Transplantation and Cellular Therapy最新文献

{"title":"Comparative Analysis of Post-Transplant Cyclophosphamide (PTCy) and ATG Platforms for Haploidentical Transplantation in Resource-Constrained Settings: A Preliminary Experience.","authors":"Debabrata Mohapatra MD, DM ,&nbsp;Sabitha Paramasivam ,&nbsp;Sushant Chib ,&nbsp;Ranjit Kumar Sahoo ,&nbsp;Deepam Pushpam ,&nbsp;Sameer Bakhshi","doi":"10.1016/j.jtct.2025.01.028","DOIUrl":"10.1016/j.jtct.2025.01.028","url":null,"abstract":"<div><h3>Background</h3><div>Worldwide, two common platforms for haploidentical-stemcell-transplantation are being used based either on post-transplant-cyclophosphamide (PTCy), developed by the Baltimore group or on anti-thymocyte globulin (ATG) developed by the Beijing group. The ideal platform that suits for countries with limited resources is not known. In this study, we analysed the outcomes of the haploidentical transplants at our center, to derive a comparison between the two platforms.</div></div><div><h3>Method</h3><div>A retrospective chart review of all haploidentical-transplantation done between December 2020 to July 2024 was conducted. Patients had been nonrandomly assigned to either of the two platforms based on different treating teams beforehand.</div></div><div><h3>Results</h3><div>Out of total 60 patients, 27 received ATG and 33 received PTCy based haploidentical-transplant-conditioning. Majority were males (63.3%), with median age 20(2-48) years. Apart from the median age (25vs14 yrs), CD34/CD3 cell-doses, all baseline parameters were comparable between two groups (<strong>Table1</strong>).</div><div>While, time to neutrophil-engraftment was similar (14 vs 15 days), platelet engraftment was delayed (20 vs 16 days), requiring more frequent transfusions with ATG-platform. Overall cohort had high incidence of bacterial (63.3%), fungal (26.7%) and CMV (73.3%) infections, irrespective of the platform. Although, duration of hospitalization was higher in ATG group, rates of acute-graft-versus-host-disease (aGVHD), chronic-GVHD, transplant-associated-microangiopathy (TMA), sinusoidal-obstruction-syndrome (SOS), post-transplant hemophagocytic lymphohistiocytosis (HLH) and non-relapse mortality (NRM) were all comparable between the two groups. With a median follow-up of 249 (11-1512) days, projected 1yr-disease-free-survival (DFS), although seemingly higher with ATG-platform (80.8% vs 70.0%), is not statistically different from the PTCy-platform, possibly due to lesser sample size (<strong>Figure 1</strong>).</div></div><div><h3>Conclusions</h3><div>In this preliminary report, we found comparable short-term survival-outcomes between ATG and PTCy platforms. Larger comparative studies with longer follow-up are needed to find whether the two haploidentical-platforms are comparable in terms of outcomes, toxicity and need of resources and supportive-care.</div></div>","PeriodicalId":23283,"journal":{"name":"Transplantation and Cellular Therapy","volume":"31 2","pages":"Pages S16-S17"},"PeriodicalIF":3.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143488186","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":"Accelerated Brain Aging and Cognitive Decline in Hematologic Cancer Survivors Post-Transplant: Insights from Brain Age Gap and White Matter Hyperintensities","authors":"Noha Sharafeldin MD, MSc, PhD ,&nbsp;Jose Perucho PhD ,&nbsp;Andie Grimm MPH ,&nbsp;Yun-Chi Lin BA ,&nbsp;Frema Kwarteng BS, MPH ,&nbsp;Michelle Trent B.S. ,&nbsp;Lindsey Hageman MPH ,&nbsp;Nora Balas MSPH, PhD ,&nbsp;Liton Francisco BS ,&nbsp;Donna Murdaugh Ph.D., ABPP-CN ,&nbsp;Yu-Hua Fang PhD ,&nbsp;Smita Bhatia MD, MPH","doi":"10.1016/j.jtct.2025.01.010","DOIUrl":"10.1016/j.jtct.2025.01.010","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background&lt;/h3&gt;&lt;div&gt;Brain age gap (BAG – estimated as the difference between magnetic resonance imaging (MRI)-derived brain age and chronological age) and white matter hyperintensities (WMH) are markers of cognitive and vascular brain aging associated with cognitive decline in the general population. Associations between these markers of aging and cognitive function remain unexplored in adult hematologic cancer survivors.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;We enrolled 24 adult hematologic malignancy survivors (41.7% acute myeloid leukemia, 16.7% acute lymphoblastic leukemia, 25% myelodysplastic neoplasms, 8.3% multiple myeloma; 93% treated with allogeneic and 3.5% with autologous transplant. In-person neurocognitive assessments of executive function, processing speed, attention, and memory /learning were used to calculate a global deficit score (GDS). Brain MRI images were obtained concurrently on a Siemens MAGNETOM Prisma Scanner. We identified 33 adult healthy controls matched on age and sex from the National Institute of Mental Health Healthy Volunteer Dataset with available structural MRI data. In both cohorts, MRI-derived brain age was estimated using a robust deep learning model (DeepBrainNet). WMHs were categorized into deep and periventricular WMH based on distance from the ventricles. T-tests were used to compare BAG and WMH markers between controls and survivors. Linear regression was used to test associations with cognitive scores.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;Median age at time of assessments in survivors was 56.6y (range: 23-74.5y), 75% were males, 66.7% were non-Hispanic Whites, 54.2% had college or higher education. Median time since diagnosis was 20.1 months (range: 11.5 – 56). Mean estimated BAG was significantly higher in survivors compared to controls (10.5y (95%CI: 6.3-14.7) vs 4.7y (95%CI: 1.9-7.4), p=0.015). Deep and periventricular WMH volumes standardized by total white matter volume were significantly higher in survivors compared to controls (p&lt;0.001). A greater BAG was significantly associated with worse GDS (OR=1.14, 95%CI 1.0-1.28, p=0.04). Adjusted for age, sex, and education, a greater BAG was associated with worse processing speed scores (β=-0.89, p=0.01) corresponding to 4y of older brain age in patients with worse scores; attention scores (β=-0.87, p=0.046; corresponding to 2.7y older brain age); and memory/learning scores (β=-1.04, p=0.02; corresponding to 2.5y older brain age). Greater deep and periventricular WMH volumes were associated with worse processing speed (p=0.005 and p=0.003) and executive functioning scores (p=0.02 and p=0.02).&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusions&lt;/h3&gt;&lt;div&gt;Hematologic cancer survivors experience significant brain age acceleration compared to healthy controls, that is associated with worse neurocognitive functioning. MRI-based structural markers of brain aging represent promising predictors of declining cognitive function and could be used as targets for early interve","PeriodicalId":23283,"journal":{"name":"Transplantation and Cellular Therapy","volume":"31 2","pages":"Page S4"},"PeriodicalIF":3.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143488368","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":"Personalized Transplant Decision Model for Myelofibrosis","authors":"Nico Gagelmann ,&nbsp;Barbara Mora ,&nbsp;Filippo Branzanti ,&nbsp;Ruxo M.F. cohort ,&nbsp;Mysec Cohort ,&nbsp;Transplant M.F. Consortium ,&nbsp;Nicolaus Kröger MD ,&nbsp;Francesco Passamonti ,&nbsp;Francesca Palandri","doi":"10.1016/j.jtct.2025.01.014","DOIUrl":"10.1016/j.jtct.2025.01.014","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background&lt;/h3&gt;&lt;div&gt;Here, we aimed to develop a uniform decision model to define the optimal timing of treatment in MF patients based on clinical and genomic information in the modern era of JAK inhibition.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Patients and methods&lt;/h3&gt;&lt;div&gt;We studied a retrospective, international cohort of 1913 patients with primary (PMF, 58%) or secondary MF (SMF, 42%), of whom 1010 patients underwent HCT. All patients who did not undergo HCT were treated with ruxolitinib.&lt;/div&gt;&lt;div&gt;First, we developed a multi-state model to estimate transition hazards between different disease-specific categories. Next, we simulated a randomized clinical trial where subjects are selected to receive HCT at different time points, stratified according to transplant-specific risk and response to ruxolitinib.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;Considering the scenario of PMF, a low/intermediate MTSS was associated with better outcomes for early transplantation in all DIPSS categories as well as MIPSS70 intermediate/high risk. Ideal timing of HCT was suggested within first 3 years from diagnosis for DIPSS low/intermediate-1, 2 years for MIPSS70 intermediate, and within 1 year from diagnosis for both DIPSS intermediate-2/high and MIPSS70 high. In contrast, considering a scenario of MTSS high/very high risk, prolonged life expectancy for transplantation was only found for MIPSS70 intermediate/high and DIPSS intermediate-2/high, suggesting delay HCT by an average of 0.5 years.&lt;/div&gt;&lt;div&gt;Considering SMF, a scenario of low/intermediate MTSS was associated with better outcomes for transplantation only for a MYSEC-PM intermediate-2/high risk constellation. Ideal timing of HCT for achieving prolonged life expectancy of patients was suggested within first 1.5 years from diagnosis.&lt;/div&gt;&lt;div&gt;In a next step considering response to ruxolitinib suggested earlier transplantation by an average of 0.5 years for RR6 high risk, while RR6 low risk suggested delayed transplantation by an average of 1 year. Importantly, high risk RR6 suggested earlier HCT for patients with intermediate DIPSS and MYSEC-PM.&lt;/div&gt;&lt;div&gt;Additional genomic constellations significantly affected decision modelling (P&lt;0.001). First, present &lt;em&gt;ASXL1&lt;/em&gt; drove the decision towards delayed transplantation for patients with MYSEC-PM low/intermediate-1 and MTSS low/intermediate risk. Second, patients with &lt;em&gt;TP53&lt;/em&gt; mutation (irrespective of disease type and risk) benefitted from early transplantation within 1 year of diagnosis.&lt;/div&gt;&lt;div&gt;Finally, we developed a novel uniform decision and prognostic model for PMF and SMF and HCT outperforming all current prognostic systems (transplant and nontransplant) with a uniform website application (will be presented at the meeting).&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusion&lt;/h3&gt;&lt;div&gt;We provided evidence for the relevance of combining all clinico-genomic and treatment-specific in the modern era of genomics and JAK inhibition, enabling personalized decision making in MF","PeriodicalId":23283,"journal":{"name":"Transplantation and Cellular Therapy","volume":"31 2","pages":"Pages S6-S7"},"PeriodicalIF":3.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143488842","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":"Combinatorial Immunotherapy of Mcam Targeting Chimeric Antigen Receptor Modified Expanded Natural Killer Cells and IL-15 Agonist Against Neuroblastoma","authors":"Wen Luo PhD ,&nbsp;Hongwen Zhu ,&nbsp;Shiori Eguchi ,&nbsp;Meijuan Tian PhD ,&nbsp;Yanling Liao PhD ,&nbsp;Alexandra Sobocinski ,&nbsp;Diane Hurwitz ,&nbsp;Thomas Hefele ,&nbsp;Janet Ayello MS, MT(ASCP) ,&nbsp;Timothy P Cripe MD PhD ,&nbsp;Dean Anthony Lee MD, PhD ,&nbsp;Mitchell S. Cairo MD","doi":"10.1016/j.jtct.2025.01.087","DOIUrl":"10.1016/j.jtct.2025.01.087","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Objectives&lt;/h3&gt;&lt;div&gt;Patients with recurrent metastatic neuroblastoma (NB) have a dismal survival. Natural Killer (NK) cells have long been recognized as important in treating pediatric solid tumors, including NB. To enhance the cytotoxicity of NK cells and facilitate specific targeting of tumor cells, we and others have engineered NK cells to express chimeric antigen receptors (CARs) against molecular targets. The melanoma cell adhesion molecule (MCAM) is expressed in NB and constitutes a novel target for immunotherapy. NKTR-255 is polymer-conjugated recombinant human IL-15 receptor agonist that stimulates proliferation and survival of NK cells. Here we develop an ex-vivo expanded CAR NK cell targeting MCAM and combine it with NKTR-255 to facilitate increased anti-tumor efficacy against NB.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;PBMCs were expanded into NK cells using K562-mbIL21-41BBL feeder cells. The anti-MCAM CAR NK cells were generated by electroporation of CAR mRNA into expanded NK cells. NK cell cytotoxicity was evaluated by luciferase based cytotoxicity assay. IFN-γ and perforin secretion were analyzed by ELISA. CRISPR-Cas9 approach was utilized to knockout MCAM in NB cells. A NB xenograft mouse model in NSG mice was utilized for evaluating in vivo tumor growth and animal survival.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;We found that electroporation resulted in CAR expression in &gt;60% of NK cells with a duration for about 6 days. Compared to mock NK cells, expression of MCAM CAR significantly enhanced NK cytotoxic activity against MCAM&lt;sup&gt;high&lt;/sup&gt; SKNFI and CHLA255 cells but not MCAM&lt;sup&gt;low&lt;/sup&gt; Be2C cells at the effector to target (E:T) ratios of 0.2:1 and 0.5:1 (p&lt;0.05). CAR NK cells had significantly higher interferon γ and perforin secretion than mock NK when incubated with SKNFI cells (p&lt;0.05). The enhanced cytotoxic activity of CAR NK cells was due to specific targeting of MCAM because we did not observe the enhanced cytotoxicity in MCAM&lt;sup&gt;KO&lt;/sup&gt; NB cells. Furthermore, CAR NK significantly decreased tumor growth and prolonged animal survival in vivo (p&lt;0.05). NKTR-255 markedly increased the expression levels of NK activating receptors NKp30, NKG2D, and NKp44 and significantly improved NK cell survival and maintained NK cell expansion in the absence of IL-2 in vitro (p&lt;0.01). NKTR-255 significantly enhanced the cytotoxic activity of CAR NK cells targeting SKNFI cells at an E:T ratio of 0.5:1 (p&lt;0.01) (Fig 1A) with significantly enhanced secretion of interferon γ and perforin (p&lt;0.01) (Fig 1B, C). Combination with NKTR-255 further enhanced the anti-tumor effects of CAR NK cells (p &lt; 0.001 compared to vehicle control, p &lt; 0.05 compared to CAR NK), and further prolonged animal survival (100% vs 30% survival at day 126 compared to CAR NK, p &lt; 0.05) (Fig 1D, E).&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusions&lt;/h3&gt;&lt;div&gt;Our studies demonstrate that ex vivo expanded and modified anti-MCAM CAR NK cells alone and/or ","PeriodicalId":23283,"journal":{"name":"Transplantation and Cellular Therapy","volume":"31 2","pages":"Pages S54-S55"},"PeriodicalIF":3.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143488862","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":"Evidence into Practice: Changes in Haploidentical Versus Umbilical Cord Blood Graft Utilization for Hematopoietic Cell Transplantation in the U.S. in Relation to a Pivotal Randomized Clinical Trial","authors":"Danh T. Tran MD, PhD ,&nbsp;Ruyun Jin MD, MCR ,&nbsp;Hong Zhu PhD ,&nbsp;Gabrielle Schmidt MPH ,&nbsp;Stephen R. Spellman MBS ,&nbsp;Karen Ballen MD","doi":"10.1016/j.jtct.2025.01.079","DOIUrl":"10.1016/j.jtct.2025.01.079","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Introduction&lt;/h3&gt;&lt;div&gt;Umbilical cord blood (UCB) and haploidentical (haplo) relatives are donor sources for hematopoietic cell transplant (HCT) patients who do not have a fully matched donor. The BMT-CTN-1101 trial (2012-2018) compared outcomes of double UCB and haplo bone marrow (BM) transplants after reduced intensity conditioning. The trial showed a similar two-year progression-free survival but a lower two-year overall survival after UCB compared to haplo.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Objectives&lt;/h3&gt;&lt;div&gt;Here, we quantified the change in graft utilization in the U.S. after the trial's publication.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;11,190 HCT patients 18-70 years of age who received either UCB (single or double units) or haplo transplants (BM or peripheral blood stem cells), for leukemia, lymphoma, myelodysplastic syndrome, myeloproliferative neoplasm, were analyzed by 3 time periods: 2010-2012 (pre-study), 2013-2018 (during study), and 2019-2022 (post-study). We also expanded our analyses to a cohort of 61,880 patients to include patients who received MUD, mMUD, and HLA-matched and 1-antigen mismatched related donor transplants to assess the growth in all donor sources.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;There was a practice change with an increase in haplo versus UCB transplants (number of haplo transplants on average per year, pre-study: 153, during-study: 561, post-study: 1,098; 32%, 68%, 91% haplo of the total haplo and UCB transplants for pre-, during- and post-period, respectively) &lt;strong&gt;(Fig. 1)&lt;/strong&gt;. Increased haplo utilization began in 2013 during the CTN-1101 study and further accelerated post-study (odds ratio (OR) of 4.6 and 20.8 during-study and post-study compared to pre-study, respectively, p&lt;0.001; OR of 4.5 post-study compared to during-study, p&lt;0.001). Compared to non-Hispanic White (NHW) patients, Black patients were more likely to receive haplo (OR=1.74, p&lt;0.001), and Asian patients were less likely to receive haplo (OR=0.75, p=0.002). Latinx patients received haplo similarly to NHW patients (OR=1.03, p=0.665). In expanded analyses of the 61,880 patients, transplants from all graft sources increased (the number of transplants of any graft on average per year was: pre-study: NHW: 3191, Black: 242, Latinx: 380, Asian: 141; during-study: NHW: 3597, Black: 304, Latinx: 525, Asian: 187; post-study: NHW: 3585, Black: 362, Latinx: 701, Asian: 236), particularly from mismatched grafts (mMUD, mMRD, haplo, UCB) for all racial/ethnic groups &lt;strong&gt;(Fig. 2)&lt;/strong&gt;.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusions&lt;/h3&gt;&lt;div&gt;Practice change toward haplo graft utilization had begun before the CTN-1101 trial's publication and continued to significantly increase after its publication, suggesting an important impact of the randomized trial. Collectively, utilization of all graft sources increased over time, particularly from mismatched grafts for patients of diverse race/ethnicity. The CTN 1101 and subsequent studies have allowed patie","PeriodicalId":23283,"journal":{"name":"Transplantation and Cellular Therapy","volume":"31 2","pages":"Page S49"},"PeriodicalIF":3.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143488869","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":"Generosity of the Unrelated Stem Cell Transplant Donor: Moving from Hope to Reality While Overcoming Challenges to Deliver the Gift of Life","authors":"Steven M. Devine","doi":"10.1016/j.jtct.2025.01.033","DOIUrl":"10.1016/j.jtct.2025.01.033","url":null,"abstract":"","PeriodicalId":23283,"journal":{"name":"Transplantation and Cellular Therapy","volume":"31 2","pages":"Pages 59-62"},"PeriodicalIF":3.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143080920","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":"RBC Alloimmunization in SCD: Chipping Away at the Iceberg of Implications","authors":"RCG Azbell ,&nbsp;PC Desai","doi":"10.1016/j.jtct.2025.01.035","DOIUrl":"10.1016/j.jtct.2025.01.035","url":null,"abstract":"","PeriodicalId":23283,"journal":{"name":"Transplantation and Cellular Therapy","volume":"31 2","pages":"Pages 66-68"},"PeriodicalIF":3.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143081019","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":"Letermovir for Prevention of Recurrent Cytomegalovirus in High-Risk Allogeneic Hematopoietic Cell Transplantation Recipients","authors":"Gyuri Han ,&nbsp;Anat Stern ,&nbsp;Yeon Joo Lee ,&nbsp;Yuxuan Li ,&nbsp;Parastoo B. Dahi ,&nbsp;Roni Tamari ,&nbsp;Boglarka Gyurkocza ,&nbsp;Ann A. Jakubowski ,&nbsp;Esperanza B. Papadopoulos ,&nbsp;Brian Shaffer ,&nbsp;Miguel-Angel Perales ,&nbsp;Karam M. Obeid ,&nbsp;Jo-Anne H. Young ,&nbsp;Genovefa A. Papanicolaou","doi":"10.1016/j.jtct.2024.12.010","DOIUrl":"10.1016/j.jtct.2024.12.010","url":null,"abstract":"<div><div>We evaluated letermovir (LTV) for secondary prophylaxis for cytomegalovirus (CMV) in allogeneic hematopoietic cell transplant recipients (HCT) at high-risk for CMV recurrence. This open-label study was conducted at Memorial Sloan Kettering Cancer Center and the University of Minnesota. Patients with clinically significant CMV infection (cs-CMVi) and ≥1 high-risk criteria for CMV who achieved viral suppression with standard CMV antivirals received LTV secondary prophylaxis for up to 14 weeks. The primary endpoint was cs-CMVi at week 14; secondary endpoints included LTV resistance, CMV end-organ disease (EOD), CMV-related death, and LTV-related adverse events at week 14. Thirty-six patients were analyzed (CMV seropositive, n = 33; T cell-depleted HCT, n = 25; cord blood allograft, n = 5). By week 14 post-transplantation, 5 patients met the primary endpoint of cs-CMVi, for a cumulative incidence of 14.9% (95% confidence interval, 2.6% to 27.1%). Four patients developed LTV breakthrough cs-CMVi (including 2 patients with confirmed LTV resistance). The remaining patient developed rebound cs-CMVi after premature discontinuation of LTV due to enrollment in a clinical trial. There were no cases of CMV EOD, CMV-related death, or LTV-related adverse events by week 14 or by week 24. Our data support that LTV secondary prophylaxis is safe and effective in high-risk HCT recipients.</div></div>","PeriodicalId":23283,"journal":{"name":"Transplantation and Cellular Therapy","volume":"31 2","pages":"Pages 105.e1-105.e9"},"PeriodicalIF":3.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142865548","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":"Safety and Efficacy of Autologous CD34+ Base Edited Hematopoietic Stem Cells (BEAM-101) for the Treatment of Sickle Cell Disease with Severe Vaso-Occlusive Crises: Results from the Ongoing Phase 1/2 Beacon Study","authors":"Ashish O. Gupta MD, MPH ,&nbsp;Akshay Sharma MBBS, MSc ,&nbsp;Haydar Frangoul MD, MS ,&nbsp;Jignesh Dalal MD ,&nbsp;Julie Kanter MD ,&nbsp;Asif Alavi MD ,&nbsp;John F. DiPersio MD, PhD ,&nbsp;Mary Eapen MRCPI, MBBS, MS ,&nbsp;Dr. Jennifer J. Jaroscak MD ,&nbsp;Ernesto Ayala MD ,&nbsp;Edward D. Ziga MD, MPH ,&nbsp;Stacey Rifkin-Zenenberg DO ,&nbsp;Alex C. Minella MD ,&nbsp;Guo Chen PhD ,&nbsp;Yinzhong Chen PhD ,&nbsp;Priya S. Chockalingam PhD ,&nbsp;Ling Lin PhD ,&nbsp;Marcelyne Joseney-Antoine ,&nbsp;Leanne Ianniello MPH ,&nbsp;Beth Gardner BSc, EMBA, PMP ,&nbsp;Matthew M. Heeney MD","doi":"10.1016/j.jtct.2025.01.040","DOIUrl":"10.1016/j.jtct.2025.01.040","url":null,"abstract":"&lt;div&gt;&lt;div&gt;BEAM-101 is an investigational base edited autologous cell therapy for the treatment (tx) of SCD through upregulation of anti-sickling fetal hemoglobin (HbF). We present initial data from BEACON (NCT05456880), a Phase 1/2, single-arm, open-label study evaluating the safety and efficacy of BEAM-101 in patients (pts) with SCD with severe vaso-occlusive crises (sVOCs).&lt;/div&gt;&lt;div&gt;Pts aged 18–35 with SCD and ≥4 sVOCs in the 2 years pre-screening were eligible per trial criteria. After plerixafor mobilization, autologous CD34+ HSPCs were collected by leukapheresis and edited with an adenine base editor. After myeloablative conditioning with busulfan, pts received a single infusion of BEAM-101 (≥3.0 × 10&lt;sup&gt;6&lt;/sup&gt; viable CD34+ cells/kg) and are monitored for 24 months (m).&lt;/div&gt;&lt;div&gt;As of July 2, 2024, 6 pts have been dosed. Demographics: 5/6 β&lt;sup&gt;S&lt;/sup&gt;/β&lt;sup&gt;S&lt;/sup&gt;, 1/6 β&lt;sup&gt;S&lt;/sup&gt;/β&lt;sup&gt;0&lt;/sup&gt;, 50% female, 19–27 years. Half (n=3) required a single mobilization cycle and half required 2. Pts received a mean BEAM-101 dose of 11.9 × 10&lt;sup&gt;6&lt;/sup&gt; (5.2–23.4) viable CD34+ cells/kg.&lt;/div&gt;&lt;div&gt;Besides safety data that include all pts dosed (n=6), the following data are from pts dosed with ≥1m of follow up (n=4; 6, 5, 2, and 1m[s] post-tx, each). All 4 pts with ≥1m of follow up achieved neutrophil and platelet engraftment at a median of 17 (15–19) and 20 (11–34) days, respectively. One pt died due to respiratory failure, likely related to busulfan conditioning, 4m after infusion. In all pts dosed (n=6), there have been no ≥Grade 3 AEs or serious AEs related to BEAM-101.&lt;/div&gt;&lt;div&gt;Using central lab data, pts’ total Hb increased from baseline (mean 9.3 [7.9–10.9] g/dL) to 17.9, 18.2, 11.0, and 11.8 g/dL at last time point available (LTPA) for P1, P2, P3, and P4, respectively. No signs/symptoms or interventions were needed for high total Hb. All pts achieved &gt;60% HbF of non-transfused (NT) Hb (total Hb − HbA) at Month (M) 1 and sustained this elevation to the LTPA. By M1, HbS% in NT blood dropped to ≤36% in all 4 pts and was sustained through LTPA. In total blood, % F-cells were 99.6% in P1 at M6, 94.4% in P2 at M4, 52.0% in P3 at M2, and 13.3% in P4 at M1 with all pts having &gt;19 pg HbF/F-cell at LTPA. Peripheral blood editing in nucleated cells, measured in P1 (at M6) and P2 (at M3), was 69.9% and 76.1%, respectively. Markers of hemolysis have normalized or improved for all pts. No VOCs have been reported by investigators following BEAM-101 tx.&lt;/div&gt;&lt;div&gt;These initial data show a safety profile for BEAM-101 consistent with busulfan conditioning and autologous HSCT. Tx with BEAM-101 resulted in rapid engraftment and marked improvement of anemia in all 4 dosed pts. We observed rapid and robust HbF induction in NT blood in all post-tx assessments. No VOCs were reported by investigators post-tx. These initial data support base editing of the &lt;em&gt;HBG1/2&lt;/em&gt; promoters as an effective therapeutic modality for the tx of SCD and will continue ","PeriodicalId":23283,"journal":{"name":"Transplantation and Cellular Therapy","volume":"31 2","pages":"Page S22"},"PeriodicalIF":3.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143488156","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":"A Novel R Shiny Tool TVCurveTM for Survival Analysis with Time-Varying Covariate in Oncology Clinical Studies: Overcoming Biases and Enhancing Collaboration","authors":"Yimei Li PhD ,&nbsp;Yang Qiao ,&nbsp;Fei Gao PhD ,&nbsp;Jordan Gauthier MD, MSc ,&nbsp;Qiang Ed Zhang ,&nbsp;Jenna M Voutsinas MSc ,&nbsp;Wendy M. Leisenring ScD ,&nbsp;Ted A. Gooley PhD ,&nbsp;Corinne Summers MD ,&nbsp;Alexandre V. Hirayama ,&nbsp;Cameron J. Turtle MBBS, PhD ,&nbsp;Rebecca A. Gardner MD ,&nbsp;Jarcy Zee PhD ,&nbsp;Qian Vicky Wu PhD","doi":"10.1016/j.jtct.2025.01.042","DOIUrl":"10.1016/j.jtct.2025.01.042","url":null,"abstract":"<div><div>In oncology studies, analyzing survival outcomes with time-varying covariates (TVCs), like the impact of receiving hematopoietic cell transplantation (HCT) after chimeric antigen receptor T cell (CAR-T) infusion, faces challenges for standard methods like Cox models and Kaplan-Meier curves, which assume TVC status is fixed at baseline, causing biased estimates. Landmark analysis is an alternative but is limited by its dependence on a chosen start time. Time-dependent (TD) Cox model is better suited for TVC analysis, though its visualization can be complex. A novel visualization, Smith-Zee, based on a TD Cox model, addresses this issue by mimicking new patients with TVC status change at different times, which addresses drawbacks of the Naïve and Landmark methods. However, software to implement these methods is limited.</div><div>To address this, we developed TVCurve^TM, an R Shiny tool that integrates various models (Naïve, landmark, and TD Cox) and curves (Naïve KM, Landmark KM, Smith-Zee, and Extended KM). <span><span>https://samplen.shinyapps.io/TVCurve/</span><svg><path></path></svg></span>.</div><div>Using two CAR-T trials as examples (Fred Hutch: NCT01865617, Seattle Children's: NCT02028455), we re-analyzed the impact of HCT on leukemia-free survival (LFS) by applying the Naïve, landmark, and TD Cox models. We observed that the Naïve and TD Cox yielded similar hazard ratios (HRs) and p-values (Table 1), indicating consistent results from both studies. However, the choice of landmark time leads to varying HRs and p-values (Table 1), highlighting the sensitivity of the landmark approach.</div><div>To understand and demonstrate the limitations of the Naïve method, we conducted a simulation study on TVCurve^TM. Our results revealed increased bias when more patients experience late TVC changes, and minimal bias when more patients had earlier TVC changes. This aligns with the findings from our analysis of two CAR-T studies, where the administration of hematopoietic cell transplantation (HCT) occurred promptly after CAR-T infusion and a substantial majority (90%) of patients exhibited treatment response, leading to longer RFS. To visualize the impact of different parameter combinations on the bias, we provided Contour plots in the simulation panel on TVCurve^TM.</div><div>In conclusion, the TD Cox model and Smith-Zee curves are recommended for survival analysis with TVCs. More importantly, our TVCurve^TM breaks collaboration barriers since it does not require data sharing but ensure standardized analyses across datasets, offering a vital tool for advancing survival analysis in oncology research.</div></div>","PeriodicalId":23283,"journal":{"name":"Transplantation and Cellular Therapy","volume":"31 2","pages":"Pages S23-S24"},"PeriodicalIF":3.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143488159","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}