Transplantation and Cellular Therapy最新文献

{"title":"The Safety and Feasibility of a Pediatric Ambulatory CAR-T Program","authors":"Samantha Forrest BSN, RN, BMTCN ,&nbsp;Amelia Fleming BSN, RN, BMTCN ,&nbsp;Kathleen Magee DNP, RN, CPHON ,&nbsp;April Lyle BSN, RN, CPHON ,&nbsp;Jill Sarro MSN, CPHON ,&nbsp;Graciela Guerrero BSN, RN, BMTCN ,&nbsp;Sharon Staton MS SSEM, BSN, RN, CPHON, BMTCN ,&nbsp;David H.M. Steffin MD ,&nbsp;Gabriela Llaurador MD ,&nbsp;Rayne H. Rouce MD ,&nbsp;Anil P. George MD ,&nbsp;Baheyeldin Salem MD ,&nbsp;Caridad Martinez MD","doi":"10.1016/j.jtct.2025.01.116","DOIUrl":"10.1016/j.jtct.2025.01.116","url":null,"abstract":"<div><h3>Topic Significance &amp; Study Purpose/Background/Rationale</h3><div>Chimeric antigen receptor T-cells (CAR-T cells) are a novel immunotherapy involving genetically modified T-lymphocytes designed to target tumor-specific antigens. At Texas Children's Hospital, an accredited Good Manufacturing Practice facility, we have established the infrastructure to support both commercial and investigational CAR-T-cell therapies in an outpatient setting, enhancing patient access and convenience.</div></div><div><h3>Methods, Intervention, &amp; Analysis</h3><div>Our CAR-T nurse coordinator serves as the primary liaison, facilitating pre-workup testing and patient education at home or in-house. This role includes coordinating home healthcare for intravenous hydration prior to chemotherapy. The outpatient treatment regimen consists of 3-5 days of lymphodepleting chemotherapy, followed by cell infusion and a 28-day monitoring period with weekly clinic visits. Caregivers receive a patient-specific safety card on day zero, outlining fever-monitoring protocols (temperature checks twice daily), emphasizing not masking fevers, and providing direct communication channels with the care team. Comprehensive training for nursing staff is supported by standard practice guidelines and educational pathways tailored for critical care. Educating caregivers about potential side effects, particularly cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), is essential for ensuring patient safety and promoting timely follow-up.</div></div><div><h3>Findings &amp; Interpretation</h3><div>Since November 2017-May 2024, TCH has successfully conducted 109 research infusions and 79 commercial CAR-T infusions. For commercial infusions, 65% were performed in the outpatient setting. We tracked admission data for these patients, revealing that 25 out of 52 patients required hospitalization post-infusion for CRS. Among those admitted, 17 presented with grade 1 CRS, while 8 experienced grades 2 and 3; 28% of these patients were transferred to the Pediatric Intensive Care Unit (PICU). Importantly, there were no grade 4 CRS admissions.</div></div><div><h3>Discussion &amp; Implications</h3><div>Our findings demonstrate that CAR-T therapy can be safely administered in an ambulatory setting, offering cost-saving benefits and increased patient satisfaction. The success of this program underscores the critical role of a skilled nursing team in managing outpatient CAR-T therapy and ensuring patient safety.</div></div>","PeriodicalId":23283,"journal":{"name":"Transplantation and Cellular Therapy","volume":"31 2","pages":"Page S74"},"PeriodicalIF":3.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143488602","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":"Long-Term Outcomes of Cardiac-Safe Hematopoietic Stem Cell Transplantation (HSCT) for Systemic Sclerosis (SSc) Patients with Impaired Cardiac Function","authors":"Yonatan Moshe Lean B.S. ,&nbsp;George E. Georges MD","doi":"10.1016/j.jtct.2025.01.107","DOIUrl":"10.1016/j.jtct.2025.01.107","url":null,"abstract":"<div><h3>Introduction</h3><div>SSc is a devastating autoimmune disease that affects multiple organ systems with high risk of mortality. Three trials (ASSIST, ASTIS, SCOT) established that high-dose conditioning and autologous HSCT can significantly reduce disease severity and improve overall survival for SSc patients (pts). However, due to the cardiotoxic effects of high-dose cyclophosphamide (CY) used in the conditioning regimen, current guidelines recommend excluding pts with SSc cardiac involvement from high-intensity conditioning HSCT. The Cardiac-Safe Transplantation for SSc Trial (CAST) conducted at Northwestern Memorial Hospital was a sequential, non-randomized study that evaluated reduced intensity conditioning for SSc pts with impaired cardiac function. Between 2015-2019, 42 pts received reduced-intensity autologous HSCT conditioning (Fludarabine 120 mg/m² +ATG 6 mg/kg + CY 60 mg/kg ± Rituximab, 500 or 1000 mg, ± IVIG). Initial results with 1-year follow-up were favorable; however, the long-term outcomes of CAST trial pts were unknown.</div></div><div><h3>Objective</h3><div>To determine the long-term outcomes of reduced intensity autologous HSCT in SSc pts with cardiac involvement.</div></div><div><h3>Methods</h3><div>To determine long-term outcomes after reduced intensity conditioning, CAST pts were consented by telephone to the current IRB-approved study and were administered a questionnaire regarding SSc disease status, medication usage, and organ function. Relapse was defined as reinitiating disease modifying anti-rheumatic drugs (DMARDs). If pts contact was not possible, survival status was determined through public records search. Overall survival (OS) and relapse-free survival (RFS) estimates were determined by Kaplan Meier method, and Cox regression was used to determine if pre-transplant parameters were associated with OS or RFS.</div></div><div><h3>Results</h3><div>The median age of pts was 49 years (20-65), and 62% were female. 2 of 42 (5%) pts were lost to follow-up prior to 5 years post-transplant. The 5-year OS was 75% (95% CI: 63-90%, Fig 1). The 5-year RFS was 61.3% (95% CI: 48-78%, Fig 2). Post-transplant, 1 (3%) pts developed malignancy (breast cancer), and 6 pts (14%) developed new autoimmune disease. Age and sex were not associated with outcome. Table 1 shows the pre-transplant parameters that were associated with increased mortality post-HSCT. Only the presence of SCL-70 antibodies was significantly associated with increased relapse (Hazard Ratio 2.8, 95% CI: 1.1-7.0, p-value = .03, Fig 3).</div></div><div><h3>Conclusion</h3><div>These data suggest that a reduced intensity conditioning regimen autologous HSCT is a potentially effective treatment option for certain SSc pts with cardiac involvement.</div></div>","PeriodicalId":23283,"journal":{"name":"Transplantation and Cellular Therapy","volume":"31 2","pages":"Page S68"},"PeriodicalIF":3.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143488672","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":"Graft-Versus-Host Disease (GVHD) and Senescence-Associated Biomarkers Correlate with Frailty and Survival in Older Adults Undergoing Hematopoietic Cell Transplantation (HCT)","authors":"Ashley D. Hadjis MD ,&nbsp;Honghong Sun PhD ,&nbsp;Yangzhu Du PhD ,&nbsp;Rebecca T. Brown MD, MPH ,&nbsp;Pashna Munshi MD ,&nbsp;Saar I. Gill MBBS, PhD, FRACP ,&nbsp;Nasheed M. Hossain MD ,&nbsp;Sarah Skuli MD ,&nbsp;Noelle V. Frey MD ,&nbsp;Elizabeth O Hexner MD ,&nbsp;Ximena Jordan Bruno MD ,&nbsp;Catherine E. Lai MD, MPH ,&nbsp;Mary Ellen Martin MD ,&nbsp;Selina M. Luger MD ,&nbsp;David L Porter MD ,&nbsp;Alison W. Loren MD, MSCE ,&nbsp;Shannon R. McCurdy MD","doi":"10.1016/j.jtct.2025.01.077","DOIUrl":"10.1016/j.jtct.2025.01.077","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Introduction&lt;/h3&gt;&lt;div&gt;We previously demonstrated that Fried's Frailty Phenotype (FFP) was associated with overall survival (OS) in older adults undergoing hematopoietic stem cell transplantation (HCT). We also showed that FFP is dynamic post-HCT and that declining FFP scores at 1 and 6 months correlate with inferior OS. Whether biomarkers associated with senescence-associated secretory phenotype (SASP) or graft-versus-host disease (GVHD) are associated with frailty and post-HCT outcomes in older adults remains unexplored. We examined 21 potential biomarkers related to HCT, aging, and SASP in a cohort of older adults undergoing HCT to determine their association with FFP and OS.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;HCT recipients ≥ 60 years with hematologic malignancies were prospectively enrolled at our institution. FFP was assessed pre-HCT and at 1, 6, and 12 months post-HCT. Forty patients had pre-HCT, 1, 6, and/or 12-month post-HCT samples available for analysis. Biomarker selection was based on literature review and included: receptor for IL-33 (ST2), TNF-R1, TNF-RII, IL-1α, IL-1β, IL-2, IL-6, IL-7, IL-8, IL-13, IL-15, CCL2, C-X-C motif chemokine ligand 9 (CXCL9), CCL3, CCL4, PDGFAA, TNFα, VEGFα, TGFβ1, TGFβ2, and Reg3α. Biomarkers were assessed in plasma using Luminex at the aforementioned timepoints. High versus low levels for OS analyses were based on means.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;The median age of the cohort was 67 (range 60-75) years. Sixty percent of patients had an HCT-specific comorbidity index ≥ 3, all patients had a disease risk index of intermediate or high-risk, and 55% had mutations associated with clonal hematopoiesis. For the entire cohort, OS was 77.5% and 58.6% at 1 and 2 years, respectively. Mean ST2, TNFR1, and IL-15 levels were significantly elevated at day +28 and CXCL9 levels were significantly elevated at 6 months compared to pre-HCT levels (Figure 1A). ST2 and IL-15 levels were significantly higher in frail and pre-frail compared with fit patients (Figure 1B). While ST2 levels were not associated with GVHD development, in patients who develop GVHD after day 28 elevated ST2 levels were associated with inferior OS (p=0.023; data not shown). Higher levels of ST2 (p=0.0352), IL-6 (p&lt;0.0001), IL-8 (p=0.0067), and IL-15 (p=0.0143) at 6-months post-HCT were associated with inferior OS compared with lower levels (Figure 2).&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusions&lt;/h3&gt;&lt;div&gt;Elevations in IL-15 and ST2 were associated with frail phenotypes and higher ST2 was also associated with inferior OS after GVHD. Concentrations of ST2, IL-6, IL-8, and IL-15 at 6 months were associated with OS. Our next steps include machine learning models to identify optimal cut points to expand our understanding of the relationship of biomarkers with frailty and HCT outcomes. Further work is also needed to determine whether biomarker-guided interventions, like the initiation of ruxolitinib or other inflammatory mediators, can improve OS ","PeriodicalId":23283,"journal":{"name":"Transplantation and Cellular Therapy","volume":"31 2","pages":"Pages S47-S48"},"PeriodicalIF":3.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143488868","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":"In Vitro and In Vivo Characterization of Axicabtagene Ciloleucel Identifies Features Associated with Treatment Resistance in Patients, Including a Dysfunctional CD8+ T Cell State Characterized By Overexpression of GATA3 Transcript","authors":"Soumya Poddar PhD","doi":"10.1016/j.jtct.2025.01.091","DOIUrl":"10.1016/j.jtct.2025.01.091","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background&lt;/h3&gt;&lt;div&gt;Autologous anti-CD19 CAR T cell therapy is a curative-intent treatment for B cell malignancies. Still, over 50% of patients either fail to respond or relapse. Tumor intrinsic factors like high disease burden, low antigen expression, or an immune-suppressive microenvironment are associated with disease progression. A less-differentiated, naïve-like T cell phenotype and CAR T cell expansion are linked to favorable outcome. These factors, however, could only partially explain treatment outcome, and understanding of product features associated with resistance remains limited.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;We performed genomic and functional assessments of axicabtagene ciloleucel (axi-cel) products from 36 LBCL patients in ZUMA-1. Genomic evaluation included both single-cell RNA sequencing (scRNAseq) and epigenetic sequencing (scATACseq). Functional assays measured cytokine secretion after CAR T cell stimulation with CD19-coated red blood cells (RBC) or CD19+ cancer cells. Additionally, tumor bearing NSG-MHC I/II DKO mice were treated with axi-cel from 19 patients to evaluate in vivo efficacy, including CAR T-cell pharmacokinetics and cytokine levels. Correlative analyses between assay results and matched patients’ clinical outcomes were performed.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;CD19 antigen stimulation in vitro induced production of Th1 (IL2, IFNγ) and Th2 (IL4, IL5, IL13) cytokines, highlighting differences in Th1 polarization. A scaled Th1-Th2 index was strongly linked to clinical efficacy (P &lt; 0.05), especially with CD19-cross-linked RBC stimulation. scRNA-seq of axi-cel products from ZUMA-1 patients revealed 12 transcriptionally distinct T cell clusters. We identified strong association (P=0.029) between disease progression and a CD8+ cluster overexpressing Th2 master regulator, GATA3. Additionally, a hypoproliferative exhausted T cell cluster was found to be associated with lack of response. Both clusters showed enrichment of exhaustion marker, TIGIT. Matched scATAC-seq confirmed these findings and presented an enrichment in chromatin accessibility in the GATA3 promoter of CD8+ T cells from non-responders. Lastly, tumor-bearing mice treated with CAR T products from patients with durable responses showed superior tumor clearance and survival, compared to those treated with products from relapsed or non-responder patients. Patient clinical response was associated with mouse survival (P = 0.08). Further, tumor control in vivo significantly correlated with CAR T cell expansion in both mice and patients (P = 0.01), as well as with the Th1-Th2 index in mice and patients.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusions&lt;/h3&gt;&lt;div&gt;Functional assays, as well as transcriptomic and epigenetic profiling with axi-cel, demonstrate the importance and relative ranking of product features in driving treatment outcomes. These findings can inform on mechanisms of resistance and development of next generation CAR T-cell therapies.&lt;/div&gt;&lt;/","PeriodicalId":23283,"journal":{"name":"Transplantation and Cellular Therapy","volume":"31 2","pages":"Page S57"},"PeriodicalIF":3.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143488873","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":"Modulators of Relapse Risk after Hematopoietic Cell Transplantation for Adults with Acute Myeloid Leukemia Allografted in Measurable Residual Disease (MRD)-Positive Remission","authors":"Margery Gang MA/MD ,&nbsp;Megan Othus PhD ,&nbsp;Prof. Brenda M. Sandmaier MD ,&nbsp;Chris Davis MS ,&nbsp;Ryan Basom BS ,&nbsp;Roland B. Walter MD, PhD, MS","doi":"10.1016/j.jtct.2025.01.094","DOIUrl":"10.1016/j.jtct.2025.01.094","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Introduction&lt;/h3&gt;&lt;div&gt;Measurable residual disease (MRD) before hematopoietic cell transplantation (HCT) identifies adults allografted for acute myeloid leukemia (AML) in remission who are at high risk of relapse and poor survival. The factors that modulate these outcomes are poorly characterized.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;We conducted a single-center retrospective study of adults age ≥18 years with AML in first or second remission with MRD by multiparameter flow cytometry who underwent allogeneic HCT between 5/2006 and 3/2023.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;We identified 207 patients (median age: 51 [range: 18-74] years) for study inclusion. Donor sources included 10/10-HLA matched related or unrelated donors (n=146), 1-2 allele mismatched unrelated donors (MMUD; n=24), haploidentical donors (n=11), and umbilical cord blood (n=26). In the whole cohort, 126 (61%) underwent myeloablative conditioning (MAC) while 81 (39%) received non-MAC conditioning. MAC recipients were younger and had lower treatment-related mortality (TRM) scores, though other characteristics (including secondary AML [sAML], first vs. second remission, disease risk, presence of residual cytogenetic abnormalities at HCT, and blood counts before HCT) were similar. With a median follow up of 64 months among survivors, the 3-year relapse incidence was 65% (58-71%) while non-relapse mortality (NRM) was 4% (2-8%) and 12% (8-16%) at 100 days and 18 months, respectively. This translated into 3-year overall survival (OS) and relapse-free survival (RFS) estimates of 34% (28-41%) and 24% (18-30%), respectively. There were no differences in OS, RFS, relapse, or NRM between MAC and non-MAC recipients. After adjusting for TRM scores and conditioning intensity, we found that adverse disease risk (hazard ratio [HR]=1.74 [1.20-2.51]), residual cytogenetic abnormalities at HCT (HR=1.50 [1.05-2.14]), and poor blood count recovery before HCT (HR=2.91 [1.53-5.56]) were associated with increased risk of relapse (table 1). While 3-year relapse incidence for MRD&lt;sup&gt;pos&lt;/sup&gt; patients with intermediate risk disease and normalized cytogenetics at HCT was 61% (34-80%, n = 18), it was as high as 81% (65-90%, n=45) in MRD&lt;sup&gt;pos&lt;/sup&gt; patients with adverse risk disease and residual cytogenetic abnormalities at HCT. In turn, TRM score (HR=1.81 [1.21-2.71]) and non-MAC (HR = 2.37 [1.12-5.02] were associated with increased NRM, and poor blood counts at HCT (HR = 2.01 [1.06-3.79]) were associated with shorter OS. Sex, hematopoietic cell transplantation-specific comorbidity index (HCT-CI), sAML, and second remission had no impact on risk of relapse, NRM, or OS.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusion&lt;/h3&gt;&lt;div&gt;In adults with AML allografted in MRD&lt;sup&gt;pos&lt;/sup&gt; remission, additional factors including adverse cytogenetics, residual cytogenetic abnormalities, and poor blood counts at transplant modulate relapse risks. Consideration of these risk factors may inform patient selection and decision m","PeriodicalId":23283,"journal":{"name":"Transplantation and Cellular Therapy","volume":"31 2","pages":"Pages S58-S59"},"PeriodicalIF":3.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143488875","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":"Addressing Ethnically Diverse Patient Representation in Hematopoietic Cell Transplant Clinical Trials: Insights Gained through the Access Trial","authors":"Dr. Jeffery J. Auletta MD ,&nbsp;Stephanie Bo-Subait MPH ,&nbsp;Dr. Abeer Madbouly PhD ,&nbsp;Jaime M. Preussler MS ,&nbsp;Janelle Olson PhD ,&nbsp;Lindsay Bankole BA ,&nbsp;Sarah Smith ,&nbsp;Martin Maiers MS ,&nbsp;Yung-Tsi Bolon ,&nbsp;Jennifer Novakovich ,&nbsp;Kelly Buck ,&nbsp;Craig Malmberg ,&nbsp;Kimberly Wadsworth PhD ,&nbsp;Stephanie Fingerson ,&nbsp;Christa L. Meyer MS ,&nbsp;Anna M. DeSalvo MS, CGC ,&nbsp;Katie Schoeppner MSW, LICSW ,&nbsp;Jackie Foster MPH, RN, OCN ,&nbsp;Ben Tweeten MSW, LICSW ,&nbsp;Rachel Cusatis PhD ,&nbsp;Steven M. Devine MD","doi":"10.1016/j.jtct.2025.01.083","DOIUrl":"10.1016/j.jtct.2025.01.083","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background&lt;/h3&gt;&lt;div&gt;The NMDP-sponsored, CIBMTR-led ACCESS (NCT04904588) trial studied safety and efficacy of peripheral blood stem cell allografts from mismatched unrelated donors (MMUD) in adults with hematologic malignancies using post-transplant cyclophosphamide-based graft-versus-host disease prophylaxis. Analysis from the initial reduced intensity conditioning (RIC) cohort showed that 51% (n=36) of patients were ethnically diverse (ED) and had a 1-year overall survival of 79% (Al Malki et al. ASCO 2024). ED patients were younger and had higher financial toxicity and social vulnerability index (SVI) than non-Hispanic White (NHW) patients (Yusuf et al. 2024 Tandem Meetings). As adult enrollment on both RIC and myeloablative conditioning strata was completed in February 2024, we defined study patient profiles that might inform social needs and trial participation of ED patients.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;To enroll on ACCESS, patients required an unrelated donor (URD) matched at 4-7/8 HLA alleles (HLA-A, B, C, and DRB1) and aged 18-35 years. Recipients without an available 8/8 related or URD and lacking HLA-specific antibody (anti-HLA Ab) to any mismatched allele/antigen were eligible. ED patients had any race and ethnicity besides NHW. Donor ancestry and recipient utilization of patient services were collected through NMDP operations. COmprehensive Score for financial Toxicity (COST), SVI, and patient reported outcomes (PRO) were compared between NHW and ED subjects (significance p&lt;0.05).&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;Of 268 adult patients, 51% were males, 69% had acute leukemia, and 51% were ED (&lt;strong&gt;Figure 1A&lt;/strong&gt;). Most patients received RIC (n=193, 72%) using 7/8 MMUD (n=183, 68%). No differences in HCT comorbidity indices between NHW and ED patients were seen (p=0.42).&lt;/div&gt;&lt;div&gt;Median donor age was 25 years (18-35y). Of 153 patients with anti-HLA Ab (&lt;strong&gt;Figure 1B&lt;/strong&gt;), 58% were female with higher incidence of anti-HLA-Ab noted in patients utilizing MMUD with higher degree of HLA mismatch: 7/8 (n=96) 58%; 6/8 (n=45) 67%; 5/8 (n=9) 75%; and 4/8 (n=3) 100%.&lt;/div&gt;&lt;div&gt;Compared to NHW patients (&lt;strong&gt;Figure 1C&lt;/strong&gt;), ED patients were younger, had higher overall SVI, and lived closer to a transplant center. More ED patients reported lower educational attainment, lower personal income, higher financial toxicity, and acknowledged needing a caregiver versus NHW patients.&lt;/div&gt;&lt;div&gt;Of 162 (60%) patients receiving support services, 90 (56%) were ED and most frequently received patient navigation and financial assistance. Compared to those who did not receive support services, patients who did lived in an area (ZIP code) associated with a lower percentage of the population having a bachelor or graduate degree and lower median income.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusions&lt;/h3&gt;&lt;div&gt;Half of adult patients enrolled on the ACCESS trial were ED and had high social vulnerability, highlighting the need for patie","PeriodicalId":23283,"journal":{"name":"Transplantation and Cellular Therapy","volume":"31 2","pages":"Pages S52-S53"},"PeriodicalIF":3.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143488886","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":"Tandem CD20-CD19-Directed Non-Cryopreserved CAR T Cells - Zamtocabtagene Autoleucel (Zamto-Cel) in Patients with Relapsed/Refractory Diffuse Large B Cell Lymphoma - Interim Results from a Phase 2 Pivotal Study (DALY II USA)","authors":"Nirav N. Shah MD ,&nbsp;Richard T Maziarz MD ,&nbsp;Caron A. Jacobson MD, MMSc ,&nbsp;Patrick B Johnston MD, PhD ,&nbsp;Sunil H. Abhyankar MD ,&nbsp;Iris Isufi ,&nbsp;Miguel Angel Perales MD ,&nbsp;Monalisa Gosh MD ,&nbsp;Matthew L. Ulrickson MD ,&nbsp;Allison Rosenthal DO ,&nbsp;Javier Munoz MD, MBA ,&nbsp;Dr. Nancy Maureen Hardy MD ,&nbsp;Aaron P. Rapoport MD ,&nbsp;Reem Karmali MD, MS ,&nbsp;Farrukh T Awan MD ,&nbsp;Matthew McKinney MD ,&nbsp;Mitchell Horwitz MD ,&nbsp;Matthew Lunning DO, FACP ,&nbsp;Nathan Denlinger DO, MS ,&nbsp;Marek Ancukiewicz PhD ,&nbsp;David B. Miklos MD, PhD","doi":"10.1016/j.jtct.2025.01.046","DOIUrl":"10.1016/j.jtct.2025.01.046","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background&lt;/h3&gt;&lt;div&gt;Zamto-cel is an investigational autologous tandem CD20-CD19-directed non-cryopreserved CAR-T cell product for patients (pts) with relapsed/refractory diffuse large b cell lymphoma (r/r DLBCL) in the DALY II USA clinical trial (NCT04792489), a multicenter, open label, single-arm Phase 2 study. Here, we report efficacy and safety outcomes as part of a pre-planned interim analysis.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;Eligible adults had r/r DLBCL after at least 2 prior lines of treatment and measurable disease per Lugano 2014 classification. Zamto-cel was manufactured utilizing CliniMACS Prodigy® (Miltenyi Biotec), a closed, automated system with a 14-day vein-to -vein time. The primary endpoint was overall response rate (ORR) defined as best overall response (BOR) of either complete response (CR) or partial response (PR). Secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), safety, and CD19 and CD20 antigen expression at relapse.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;As of March 29, 2024, 69 pts received zamto-cel of which 59 were evaluable having received a fresh, conforming product and completed a minimum of 3 months follow-up. Median age was 63 years (range 25-85), 39 (66%) were male. The majority of pts presented with high risk factors including elevated LDH at study entry (53%), and 49% had ≥ 2 extranodal lesions. Successful manufacturing of a fresh, in specification product occurred in 91.3% out of 69 treated pts. No patient died or withdrew during the manufacturing process.&lt;/div&gt;&lt;div&gt;The ORR in the evaluable patient population (n=59) was 72.9% (95% CI, 59.7-83.6), with a CRR of 49.2% (95% CI,35.9-62.5). The 6 month and 12 month-PFS was 55% (95%CI, 41-67) and 42% (95%CI, 28-56), respectively; 12 month-OS was 72% (95%CI, 57-83) (Fig.1). The median DOR was 11.4 months (Fig. 2).&lt;/div&gt;&lt;div&gt;All 69 treated pts were assessed for safety outcomes. Thirty-two pts (46.4%) experienced cytokine release syndrome (CRS), all grade 1-2. Immune effector cell-associated neurotoxicity syndrome (ICANS) was reported in 12 pts (17.4%), grade 1-2 (9 pts; 13.1%); grade 3 (3 pts; 4.3%) (Fig.3). One patient experienced immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS), which resolved after 2 days.&lt;/div&gt;&lt;div&gt;Biopsies at progression were available in 24 pts. Only one patient experienced loss of both antigens compared to pre-treatment status, demonstrating maintenance of target antigen expression at relapse.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusion&lt;/h3&gt;&lt;div&gt;This pre-planned interim analysis represents the first pivotal trial of a tandem CD20-CD19 directed non-cryopreserved CAR-T cell product for patients with third-line r/r DLBCL. The results show encouraging activity and a favorable safety profile. Unlike currently registered CAR-T cell products, zamto-cel is administered as a fresh product with a short vein-to-vein time with a high manufacturing success","PeriodicalId":23283,"journal":{"name":"Transplantation and Cellular Therapy","volume":"31 2","pages":"Page S34"},"PeriodicalIF":3.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143488448","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":"Comparative Analysis of CRISPR-Cas9, Lentiviral Transduction, and Base Editing for Sickle Cell Disease Therapy in a Murine Model","authors":"Henna Butt MD ,&nbsp;Shruti Sathish ,&nbsp;Evan London ,&nbsp;Anh Le ,&nbsp;Quan Li ,&nbsp;Bjorg Gudmundsdottir ,&nbsp;Duck Yeon-Lee ,&nbsp;Emma V Burke ,&nbsp;Bradley P Yates ,&nbsp;David R Liu PhD ,&nbsp;Gregory A Newby ,&nbsp;Matthew Hsieh MD ,&nbsp;William A Eaton ,&nbsp;Naoya Uchida M.D., Ph.D. ,&nbsp;Francis J. Pierciey Jr. ,&nbsp;John F. Tisdale MD ,&nbsp;Selami Demirci PhD","doi":"10.1016/j.jtct.2025.01.007","DOIUrl":"10.1016/j.jtct.2025.01.007","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Introduction&lt;/h3&gt;&lt;div&gt;Sickle cell disease (SCD) is a red blood cell (RBC) disorder resulting from a point mutation in the β-globin gene resulting in sickle hemoglobin (HbS) polymerization under hypoxic conditions&lt;sup&gt;1&lt;/sup&gt;. The FDA approved Casgevy® and Lyfgenia &lt;sup&gt;TM&lt;/sup&gt; for patients with SCD&lt;sup&gt;2,3&lt;/sup&gt;. These options have both led to similar promising clinical outcomes, making it unclear which approach is best for patients at this time&lt;sup&gt;4,5&lt;/sup&gt;. Utilizing a base editing approach may reduce the risk of insertional mutagenesis and large-scale genomic rearrangements. This approach converts HbS into Makassar hemoglobin (HbG), a benign naturally occurring variant&lt;sup&gt;6,7&lt;/sup&gt;. Herein, we sought to study the differences between each gene therapy approach described above in an immunocompromised mouse model.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;We optimized conditions &lt;em&gt;ex vivo&lt;/em&gt; with all three editing techniques in both healthy and sickle CD34+ hematopoietic stem and progenitor cells (HSPCs) using bluebird bio's BB305 β&lt;sup&gt;A-T87Q&lt;/sup&gt;-globin vector for the transduction group, CRISPR-Cas9 ribonucleoprotein to target the erythroid specific BCL11A +58 enhancer, or an adenine base editor mRNA to convert HbS to HbG-Makassar. Edited SCD CD34+ HSPCs were infused into busulfan conditioned NBSGW mice (n = 5 mice for each technique, including a non-edited group as a control and a group infused with a 1:1:1 mixture of all three products).&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;&lt;em&gt;Ex vivo&lt;/em&gt; analysis of the infused cells showed ∼95% editing of BCL11A enhancer, ∼75% base editing at β-globin, and a vector copy number (VCN) of ∼0.9 copies/diploid genome. At 16 weeks of transplantation, bone marrow (BM) analyses showed similar human CD45+ cell engraftment frequencies across all groups (22-94%). In engrafted mice, there was 95.8% BCL11A editing and 62.8% β-globin base editing. VCN in mice infused with transduced cells were 2 copies/diploid genome. In the competitive transplantation group, there was 8% &lt;em&gt;BCL11A&lt;/em&gt; enhancer editing, 26% base editing and a VCN of 0.3 copies/diploid genome detected (Figure 1). Higher F-cells (%) in BCL11A-edited and the competitive transplantation groups were detected in comparison to the remainder of groups (p&lt;0.05). Using RP-HPLC and mass spectrometry, we found 73% HbG production in the base editing group, 62% γ-globin production in BCL11A edited group, 38% β&lt;sup&gt;A-T87Q&lt;/sup&gt; production in the BB305 group (Figure 2). An anti-sickling assay showed a 65%, 30%, 50%, and 63% reduction in BM RBC sickling in Makassar, BCL11A, BB305, and Mix groups, respectively (Figure 3).&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusions&lt;/h3&gt;&lt;div&gt;This study compared three gene therapy approaches - CRISPR-Cas9, lentiviral transduction, and base editing - in an immunocompromised mouse model. All methods showed significant therapeutic potential, with the increase in respective globins and reduced sickling. In the competitive transplantation","PeriodicalId":23283,"journal":{"name":"Transplantation and Cellular Therapy","volume":"31 2","pages":"Pages S1-S2"},"PeriodicalIF":3.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143488365","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":"Autoimmune Outcomes in Patients with Concurrent Autoimmune Disease Receiving CD19- or BCMA-Targeted CAR T-Cell Therapy for Lymphoma or Multiple Myeloma","authors":"Jennifer J. Huang MD, PhD ,&nbsp;Namrata Singh MD ,&nbsp;Ryan Basom BS ,&nbsp;Andrea Kalus MD ,&nbsp;Andrew J. Portuguese MD ,&nbsp;Emily C. Liang MD ,&nbsp;Natalie Wuliji DO ,&nbsp;Alexandre V. Hirayama ,&nbsp;Aude G. Chapuis MD ,&nbsp;Folashade Otegbeye MBChB, MPH ,&nbsp;Filippo Milano MD, PhD ,&nbsp;Ryan D. Cassaday MD ,&nbsp;Ajay K Gopal MD ,&nbsp;Brian G Till MD ,&nbsp;Edus H Warren MD, PhD ,&nbsp;Jordan Gauthier MD, MSc ,&nbsp;Lawrence Fong MD ,&nbsp;David G. Maloney MD, PhD ,&nbsp;Mazyar Shadman","doi":"10.1016/j.jtct.2025.01.112","DOIUrl":"10.1016/j.jtct.2025.01.112","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Introduction&lt;/h3&gt;&lt;div&gt;Chimeric antigen receptor T-cell therapy (CAR-T) has revolutionized the treatment of lymphoma and myeloma. Recent studies indicate that CAR-T may have significant activity in refractory autoimmune disease (AID). We sought to determine the impact of CAR-T on AID.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;This is a retrospective, single-center analysis of patients with a history of AID who received commercial CD19- or BMCA- targeted CAR T-cells for lymphoma or multiple myeloma at Fred Hutchinson Cancer Center from 1/2018-5/2024. Products included axicabtagene ciloleucel, brexucabtagene autoleucel, ciltacabtagene autoleucel, idecabtagene vicleucel, lisocabtagene maraleucel, and tisagenlecleucel. AID manifestations were graded on subjective improvement or exacerbation of symptoms and adjustment of treatment.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;Of the 386 patients who have received CD19- or BCMA- directed CAR-T, we identified a total of 35 patients with concurrent AID (Table 1). The oncologic complete response rate was 62.9% (n=22) by day +30 post-CAR-T, and 40.0% (n=14) experienced relapsed disease.&lt;/div&gt;&lt;div&gt;Twenty-eight patients had a history of treatment for their AID with 18 patients on active therapy at time of their lymphoma or multiple myeloma diagnosis. Ten patients remained on AID-directed treatment during their cancer-targeted treatment, and 8 patients remained on active treatment at time of CAR T-cell therapy (Figure 1A-C).&lt;/div&gt;&lt;div&gt;Of the 8 patients on active therapy for their AID, all whom received CD19-targeted CAR-T, 4 (50%) experienced an improvement in their disease status after CAR-T. Three patients discontinued or decreased the intensity of their AID-directed therapy without exacerbation of symptoms at time of last follow-up (range: 12-30 months post CAR-T). The fourth patient experienced improvement in symptom burden but remained on treatment (last follow-up 2 months post-CAR-T). Meanwhile, three patients (37.5%), all asymptomatic at the time of CAR-T, continued on their prior regimen. One patient (12.5%) experienced exacerbation of their symptoms though did not require systemic therapy. Two patients who were not on AID-directed therapy at time of CAR T-cell therapy experienced exacerbation of their disease within the first month after infusion but neither required treatment.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusion&lt;/h3&gt;&lt;div&gt;In our center's experience, half of patients on active treatment for AID prior to CAR-T experienced improvement in AID symptoms and/or cessation or decrease in intensity of AID-directed therapy. Worsening of AID, a feared complication with CAR-T, is fortunately uncommon. CAR-T may be a potential treatment option for patients with severe AID. Although our study was limited by a small sample size, these data support prospective trials to determine both the efficacy and toxicity of CAR-T for patients with AID. They also dispute the notion that concomitant AID should exclude patients who are othe","PeriodicalId":23283,"journal":{"name":"Transplantation and Cellular Therapy","volume":"31 2","pages":"Page S72"},"PeriodicalIF":3.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143488688","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 Single Center Prospective Study of Ruxolitinib in Addition to Standard Graft Versus Host Disease Prophylaxis in Patients with Myelofibrosis Demonstrates Encouraging Outcomes.","authors":"Rachel B. Salit MD ,&nbsp;Kevin Ng MS ,&nbsp;Nellie Ratsamee ,&nbsp;Anna B. Halpern MD ,&nbsp;Raya Mawad MD ,&nbsp;Cristina Ghiuzeli ,&nbsp;Bart Scott MD ,&nbsp;H. Joachim Deeg","doi":"10.1016/j.jtct.2025.01.053","DOIUrl":"10.1016/j.jtct.2025.01.053","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background&lt;/h3&gt;&lt;div&gt;In the last decade, hematopoietic cell transplantation (HCT) outcomes in patients with myelofibrosis (MF) have greatly improved. However, the incidence of Grade II-IV acute (74%) and all grades chronic (52%) graft versus host disease (GVHD) with standard GVHD prophylaxis is still high at our Center. In 2019 and 2021, ruxolitinib (Rux), previously only FDA approved for the treatment of MF, was approved for the treatment of steroid refractory acute GVHD and chronic GVHD respectively. Whether Rux is useful in the GVHD prophylaxis setting has only begun to be explored.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;We conducted a Phase II single center prospective study of pre-, peri-, and post-HCT Rux in HCT eligible patients with primary and secondary MF with a primary endpoint of Grade II-IV acute GVHD. Patients had to have at least Dynamic International Prognostic Staging System (DIPSS) Intermediate I stage disease, not have received prior HCT, and not transformed to AML. Patients were treated with at least 8 weeks of planned Rux prior to conditioning chemotherapy (cyclophosphamide 120 mg/kg and targeted 4-day busulfan, or fludarabine 150 mg/m2, and melphalan 140 mg/m2). Rux was then tapered to 5mg BID by Day -4 pre-HCT and could be increased up to 10mg BID after post-HCT Day +28 if tolerated. In addition to Rux, GVHD prophylaxis included tacrolimus (tac) (target level 5-10) and MTX 10mg/m2 on Days 1, 3, 6 and 11; Rux taper started 1 month after completion of tacrolimus and was tapered by month 9 - 12 per clinician discretion.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;Twenty-five patients median age 66 (range 42-71) were enrolled on study between 2020-2024. The majority had primary MF (60%), were JAK2 mutated (68%), had intermediate-2 or high-risk DIPSS (72%) and had at least 1 high molecular risk mutation (54%). Most had unrelated donors (76%) and fludarabine/melphalan conditioning (68%). Patients were on Rux for a median of 6 (range 2-24) months prior to conditioning and were continued until a median of 12 (3-34) months post-HCT. 96% of patients engrafted at median Day 20 (range 15 – 26); one patient engrafted at Day 43. Acute GVHD grade II-IV was diagnosed in 36% (n = 9), and grades III-IV in 8% (n = 2); 2 patients required topical therapy only. Rux was held for at least 1 week in 3 patients prior to day 100 resulting in 2 of the 9 cases of GVHD. Chronic GVHD was seen in 12% of patients at 1 year; 2 additional patients developed de novo chronic GVHD at &gt; 1 year once they were off Rux. Kaplan Meier estimates of survival at 1 year and 2 years are 100% and 87% respectively. Relapse and NRM were each seen in 8% (n = 2) of patients.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusions&lt;/h3&gt;&lt;div&gt;Compared to patients given standard GVHD prophylaxis at our Center, the incidence of acute and chronic GVHD was considerably reduced in patients who received pre-, peri- and post-transplant Rux. Non-relapse mortality was low and 1- year overall survival was 100%.","PeriodicalId":23283,"journal":{"name":"Transplantation and Cellular Therapy","volume":"31 2","pages":"Pages S30-S31"},"PeriodicalIF":3.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143487953","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}