Pub Date : 2026-02-01DOI: 10.1016/j.jtct.2025.12.072
Bonnie YeungLuk PhD , Yiouli P. Ktena MD , Margarita Dionysiou MD , Azeb Haile MS , Sarah Watt MD , Samara P Singh PhD , Anant Mashalkar Student , Johanna Tenaglia Student , Brianna Lee Student , Dheeksha Sudhakar BS , Ethan Sherman Student , Kenneth R. Cooke MD
<div><h3>Background</h3><div>Idiopathic pneumonia syndrome (IPS) is a major noninfectious lung complication following allogeneic bone marrow transplantation (AlloBMT). It arises from endothelial cell (EC) activation and injury, resulting in vascular leak and immune cell infiltration into the lung. The angiopoietin (Ang)-Tie2 signaling pathway plays a central role in regulating vascular integrity: Ang-1 stabilizes blood vessels and maintains EC quiescence, while Ang-2 acts as a functional antagonist, disrupting Tie2 signaling, promoting vascular permeability, and sensitizing ECs to inflammatory cytokines like TNFα. We hypothesize that dysregulation of the Ang:Tie2 axis drives EC dysfunction, inflammation, and lung injury characteristic of IPS.</div></div><div><h3>Methods</h3><div>We interrogated the proteome of blood samples from patients with IPS. Clinical insights were brought back to the bench using established murine BMT models.</div></div><div><h3>Results</h3><div>Antibody microarrays revealed that IPS patients had significant elevations in plasma TNFα and EC activation markers, including Ang-2 VCAM-1 and E-selectin. ELISA confirmed markedly increased Ang-2 and decreased Ang-1 at IPS onset compared with baseline and with uncomplicated BMT recipients. Importantly, Ang-2 levels decreased and Ang-1 levels normalized in patients responding to treatment, whereas both remained abnormal in those with progressive disease, indicating their biomarker potential for IPS activity and response.</div><div>Preclinical studies using a B6->F1 BMT model demonstrated elevated Ang2 mRNA and protein expression as early as day7 post AlloBMT, persisting through day14. Western blots on whole lung lysates (D14) showed down regulation of phospho-Tie2, PI3K, and Akt consistent with Ang2-mediated control of Tie2 signaling (Fig1). To determine therapeutic relevance, AlloBMT recipients were treated with the Ang-2 blocking antibody L1-10 (Amgen) subQ from day -1 through day+42. Compared to saline-treated controls, L1-10 treated mice exhibited significantly reduced bronchoalveolar lavage cellularity, CD4+, CD8+T-cell, and macrophage infiltration and lower lung pathology scores. Functionally, L1-10 treatment led to significant improvements in pulmonary physiology. Early blockade of Ang2 signaling also decreased EC apoptosis at D7 post BMT as evidenced by reduced annexin V and caspase 3/7 staining (Fig2). Notably, TNFa enhances Ang2, IL-6, and adhesion molecule gene expression while reducing EC resistance and increasing EC permeability in a novel ex vivo EC system (Fig3).</div></div><div><h3>Conclusions</h3><div>Elevated Ang-2 and suppressed Ang-1 signaling disrupts EC stability, amplifying cytokine sensitivity and lung injury. These results identify the Ang2 axis as a pivotal regulator of TNFa mediated EC activation, permeability, and immune driven inflammation in IPS, and highlight Ang-2 inhibition as a promising therapeutic strategy for this life-threatening complication
{"title":"The Ang2:Tie2 Axis Regulates Pulmonary Vascular Endothelial Cell Injury and Activation Responsible for the Development of Idiopathic Pneumonia Syndrome Following Allogeneic Blood and Marrow Transplantation","authors":"Bonnie YeungLuk PhD , Yiouli P. Ktena MD , Margarita Dionysiou MD , Azeb Haile MS , Sarah Watt MD , Samara P Singh PhD , Anant Mashalkar Student , Johanna Tenaglia Student , Brianna Lee Student , Dheeksha Sudhakar BS , Ethan Sherman Student , Kenneth R. Cooke MD","doi":"10.1016/j.jtct.2025.12.072","DOIUrl":"10.1016/j.jtct.2025.12.072","url":null,"abstract":"<div><h3>Background</h3><div>Idiopathic pneumonia syndrome (IPS) is a major noninfectious lung complication following allogeneic bone marrow transplantation (AlloBMT). It arises from endothelial cell (EC) activation and injury, resulting in vascular leak and immune cell infiltration into the lung. The angiopoietin (Ang)-Tie2 signaling pathway plays a central role in regulating vascular integrity: Ang-1 stabilizes blood vessels and maintains EC quiescence, while Ang-2 acts as a functional antagonist, disrupting Tie2 signaling, promoting vascular permeability, and sensitizing ECs to inflammatory cytokines like TNFα. We hypothesize that dysregulation of the Ang:Tie2 axis drives EC dysfunction, inflammation, and lung injury characteristic of IPS.</div></div><div><h3>Methods</h3><div>We interrogated the proteome of blood samples from patients with IPS. Clinical insights were brought back to the bench using established murine BMT models.</div></div><div><h3>Results</h3><div>Antibody microarrays revealed that IPS patients had significant elevations in plasma TNFα and EC activation markers, including Ang-2 VCAM-1 and E-selectin. ELISA confirmed markedly increased Ang-2 and decreased Ang-1 at IPS onset compared with baseline and with uncomplicated BMT recipients. Importantly, Ang-2 levels decreased and Ang-1 levels normalized in patients responding to treatment, whereas both remained abnormal in those with progressive disease, indicating their biomarker potential for IPS activity and response.</div><div>Preclinical studies using a B6->F1 BMT model demonstrated elevated Ang2 mRNA and protein expression as early as day7 post AlloBMT, persisting through day14. Western blots on whole lung lysates (D14) showed down regulation of phospho-Tie2, PI3K, and Akt consistent with Ang2-mediated control of Tie2 signaling (Fig1). To determine therapeutic relevance, AlloBMT recipients were treated with the Ang-2 blocking antibody L1-10 (Amgen) subQ from day -1 through day+42. Compared to saline-treated controls, L1-10 treated mice exhibited significantly reduced bronchoalveolar lavage cellularity, CD4+, CD8+T-cell, and macrophage infiltration and lower lung pathology scores. Functionally, L1-10 treatment led to significant improvements in pulmonary physiology. Early blockade of Ang2 signaling also decreased EC apoptosis at D7 post BMT as evidenced by reduced annexin V and caspase 3/7 staining (Fig2). Notably, TNFa enhances Ang2, IL-6, and adhesion molecule gene expression while reducing EC resistance and increasing EC permeability in a novel ex vivo EC system (Fig3).</div></div><div><h3>Conclusions</h3><div>Elevated Ang-2 and suppressed Ang-1 signaling disrupts EC stability, amplifying cytokine sensitivity and lung injury. These results identify the Ang2 axis as a pivotal regulator of TNFa mediated EC activation, permeability, and immune driven inflammation in IPS, and highlight Ang-2 inhibition as a promising therapeutic strategy for this life-threatening complication","PeriodicalId":23283,"journal":{"name":"Transplantation and Cellular Therapy","volume":"32 2","pages":"Pages S45-S46"},"PeriodicalIF":4.4,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146098673","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}
Pub Date : 2026-02-01DOI: 10.1016/j.jtct.2025.12.070
Van Anh Do-Thi PhD , Jathniel Hernandez BS , Emma Bratch BS , Pavan Reddy MD , Daniel Peltier MD, PhD
<div><div>Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is often complicated by acute graft-versus-host disease (aGVHD), a potentially life-threatening condition driven by donor allo-reactive T cells. Mechanisms regulating allo-T cell function remain incompletely understood. Emerging evidence suggests that noncanonical microproteins (<100 amino acids) act as cell type-specific immune regulators, yet their roles in T cell-intrinsic function are largely unknown.</div><div>Noncanonical microproteins are frequently encoded by long noncoding RNAs (lncRNAs) with ribosomal access (i.e. cytoplasmic). These lncRNA-encoded microproteins can function independent of their parent transcripts, creating “bifunctional” genes whose RNA and protein products may act concordantly or separately.</div><div>We previously identified a T cell-specific lncRNA, <em>ReLoT/LINC00402</em>, as a biomarker for aGVHD (Peltier et al., <em>Sci. Transl. Med.</em>, 2021). Because <em>ReLoT</em> is cytoplasmic, we performed an <em>in vitro</em> transcription-translation assay, revealing a 10 kDa microprotein. Translation prediction algorithms identified a small open reading frame (sORF) near the 5′ end of <em>ReLoT</em> consistent with this size. Using deletion and frameshift mutants and a custom polyclonal antibody, we confirmed that this sORF encodes the 90-amino acid <em>ReLoT</em> microprotein. When ectopically expressed in Jurkat T cells, the microprotein localized to cytoplasmic and mitochondrial compartments and was detected endogenously in primary human T cells.</div><div>To dissect RNA- versus microprotein-dependent functions, we overexpressed <em>ReLoT</em> mutants enabling either or both activities in Jurkat T cells lacking endogenous <em>ReLoT</em>. Both the lncRNA and microprotein independently suppressed IL-2 production after T cell receptor activation (p<0.01), without affecting ERK phosphorylation, suggesting cooperative inhibition of IL-2.</div><div>We next introduced these constructs into primary murine T cells via lentiviral transduction of hematopoietic stem cells, followed by adoptive transfer into congenic mice. Naïve T cell proliferation in response to anti-CD3/CD28 stimulation was microprotein-dependent (p<0.05), and Ki67 expression was reduced in splenic T cells following allo-HSCT using donor T cells expressing microprotein-only constructs (p<0.05). Conversely, CRISPR/Cas9 disruption of the sORF in human T cells increased proliferation (p<0.01).</div><div>In an MHC-mismatched (B6→BALB/c) murine aGVHD model, recipients of T cells expressing microprotein-only constructs exhibited reduced mortality and clinical scores (mortality p=0.01; score p=0.007), with similar trends for RNA-only constructs (mortality p=0.06; score p=0.06).</div><div>These findings establish <em>ReLoT</em> as a bifunctional, T cell-intrinsic regulator of alloimmunity. Modulating either the <em>ReLoT</em> RNA or its microprotein may offer a novel strategy to
{"title":"A Long Noncoding RNA-Encoded Noncanonical Microprotein Regulates Allogeneic T cell-Driven Acute Graft-Versus-Host Disease","authors":"Van Anh Do-Thi PhD , Jathniel Hernandez BS , Emma Bratch BS , Pavan Reddy MD , Daniel Peltier MD, PhD","doi":"10.1016/j.jtct.2025.12.070","DOIUrl":"10.1016/j.jtct.2025.12.070","url":null,"abstract":"<div><div>Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is often complicated by acute graft-versus-host disease (aGVHD), a potentially life-threatening condition driven by donor allo-reactive T cells. Mechanisms regulating allo-T cell function remain incompletely understood. Emerging evidence suggests that noncanonical microproteins (<100 amino acids) act as cell type-specific immune regulators, yet their roles in T cell-intrinsic function are largely unknown.</div><div>Noncanonical microproteins are frequently encoded by long noncoding RNAs (lncRNAs) with ribosomal access (i.e. cytoplasmic). These lncRNA-encoded microproteins can function independent of their parent transcripts, creating “bifunctional” genes whose RNA and protein products may act concordantly or separately.</div><div>We previously identified a T cell-specific lncRNA, <em>ReLoT/LINC00402</em>, as a biomarker for aGVHD (Peltier et al., <em>Sci. Transl. Med.</em>, 2021). Because <em>ReLoT</em> is cytoplasmic, we performed an <em>in vitro</em> transcription-translation assay, revealing a 10 kDa microprotein. Translation prediction algorithms identified a small open reading frame (sORF) near the 5′ end of <em>ReLoT</em> consistent with this size. Using deletion and frameshift mutants and a custom polyclonal antibody, we confirmed that this sORF encodes the 90-amino acid <em>ReLoT</em> microprotein. When ectopically expressed in Jurkat T cells, the microprotein localized to cytoplasmic and mitochondrial compartments and was detected endogenously in primary human T cells.</div><div>To dissect RNA- versus microprotein-dependent functions, we overexpressed <em>ReLoT</em> mutants enabling either or both activities in Jurkat T cells lacking endogenous <em>ReLoT</em>. Both the lncRNA and microprotein independently suppressed IL-2 production after T cell receptor activation (p<0.01), without affecting ERK phosphorylation, suggesting cooperative inhibition of IL-2.</div><div>We next introduced these constructs into primary murine T cells via lentiviral transduction of hematopoietic stem cells, followed by adoptive transfer into congenic mice. Naïve T cell proliferation in response to anti-CD3/CD28 stimulation was microprotein-dependent (p<0.05), and Ki67 expression was reduced in splenic T cells following allo-HSCT using donor T cells expressing microprotein-only constructs (p<0.05). Conversely, CRISPR/Cas9 disruption of the sORF in human T cells increased proliferation (p<0.01).</div><div>In an MHC-mismatched (B6→BALB/c) murine aGVHD model, recipients of T cells expressing microprotein-only constructs exhibited reduced mortality and clinical scores (mortality p=0.01; score p=0.007), with similar trends for RNA-only constructs (mortality p=0.06; score p=0.06).</div><div>These findings establish <em>ReLoT</em> as a bifunctional, T cell-intrinsic regulator of alloimmunity. Modulating either the <em>ReLoT</em> RNA or its microprotein may offer a novel strategy to ","PeriodicalId":23283,"journal":{"name":"Transplantation and Cellular Therapy","volume":"32 2","pages":"Pages S44-S45"},"PeriodicalIF":4.4,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146098703","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}
Pub Date : 2026-02-01DOI: 10.1016/j.jtct.2025.12.093
Nosha Farhadfar MD , Brent R Logan PhD , Naya He MPH , Joseph A. Pidala MD, PhD , Heather J. Symons MD , Jason Dehn MPH , Asad Bashey MD, PhD , Steven M Devine MD , Michael R. Grunwald MD , Brandon Hayes-Lattin MD , William J. Hogan MB, BCh , Eric Leifer PhD , Peter Westervelt MD , Stefan O. Ciurea MD , Mary M. Horowitz MD, MS , Stephanie J. Lee MD, MPH , Bronwen E. Shaw MD, PhD
Introduction
Quality of life (QoL) is a critical indicator of therapeutic benefit and long-term recovery after allogeneic hematopoietic cell transplantation (HCT). BMT CTN 1702 trial (NCT03904134), a multicenter study (2019-2022) evaluating donor search, selection practices and outcomes of HCT using alternative donor sources, incorporated QoL as a secondary endpoint.
Objectives
The aim of the QoL sub-study was to explore the long-term QoL in a more homogenous subset of patients with AML/ALL in CR1/early stage MDS who provided additional clinical and patient-reported outcomes (PRO) data and compare those receiving MUD or Haplo donors.
Methods
QoL was assessed using PROMIS measures and Lee Symptom Scale (LSS). PROs were completed at baseline, 1 and 2 years post-HCT. PRO analysis was done using a generalized estimating equation linear regression model with an independent working covariance matrix to model the mean PRO outcome at each time point. Late effects, infection rates, and healthcare utilization were also compared. Statistical significance was defined as p-value ≤ 0.01.
Results
304 patients were analyzed (61 Haplo and 243 MUD). Some characteristics differed at baseline (Table 1), but consistent with findings from the parent study. No significant differences were observed in any clinical outcomes including Graft versus Host Disease (GvHD) or GVHD-free survival (GRFS). While PRO submission rates at baseline were similar (MUD 67%, Haplo 64%), retention in the MUD cohort was higher than Haplo (80% and 83% vs. 58% and 60% at year 1, at year 2, respectively). In univariate analysis, there was no significant difference in median PROs score between the two cohorts at any timepoint. Similarly, in multivariable analysis, there were no significant differences in post-HCT trajectory of QoL domains. No significant differences in late effects including pulmonary, cardiac, or renal complications were observed. The use of Haplo donors were associated with significantly more hospital days (median days 27.0 vs. 21.0, p<0.01) and viral infections (49.2% vs. 31.8%, p=0.01) in the first 100 days.
Conclusion
Despite similar QoL trajectories, the increased hospital days and viral infections in Haplo HCT may reflect differences in post-transplant burden, possible associated with the treatment strategy. These findings suggest that QoL data meaningfully inform donor selection and long-term care strategies.
生活质量（QoL）是异体造血细胞移植（HCT）后治疗效果和长期恢复的重要指标。BMT CTN 1702试验（NCT03904134）是一项多中心研究（2019-2022），评估使用替代供体来源的HCT供体搜索、选择实践和结果，将生活质量作为次要终点。生活质量亚研究的目的是探索更同质的CR1/早期MDS AML/ALL患者的长期生活质量，这些患者提供了额外的临床和患者报告的结果（PRO）数据，并比较接受MUD或Haplo供体的患者。方法采用PROMIS量表和Lee症状量表（LSS）进行满意度评价。在hct后的基线、1年和2年完成PROs。PRO分析采用广义估计方程线性回归模型，采用独立工作协方差矩阵对每个时间点的平均PRO结果进行建模。后期效应、感染率和医疗保健利用率也进行了比较。统计学意义定义为p值≤0.01。结果共分析304例患者（Haplo 61例，MUD 243例）。一些特征在基线时有所不同（表1），但与母体研究的结果一致。在包括移植物抗宿主病（GvHD）或无GvHD生存（GRFS）在内的任何临床结果中均未观察到显著差异。虽然基线时PRO提交率相似（MUD 67%, Haplo 64%），但MUD队列的保留率高于Haplo（第一年和第二年分别为80%和83%，第二年分别为58%和60%）。在单变量分析中，两个队列在任何时间点的pro评分中位数均无显著差异。同样，在多变量分析中，hct后生活质量域的轨迹没有显著差异。包括肺、心脏或肾脏并发症在内的晚期效应未观察到显著差异。使用Haplo供体与前100天住院天数（中位天数27.0 vs. 21.0, p=0.01）和病毒感染（49.2% vs. 31.8%, p=0.01）显著增加相关。结论：尽管生活质量轨迹相似，但Haplo HCT患者住院天数和病毒感染增加可能反映了移植后负担的差异，这可能与治疗策略有关。这些发现表明，生活质量数据对供体选择和长期护理策略有意义。
{"title":"Quality of Life and Late Effects Following Haploidentical Vs. Matched Unrelated Donor Allogeneic Hematopoietic Cell Transplantation: Secondary Analysis of BMT CTN 1702","authors":"Nosha Farhadfar MD , Brent R Logan PhD , Naya He MPH , Joseph A. Pidala MD, PhD , Heather J. Symons MD , Jason Dehn MPH , Asad Bashey MD, PhD , Steven M Devine MD , Michael R. Grunwald MD , Brandon Hayes-Lattin MD , William J. Hogan MB, BCh , Eric Leifer PhD , Peter Westervelt MD , Stefan O. Ciurea MD , Mary M. Horowitz MD, MS , Stephanie J. Lee MD, MPH , Bronwen E. Shaw MD, PhD","doi":"10.1016/j.jtct.2025.12.093","DOIUrl":"10.1016/j.jtct.2025.12.093","url":null,"abstract":"<div><h3>Introduction</h3><div>Quality of life (QoL) is a critical indicator of therapeutic benefit and long-term recovery after allogeneic hematopoietic cell transplantation (HCT). BMT CTN 1702 trial (NCT03904134), a multicenter study (2019-2022) evaluating donor search, selection practices and outcomes of HCT using alternative donor sources, incorporated QoL as a secondary endpoint.</div></div><div><h3>Objectives</h3><div>The aim of the QoL sub-study was to explore the long-term QoL in a more homogenous subset of patients with AML/ALL in CR1/early stage MDS who provided additional clinical and patient-reported outcomes (PRO) data and compare those receiving MUD or Haplo donors.</div></div><div><h3>Methods</h3><div>QoL was assessed using PROMIS measures and Lee Symptom Scale (LSS). PROs were completed at baseline, 1 and 2 years post-HCT. PRO analysis was done using a generalized estimating equation linear regression model with an independent working covariance matrix to model the mean PRO outcome at each time point. Late effects, infection rates, and healthcare utilization were also compared. Statistical significance was defined as p-value ≤ 0.01.</div></div><div><h3>Results</h3><div>304 patients were analyzed (61 Haplo and 243 MUD). Some characteristics differed at baseline (Table 1), but consistent with findings from the parent study. No significant differences were observed in any clinical outcomes including Graft versus Host Disease (GvHD) or GVHD-free survival (GRFS). While PRO submission rates at baseline were similar (MUD 67%, Haplo 64%), retention in the MUD cohort was higher than Haplo (80% and 83% vs. 58% and 60% at year 1, at year 2, respectively). In univariate analysis, there was no significant difference in median PROs score between the two cohorts at any timepoint. Similarly, in multivariable analysis, there were no significant differences in post-HCT trajectory of QoL domains. No significant differences in late effects including pulmonary, cardiac, or renal complications were observed. The use of Haplo donors were associated with significantly more hospital days (median days 27.0 vs. 21.0, p<0.01) and viral infections (49.2% vs. 31.8%, p=0.01) in the first 100 days.</div></div><div><h3>Conclusion</h3><div>Despite similar QoL trajectories, the increased hospital days and viral infections in Haplo HCT may reflect differences in post-transplant burden, possible associated with the treatment strategy. These findings suggest that QoL data meaningfully inform donor selection and long-term care strategies.</div></div>","PeriodicalId":23283,"journal":{"name":"Transplantation and Cellular Therapy","volume":"32 2","pages":"Page S62"},"PeriodicalIF":4.4,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146098795","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}
Pub Date : 2026-02-01DOI: 10.1016/j.jtct.2025.12.086
Uday R. Popat MD , Chitra Hosing MD , Roland L. Bassett MS , Amin M. Alousi MD , Gheath Alatrash DO, PhD , Yosra M. Aljawai MD , Qaiser Bashir MD , George L. Chen MD , Warren B. Fingrut MD , Jin S. Im MD, PhD , Partow Kebriaei MD , David Marin MD , Yago Nieto MD, PhD , Amanda L. Olson MD , Betul Oran MD, MS , Muzaffar H. Qazilbash MD , Jeremy L. Ramdial MD , Neeraj Y. Saini MD , Portia Smallbone MBBS (Hons) , Samer A. Srour MB ChB, MS , Elizabeth J. Shpall MD
<div><h3>Background</h3><div>Patients with high-risk myelodysplastic syndrome (MDS) have poor outcomes despite the use of stem cell transplantation (SCT). Non-relapse mortality (NRM) post SCT is often driven by conditioning regimen toxicity and graft-versus-host disease (GVHD). To reduce conditioning toxicity, we extended the schedule of myeloablative busulfan (Bu) to 3 weeks. To address GVHD, we used post-transplant cyclophosphamide (PTCy). To reduce relapse, we added cladribine, thiotepa, and venetoclax. This regimen was evaluated in a prospective phase 2 trial in high-risk MDS.</div></div><div><h3>Methods</h3><div>High-risk MDS was defined as IPSS-R >3.5, poor or very poor risk cytogenetics, bone marrow blasts ≥5%, or mutated TP53 or RAS pathway genes. Eligible patients were 18–70 years old and had a matched or haploidentical related donor, or a 7/8 or 8/8 HLA-matched unrelated donor. The conditioning regimen included outpatient Bu 100 mg/m² on days -20 and -13, fludarabine 10 mg/m², cladribine 10 mg/m², and Bu pharmacokinetically dosed to reach a total systemic exposure of 20,000 ±12% µmol/min on days -6 to -3. Venetoclax 400 mg was given daily from days -22 to -3. GVHD prophylaxis was PTCy 50 mg/kg on days 3 and 4, tacrolimus ± MMF. The primary endpoint was progression-free survival (PFS). A sample size of 50 provided >80% power to detect an increase in 1-year PFS from 30% (historical) to 47%, with a 5% Type I error rate (ClinicalTrials.gov: NCT04708054).</div></div><div><h3>Results</h3><div>Fifty patients (23 female, 27 male) with a median age of 63 years (range: 33–69) were enrolled from December 2021 to August 2023. Disease characteristics included IPSS-R high/very high (58%), IPSS-M moderate high/high/very high (72%). TP53 mutations were present in 28% of patients. Donors were matched unrelated (50%), matched sibling (34%), haploidentical (4%), and mismatched unrelated (12%). Median HCT-CI score was 2 (range: 0–8); 38% had a Karnofsky performance score ≤80%.</div><div>At a median follow up of 24 months, median PFS was not reached (95% CI: 11 months–NR). One-year and 3-year PFS were 62% (50–77) and 60% (48–75), respectively. Three-year overall survival (OS), NRM, and relapse rates were 60% (48-75), 30% (17-43), and 10% (2-18), respectively. Outcomes in TP53 wildtype patients vs mutated patients at 3 years were: OS of 64% vs 50% (P=0.51), PFS of 64% vs 50% (P=0.34), and relapse rate of 6% vs 21% (P=0.031).</div><div>Median time to neutrophil and platelet engraftment were 16 (range: 13–32) and 23 days (range: 10–221), respectively. At day 30, median T cell and myeloid donor chimerism were 100%. Grade 2–4 acute GVHD occurred in 36% (23–50), grade 3–4 in 10% (2–18), chronic GVHD in 56% (42–70), and moderate-to-severe chronic GVHD in 36% (23–50).</div></div><div><h3>Conclusion</h3><div>This study met its primary endpoint, demonstrating promising 3-year PFS in patients with high-risk MDS. These findings support further investigation of th
高危骨髓增生异常综合征（MDS）患者尽管使用干细胞移植（SCT），但预后较差。SCT后的非复发死亡率（NRM）通常由调节方案毒性和移植物抗宿主病（GVHD）驱动。为了减少调节毒性，我们将清髓丁硫丹（Bu）的治疗时间延长至3周。为了治疗GVHD，我们使用了移植后环磷酰胺（PTCy）。为了减少复发，我们添加了克拉德滨、硫替帕和维托克拉克斯。该方案在高风险MDS的前瞻性2期试验中进行了评估。方法高危MDS定义为IPSS-R >；3.5，细胞遗传学差或极差风险，骨髓原细胞≥5%，TP53或RAS通路基因突变。符合条件的患者年龄为18-70岁，有匹配或单倍体相同的亲属供体，或7/8或8/8 hla匹配的非亲属供体。调节方案包括门诊治疗，第-20和-13天服用100 mg/m²，氟达拉滨10 mg/m²，克拉德滨10 mg/m²，第-6至-3天服用药物动力学剂量达到全身总暴露量20,000±12%µmol/min。Venetoclax从-22天至-3天每天给予400mg。预防GVHD的方法为PTCy 50 mg/kg，第3、4天，他克莫司±MMF。主要终点为无进展生存期（PFS）。50个样本量提供了80%的能力来检测1年PFS从30%（历史）增加到47%，I型错误率为5% （ClinicalTrials.gov: NCT04708054）。结果从2021年12月至2023年8月入组50例患者，其中女性23例，男性27例，中位年龄63岁（范围：33-69岁）。疾病特征包括IPSS-R高/非常高（58%），IPSS-M中高/高/非常高（72%）。28%的患者存在TP53突变。献血者为非亲属配对（50%）、兄弟姐妹配对（34%）、单倍体配对（4%）和非亲属配对（12%）。HCT-CI评分中位数为2（范围：0-8）；38%的人Karnofsky评分≤80%。在中位随访24个月时，中位PFS未达到（95% CI: 11个月- nr）。1年和3年PFS分别为62%（50-77）和60%（48-75）。3年总生存率（OS）为60% (48-75)，NRM为30%(17-43)，复发率为10%（2-18）。TP53野生型患者与突变型患者的3年预后为：OS为64% vs 50% (P=0.51)， PFS为64% vs 50% (P=0.34)，复发率为6% vs 21% （P=0.031）。中性粒细胞和血小板植入的中位时间分别为16天（范围：13-32）和23天（范围：10-221）。第30天，T细胞与骨髓供体嵌合率中位数为100%。2-4级急性GVHD发生率为36%(23-50)，3-4级发生率为10%(2-18)，慢性GVHD发生率为56%(42-70)，中重度慢性GVHD发生率为36%（23-50）。结论：该研究达到了主要终点，表明高危MDS患者的3年PFS有希望。这些发现支持对该方案的进一步研究。
{"title":"A Phase 2 Trial of Myeloablative Fractionated Busulfan, Fludarabine, Cladribine, Thiotepa, and Venetoclax (Cladillac) Conditioning for High-Risk MDS","authors":"Uday R. Popat MD , Chitra Hosing MD , Roland L. Bassett MS , Amin M. Alousi MD , Gheath Alatrash DO, PhD , Yosra M. Aljawai MD , Qaiser Bashir MD , George L. Chen MD , Warren B. Fingrut MD , Jin S. Im MD, PhD , Partow Kebriaei MD , David Marin MD , Yago Nieto MD, PhD , Amanda L. Olson MD , Betul Oran MD, MS , Muzaffar H. Qazilbash MD , Jeremy L. Ramdial MD , Neeraj Y. Saini MD , Portia Smallbone MBBS (Hons) , Samer A. Srour MB ChB, MS , Elizabeth J. Shpall MD","doi":"10.1016/j.jtct.2025.12.086","DOIUrl":"10.1016/j.jtct.2025.12.086","url":null,"abstract":"<div><h3>Background</h3><div>Patients with high-risk myelodysplastic syndrome (MDS) have poor outcomes despite the use of stem cell transplantation (SCT). Non-relapse mortality (NRM) post SCT is often driven by conditioning regimen toxicity and graft-versus-host disease (GVHD). To reduce conditioning toxicity, we extended the schedule of myeloablative busulfan (Bu) to 3 weeks. To address GVHD, we used post-transplant cyclophosphamide (PTCy). To reduce relapse, we added cladribine, thiotepa, and venetoclax. This regimen was evaluated in a prospective phase 2 trial in high-risk MDS.</div></div><div><h3>Methods</h3><div>High-risk MDS was defined as IPSS-R >3.5, poor or very poor risk cytogenetics, bone marrow blasts ≥5%, or mutated TP53 or RAS pathway genes. Eligible patients were 18–70 years old and had a matched or haploidentical related donor, or a 7/8 or 8/8 HLA-matched unrelated donor. The conditioning regimen included outpatient Bu 100 mg/m² on days -20 and -13, fludarabine 10 mg/m², cladribine 10 mg/m², and Bu pharmacokinetically dosed to reach a total systemic exposure of 20,000 ±12% µmol/min on days -6 to -3. Venetoclax 400 mg was given daily from days -22 to -3. GVHD prophylaxis was PTCy 50 mg/kg on days 3 and 4, tacrolimus ± MMF. The primary endpoint was progression-free survival (PFS). A sample size of 50 provided >80% power to detect an increase in 1-year PFS from 30% (historical) to 47%, with a 5% Type I error rate (ClinicalTrials.gov: NCT04708054).</div></div><div><h3>Results</h3><div>Fifty patients (23 female, 27 male) with a median age of 63 years (range: 33–69) were enrolled from December 2021 to August 2023. Disease characteristics included IPSS-R high/very high (58%), IPSS-M moderate high/high/very high (72%). TP53 mutations were present in 28% of patients. Donors were matched unrelated (50%), matched sibling (34%), haploidentical (4%), and mismatched unrelated (12%). Median HCT-CI score was 2 (range: 0–8); 38% had a Karnofsky performance score ≤80%.</div><div>At a median follow up of 24 months, median PFS was not reached (95% CI: 11 months–NR). One-year and 3-year PFS were 62% (50–77) and 60% (48–75), respectively. Three-year overall survival (OS), NRM, and relapse rates were 60% (48-75), 30% (17-43), and 10% (2-18), respectively. Outcomes in TP53 wildtype patients vs mutated patients at 3 years were: OS of 64% vs 50% (P=0.51), PFS of 64% vs 50% (P=0.34), and relapse rate of 6% vs 21% (P=0.031).</div><div>Median time to neutrophil and platelet engraftment were 16 (range: 13–32) and 23 days (range: 10–221), respectively. At day 30, median T cell and myeloid donor chimerism were 100%. Grade 2–4 acute GVHD occurred in 36% (23–50), grade 3–4 in 10% (2–18), chronic GVHD in 56% (42–70), and moderate-to-severe chronic GVHD in 36% (23–50).</div></div><div><h3>Conclusion</h3><div>This study met its primary endpoint, demonstrating promising 3-year PFS in patients with high-risk MDS. These findings support further investigation of th","PeriodicalId":23283,"journal":{"name":"Transplantation and Cellular Therapy","volume":"32 2","pages":"Page S57"},"PeriodicalIF":4.4,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146098838","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}
Pub Date : 2026-02-01DOI: 10.1016/j.jtct.2025.12.025
Zachariah DeFilipp MD , Carrie L. Kitko MD , Iskra Pusic MD, MSCI , Trent P. Wang DO , Britnie Thomas PhD , Zhenyi Xue PhD , John Galvin MD, MS, MPH , Amandeep Salhotra MD
<div><h3>Introduction</h3><div>Lung manifestations of chronic graft-versus-host-disease (cGVHD), particularly bronchiolitis obliterans syndrome (BOS), are associated with high morbidity/mortality and poor responses to conventional treatment. Axatilimab treatment demonstrated clinical benefit in patients with pulmonary cGVHD in a phase 1/2 study (NCT03604692) and in the pivotal AGAVE-201 study (NCT04710576).</div></div><div><h3>Objectives</h3><div>To describe clinical outcomes of axatilimab treatment in patients with cGVHD-BOS in 2 clinical studies.</div></div><div><h3>Methods</h3><div>In the phase 2 dose expansion study, intravenous (IV) axatilimab 1 mg/kg every 2 weeks (Q2W) was assessed. In the pivotal AGAVE-201 study, patients were randomized to IV axatilimab 0.3 mg/kg Q2W, 1 mg/kg Q2W, or 3 mg/kg every 4 weeks (Q4W). Responses were assessed by 2014 National Institutes of Health (NIH) cGVHD consensus criteria, which included forced expiratory volume in 1 second (FEV<sub>1</sub>) and lung symptom score. This analysis evaluated lung-specific clinical responses by baseline FEV<sub>1</sub> and lung symptom score, as well as improvement in modified Lee Symptom Scale shortness of breath (SOB) scores among patients with cGVHD-BOS (obstructive lung defect with FEV<sub>1</sub> <75% predicted, FEV<sub>1</sub>:vital capacity ratio <0.07, evidence of air trapping, and absence of infection). Logistic regression analysis was performed to investigate factors associated with NIH lung response.</div></div><div><h3>Results</h3><div>Of 117 patients with cGVHD-BOS at baseline, 84.6% had prior treatment with belumosudil, ibrutinib, and/or ruxolitinib, and the median (range) number of organs involved at baseline was 4 (1–9; <strong>Table 1</strong>). The NIH lung response rate on study was 38.5% (<strong>Table 2</strong>); the median (range) time to first response was 2.6 (1.0–14.8) months. Responses were 37.1% and 40.5% for patients with baseline FEV<sub>1</sub> >39% and ≤39%, respectively, and were 37.0% and 40.2% for patients with baseline NIH lung scores of 3 and <3, respectively. A ≥2-point improvement in SOB at rest or with exercise was observed regardless of NIH response (<strong>Table 2</strong>). Based on univariate analysis, there was no significant association between baseline clinical features (eg, lung score, FEV<sub>1</sub>, best response to last therapy) and lung response. The most common infections among patients with cGVHD-BOS were pneumonia (n=24; 20.5%), upper respiratory tract infection (n=22; 18.8%), and COVID-19 (n=19; 16.2%), which were grade ≥3 in 17 (14.5%), 2 (1.7%), and 7 (6.0%) patients, respectively.</div></div><div><h3>Conclusion</h3><div>Axatilimab demonstrated clinical and symptom responses in patients with cGVHD-BOS across a spectrum of lung involvement, including those with FEV<sub>1</sub> ≤39% and NIH lung scores of 3. Symptom responses were observed in some patients who were NIH nonresponders. There were no statistica
{"title":"A Comprehensive Analysis of Axatilimab in Patients with Chronic Graft-Versus-Host Disease and Related Bronchiolitis Obliterans Syndrome: Integrated Analysis from 2 Clinical Studies","authors":"Zachariah DeFilipp MD , Carrie L. Kitko MD , Iskra Pusic MD, MSCI , Trent P. Wang DO , Britnie Thomas PhD , Zhenyi Xue PhD , John Galvin MD, MS, MPH , Amandeep Salhotra MD","doi":"10.1016/j.jtct.2025.12.025","DOIUrl":"10.1016/j.jtct.2025.12.025","url":null,"abstract":"<div><h3>Introduction</h3><div>Lung manifestations of chronic graft-versus-host-disease (cGVHD), particularly bronchiolitis obliterans syndrome (BOS), are associated with high morbidity/mortality and poor responses to conventional treatment. Axatilimab treatment demonstrated clinical benefit in patients with pulmonary cGVHD in a phase 1/2 study (NCT03604692) and in the pivotal AGAVE-201 study (NCT04710576).</div></div><div><h3>Objectives</h3><div>To describe clinical outcomes of axatilimab treatment in patients with cGVHD-BOS in 2 clinical studies.</div></div><div><h3>Methods</h3><div>In the phase 2 dose expansion study, intravenous (IV) axatilimab 1 mg/kg every 2 weeks (Q2W) was assessed. In the pivotal AGAVE-201 study, patients were randomized to IV axatilimab 0.3 mg/kg Q2W, 1 mg/kg Q2W, or 3 mg/kg every 4 weeks (Q4W). Responses were assessed by 2014 National Institutes of Health (NIH) cGVHD consensus criteria, which included forced expiratory volume in 1 second (FEV<sub>1</sub>) and lung symptom score. This analysis evaluated lung-specific clinical responses by baseline FEV<sub>1</sub> and lung symptom score, as well as improvement in modified Lee Symptom Scale shortness of breath (SOB) scores among patients with cGVHD-BOS (obstructive lung defect with FEV<sub>1</sub> <75% predicted, FEV<sub>1</sub>:vital capacity ratio <0.07, evidence of air trapping, and absence of infection). Logistic regression analysis was performed to investigate factors associated with NIH lung response.</div></div><div><h3>Results</h3><div>Of 117 patients with cGVHD-BOS at baseline, 84.6% had prior treatment with belumosudil, ibrutinib, and/or ruxolitinib, and the median (range) number of organs involved at baseline was 4 (1–9; <strong>Table 1</strong>). The NIH lung response rate on study was 38.5% (<strong>Table 2</strong>); the median (range) time to first response was 2.6 (1.0–14.8) months. Responses were 37.1% and 40.5% for patients with baseline FEV<sub>1</sub> >39% and ≤39%, respectively, and were 37.0% and 40.2% for patients with baseline NIH lung scores of 3 and <3, respectively. A ≥2-point improvement in SOB at rest or with exercise was observed regardless of NIH response (<strong>Table 2</strong>). Based on univariate analysis, there was no significant association between baseline clinical features (eg, lung score, FEV<sub>1</sub>, best response to last therapy) and lung response. The most common infections among patients with cGVHD-BOS were pneumonia (n=24; 20.5%), upper respiratory tract infection (n=22; 18.8%), and COVID-19 (n=19; 16.2%), which were grade ≥3 in 17 (14.5%), 2 (1.7%), and 7 (6.0%) patients, respectively.</div></div><div><h3>Conclusion</h3><div>Axatilimab demonstrated clinical and symptom responses in patients with cGVHD-BOS across a spectrum of lung involvement, including those with FEV<sub>1</sub> ≤39% and NIH lung scores of 3. Symptom responses were observed in some patients who were NIH nonresponders. There were no statistica","PeriodicalId":23283,"journal":{"name":"Transplantation and Cellular Therapy","volume":"32 2","pages":"Pages S8-S9"},"PeriodicalIF":4.4,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146098877","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}
Pub Date : 2026-02-01DOI: 10.1016/j.jtct.2025.12.097
Saurabh Dahiya MD, FACP , Matthew L. Ulrickson MD , Jean A. Yared MD , Patrick M. Reagan MD , Timothy Voorhees MD, MSCR , Ran Reshef MD, MSc , Cameron J. Turtle MBBS, PhD , Lizamarie Bachier-Rodriguez MD , Marie José Kersten MD, PhD , Max S. Topp MD , Gary L. Simmons DO, MSHA , Robin Sanderson FRCPath, PhD , Loretta J. Nastoupil MD , A. Scott Jung MD , Enrique Granados MD , Jinghui Dong PhD , Joshua Winters MS , Rhine R. Shen PhD , Justyna Kanska PhD, MSc , Myrna Nahas MD , Sairah Ahmed MD
Introduction
KITE-363 and KITE-753 are bicistronic, autologous CAR T-cell therapies designed to prevent antigen escape and relapse through dual targeting CD19 and CD20. KITE-753 preserves more juvenile T cells in the product than KITE-363 through using a shortened manufacturing process.
Objective
To report the safety and efficacy results from an open-label, multicenter, Phase 1 study of KITE-753 or KITE-363 in relapsed/refractory (R/R) B-cell lymphoma.
Methods
Eligible adults with B-cell lymphoma R/R after ≥2 lines of therapy (second-line primary refractory large B-cell lymphoma [LBCL] allowed) were enrolled in dose escalation (1A) and expansion (1B; LBCL only) cohorts. Patients received KITE-753 or KITE-363 at 1 of 3 dose levels (DLs). Primary endpoints were incidence of dose-limiting toxicities (DLTs; Phase 1A) and investigator-assessed objective response rate (ORR; Phase 1B).
Results
As of 03/18/25, 59 patients were enrolled; 14 received KITE-753 (11 in DL1/2, 3 in DL3) and 37 received KITE-363 (Table).
No DLTs occurred with KITE-753. Grade ≥3 adverse events (AEs) occurred in 79% of patients (100% in DL3), primarily cytopenias, and serious AEs in 36% (DL3, 0%). One patient had Grade 3 cytokine release syndrome (CRS; LBCL; DL2). Median onset of CRS was 9.5 days with median duration of 6.5 days. No Grade ≥3 immune effector cell–associated neurotoxicity syndrome (ICANS) occurred. Median onset of ICANS was 12.5 days with median duration of 6.5 days. Three patients died (DL2; 2 to infections unrelated to KITE-753 and 1 to progression). At 4.4-mo median follow-up (mFU), all patients in DL3 had a complete response (CR). In DL1/2, ORR was 64% and CR rate was 45%.
No DLTs occurred with KITE-363. One patient had Grade 3 CRS; 3 patients had Grade 3 ICANS; no Grade ≥4 CRS/ICANS occurred. At 11.1-mo mFU in DL3, ORR in CAR-naive patients (n=23) was 87% and CR rate was 78%; median duration of CR (DOCR) was not reached (95% CI, 5.2-not estimable) and the 6-mo DOCR rate was 71.4%. Among all treated patients, 9 died (8 to progression).
Immune reconstitution was improved with KITE-363 compared to axicabtagene ciloleucel (axi-cel; Locke et al. N Engl J Med. 2022). B-cell aplasia and recovery was comparable to axi-cel despite greater CAR T-cell expansion.
Conclusions
KITE-363 showed high response rates with encouraging durability in DL3 and a manageable safety profile. KITE-753’s process, preserving a juvenile product phenotype, and its bicistronic CAR design were associated with low incidence of CRS and ICANS, mostly Grade 1/2. The preliminary efficacy profile of KITE-753 DL3 was promising; the expansion phase with DL3 in LBCL is ongoing.
{"title":"A Phase 1 Study of KITE-753 or KITE-363 in Patients with Relapsed/Refractory B-cell Lymphoma: Initial Safety and Preliminary Efficacy of KITE-753 and Updated Results of KITE-363","authors":"Saurabh Dahiya MD, FACP , Matthew L. Ulrickson MD , Jean A. Yared MD , Patrick M. Reagan MD , Timothy Voorhees MD, MSCR , Ran Reshef MD, MSc , Cameron J. Turtle MBBS, PhD , Lizamarie Bachier-Rodriguez MD , Marie José Kersten MD, PhD , Max S. Topp MD , Gary L. Simmons DO, MSHA , Robin Sanderson FRCPath, PhD , Loretta J. Nastoupil MD , A. Scott Jung MD , Enrique Granados MD , Jinghui Dong PhD , Joshua Winters MS , Rhine R. Shen PhD , Justyna Kanska PhD, MSc , Myrna Nahas MD , Sairah Ahmed MD","doi":"10.1016/j.jtct.2025.12.097","DOIUrl":"10.1016/j.jtct.2025.12.097","url":null,"abstract":"<div><h3>Introduction</h3><div>KITE-363 and KITE-753 are bicistronic, autologous CAR T-cell therapies designed to prevent antigen escape and relapse through dual targeting CD19 and CD20. KITE-753 preserves more juvenile T cells in the product than KITE-363 through using a shortened manufacturing process.</div></div><div><h3>Objective</h3><div>To report the safety and efficacy results from an open-label, multicenter, Phase 1 study of KITE-753 or KITE-363 in relapsed/refractory (R/R) B-cell lymphoma.</div></div><div><h3>Methods</h3><div>Eligible adults with B-cell lymphoma R/R after ≥2 lines of therapy (second-line primary refractory large B-cell lymphoma [LBCL] allowed) were enrolled in dose escalation (1A) and expansion (1B; LBCL only) cohorts. Patients received KITE-753 or KITE-363 at 1 of 3 dose levels (DLs). Primary endpoints were incidence of dose-limiting toxicities (DLTs; Phase 1A) and investigator-assessed objective response rate (ORR; Phase 1B).</div></div><div><h3>Results</h3><div>As of 03/18/25, 59 patients were enrolled; 14 received KITE-753 (11 in DL1/2, 3 in DL3) and 37 received KITE-363 (Table).</div><div>No DLTs occurred with KITE-753. Grade ≥3 adverse events (AEs) occurred in 79% of patients (100% in DL3), primarily cytopenias, and serious AEs in 36% (DL3, 0%). One patient had Grade 3 cytokine release syndrome (CRS; LBCL; DL2). Median onset of CRS was 9.5 days with median duration of 6.5 days. No Grade ≥3 immune effector cell–associated neurotoxicity syndrome (ICANS) occurred. Median onset of ICANS was 12.5 days with median duration of 6.5 days. Three patients died (DL2; 2 to infections unrelated to KITE-753 and 1 to progression). At 4.4-mo median follow-up (mFU), all patients in DL3 had a complete response (CR). In DL1/2, ORR was 64% and CR rate was 45%.</div><div>No DLTs occurred with KITE-363. One patient had Grade 3 CRS; 3 patients had Grade 3 ICANS; no Grade ≥4 CRS/ICANS occurred. At 11.1-mo mFU in DL3, ORR in CAR-naive patients (n=23) was 87% and CR rate was 78%; median duration of CR (DOCR) was not reached (95% CI, 5.2-not estimable) and the 6-mo DOCR rate was 71.4%. Among all treated patients, 9 died (8 to progression).</div><div>Immune reconstitution was improved with KITE-363 compared to axicabtagene ciloleucel (axi-cel; Locke et al. N Engl J Med. 2022). B-cell aplasia and recovery was comparable to axi-cel despite greater CAR T-cell expansion.</div></div><div><h3>Conclusions</h3><div>KITE-363 showed high response rates with encouraging durability in DL3 and a manageable safety profile. KITE-753’s process, preserving a juvenile product phenotype, and its bicistronic CAR design were associated with low incidence of CRS and ICANS, mostly Grade 1/2. The preliminary efficacy profile of KITE-753 DL3 was promising; the expansion phase with DL3 in LBCL is ongoing.</div></div>","PeriodicalId":23283,"journal":{"name":"Transplantation and Cellular Therapy","volume":"32 2","pages":"Pages S64-S65"},"PeriodicalIF":4.4,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146098887","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}
<div><h3>Introduction</h3><div>Ciltacabtagene autoleucel (cilta-cel) has shown high efficacy in relapsed MM, but further efforts are needed to mitigate non-ICANS delayed neurotoxicity (DNT) and non-relapse mortality (NRM). Identifying risk factors for DNT and NRM may aid risk mitigation and clinical decision making.</div></div><div><h3>Methods</h3><div>In this multi-center retrospective study from the US MM Immunotherapy Consortium, we evaluated 761 patients treated at 15 centers receiving standard of care cilta-cel for relapsed MM between May 2022 to December 2024. Risk factors for DNT, particularly Parkinsonism and NRM, were evaluated by univariable and multivariable analysis. NRM events post-disease progression were censored.</div></div><div><h3>Results</h3><div>The median age was 65 (range: 30-88) with median prior lines of therapy (pLoT) being 5 (range: 1-23). Cilta-cel was used in earlier relapse (1-3 pLoT) in 16% of patients. High-risk cytogenetics (del 17p, t(14;16), t(4;14)) were present in 39%, with extramedullary disease (EMD) in 27%, and R-ISS stage III in 18%. 86% patients received bridging therapy, with ≥ partial response seen in 33%; median follow-up was 10.1 months, response rate was 92%, and CR rate was 70%.</div><div>DNT was seen in 10% of patients: Parkinsonism (2.9%, n=22), cranial nerve palsy (4.6%, n=35), other DNT (2.4%). Risk of DNT was higher in patients who did not respond to bridging therapy (Any DNT: 12% vs 6%; Parkinsonism: 5% vs 0.5%, p<0.05). Of 22 Parkinsonism cases, 21 (95%) did not respond to bridging despite achieving post-CAR-T response (ORR 91%, ≥ CR 68%).</div><div>Absolute lymphocyte count (ALC) was higher in patients with DNT, especially Parkinsonism (p<0.05 for all). Median peak ALC for patients with vs without Parkinsonism: 5.88 vs 1.17/uL (p<0.001). Evaluating Parkinsonism risk with ALC thresholds: peak ALC > 1000/uL: 100% vs 57%, > 2500/uL: 73% vs 19%, > 3000/uL: 68% vs 14% (p<0.001). Absolute Parkinsonism risk with ALC > 3000 vs ≤ 3000/uL: 12% vs 1%, p<0.001; ALC > 2500 vs ≤ 2500uL: 9% vs 1%, p<0.001. Multivariable analysis identified peak ALC > 3000/uL (OR: 12.7, p<0.001) and non-response to bridging therapy (OR: 9.9, p=0.03) as independent risk factors for Parkinsonism.</div><div>NRM estimates at 1 and 2 year were 9% and 10% respectively, with infection complications being the most common cause (56%), followed by immune-mediated acute AEs (22%), delayed AEs like DNT and colitis (9.5%), second cancers (8%), and other causes (5%). Multivariable analysis identified non-response to bridging (HR 2.41, p=0.046), poor performance status ≥ 2, high-risk cytogenetics, and age ≥ 70 years as independent NRM predictors.</div></div><div><h3>Conclusion</h3><div>In a large cohort, we identified potentially modifiable predictors for Parkinsonism and NRM, including non-response to bridging therapy and peak ALC > 3000/uL for Parkinsonism. Peak ALC could be a biomarker to identi
cilta-cel已显示出对复发性MM的高疗效，但需要进一步努力减轻非icans延迟性神经毒性（DNT）和非复发性死亡率（NRM）。确定DNT和NRM的风险因素可能有助于降低风险和临床决策。方法在这项来自美国MM免疫治疗联盟的多中心回顾性研究中，我们评估了在2022年5月至2024年12月期间在15个中心接受cilta-cel标准治疗的复发性MM的761例患者。通过单变量和多变量分析评估DNT的危险因素，特别是帕金森病和NRM。NRM事件在疾病进展后被删除。结果中位年龄为65岁（范围：30-88岁），中位既往治疗线（pLoT）为5条（范围：1-23条）。在16%的患者中，Cilta-cel用于早期复发（1-3 pLoT）。高危细胞遗传学(del 17p, t（14;16), t(4;14)）占39%，髓外疾病（EMD）占27%，R-ISS III期占18%。86%的患者接受了桥接治疗，33%的患者出现≥部分缓解；中位随访10.1个月，有效率92%，CR率70%。10%的患者出现DNT：帕金森病（2.9%,n=22），脑神经麻痹（4.6%,n=35），其他DNT（2.4%）。对桥接治疗无反应的患者发生DNT的风险更高（任何DNT: 12% vs 6%；帕金森：5% vs 0.5%, p < 0.05）。在22例帕金森患者中，21例（95%）尽管达到car - t后反应，但桥接没有反应（ORR 91%,≥CR 68%）。绝对淋巴细胞计数（ALC）在DNT患者中较高，尤其是帕金森患者（p < 0.05）。帕金森病患者与非帕金森病患者ALC的中位峰值：5.88 vs 1.17/uL （p<0.001）。用ALC阈值评估帕金森病风险：ALC峰值>； 1000/uL: 100% vs 57%, > 2500/uL: 73% vs 19%, > 3000/uL: 68% vs 14% （p<0.001）。ALC = 3000 vs≤3000/uL的绝对帕金森病风险：12% vs 1%， p<0.001；ALC 2500 vs≤2500uL: 9% vs 1%, p<0.001。多变量分析确定ALC峰值3000/uL （OR: 12.7, p<0.001）和对桥接治疗无反应（OR: 9.9, p=0.03）是帕金森病的独立危险因素。1年和2年的NRM估计分别为9%和10%，感染并发症是最常见的原因（56%），其次是免疫介导的急性ae(22%)，延迟ae如DNT和结肠炎（9.5%），第二次癌症（8%）和其他原因（5%）。多变量分析发现，桥接无反应（HR 2.41, p=0.046）、不良状态≥2、高危细胞遗传学和年龄≥70岁是独立的NRM预测因子。结论：在一个大型队列中，我们确定了帕金森病和NRM的潜在可修改的预测因素，包括对桥接治疗无反应和帕金森病的ALC峰值3000/uL。ALC峰值可作为识别患者进行干预的生物标志物。需要有效的桥接策略来降低cilta- cell的帕金森病和NRM风险。
{"title":"Enhancing the Safety of Ciltacabtagene Autoleucel in Relapsed Multiple Myeloma (MM):Identification of Potentially Modifiable Risk-Factors Associated with Delayed Neurotoxicity and Non-Relapse Mortality","authors":"Surbhi Sidana MD , Brett Reid PhD , Danai Dima MD , Lauren C Peres PhD, MPH , Mahmoud Gaballa MD , Rahul Banerjee MD , Oren Pasvolsky MD , Aimaz Afrough MD , Christen Dillard MD , Christpoher Ferreri MD , Shebli Atrash MD , Cindy Varga M.D. , Andrew J. Portuguese MD , Masooma Shifa Rana MD , Hitomi Hosoya MD, PhD , Lekha Mikkilineni MD , Vanna Hovanky MS , Saurabh S. Zanwar MBBS , Nilesh Kalariya PhD, RN, AGPCNP-BC , Damian Mikulski MD , Doris K. Hansen MD","doi":"10.1016/j.jtct.2025.12.026","DOIUrl":"10.1016/j.jtct.2025.12.026","url":null,"abstract":"<div><h3>Introduction</h3><div>Ciltacabtagene autoleucel (cilta-cel) has shown high efficacy in relapsed MM, but further efforts are needed to mitigate non-ICANS delayed neurotoxicity (DNT) and non-relapse mortality (NRM). Identifying risk factors for DNT and NRM may aid risk mitigation and clinical decision making.</div></div><div><h3>Methods</h3><div>In this multi-center retrospective study from the US MM Immunotherapy Consortium, we evaluated 761 patients treated at 15 centers receiving standard of care cilta-cel for relapsed MM between May 2022 to December 2024. Risk factors for DNT, particularly Parkinsonism and NRM, were evaluated by univariable and multivariable analysis. NRM events post-disease progression were censored.</div></div><div><h3>Results</h3><div>The median age was 65 (range: 30-88) with median prior lines of therapy (pLoT) being 5 (range: 1-23). Cilta-cel was used in earlier relapse (1-3 pLoT) in 16% of patients. High-risk cytogenetics (del 17p, t(14;16), t(4;14)) were present in 39%, with extramedullary disease (EMD) in 27%, and R-ISS stage III in 18%. 86% patients received bridging therapy, with ≥ partial response seen in 33%; median follow-up was 10.1 months, response rate was 92%, and CR rate was 70%.</div><div>DNT was seen in 10% of patients: Parkinsonism (2.9%, n=22), cranial nerve palsy (4.6%, n=35), other DNT (2.4%). Risk of DNT was higher in patients who did not respond to bridging therapy (Any DNT: 12% vs 6%; Parkinsonism: 5% vs 0.5%, p<0.05). Of 22 Parkinsonism cases, 21 (95%) did not respond to bridging despite achieving post-CAR-T response (ORR 91%, ≥ CR 68%).</div><div>Absolute lymphocyte count (ALC) was higher in patients with DNT, especially Parkinsonism (p<0.05 for all). Median peak ALC for patients with vs without Parkinsonism: 5.88 vs 1.17/uL (p<0.001). Evaluating Parkinsonism risk with ALC thresholds: peak ALC > 1000/uL: 100% vs 57%, > 2500/uL: 73% vs 19%, > 3000/uL: 68% vs 14% (p<0.001). Absolute Parkinsonism risk with ALC > 3000 vs ≤ 3000/uL: 12% vs 1%, p<0.001; ALC > 2500 vs ≤ 2500uL: 9% vs 1%, p<0.001. Multivariable analysis identified peak ALC > 3000/uL (OR: 12.7, p<0.001) and non-response to bridging therapy (OR: 9.9, p=0.03) as independent risk factors for Parkinsonism.</div><div>NRM estimates at 1 and 2 year were 9% and 10% respectively, with infection complications being the most common cause (56%), followed by immune-mediated acute AEs (22%), delayed AEs like DNT and colitis (9.5%), second cancers (8%), and other causes (5%). Multivariable analysis identified non-response to bridging (HR 2.41, p=0.046), poor performance status ≥ 2, high-risk cytogenetics, and age ≥ 70 years as independent NRM predictors.</div></div><div><h3>Conclusion</h3><div>In a large cohort, we identified potentially modifiable predictors for Parkinsonism and NRM, including non-response to bridging therapy and peak ALC > 3000/uL for Parkinsonism. Peak ALC could be a biomarker to identi","PeriodicalId":23283,"journal":{"name":"Transplantation and Cellular Therapy","volume":"32 2","pages":"Pages S11-S12"},"PeriodicalIF":4.4,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146098878","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}
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains a cornerstone curative strategy for patients with high-risk hematological malignancies. However, its therapeutic efficacy is often compromised by graft-versus-host disease (GVHD), a potentially life-threatening complication driven by the dysregulated immune response of donor-derived cells against host tissues. The current first-line management of GVHD primarily relies on glucocorticoids and broad-spectrum immunosuppressants; nevertheless, 30% to 50% of patients develop steroid-refractory GVHD or suffer from serious treatment-related toxicities, underscoring the urgent need for more precise and effective therapeutic approaches. In recent years, the complement system-traditionally regarded as a key component of innate immunity-has emerged as a critical modulator of adaptive immune responses in GVHD pathogenesis. Increasing evidence implicates the complement cascade, particularly the C3a/C5a-C3aR/C5aR signaling axis, in promoting Th1/Th17 polarization and effector T cell infiltration, while concurrently impairing regulatory T cell (Treg) function, thereby exacerbating immune dysregulation and tissue injury. This review provides a comprehensive overview of the complement system’s role in GVHD, focusing on 2 key aspects: (1) the molecular mechanisms through which complement components influence T and B cell activation and contribute to target organ damage; and (2) recent preclinical advances in complement-targeted therapeutic strategies. By integrating current findings, we aim to establish a theoretical framework for the development of safer and more effective complement-directed therapies, and to explore their potential in achieving personalized GVHD management.
{"title":"Bridging Innate and Adaptive Immunity: Understanding and Targeting the Complement System in GVHD Pathogenesis and Therapy","authors":"Xianhui Wu , Jiejing Qian , Hongyan Tong , Xianbo Huang","doi":"10.1016/j.jtct.2025.10.014","DOIUrl":"10.1016/j.jtct.2025.10.014","url":null,"abstract":"<div><div>Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains a cornerstone curative strategy for patients with high-risk hematological malignancies. However, its therapeutic efficacy is often compromised by graft-versus-host disease (GVHD), a potentially life-threatening complication driven by the dysregulated immune response of donor-derived cells against host tissues. The current first-line management of GVHD primarily relies on glucocorticoids and broad-spectrum immunosuppressants; nevertheless, 30% to 50% of patients develop steroid-refractory GVHD or suffer from serious treatment-related toxicities, underscoring the urgent need for more precise and effective therapeutic approaches. In recent years, the complement system-traditionally regarded as a key component of innate immunity-has emerged as a critical modulator of adaptive immune responses in GVHD pathogenesis. Increasing evidence implicates the complement cascade, particularly the C3a/C5a-C3aR/C5aR signaling axis, in promoting Th1/Th17 polarization and effector T cell infiltration, while concurrently impairing regulatory T cell (Treg) function, thereby exacerbating immune dysregulation and tissue injury. This review provides a comprehensive overview of the complement system’s role in GVHD, focusing on 2 key aspects: (1) the molecular mechanisms through which complement components influence T and B cell activation and contribute to target organ damage; and (2) recent preclinical advances in complement-targeted therapeutic strategies. By integrating current findings, we aim to establish a theoretical framework for the development of safer and more effective complement-directed therapies, and to explore their potential in achieving personalized GVHD management.</div></div>","PeriodicalId":23283,"journal":{"name":"Transplantation and Cellular Therapy","volume":"32 2","pages":"Pages 141-155"},"PeriodicalIF":4.4,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145432142","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}
Pub Date : 2026-02-01DOI: 10.1016/j.jtct.2025.12.956
Masumi Ueda Oshima MD , Isaac C Jenkins MS , Timothy W Randolph PhD , Jerald P. Radich MD , Karol Bomsztyk MD , Rainer Storb MD
<div><h3>Introduction</h3><div>In hematopoietic cell transplantation (HCT), donor hematopoietic cells (HC) must engraft and maintain hematopoiesis for a recipient's lifetime. Epigenetic regulation, in particular DNA methylation, plays a critical role in HC self-renewal. Prior comparison of donor-recipient pairs after HCT show epigenetic age acceleration in recipients a few years post-HCT using Horvath's ‘epigenetic clock’ based on 353 CpG sites.</div></div><div><h3>Objective</h3><div>Here we investigated genome-wide DNA methylation to characterize differential patterns in very long-term surviving donor-recipient pairs post-HCT, using an agnostic approach that, to our knowledge that has not previously been reported.</div></div><div><h3>Methods</h3><div>We analyzed blood sampled from 12 pairs of recipients and related donors at a median of 36 years post-HCT (Table 1). Genomic DNA was isolated from blood mononuclear cells and processed using high-throughput multi-omics PIXUL–Methylated DNA immunoprecipitation sequencing platform. Using R, DiffBind, and edgeR software, we performed differential binding analysis of genome-wide DNA methylation data comparing donors and recipients. Sites with false discovery rate (FDR) <0.5 were analyzed using linear regression to examine associations between DNA methylation differences (recipient minus donor normalized peak scores) and donor/recipient age at HCT, time since HCT, and hematopoietic age (donor age at HCT + time since HCT).</div></div><div><h3>Results</h3><div>We detected 181311 shared donor-recipient CpG binding regions, representing 84% and 80% of total CpG binding regions in donors (n=214650) and recipients (n=227378). Of the 37 sites with FDR < 0.5, differential methylation density by normalized score was observed in donors vs. recipients (Fig. 1), with 28 (76%) sites showing higher methylation in recipients. The top 10 differentially methylated regions included 7 genes (Table 2) including KLF14, a known epigenetic marker of aging. Time since HCT and hematopoietic age were positively associated with greater recipient-donor DNA methylation differences at 18 (49%) and 21 (57%) sites, respectively.</div></div><div><h3>Conclusions</h3><div>Epigenetics analysis of blood cells from donors and recipients >3 decades post-HCT show high concordance of methylated sites, and most sites show higher methylation in recipients. Time since HCT and hematopoietic age were associated with higher methylation in recipients compared to donors in about half of binding sites. Hypermethylation of sites associated with gene regulation and transcription were predominant in recipients, whereas none of the genes hypermethylated in donors were transcription factors. In addition to expanding the cohort, future studies will decipher how progressive epigenetic remodeling of long-term engrafted HCs shapes the transcriptome, proteome, and metabolome, thereby elucidating the functional consequences of these enduring epigenetic ch
{"title":"Genome-Wide Epigenetic Comparisons in Long-Term Donor-Recipient Pairs Decades after Allogeneic Hematopoietic Cell Transplantation","authors":"Masumi Ueda Oshima MD , Isaac C Jenkins MS , Timothy W Randolph PhD , Jerald P. Radich MD , Karol Bomsztyk MD , Rainer Storb MD","doi":"10.1016/j.jtct.2025.12.956","DOIUrl":"10.1016/j.jtct.2025.12.956","url":null,"abstract":"<div><h3>Introduction</h3><div>In hematopoietic cell transplantation (HCT), donor hematopoietic cells (HC) must engraft and maintain hematopoiesis for a recipient's lifetime. Epigenetic regulation, in particular DNA methylation, plays a critical role in HC self-renewal. Prior comparison of donor-recipient pairs after HCT show epigenetic age acceleration in recipients a few years post-HCT using Horvath's ‘epigenetic clock’ based on 353 CpG sites.</div></div><div><h3>Objective</h3><div>Here we investigated genome-wide DNA methylation to characterize differential patterns in very long-term surviving donor-recipient pairs post-HCT, using an agnostic approach that, to our knowledge that has not previously been reported.</div></div><div><h3>Methods</h3><div>We analyzed blood sampled from 12 pairs of recipients and related donors at a median of 36 years post-HCT (Table 1). Genomic DNA was isolated from blood mononuclear cells and processed using high-throughput multi-omics PIXUL–Methylated DNA immunoprecipitation sequencing platform. Using R, DiffBind, and edgeR software, we performed differential binding analysis of genome-wide DNA methylation data comparing donors and recipients. Sites with false discovery rate (FDR) <0.5 were analyzed using linear regression to examine associations between DNA methylation differences (recipient minus donor normalized peak scores) and donor/recipient age at HCT, time since HCT, and hematopoietic age (donor age at HCT + time since HCT).</div></div><div><h3>Results</h3><div>We detected 181311 shared donor-recipient CpG binding regions, representing 84% and 80% of total CpG binding regions in donors (n=214650) and recipients (n=227378). Of the 37 sites with FDR < 0.5, differential methylation density by normalized score was observed in donors vs. recipients (Fig. 1), with 28 (76%) sites showing higher methylation in recipients. The top 10 differentially methylated regions included 7 genes (Table 2) including KLF14, a known epigenetic marker of aging. Time since HCT and hematopoietic age were positively associated with greater recipient-donor DNA methylation differences at 18 (49%) and 21 (57%) sites, respectively.</div></div><div><h3>Conclusions</h3><div>Epigenetics analysis of blood cells from donors and recipients >3 decades post-HCT show high concordance of methylated sites, and most sites show higher methylation in recipients. Time since HCT and hematopoietic age were associated with higher methylation in recipients compared to donors in about half of binding sites. Hypermethylation of sites associated with gene regulation and transcription were predominant in recipients, whereas none of the genes hypermethylated in donors were transcription factors. In addition to expanding the cohort, future studies will decipher how progressive epigenetic remodeling of long-term engrafted HCs shapes the transcriptome, proteome, and metabolome, thereby elucidating the functional consequences of these enduring epigenetic ch","PeriodicalId":23283,"journal":{"name":"Transplantation and Cellular Therapy","volume":"32 2","pages":"Pages S76-S77"},"PeriodicalIF":4.4,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146098508","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}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：