sup&gt; levels were stable by month 6, sustained across studies up to 10 y, and were higher in phase 3 vs phase 1/2 following beti-cel drug product manufacturing optimization, which is similar to the commercial process. In phase 1/2, 15/22 (68.2%) participants achieved transfusion independence (TI; median [range] weighted average hemoglobin (Hb) during TI, 10.24 [9.1-13.1] g/dL). In phase 3, 37/41 (90.2%) participants achieved TI (&lt;strong&gt;Figure&lt;/strong&gt;; weighted average Hb, 11.24 [9.8-13.9] g/dL). Transduction efficiency, pharmacodynamics, TI rate, and weighted average Hb were similar across genotypes (β&lt;sup&gt;0&lt;/sup&gt;/β&lt;sup&gt;0&lt;/sup&gt; vs non-β&lt;sup&gt;0&lt;/sup&gt;/β&lt;sup&gt;0&lt;/sup&gt;) and ages. Among phase 1/2 and phase 3 participants who achieved TI, median (range) change from baseline in serum ferritin at month 60 was -1951.0 (-7079 to 1345) ng/mL (n=39), and liver iron concentration (LIC) was -2.9 (-20.6 to 9.6) mg Fe/g dry weight (dw; n=31). At physician discretion, 28/37 (75.7%) phase 3 participants were no longer receiving iron chelation therapy, and 22 of those 28 (78.6%) had LIC &lt;5 mg Fe/g dw. Clinically meaningful improvements in the Short Form-36 Health Survey Questionnaire (SF-36) mental component summary at month 24 and SF-36 physical component summary and Pediatric Quality of Life Inventory total score at month 36 were sustained above the normative population mean at month 60. All 26 participants who completed a questionnaire reported an overall benefit with beti-cel. No beti-cel–related serious adverse events occurred &gt;2 y after infusion. No malignancies, insertional oncogenesis, or vector-derived replication-competent lentivirus were reported.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusion&lt;/h3&gt;&lt;div&gt;Beti-cel is a potentially curative therapy for patients with TDT across genotypes and ages through achievement of durable TI and a favorable safety profile up to 10 y. These da","PeriodicalId":23283,"journal":{"name":"Transplantation and Cellular Therapy","volume":"31 2","pages":"Page S20"},"PeriodicalIF":3.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143488209","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phase II Trial of Allogeneic Hematopoietic Cell Transplantation for Mature NK/T Cell Neoplasms – Potent Graft Vs Tumor Effect Affords Remission Even with Refractory Disease","authors":"Kamil A. Rechache MD ,&nbsp;Jennifer Sponaugle PA ,&nbsp;Amy Chai RN ,&nbsp;Jessenia Campos RN ,&nbsp;Thomas E. Hughes PharmD ,&nbsp;Syed Muhammad Salman Shah ,&nbsp;Alicia Peluso ,&nbsp;Christi McKeown NP ,&nbsp;Anita Stokes NP ,&nbsp;Scott Napier PA ,&nbsp;Ruby Sabina NP ,&nbsp;Jennifer Wilder DNP ,&nbsp;Kristen M. Cole BSN ,&nbsp;Mustafa A. Hyder MD ,&nbsp;Christopher G. Kanakry MD ,&nbsp;Dimana Dimitrova MD ,&nbsp;Jennifer A. Kanakry MD","doi":"10.1016/j.jtct.2025.01.049","DOIUrl":"10.1016/j.jtct.2025.01.049","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Introduction&lt;/h3&gt;&lt;div&gt;Peripheral (mature) T and NK-cell lymphomas (PTCL) are aggressive and poorly responsive to chemotherapy. Allogeneic hematopoietic cell transplantation (alloHCT) is a potentially curative cellular immunotherapy. Unfortunately, alloHCT remains understudied prospectively. Herein, we present the results of a prospective trial of alloHCT for PTCL.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;This single-center, prospective phase II trial (NCT03922724) is being conducted at the NIH from April 18, 2019 to present. The data from all patients enrolled and evaluable through August 23, 2022 are included. Patients received reduced-intensity conditioning (RIC) incorporating distally-timed horse antithymocyte globulin, pentostatin, low-dose, hyperfractionated cyclophosphamide and 2-days of busulfan, followed by a T-cell replete PBSC graft, with PTCy, MMF, and sirolimus for GVHD prophylaxis. GCSF was given on day -12, -8, and -4 in a subset of patients (n=10, mRIC arm) and compared to the prior 21 patients (RIC arm). Endpoints included progression-free survival (PFS), overall survival (OS), cumulative incidences (CuIs) of acute GVHD (aGVHD), chronic GVHD (cGVHD), progression/relapse, and transplant-related mortality (TRM).&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;Patients transplanted (n=31) were high-risk, in disease subtype, HCT-CI scores, and disease status at HCT (Fig 1). With median follow-up of 3.5 years for surviving patients, 1-year PFS was 53% (95% CI 29-72%) for the RIC arm and 60% (95% CI 25-83%) for the mRIC arm. For the whole cohort, the estimated 3-year PFS was 52% (95% CI 33-68%), with 3-year OS of 61% (95% CI 42-76%). The 3-year CuI of relapse was 18% (95% CI 6-34%) (Fig 2A), with 100-day and 1-year Cul of TRM of 17% (95% CI 6-32%) and 24% (95% CI 10-41%) respectively (Fig 2B). The Cul of TRM at 1 year was 11% (95% CI 2-29%) for patients ≤60 years but 56% (95% CI 17-82%) for patients &gt;60, p=0.011 (Fig 2C). No patients developed grade III-IV aGVHD. The 1-year Cul of grades II-IV aGVHD was 16% (95% CI 6-31%) in all patients. The 2-year CuI of cGVHD was 23% (95% CI 10-39%) with 2-year Cul of 30% (95% CI 6-60%) for recipients of HLA-matched grafts and 19% (95% CI 5-39%) for recipients of HLA-mismatched grafts. Immune reconstitution was robust overall with 90% of surviving, engrafted patients having CD4+ T cells &gt; 50 cells/uL by day +100. Immune subset recovery to normal levels was reached by day +60 for NK cells (Fig 3A), day +180 for CD8+ T Cells (Fig 3B), day +100-180 for B cells (Fig 3C), and 2 years for CD4+ T Cells (Fig 3D).&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusions&lt;/h3&gt;&lt;div&gt;Despite most patients being transplanted with high-risk, active disease, and significant comorbidities, outcomes were promising, providing compelling justification for the role of alloHCT in PTCL, even when remission is not obtained pre-HCT. The prospective study of alloHCT for PTCL is ongoing at NCI, aiming to decrease early TRM in older patients and further","PeriodicalId":23283,"journal":{"name":"Transplantation and Cellular Therapy","volume":"31 2","pages":"Pages S36-S37"},"PeriodicalIF":3.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143488451","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Memory T-Cell Add Back and Prophylactic blinatumomab Post Tcrαβ Depleted Haploidentical Transplantation Results in Promising Outcomes in Pediatric Patients with High-Risk Acute Leukemia","authors":"Swati Naik MBBS ,&nbsp;Ying Li MD ,&nbsp;Emily Zeng ,&nbsp;Subodh Selukar PhD ,&nbsp;Senthil Velan Bhoopalan MBBS, PhD ,&nbsp;Dr. Rebecca Epperly MD ,&nbsp;Renee Madden MD ,&nbsp;Ewelina Mamcarz ,&nbsp;Esther A Obeng MD, PhD ,&nbsp;Amr Qudeimat MD ,&nbsp;Akshay Sharma MBBS, MSc ,&nbsp;Ashok Srinivasan MD ,&nbsp;Ali Suliman MD, MSc ,&nbsp;Aimee C. Talleur MD ,&nbsp;Paulina Velasquez ,&nbsp;Caitlin Zebley MD, PhD ,&nbsp;Sarah S Schell ,&nbsp;Polly Adams ,&nbsp;Jean-Yves Metais PhD ,&nbsp;Salem Akel PhD ,&nbsp;Brandon M Triplett MD","doi":"10.1016/j.jtct.2025.01.095","DOIUrl":"10.1016/j.jtct.2025.01.095","url":null,"abstract":"&lt;div&gt;&lt;div&gt;TCRαβ depletion of haploidentical donor (haplo) grafts allows for low rates of GVHD but delays immune reconstitution (IR) in hematopoietic cell transplant (HCT) recipients. CD45RA-negative (memory) T cells have low alloreactivity, retain specificity for viral antigens, and can enhance IR without risk of GVHD. In this prospective clinical trial (NCT03849651), we addback memory T cells following TCRαβ/CD19 depleted haploHCT for children with hematological malignancies and administer prophylactic blinatumomab (blina) for patients with B-cell ALL to mitigate risk of relapse and avoid total body irradiation (TBI).&lt;/div&gt;&lt;div&gt;From 2019 to 2023, 69 patients received haplo HCT (ALL: 34, AML:33, MDS:1, NHL: 1) with a median age of 8.8 years (range: 0.5-21.6). Disease status at HCT was complete remission (CR)1 (n=28), CR2 (n=29), CR≥3 (n=11), and MDS (n=1). Donors included a parent (n=64) or sibling/other (n=5). All patients received a preparative regimen consisting of fludarabine, melphalan, cyclophosphamide, thiotepa, and anti-thymocyte globulin. No post-HCT GVHD prophylaxis was used. Patients received memory T cells in 2 cohorts: a dose escalation cohort (n=29 patients with T cell dose/kg: 1 × 10&lt;sup&gt;5&lt;/sup&gt;: n=9; 1 × 10&lt;sup&gt;6&lt;/sup&gt;: n=10; 1 × 10&lt;sup&gt;7&lt;/sup&gt;: n=10) and a dose expansion cohort (n=40 additional patients based on maximal effective dose of 1 × 10&lt;sup&gt;7&lt;/sup&gt; T cells/kg).&lt;/div&gt;&lt;div&gt;All patients but one engrafted with a median time to neutrophil engraftment of 10 days (range: 9-12). At a median of day +29 post-HCT (range: 22-57), 67 patients received memory T cell addback. At 4 weeks post-memory T cell addback, an increase in the mean CD3, CD8, and CD45RO+ T-cell counts (p&lt;0.0001, p=0.001, p=0.0001) was observed. Emerging memory T cells were functional as judged by Elispot assays. TCR repertoire was comparable to donor by month 6. The incidence of acute GVHD within 28 days of memory T cells addback at dose level 1, 2 and 3 was 0% (0/9), 30% (3/10), and 2% (1/48) respectively. For the entire cohort, cumulative incidence of any grade acute GVHD, grade III-IV acute GVHD and chronic GVHD at 1 year was 26.1%, 10.1% and 4.3% respectively.&lt;/div&gt;&lt;div&gt;At a median of 32 days after memory T cell addback, 26 patients with ALL received blina. Of 21 evaluable patients, 61.9% (13/21) responded with B-cell aplasia (BCA). Median CD3 count prior to blina was significantly higher in patients who developed BCA (440/μL) compared to those did not (135/μL) (p&lt;0.05). Relapses after blina occurred in 3/13 patients with BCA (CD19-pos: 2, unknown: 1), and 5/8 without BCA (CD19-pos: 3, unknown: 2).&lt;/div&gt;&lt;div&gt;For the entire cohort, OS and EFS at 1-year were 87.7% and 73.9%. The cumulative incidence of relapse and non-relapse mortality at 1-year were 23.2% and 2.9%.&lt;/div&gt;&lt;div&gt;In conclusion, our strategy led to overall promising outcomes. Addback of up to 1 × 10&lt;sup&gt;7&lt;/sup&gt; memory T cells/kg led to robust IR with low rates of severe GVHD and use of prophylac","PeriodicalId":23283,"journal":{"name":"Transplantation and Cellular Therapy","volume":"31 2","pages":"Page S59"},"PeriodicalIF":3.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143488746","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TCRα/ß Depleted Mobilized Pbscs without Calcineurin Inhibitors in Patients with Fanconi Anemia","authors":"Margaret L MacMillan MD, MSc, FRCPC ,&nbsp;Qing Cao MS ,&nbsp;Martin Felices PhD ,&nbsp;Megan Larson ,&nbsp;David H. McKenna MD ,&nbsp;Meera Srikanthan ,&nbsp;John E. Wagner MD","doi":"10.1016/j.jtct.2025.01.102","DOIUrl":"10.1016/j.jtct.2025.01.102","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background&lt;/h3&gt;&lt;div&gt;We performed a single center phase II prospective clinical trial (NCT03579875) to test the hypothesis that TCRα/ß depletion would sufficiently deplete GVHD causing α/ß T cells to eliminate the need for prolonged immunosuppression after PBSC transplantation in patients with FA.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;Patients received conditioning regimen (MacMillan, Blood 2015) with fludarabine, cyclophosphamide and methylprednisolone alone if the patient had marrow failure only and an HLA matched sibling donor (n=2), or with total body irradiation with thymic shielding (n=12) or busulfan (n=17) if there was clonal disease, or if a haploidentical related or HLA matched or mismatched unrelated donor. All but the first patient received one dose of rituximab on day-1 for B cell depletion. Mycophenolate mofetil was given after transplant if the TCRα/ß dose ≥2 × 10&lt;sup&gt;5&lt;/sup&gt; TCR α/β T cells/kg recipient (n=4). Mass cytometry (CyTOF) studies included targeting markers for delineating naïve, effector and effector memory CD4 cells and naïve, stem memory, central memory and effector memory CD8 cells, as well as T regulatory, B and γδ T cell subpopulations.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;31 patients with FA, median 9.5 years (range 1.7-43.8) were enrolled. Patients had marrow failure (n=18), MDS (n=4), relapsed MDS (n=1), APML (n=1), ALL (n=1), immune deficiency (n=1), BRCA2 with clonal abnormality (n=2) or pre-emptively for BRCA2 (n=3), with 2 patients having had a prior transplant. Neutrophil engraftment occurred in all patients, median 9 days (Figure A). Platelet recovery occurred in 30 patients, median 15 days. To date, 3 patients developed grade II-IV acute GVHD. No patient has developed chronic GVHD requiring systemic therapy (Figure B). Probability of survival at 2 years is 90%, including 5/6 BRCA2 patients and all 7 adult patients (Figure C).&lt;/div&gt;&lt;div&gt;By 1 year, only 6 patients developed viral infections requiring systemic therapy. Immune recovery in 15 patients was compared to 10 historical FA patients similarly transplanted except for GVHD prophylaxis (TCD by CD34+ selection with calcineurin inhibitor, CNI). Significant finding were: lower proportions of total CD4+ cells (43.0% vs 76.7%, p &lt;0.0002), and memory Tregs (4.8% vs 14.6%, p&lt;0.01), and higher proportions of γδ T cells (30.8% vs 4.8%, p&lt;0.0003) in recipients of TCRα/ß PBSC at day 28. Analysis of γδ T cell proportions at 6 months (16.2% vs 3.2%, p=0.0106; TCRa/bPBSC vs. CD34 selection) indicated that TCRα/ß depletion resulted in a lasting immune imprint, underpinning the differences in reconstitution between these two transplant methodologies (Figure D).&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusions&lt;/h3&gt;&lt;div&gt;TCRα/ß depleted PBSC transplantation without CNI results in excellent engraftment, minimal GVHD, few viral infections and excellent survival in FA patients with promising outcomes in those with hematologic malignancy, biallelic BRCA2 genotype and older age","PeriodicalId":23283,"journal":{"name":"Transplantation and Cellular Therapy","volume":"31 2","pages":"Pages S64-S65"},"PeriodicalIF":3.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143488751","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NKTR-255 Vs Placebo to Enhance Complete Responses and Durability Following CD19-Directed CAR-T Therapy in Patients with Relapsed/ Refractory (R/R) Large B-Cell Lymphoma (LBCL)","authors":"Sairah Ahmed MD ,&nbsp;John F. DiPersio MD, PhD ,&nbsp;James Essell MD ,&nbsp;Catherine Diefenbach MD ,&nbsp;Miguel-Angel Perales MD ,&nbsp;Christina Castilla Llorente MD ,&nbsp;Saurabh Dahiya MD ,&nbsp;Heng Xu PhD ,&nbsp;Christie Fanton PhD ,&nbsp;Sohail Chaudhry MD, PhD ,&nbsp;Zachary Lee PharmD ,&nbsp;Mario Q. Marcondes MD, PhD ,&nbsp;Mary A. Tagliaferri MD ,&nbsp;Jonathan Zalevsky PhD ,&nbsp;David B. Miklos MD, PhD ,&nbsp;Cameron J. Turtle MBBS, PhD ,&nbsp;Joseph P McGuirk DO","doi":"10.1016/j.jtct.2025.01.021","DOIUrl":"10.1016/j.jtct.2025.01.021","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background&lt;/h3&gt;&lt;div&gt;CD19-directed chimeric antigen receptor (CAR) have high response rates in refractory large B-cell lymphoma (LBCL). However, more than half of patients fail to achieve remission and/or relapse. Thus, strategies to improve efficacy of CAR-T cell products are needed. NKTR-255 is an investigational polymer-conjugated IL-15 agonist that activates, proliferates and expands CD8+T and NK cells, as well as promote creation of memory CD8+ T cells. Clinical studies with NKTR-255 have shown expansion of CAR-T and CD8+T cells in R/R NHL patients who previously received CAR-T therapy (NCT04136756), and CAR-T trafficking to the tumor microenvironment (Muffly, 2024; NCT03233854). Here, we describe results of a Phase 2 trial evaluating NKTR-255 in combination with CAR-T therapy (NCT05664217).&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;This is a phase 2 randomized, double-blind, placebo-controlled study of NKTR-255 vs placebo following one of two FDA-approved CAR-T products (axicabtagene-ciloleucel or lisocabtagene-maraleucel). Eligible patients with R/R LBCL received study drug intravenously starting +14 days following CAR-T infusion for up to 5 months. Primary endpoint was complete response rate (CRR) by blinded independent central review (BICR) at month 6 after CD19-CAR-T cells. Efficacy was assessed by PET-CT according to Lugano. Key secondary and exploratory objectives included safety/tolerability, NKTR-255 PK and CAR-T PD quantified by flow-cytometry.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;15 patients with LBCL were randomized between Mar and Dec 2023. All patients received CD19-CAR-T cell therapy and ≥1 dose of study treatment; 12/15 (80%) received axi-cel and 3/15 (20%) received liso-cel. In total, 11 were randomized to the NKTR-255 (5 at 1.5 µg/kg; 3 at 3 µg/kg; 3 at 3 µg/kg then 6 µg/kg cycle 2+) and 4 were randomized to placebo. LDH and histology were similar between both groups, except tumor burden (NKTR-255 median 1408 vs 940 mm&lt;sup&gt;2&lt;/sup&gt; placebo). NKTR-255 following CAR-T was well-tolerated. Among 11 who received NKTR-255, infusion-related reaction (IRR) and fever were reported in 2/11 (18%) and 3/11 (27%) pts, respectively; all were grade 1/2 and resolved in 24 hrs. The most common grade ≥3 TRAEs with NKTR-255 in &gt;1 patient was decreased neutrophil count 5/11 (46%), platelet count 2/11 (18%), and lymphocyte count 2/11 (18%); all resolved. Per intent-to-treat, the CRR at month 6 for NKTR-255 was 8/11 (73%) vs 2/4 (50%) with placebo. Per response-evaluable analysis, CRR at month 6 for NKTR-255 was 8/10 (80%) vs 2/4 (50%) with placebo. Re-expansion of CD8+CAR-T cells occurred in 8/11 (73%) for NKTR-255. Additional PD analyses will be presented.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusions&lt;/h3&gt;&lt;div&gt;Preliminary data of NKTR-255 adjuvant to CD19-CAR-T cell therapy in LBCL was well-tolerated, safe and demonstrated superior CR rate compared to CD19-CAR-T cell therapy alone at 6-months. Confirmatory studies with NKTR-255 adjuvant to CAR-T therap","PeriodicalId":23283,"journal":{"name":"Transplantation and Cellular Therapy","volume":"31 2","pages":"Pages S11-S12"},"PeriodicalIF":3.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143488858","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}