Transplantation and Cellular Therapy最新文献

{"title":"EBV-Associated T/NK-LPD Manifesting As HLH Cured By Nivolumab and Emapalumab, Avoiding the Need for Allogeneic HCT","authors":"Eleanor Cook MBBS ,&nbsp;Lindsay Haacker ,&nbsp;Sharat Chandra MD ,&nbsp;Michael B. Jordan MD ,&nbsp;Bethany Verkamp MD ,&nbsp;Laura McCarthy ,&nbsp;Seth J Rotz MD ,&nbsp;Miza Salim Hammoud ,&nbsp;Holly Pariury ,&nbsp;Daniel McKeone ,&nbsp;Ashish Kumar MD, PhD","doi":"10.1016/j.jtct.2025.01.070","DOIUrl":"10.1016/j.jtct.2025.01.070","url":null,"abstract":"<div><h3>Introduction</h3><div>EBV-associated NK- and T-cell lymphoproliferative disorders (LPDs) manifest variably as EBV-HLH, T-cell lymphoma, or chronic-active EBV. HLH-directed therapy and cytoreductive chemotherapy lead to short-lived remissions, and inevitably lead to recurrences. Allogeneic HCT is usually the only curative therapy. Notably, people of East Asian, and Central/South American ethnicity are most affected, and finding a suitable donor is often a challenge. Nivolumab, the anti-PD-1checkpoint inhibitor increases effector T-cell activity and has shown promise in treating many cancers. Emapalumab, the anti-interferon-gamma antibody controls HLH without affecting T-cell viability.</div></div><div><h3>Methods</h3><div>We report eight patients with EBV T/NK-LPDs treated with nivolumab, often with emapalumab. The diagnosis of EBV-LPD was ascertained by high viremia and quantitative EBV PCR on sorted lymphocytes.</div></div><div><h3>Results</h3><div>Five female and three male patients, ages 14 months to 20 years, all presented with a hyper-inflammatory HLH-like syndrome, with transient response to HLH-directed cytotoxic therapy. Six patients had T-cell LPD while two had NK-LPD. Seven patients received etoposide, with three also receiving additional rounds of multi-agent chemotherapy. No HLH-causing mutations were detected. All patients were treated with Nivolumab 3mg/kg every 3 weeks. Six patients with ongoing active HLH also received Emapalumab as steroid- and etoposide-sparing therapy. Seven patients achieved complete clinical remissions that have been sustained. Five patients are off therapy, having received a median of 6 doses of nivolumab (range 2 to 9). All remain well with a median follow-up of 14 months since completion of therapy. Two recently diagnosed patients continue to receive treatment with clinical remissions and declining EBV viremia. One patient who had experienced severe chemotherapy toxicity had a response but developed myocarditis after nivolumab. Therapy was discontinued and he remains well after undergoing HCT.</div></div><div><h3>Conclusion</h3><div>Nivolumab, combined with emapalumab led to sustained remission of EBV T/NK-LPDs in this cohort, largely avoiding the need for HCT.</div></div>","PeriodicalId":23283,"journal":{"name":"Transplantation and Cellular Therapy","volume":"31 2","pages":"Page S43"},"PeriodicalIF":3.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143487754","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":"Leukocyte Telomere Shortening in Recipients after Hematopoietic Cell Transplant and Its Association with Factors That Affect Recipient Outcomes: An Analysis of BMT CTN Protocol 1202","authors":"Kyra J.W. Mendez PhD, MPH, RN ,&nbsp;Hormuzd A. Katki PhD ,&nbsp;Caitrin Bupp MPH ,&nbsp;Stephen R. Spellman MBS ,&nbsp;Dr. Valerie Stewart MS, PhD ,&nbsp;Sharon A. Savage MD ,&nbsp;John E. Levine MD ,&nbsp;Wael Saber ,&nbsp;Abraham Aviv MD ,&nbsp;Shahinaz M. Gadalla MD, PhD","doi":"10.1016/j.jtct.2025.01.072","DOIUrl":"10.1016/j.jtct.2025.01.072","url":null,"abstract":"<div><h3>Introduction</h3><div>Leukocyte telomere length (LTL) significantly shortens after hematopoietic cell transplant (HCT) because of hematopoietic cell proliferation to achieve engraftment and immune reconstitution. The magnitude of LTL shortening is associated with patient outcomes after HCT. Limited LTL shortening is associated with increased relapse risk, and excess LTL shortening is associated with higher risk of non-relapse mortality.</div></div><div><h3>Objective</h3><div>This study aimed to identify factors associated with LTL shortening in the first three-months after HCT.</div></div><div><h3>Methods</h3><div>We studied 916 HCT recipients from the Blood &amp; Marrow Transplant Clinical Trial Network 1202 Protocol who had donor blood samples available in the CIBMTR Biorepository. Southern blotting was used to measure LTL in donor pre-HCT and recipient post-HCT samples (average of 90 days). LTL shortening was calculated as donor mean LTL – recipient mean LTL. We examined LTL as a continuous outcome and in categories (limited LTL shortening: &lt;25^th percentile vs ≥25^th percentile; excess LTL shortening: &gt;75^th percentile vs ≤75^th percentile). We explored bivariate associations between LTL and donor, recipient, and clinical and transplant characteristics and included variables with P&lt;0.1 in final multivariable linear and logistic regression models.</div></div><div><h3>Results</h3><div>Multiple linear regression models found an association between less LTL shortening and older donor age (P&lt;0.001) and peripheral blood (PB) vs bone marrow (BM) graft (P=0.001). In logistic regression models, older donor age (P&lt;0.001); PB vs BM graft (P=0.003); female vs male donors (P=0.019); and lymphoid vs myeloid disease (P=0.039) were significantly associated with a higher likelihood of limited LTL shortening. Older recipient age (P=0.001); receiving Busulfan-Cyclophosphamide (Bu/Cy; P=0.046) and total body irradiation (TBI; P&lt;0.001) conditioning regimens vs Busulfan-Fludarabine (Bu/Flu); and receiving antithymocyte globulin (ATG) or Campath (P=0.01) vs not receiving ATG or Campath were associated with a lower likelihood of limited LTL shortening (Figure 1).</div><div>More LTL shortening was associated with older recipient age (P= 0.01) and conditioning regimens with Bu/Cy (P=0.02) and TBI (P&lt;0.001) vs Bu/Flu regimens. Having African American (AA) vs non-Hispanic white (NHW) donors (P=0.045); receiving T-cell depletion vs calcineurin-inhibitor/methotrexate (MTX)-based GVHD prophylaxis regimens (P=0.028); and TBI-based vs Bu/Flu conditioning regimens (P&lt;0.001) were associated with higher likelihood of excess LTL shortening (Figure 2).</div></div><div><h3>Conclusion</h3><div>This study identifies several factors associated with post-HCT telomere length shortening, which may affect recipient outcomes.</div></div>","PeriodicalId":23283,"journal":{"name":"Transplantation and Cellular Therapy","volume":"31 2","pages":"Page S44"},"PeriodicalIF":3.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143487755","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":"Jak Inhibitor Itacitinib with Ptcy and Tacrolimus to Prevent Gvhd in a Myeloablative Fractionated Busulfan Regimen: A Phase 2 Trial","authors":"Uday R. Popat MD ,&nbsp;Amin M. Alousi MD ,&nbsp;Roland L. Bassett MS ,&nbsp;Gheath Alatrash DO, PhD ,&nbsp;Yosra M. Aljawai MD ,&nbsp;Qaiser Bashir MD ,&nbsp;George L. Chen MD ,&nbsp;Warren B. Fingrut MD ,&nbsp;Chitra M. Hosing MD ,&nbsp;Jin S. Im MD, PhD ,&nbsp;Partow Kebriaei MD ,&nbsp;Issa F. Khouri MD ,&nbsp;David Marin MD ,&nbsp;Rohtesh S. Mehta MD ,&nbsp;Yago Nieto MD, PhD ,&nbsp;Amanda L. Olson MD ,&nbsp;Dr. Betul Oran MD, MS ,&nbsp;Muzaffar H. Qazilbash MD ,&nbsp;Jeremy L. Ramdial MD ,&nbsp;Neeraj Y. Saini MD ,&nbsp;Elizabeth J. Shpall MD","doi":"10.1016/j.jtct.2025.01.052","DOIUrl":"10.1016/j.jtct.2025.01.052","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background&lt;/h3&gt;&lt;div&gt;Fractionating busulfan and giving it over a longer period, along with post-transplant cyclophosphamide (PTCy) graft versus host disease (GVHD) prophylaxis, reduces toxicity and allows for the safe administration of a myeloablative regimen in older patients. Based on the activity of ruxolitinib, a Jak inhibitor, in treating GVHD, we reasoned that a Jak inhibitor may prevent GVHD. We replaced MMF with the JAK1 inhibitor itacitinib, hypothesizing that it will further reduce GVHD and improve outcomes of this novel fractionated busulfan regimen. We tested this in an investigator-initiated phase 2 study.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Patients and Methods&lt;/h3&gt;&lt;div&gt;Patients with hematologic malignancies were eligible for this study if they were 18-70 years old and had adequate organ function. Donor was a matched or haploidentical related donor or 7/8 or 8/8 unrelated donor. Busulfan was given as follows, with a total course AUC target of 16,000 ± 12%: days -20, -13, and -6 through -3. Busulfan on days -20 and -13 was dosed 100 mg/m&lt;sup&gt;2&lt;/sup&gt;, with pharmacokinetics performed on day -20 to further guide dosing and repeated on day -6. Thiotepa 5 mg/kg was given on day -7 and fludarabine 30 mg/m&lt;sup&gt;2&lt;/sup&gt; on days -6 to -3. GVHD prophylaxis was PTCy 50 mg/kg on days +3 and +4 and tacrolimus starting on day +5. Itacitinib 200 mg daily was given from day +5 to +50 and 100 mg from days 51-60 (ClinicalTrials.gov: NCT04127721).&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;31 patients with a median age of 62 (25-69) years were enrolled: 10 (32%) patients had AML, 10 (32%) myelofibrosis, 6 (19%) MDS, 1 each CLL, lymphoma, CML, myeloma, and ALL. Donor was a matched sibling in 7 (23%), matched unrelated in 17 (55%), mismatched unrelated in 2 (5%) and haploidentical in 5 (16%). Comorbidity score was ≥3 in 42%. Peripheral blood was the graft source in 28 (90%).&lt;/div&gt;&lt;div&gt;At day 100, cumulative incidence (CI) of grade 2-4 acute GVHD was 26% (10-42%), which occurred in 8 patients; 5 of which occurred after itacitinib was tapered on day 50. The CI of grade 3-4 GVHD was 6.5% (0-15%). Moderate to severe chronic GVHD was seen in 4.5% (0-13%). There were no GVHD related deaths. Seven patients died: 2 due to cardiac failure and 1 each due to bacterial infection, COVID infection, sinusoidal obstruction syndrome, graft failure and relapsed disease. Twenty-four patients are alive and disease free. With a median follow up of 18 months, 1-year overall survival, progression-free survival, GVHD-free relapse free survival, non-relapse mortality, and relapse rate are 81%, 81%, 70%, 16%, and 3.2% respectively.&lt;/div&gt;&lt;div&gt;Median time to neutrophil engraftment was 16.5 (13-29) days and platelet engraftment was 29 (13-240) days. At day 30, T cell chimerism was 100% (61-100) donor and myeloid chimerism was 100% (100-100) donor. Common (&gt;10%) grade 3-5 toxicities were bacterial infection in 39% and febrile neutropenia in 54% of patients.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusion&lt;/h3&gt;&lt;di","PeriodicalId":23283,"journal":{"name":"Transplantation and Cellular Therapy","volume":"31 2","pages":"Page S30"},"PeriodicalIF":3.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143487952","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":"Determinants of Immune Suppression Discontinuation in the Modern Era: A CIBMTR Analysis of 18,642 Subjects","authors":"Joseph A. Pidala MD, PhD ,&nbsp;Michael J. Martens PhD ,&nbsp;Stephanie J. Lee MD, MPH ,&nbsp;Stephen R. Spellman MBS ,&nbsp;Carrie L. Kitko MD ,&nbsp;Zachariah DeFilipp MD ,&nbsp;Nosha Farhadfar MD ,&nbsp;Najla El Jurdi MD ,&nbsp;Jakob D DeVos ,&nbsp;Tao Wang PhD ,&nbsp;Brent R. Logan PhD","doi":"10.1016/j.jtct.2025.01.054","DOIUrl":"10.1016/j.jtct.2025.01.054","url":null,"abstract":"&lt;div&gt;&lt;div&gt;The desired long-term outcome of allogeneic hematopoietic cell transplantation (HCT) is malignancy control, freedom from graft vs. host disease (GVHD), and durable discontinuation of immune suppression (IS). We previously examined IS discontinuation (ISD) in patients treated on BMT CTN 0201 and 0402 trials. In our current CIBMTR analysis, we aimed to study ISD in a more contemporary (HCT 2009-2019) and broadly representative cohort: We included subjects of all ages, conditioning intensity, graft source, donor type, and GVHD prevention approaches.&lt;/div&gt;&lt;div&gt;Using a multi-state model framework (health states including initial IS, acute GVHD, chronic GVHD, ISD, resumed IS for ISD failure, and absorbing state of death/relapse/second HCT), we studied the probability of ISD, and examined which baseline features were associated with ISD. Given the very large sample size, we developed and validated (against investigator review) an algorithm for identifying health state transitions from the primary data. The probability of being alive with ISD was estimated using logistic pseudo-value regression models. Comprehensive baseline patient, disease, and HCT variables were examined for association with ISD outcome, including testing for all interactions.&lt;/div&gt;&lt;div&gt;Among included subjects (N=18,642), major characteristics were the following: median age 52.8 years, male 58.6%, White 78.4%, AML/MDS 62.5%, DRI low/int 61.8% vs. high/very high 29.3%, varied donor types (matched sibling 25.8%, 8/8 matched unrelated donor (MUD) 40.5%, mismatched MUD 8.4%, haploidentical 11.5%), graft (marrow 16.4%, PBSC 69.9%, UCB 13.8%), MAC conditioning 62.5%, GVHD prophylaxis (PTCY+others 13.7%, TAC/MTX 42.3%, TAC/MMF 14.7%, TAC/other 6%, CSA/MTX 8%, CSA/MMF 10.2%, CSA/others 1%, others 4.1%), and ATG use in 27.2%. Median follow up time for survivors was 46.1 months.&lt;/div&gt;&lt;div&gt;ISD was achieved at any point for 37.1% of subjects, at a median of 6.8 months post-HCT. Median time to ISD differed by GVHD history: 5 months for no prior GVHD, 6 months for prior acute GVHD, and 20.6 months for prior chronic GVHD. ISD failure occurred in 27.5% (at a median of 4.9 months) of those who reached ISD, and only 22.7% of these ISD failures ever reached a second ISD in follow up. Only 15% of subjects were alive with ISD by 5 years from HCT. Baseline variables associated with ISD are presented in Figures 1 and 2. The impact of GVHD prevention approach on ISD outcome differed by patient age (Figure 3), while no other interactions were detected.&lt;/div&gt;&lt;div&gt;This study represents the largest and most comprehensive examination of the probability and determinants of ISD in the current era. Major applications include patient education on expected HCT outcomes, practical guidance for clinicians, and ISD benchmarks for clinical trial design. Development of dynamic prediction models (as done with our prior analysis) is underway to facilitate implementation of these findings at the point of care.&lt;/div&gt;","PeriodicalId":23283,"journal":{"name":"Transplantation and Cellular Therapy","volume":"31 2","pages":"Page S31"},"PeriodicalIF":3.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143487954","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":"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}