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}
Pub Date : 2026-02-01DOI: 10.1016/j.jtct.2025.12.958
Sameem Abedin MD , Lyndsey Runaas MD , Nirav N. Shah MD , Marcelo C. Pasquini MD, MS , Walter Longo MD , Fateeha Furqan MBBS , William R. Drobyski MD , Xue-Zhong Yu MD , Mehdi Hamadani MD
Introduction and Objectives
Post-transplant cyclophosphamide (PTCy) at 50mg/kg on days (D) +3/+4 represents standard GVHD prophylaxis in adults undergoing reduced intensity conditioning (RIC) allogeneic transplantation (HCT) from an HLA-matched donor. Recently, lower cyclophosphamide doses have been explored to mitigate drug toxicity and improve engraftment kinetics. While toxicity appears lessened, no significant improvement to GVHD control has been identified. As prior studies demonstrated a possible role for ruxolitinib as GVHD prophylaxis, we initiated a Phase II study where older adults undergoing RIC, HLA-matched HCT, receive PTCy at a lower dose, along with ruxolitinib, aiming to mitigate PTCy related toxicities and improve GVHD control.
Methods
This prospective phase II study (NCT05622318) enrolled adults ≥60 years, with hematologic malignancies, undergoing RIC peripheral blood allogeneic HCT from an HLA-matched donor. GVHD prophylaxis consisted of PTCy, 25mg/kg on D+3/4, tacrolimus (D+5-180), mycophenolate mofetil (MMF) (D+5-35), and ruxolitinib 5mg twice daily (D+28-60– 1 year). Here we report on engraftment kinetics, ruxolitinib compliance through D+100, BMT-CTN grade 2-3 infections by D+100, Grade 2-4 and 3-4 acute GVHD, chronic GVHD requiring IS, relapse, and GRFS.
Results
56 pts were enrolled/treated. Median age is 69 years (range 60-78 years), 28 pts had MDS or MPN, 27 pts had AML/ALL. RIC included Flu/Bu (N=41) or Flu/Mel100mg/m2 (N=15). Donors included MUD (N=50) or MRD (N=6). Median f/u of survivors is 267 days (range: 48-367 days). PB chimerisms confirmed donor engraftment in all patients on D+28. Median time to neutrophil and platelet engraftment was 14 days (range: 11-33 days), and 13 days (range: 10-37 days) post-HCT, respectively. Ruxolitinib was initiated at a median 34 days (range: 28-82 days) post-HCT. Ruxolitinib was interrupted in 4 pts (7%) due to ruxolitinib related AEs within the first 100 days. By day 100, the cumulative incidence of grade 2-3 infections was 11%. Incidence of grade 2-4 and 3-4 aGVHD at D180 was 13% and 4%, and incidence of cGVHD requiring IS at 1y was 2%. Incidence of relapse was 11%. Estimated 1y GRFS was 78% (+/-7%).
Conclusion
In older adults, de-escalated PTCy and ruxolitinib enables rapid and reliable engraftment and low rates of severe infections. Compared to PTCy 50 × 2, we report lower rates of G2-4 acute GVHD, but similar rates of G3+ acute GVHD. This could be explained by delayed initiation of ruxolitinib after D+28. Lower rates of chronic GVHD, and comparable relapse rates overall lead to a very favorable 1 y GRFS in an older population.
{"title":"Safety and Efficacy Results from a Phase II Trial of De-Escalated Ptcy and Ruxolitinib for GVHD Prophylaxis in Older Patients Undergoing Reduced Intensity Conditioning Allogeneic HCT","authors":"Sameem Abedin MD , Lyndsey Runaas MD , Nirav N. Shah MD , Marcelo C. Pasquini MD, MS , Walter Longo MD , Fateeha Furqan MBBS , William R. Drobyski MD , Xue-Zhong Yu MD , Mehdi Hamadani MD","doi":"10.1016/j.jtct.2025.12.958","DOIUrl":"10.1016/j.jtct.2025.12.958","url":null,"abstract":"<div><h3>Introduction and Objectives</h3><div>Post-transplant cyclophosphamide (PTCy) at 50mg/kg on days (D) +3/+4 represents standard GVHD prophylaxis in adults undergoing reduced intensity conditioning (RIC) allogeneic transplantation (HCT) from an HLA-matched donor. Recently, lower cyclophosphamide doses have been explored to mitigate drug toxicity and improve engraftment kinetics. While toxicity appears lessened, no significant improvement to GVHD control has been identified. As prior studies demonstrated a possible role for ruxolitinib as GVHD prophylaxis, we initiated a Phase II study where older adults undergoing RIC, HLA-matched HCT, receive PTCy at a lower dose, along with ruxolitinib, aiming to mitigate PTCy related toxicities and improve GVHD control.</div></div><div><h3>Methods</h3><div>This prospective phase II study (NCT05622318) enrolled adults ≥60 years, with hematologic malignancies, undergoing RIC peripheral blood allogeneic HCT from an HLA-matched donor. GVHD prophylaxis consisted of PTCy, 25mg/kg on D+3/4, tacrolimus (D+5-180), mycophenolate mofetil (MMF) (D+5-35), and ruxolitinib 5mg twice daily (D+28-60– 1 year). Here we report on engraftment kinetics, ruxolitinib compliance through D+100, BMT-CTN grade 2-3 infections by D+100, Grade 2-4 and 3-4 acute GVHD, chronic GVHD requiring IS, relapse, and GRFS.</div></div><div><h3>Results</h3><div>56 pts were enrolled/treated. Median age is 69 years (range 60-78 years), 28 pts had MDS or MPN, 27 pts had AML/ALL. RIC included Flu/Bu (N=41) or Flu/Mel100mg/m2 (N=15). Donors included MUD (N=50) or MRD (N=6). Median f/u of survivors is 267 days (range: 48-367 days). PB chimerisms confirmed donor engraftment in all patients on D+28. Median time to neutrophil and platelet engraftment was 14 days (range: 11-33 days), and 13 days (range: 10-37 days) post-HCT, respectively. Ruxolitinib was initiated at a median 34 days (range: 28-82 days) post-HCT. Ruxolitinib was interrupted in 4 pts (7%) due to ruxolitinib related AEs within the first 100 days. By day 100, the cumulative incidence of grade 2-3 infections was 11%. Incidence of grade 2-4 and 3-4 aGVHD at D180 was 13% and 4%, and incidence of cGVHD requiring IS at 1y was 2%. Incidence of relapse was 11%. Estimated 1y GRFS was 78% (+/-7%).</div></div><div><h3>Conclusion</h3><div>In older adults, de-escalated PTCy and ruxolitinib enables rapid and reliable engraftment and low rates of severe infections. Compared to PTCy 50 × 2, we report lower rates of G2-4 acute GVHD, but similar rates of G3+ acute GVHD. This could be explained by delayed initiation of ruxolitinib after D+28. Lower rates of chronic GVHD, and comparable relapse rates overall lead to a very favorable 1 y GRFS in an older population.</div></div>","PeriodicalId":23283,"journal":{"name":"Transplantation and Cellular Therapy","volume":"32 2","pages":"Pages S78-S79"},"PeriodicalIF":4.4,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146098510","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.2025.12.035
Lev Gorfinkel MD , Boya Liu PhD , Yi Liu PhD , Madhura Panditrao MS , Sukhdeep Sahambi MS , Eric Peters PhD , Sherif Sharaby PharmD , Sejong Chun MD , Victor Tkachev PhD , Matthew Warren MS , Elisa Rojas BS , Jennifer Lane DVM , Ulrike Gerdemann MD , Francesca Alvarez-Calderon MD, PhD , Leah Desrochers MS , Gwen Lavalla BS , Owen Stanbro BS , Lorenzo S Cagnin PhD , Serena De Vita MD/PhD , Susan Cellitti PhD , Leslie S. Kean MD, PhD
<div><h3>Introduction</h3><div>Chemotherapy and TBI-based conditioning for stem cell transplant and gene therapy (GT) cause significant toxicities. Antibody-drug conjugates (ADCs) offer a targeted alternative, depleting hematopoietic stem and progenitor cells (HSPCs) by antigen specificity. CD117, expressed primarily on HSPCs, is an appealing target, but prior attempts at safe and effective CD117-ADCs were limited by mast cell degranulation and payload-related toxicities. We developed a novel CD117-ADC (YTD005) with four design features: (1) An antagonistic anti-CD117 clone identified by phage display; (2) Monomeric fragment lacking Fc-effector function to reduce mast cell activation; (3) Fab’ design enabling rapid systemic clearance to limit infused stem cell loss; and (4) Incorporation of the tubulin inhibitor payload MC-MMAF at a drug-to-antibody ratio of 4. MC-MMAF is a non-cell-permeable toxin with low bystander effect and uses a non-cleavable linker, further reducing off-target payload effects.</div></div><div><h3>Objective</h3><div>To evaluate the safety and engraftment outcomes with YTD005 in a non-human primate (NHP) model of GT using CD34+ cells transduced with BCH-BB694, a lentiviral vector targeting BCL11A.</div></div><div><h3>Methods</h3><div>Three NHP underwent autologous transplantation with BCH-BB694–transduced CD34+ cells after YTD005 (1.5 mg/kg/day continuous infusion, day –9 to –2). Following 2 washout days, the GT product was infused. Animals were monitored up to 1-year for toxicity and engraftment; primary engraftment data obtained at Day +30.</div></div><div><h3>Results</h3><div>YTD005 achieved robust depletion of Lin– CD34+ HSPCs (median 98.2%; range, 97.8-99.6%) and Lin–CD34+CD90+CD45RA– cells (median 96.8%; range 94-99.6%). Conditioning was well tolerated, with no organ toxicities or mast cell activation. Animals received median 5.7×10⁶ CD34+ cells/kg (mean product VCN 4.2 per diploid genome; range 3.6-4.6c/dg). All developed transient pancytopenia: neutrophil nadirs ∼100/µL (range 100-300) at day +9 (range, day +7 - +11) with recovery by day +13 (range, +13 - +14); platelet nadirs ∼56K (range 43-102K) at day +3 (range, -4 - +7) with engraftment by day +13 (range, +7 - +14); anemia was mild.</div><div>Engraftment was assessed by peripheral blood (PB) VCN and the % of individually isolated hematopoietic bone marrow progenitor CD34-derived colonies with a VCN >1. At day +30, mean PB VCN was 0.082 ± 0.028 (∼8% of PB cells), and mean colony engraftment 15.6% (range, 13.4-20%). At 3 months (n=3), mean PB VCN was 0.094± 0.024 (∼9% of PB cells) and colony engraftment was 15.2% (range, 14.1-15.9%). One animal has been followed to 1 year, demonstrating stable engraftment (blood VCN 0.1; 15.4% colonies), with 2 animals ongoing.</div></div><div><h3>Conclusions</h3><div>YTD005 incorporates rational design features to optimize safety and efficacy. A single infusional treatment with this ADC leads to engraftment of gene-modified cel
{"title":"Refined Design of a CD117 Antibody-Drug Conjugate Safely and Effectively Conditions Non-Human Primates for Autologous Transplant-Based Gene Therapy","authors":"Lev Gorfinkel MD , Boya Liu PhD , Yi Liu PhD , Madhura Panditrao MS , Sukhdeep Sahambi MS , Eric Peters PhD , Sherif Sharaby PharmD , Sejong Chun MD , Victor Tkachev PhD , Matthew Warren MS , Elisa Rojas BS , Jennifer Lane DVM , Ulrike Gerdemann MD , Francesca Alvarez-Calderon MD, PhD , Leah Desrochers MS , Gwen Lavalla BS , Owen Stanbro BS , Lorenzo S Cagnin PhD , Serena De Vita MD/PhD , Susan Cellitti PhD , Leslie S. Kean MD, PhD","doi":"10.1016/j.jtct.2025.12.035","DOIUrl":"10.1016/j.jtct.2025.12.035","url":null,"abstract":"<div><h3>Introduction</h3><div>Chemotherapy and TBI-based conditioning for stem cell transplant and gene therapy (GT) cause significant toxicities. Antibody-drug conjugates (ADCs) offer a targeted alternative, depleting hematopoietic stem and progenitor cells (HSPCs) by antigen specificity. CD117, expressed primarily on HSPCs, is an appealing target, but prior attempts at safe and effective CD117-ADCs were limited by mast cell degranulation and payload-related toxicities. We developed a novel CD117-ADC (YTD005) with four design features: (1) An antagonistic anti-CD117 clone identified by phage display; (2) Monomeric fragment lacking Fc-effector function to reduce mast cell activation; (3) Fab’ design enabling rapid systemic clearance to limit infused stem cell loss; and (4) Incorporation of the tubulin inhibitor payload MC-MMAF at a drug-to-antibody ratio of 4. MC-MMAF is a non-cell-permeable toxin with low bystander effect and uses a non-cleavable linker, further reducing off-target payload effects.</div></div><div><h3>Objective</h3><div>To evaluate the safety and engraftment outcomes with YTD005 in a non-human primate (NHP) model of GT using CD34+ cells transduced with BCH-BB694, a lentiviral vector targeting BCL11A.</div></div><div><h3>Methods</h3><div>Three NHP underwent autologous transplantation with BCH-BB694–transduced CD34+ cells after YTD005 (1.5 mg/kg/day continuous infusion, day –9 to –2). Following 2 washout days, the GT product was infused. Animals were monitored up to 1-year for toxicity and engraftment; primary engraftment data obtained at Day +30.</div></div><div><h3>Results</h3><div>YTD005 achieved robust depletion of Lin– CD34+ HSPCs (median 98.2%; range, 97.8-99.6%) and Lin–CD34+CD90+CD45RA– cells (median 96.8%; range 94-99.6%). Conditioning was well tolerated, with no organ toxicities or mast cell activation. Animals received median 5.7×10⁶ CD34+ cells/kg (mean product VCN 4.2 per diploid genome; range 3.6-4.6c/dg). All developed transient pancytopenia: neutrophil nadirs ∼100/µL (range 100-300) at day +9 (range, day +7 - +11) with recovery by day +13 (range, +13 - +14); platelet nadirs ∼56K (range 43-102K) at day +3 (range, -4 - +7) with engraftment by day +13 (range, +7 - +14); anemia was mild.</div><div>Engraftment was assessed by peripheral blood (PB) VCN and the % of individually isolated hematopoietic bone marrow progenitor CD34-derived colonies with a VCN >1. At day +30, mean PB VCN was 0.082 ± 0.028 (∼8% of PB cells), and mean colony engraftment 15.6% (range, 13.4-20%). At 3 months (n=3), mean PB VCN was 0.094± 0.024 (∼9% of PB cells) and colony engraftment was 15.2% (range, 14.1-15.9%). One animal has been followed to 1 year, demonstrating stable engraftment (blood VCN 0.1; 15.4% colonies), with 2 animals ongoing.</div></div><div><h3>Conclusions</h3><div>YTD005 incorporates rational design features to optimize safety and efficacy. A single infusional treatment with this ADC leads to engraftment of gene-modified cel","PeriodicalId":23283,"journal":{"name":"Transplantation and Cellular Therapy","volume":"32 2","pages":"Pages S19-S20"},"PeriodicalIF":4.4,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146098513","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.2025.12.113
Kelly Terrell MBA, BSN, RN, BMTCN
Background
Efficient mobilization of hematopoietic stem and progenitor cells is essential to optimize apheresis resource utilization in autologous hematopoietic cell transplant (AHCT) programs. Motixafortide, a novel CXCR4 inhibitor, in combination with G-CSF has demonstrated enhanced stem cell mobilization potential compared to G-CSF alone but has not been directly compared to plerixafor. This analysis evaluates the impact of motixafortide on apheresis chair utilization and collection efficiency in routine clinical practice.
Methods
A retrospective analysis was conducted comparing patients with multiple myeloma who underwent stem cell mobilization with motixafortide plus G-CSF in a 12- month period to those treated with plerixafor plus G-CSF during the preceding 12 months. Collection parameters included a processing volume of 10-25 liters and a target yield of 5 × 106 CD34 cells/kg. Data collected included patient demographics, number of apheresis collections, chair utilization time, and procedure run time.
Results
The motixafortide cohort included 99 patients with 131 collections (mean 1.34 collections per patient, median 1), compared with 112 patients and 151 collections (mean 1.40 collections per patient, median 1) in the plerixafor group. Mean age was comparable (motixafortide 62.3 vs. plerixafor 63.3 years), as was sex distribution (55M/44F vs. 64M/48F).
Total apheresis chair utilization was 738 hours 26 minutes with motixafortide versus 844 hours 58 minutes with plerixafor. Mean chair time per procedure was similar (6 h 9 m motixafortide vs. 6 h 7 m plerixafor). Total procedure run time was 38,027 minutes with motixafortide compared to 43,586 minutes with plerixafor, mean run times were consistent (5 h 16 m motixafortide vs. 5 h 18 m plerixafor).
Conclusions
Motixafortide plus G-CSF demonstrated comparable apheresis efficiency to plerixafor-based mobilization in the multiple myeloma patient population, with similar mean chair and procedure run times. These findings suggest both mobilization strategies provide equivalent operational efficiency in routine clinical practice.
{"title":"Impact of Motixafortide on Apheresis Chair Utilization and Mobilization Efficiency Compared to Plerixafor in Autologous Stem Cell Transplant Candidates","authors":"Kelly Terrell MBA, BSN, RN, BMTCN","doi":"10.1016/j.jtct.2025.12.113","DOIUrl":"10.1016/j.jtct.2025.12.113","url":null,"abstract":"<div><h3>Background</h3><div>Efficient mobilization of hematopoietic stem and progenitor cells is essential to optimize apheresis resource utilization in autologous hematopoietic cell transplant (AHCT) programs. Motixafortide, a novel CXCR4 inhibitor, in combination with G-CSF has demonstrated enhanced stem cell mobilization potential compared to G-CSF alone but has not been directly compared to plerixafor. This analysis evaluates the impact of motixafortide on apheresis chair utilization and collection efficiency in routine clinical practice.</div></div><div><h3>Methods</h3><div>A retrospective analysis was conducted comparing patients with multiple myeloma who underwent stem cell mobilization with motixafortide plus G-CSF in a 12- month period to those treated with plerixafor plus G-CSF during the preceding 12 months. Collection parameters included a processing volume of 10-25 liters and a target yield of 5 × 10<sup>6</sup> CD34 cells/kg. Data collected included patient demographics, number of apheresis collections, chair utilization time, and procedure run time.</div></div><div><h3>Results</h3><div>The motixafortide cohort included 99 patients with 131 collections (<strong>mean 1.34 collections per patient</strong>, median 1), compared with 112 patients and 151 collections (<strong>mean 1.40 collections per patient</strong>, median 1) in the plerixafor group. Mean age was comparable (motixafortide 62.3 vs. plerixafor 63.3 years), as was sex distribution (55M/44F vs. 64M/48F).</div><div>Total apheresis chair utilization was 738 hours 26 minutes with motixafortide versus 844 hours 58 minutes with plerixafor. <strong>Mean chair time per procedure was similar</strong> (6 h 9 m motixafortide vs. 6 h 7 m plerixafor). Total procedure run time was 38,027 minutes with motixafortide compared to 43,586 minutes with plerixafor, <strong>mean run times were consistent</strong> (5 h 16 m motixafortide vs. 5 h 18 m plerixafor).</div></div><div><h3>Conclusions</h3><div>Motixafortide plus G-CSF demonstrated comparable apheresis efficiency to plerixafor-based mobilization in the multiple myeloma patient population, with similar mean chair and procedure run times. These findings suggest both mobilization strategies provide equivalent operational efficiency in routine clinical practice.</div></div>","PeriodicalId":23283,"journal":{"name":"Transplantation and Cellular Therapy","volume":"32 2","pages":"Page S81"},"PeriodicalIF":4.4,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146098517","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.2025.12.115
Laura Larsen APRN, CNS, DNP
Topic Significance & Study Purpose/Background/Rationale
Bone Marrow Transplant (BMT) patients traditionally require prolonged inpatient stays, particularly when caregiver support is unavailable. The Care Hotel model offers a monitored outpatient alternative for autologous transplant patients without caregivers, aiming to reduce hospital utilization while maintaining safety and satisfaction. This initiative is significant to oncology nursing as it reimagines post-transplant care delivery. The program leverages Remote Patient Monitoring (RPM) and coordinated nursing oversight to support patients in a non-hospital setting. Nurses played a central role in patient triage, education, and daily monitoring, in collaboration with providers, social workers, and transport services to ensure safe care.
Methods, Intervention, & Analysis
Seven patients undergoing autologous transplant were enrolled in the Care Hotel program. Eligibility requirements were independence in self-care, absence of caregiver support, and medical stability. Patients used RPM kits to record vitals every four hours, supported by escalation protocols. Daily outpatient visits and transportation were arranged. Data collection included hospital admissions, RPM adherence, patient satisfaction, and safety metrics. Quantitative measures tracked hospital days saved, safety events, and survey responses. Qualitative feedback was gathered via interviews and care team debriefs. Data were analyzed to assess feasibility, safety, and operational impact.
Findings & Interpretation
Several patients required short hospital admissions for fever or other medical concerns, but all completed their transplant successfully. The program saved an average of 17 hospital days per patient. No patient falls or medication errors occurred during the pilot, though some patients experienced onboarding challenges with RPM equipment. Patients reported high satisfaction with amenities, transportation, and care coordination, with 100% reporting feeling safe, understood how to contact care providers, and would recommend the program to others. These findings align with existing literature supporting outpatient transplant feasibility and RPM use in oncology settings. Nurses identified patient selection and education as critical success factors.
Discussion & Implications
The Care Hotel model demonstrates a safe and feasible alternative to inpatient care for select BMT patients, with meaningful implications for resource optimization and patient-centered care. Oncology nurses are uniquely positioned to engage in such innovations, given their expertise in patient education, symptom management, and care coordination. These results support broader implementation and future studies exploring scalability, and cost-effectiveness.
{"title":"Reimagining Post-Transplant Care: Feasibility of a Remote Monitoring-Based Care Hotel Model for Autologous Transplant Patients without Caregivers","authors":"Laura Larsen APRN, CNS, DNP","doi":"10.1016/j.jtct.2025.12.115","DOIUrl":"10.1016/j.jtct.2025.12.115","url":null,"abstract":"<div><h3>Topic Significance & Study Purpose/Background/Rationale</h3><div>Bone Marrow Transplant (BMT) patients traditionally require prolonged inpatient stays, particularly when caregiver support is unavailable. The Care Hotel model offers a monitored outpatient alternative for autologous transplant patients without caregivers, aiming to reduce hospital utilization while maintaining safety and satisfaction. This initiative is significant to oncology nursing as it reimagines post-transplant care delivery. The program leverages Remote Patient Monitoring (RPM) and coordinated nursing oversight to support patients in a non-hospital setting. Nurses played a central role in patient triage, education, and daily monitoring, in collaboration with providers, social workers, and transport services to ensure safe care.</div></div><div><h3>Methods, Intervention, & Analysis</h3><div>Seven patients undergoing autologous transplant were enrolled in the Care Hotel program. Eligibility requirements were independence in self-care, absence of caregiver support, and medical stability. Patients used RPM kits to record vitals every four hours, supported by escalation protocols. Daily outpatient visits and transportation were arranged. Data collection included hospital admissions, RPM adherence, patient satisfaction, and safety metrics. Quantitative measures tracked hospital days saved, safety events, and survey responses. Qualitative feedback was gathered via interviews and care team debriefs. Data were analyzed to assess feasibility, safety, and operational impact.</div></div><div><h3>Findings & Interpretation</h3><div>Several patients required short hospital admissions for fever or other medical concerns, but all completed their transplant successfully. The program saved an average of 17 hospital days per patient. No patient falls or medication errors occurred during the pilot, though some patients experienced onboarding challenges with RPM equipment. Patients reported high satisfaction with amenities, transportation, and care coordination, with 100% reporting feeling safe, understood how to contact care providers, and would recommend the program to others. These findings align with existing literature supporting outpatient transplant feasibility and RPM use in oncology settings. Nurses identified patient selection and education as critical success factors.</div></div><div><h3>Discussion & Implications</h3><div>The Care Hotel model demonstrates a safe and feasible alternative to inpatient care for select BMT patients, with meaningful implications for resource optimization and patient-centered care. Oncology nurses are uniquely positioned to engage in such innovations, given their expertise in patient education, symptom management, and care coordination. These results support broader implementation and future studies exploring scalability, and cost-effectiveness.</div></div>","PeriodicalId":23283,"journal":{"name":"Transplantation and Cellular Therapy","volume":"32 2","pages":"Page S82"},"PeriodicalIF":4.4,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146098518","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.2025.12.051
Kaylyn Utley Lyons MD , Lucy E. Cain MBBS , Yimei Li PhD , Diane Baniewicz NP , Colleen A. Callahan NP , Mackenzie Stewart NP, APRN , Amanda DiNofia MD , Allison B Leahy MD , Caroline Diorio MD , Susan R. Rheingold MD , Lisa Eidenschink Brodersen PhD , Shannon L Maude MD, PhD , Stephan A. Grupp MD, PhD , Kathrin Maria Bernt MD , Regina M. Myers MD
<div><h3>Background</h3><div>Infant B-cell acute lymphoblastic leukemia (B-ALL) is a highly aggressive subtype, and survival for patients with relapsed or refractory (r/r) disease remains poor. CD19 CAR T cell therapy (CART19) has demonstrated impressive initial efficacy in this population, but existing data are limited to small cohorts with short follow-up. In addition, infant B-ALL is uniquely prone to lineage switch (LS), but factors associated with LS beyond KMT2A-rearrangements are not well defined.</div></div><div><h3>Objective</h3><div>Determine long-term efficacy of CART19 for r/r infant B-ALL and explore factors associated with LS.</div></div><div><h3>Methods</h3><div>We retrospectively identified children diagnosed with B-ALL <1 year of age treated with their first murine or humanized CD19/4-1BB CART for r/r disease across 4 clinical trials or with commercial tisagenlecleucel at Children’s Hospital of Philadelphia. The primary outcome was 5-year event-free survival (EFS). Secondary outcomes included complete remission (CR) rates, overall survival (OS), and relapse immunophenotype. Exploratory analyses compared baseline and cytomolecular features of patients with or without LS.</div></div><div><h3>Results</h3><div>This analysis included 32 patients; 29 (91%) had KMT2A-rearrangements. Patient characteristics are summarized in <strong>Table 1</strong>. Of 31 evaluable patients at Day (D) 28, 30 (97%) achieved measurable residual disease-negative CR. One patient died of complications from cytokine release syndrome. With a median follow-up of 6 years, 5-year EFS and OS were 63% (95% CI, 43–78) and 68% (95% CI, 47–82) (<strong>Figure 1</strong>). A trend toward improved 5-year EFS was observed in patients who underwent prior hematopoietic cell transplant (HCT): 79% (95% CI, 47-93) v 56% (95% CI, 31-75; p=0.059) with no prior HCT (<strong>Figure 2</strong>). Among 30 patients who achieved CR, 17 remain in long-term remission without further therapy, 4 proceeded to HCT or alternative CART due to early B cell recovery and remain in remission, and 9 relapsed at a median of 1.3 months (range 0.5-11.9) after D28 (6 LS, 2 CD19-negative, 1 CD19 +). All patients who relapsed died of progressive disease.</div><div>Patients with LS (n=6) were younger at infusion (Wilcoxon p=0.003) and more likely to have primary refractory disease (Fisher p=0.015). Of the 15 patients with available molecular profiling, 5 harbored <em>RAS</em>-pathway and/or <em>TP53</em> mutations, all of whom developed LS. None of the 10 without these alterations experienced LS (1 non-response, 1 CD19+ relapse, 8 continued CR).</div></div><div><h3>Conclusions</h3><div>With extensive follow-up, we demonstrate that CART19 induces durable remissions in r/r infant B-ALL; however, post-CART relapse was uniformly fatal. Prior HCT associated with an impressive 5-year EFS of 79%, raising the question of whether post-HCT T cell-derived CARs may improve outcomes in infant ALL. LS occurred in
{"title":"CD19 CAR T-cell Therapy in Infant B-ALL: Durable Remissions, Relapse Patterns, and Molecular Correlates","authors":"Kaylyn Utley Lyons MD , Lucy E. Cain MBBS , Yimei Li PhD , Diane Baniewicz NP , Colleen A. Callahan NP , Mackenzie Stewart NP, APRN , Amanda DiNofia MD , Allison B Leahy MD , Caroline Diorio MD , Susan R. Rheingold MD , Lisa Eidenschink Brodersen PhD , Shannon L Maude MD, PhD , Stephan A. Grupp MD, PhD , Kathrin Maria Bernt MD , Regina M. Myers MD","doi":"10.1016/j.jtct.2025.12.051","DOIUrl":"10.1016/j.jtct.2025.12.051","url":null,"abstract":"<div><h3>Background</h3><div>Infant B-cell acute lymphoblastic leukemia (B-ALL) is a highly aggressive subtype, and survival for patients with relapsed or refractory (r/r) disease remains poor. CD19 CAR T cell therapy (CART19) has demonstrated impressive initial efficacy in this population, but existing data are limited to small cohorts with short follow-up. In addition, infant B-ALL is uniquely prone to lineage switch (LS), but factors associated with LS beyond KMT2A-rearrangements are not well defined.</div></div><div><h3>Objective</h3><div>Determine long-term efficacy of CART19 for r/r infant B-ALL and explore factors associated with LS.</div></div><div><h3>Methods</h3><div>We retrospectively identified children diagnosed with B-ALL <1 year of age treated with their first murine or humanized CD19/4-1BB CART for r/r disease across 4 clinical trials or with commercial tisagenlecleucel at Children’s Hospital of Philadelphia. The primary outcome was 5-year event-free survival (EFS). Secondary outcomes included complete remission (CR) rates, overall survival (OS), and relapse immunophenotype. Exploratory analyses compared baseline and cytomolecular features of patients with or without LS.</div></div><div><h3>Results</h3><div>This analysis included 32 patients; 29 (91%) had KMT2A-rearrangements. Patient characteristics are summarized in <strong>Table 1</strong>. Of 31 evaluable patients at Day (D) 28, 30 (97%) achieved measurable residual disease-negative CR. One patient died of complications from cytokine release syndrome. With a median follow-up of 6 years, 5-year EFS and OS were 63% (95% CI, 43–78) and 68% (95% CI, 47–82) (<strong>Figure 1</strong>). A trend toward improved 5-year EFS was observed in patients who underwent prior hematopoietic cell transplant (HCT): 79% (95% CI, 47-93) v 56% (95% CI, 31-75; p=0.059) with no prior HCT (<strong>Figure 2</strong>). Among 30 patients who achieved CR, 17 remain in long-term remission without further therapy, 4 proceeded to HCT or alternative CART due to early B cell recovery and remain in remission, and 9 relapsed at a median of 1.3 months (range 0.5-11.9) after D28 (6 LS, 2 CD19-negative, 1 CD19 +). All patients who relapsed died of progressive disease.</div><div>Patients with LS (n=6) were younger at infusion (Wilcoxon p=0.003) and more likely to have primary refractory disease (Fisher p=0.015). Of the 15 patients with available molecular profiling, 5 harbored <em>RAS</em>-pathway and/or <em>TP53</em> mutations, all of whom developed LS. None of the 10 without these alterations experienced LS (1 non-response, 1 CD19+ relapse, 8 continued CR).</div></div><div><h3>Conclusions</h3><div>With extensive follow-up, we demonstrate that CART19 induces durable remissions in r/r infant B-ALL; however, post-CART relapse was uniformly fatal. Prior HCT associated with an impressive 5-year EFS of 79%, raising the question of whether post-HCT T cell-derived CARs may improve outcomes in infant ALL. LS occurred in ","PeriodicalId":23283,"journal":{"name":"Transplantation and Cellular Therapy","volume":"32 2","pages":"Pages S31-S32"},"PeriodicalIF":4.4,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146098564","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.2025.12.058
Natalia Tijaro Ovalle MD , Andrew Lin PharmD, BCOP , Danielle Lutrario MS , Khayla Leiva BS , Joel Lamboy BS, MBA , Anjali Patel BS , Alyssa Kamrowski BS, MPH , Ryan Schofield MS , Hamza Hashmi MD , Hani Hassoun MD , Malin Hultcrantz MD, PhD , Neha Korde MD , Alexander M. Lesokhin MD , Kylee H. Maclachlan MBChB, PhD , Sham Mailankody MBBS , Sridevi Rajeeve MD , Urvi A. Shah MD , Carlyn Rose Tan MD , Saad Z. Usmani MD , David J. Chung MD, PhD , Gunjan L. Shah MD, MS
<div><h3>Introduction</h3><div>Conventional autologous hematopoietic cell transplantation (AHCT) using body surface area (BSA)-based melphalan dosing results in variable drug exposure among patients with multiple myeloma (MM), risking relapse in some and excessive toxicity in others, particularly in older adults. Building on our prior studies, we hypothesized that combining population pharmacokinetic (pop PK)-guided melphalan dosing with interleukin-6 (IL-6) blockade using siltuximab may improve therapeutic effectiveness and mitigate AHCT-associated symptom burden in this population.</div></div><div><h3>Objective</h3><div>1. Evaluate how PopPK-guided dosing of melphalan plus IL-6 blockade impacts efficacy and symptom burden of AHCT in older adults with MM.</div></div><div><h3>Methods</h3><div>In a single-center phase II lead-in (NCT06679829), patients ≥60 years with MM received melphalan 70 mg/m² on day -2, followed by individualized day -1 dosing using our validated pop PK model (Shah et al, <em>Clin Pharmacokinet</em>, 2022) to achieve a cumulative area under the curve (AUC) target of 13 ± 1.5 mg*h/L (InsightRx, Inc., San Francisco, CA). Siltuximab 11 mg/kg was administered on days -7 and +14. Co-primary lead-in objectives were safety and feasibility. Secondary endpoints included disease response, minimal residual disease (MRD) by next-generation flow cytometry, and engraftment kinetics.</div></div><div><h3>Results</h3><div>15 patients were treated (median age 68 [range 61–73], 53% female, 73% standard-risk cytogenetics) after receiving quadruplet induction (median 1 prior line of treatment, range 1-2). Before AHCT, disease status included complete response (CR) without MRD (MRD-) (n=2), very good partial response (VGPR) (n=7), partial response (PR) (n=5), and stable disease (SD) (n=1). The median melphalan AUC in the cohort was 13.1 mg*h/L (range 11.3–14.5), with 14/15 (93%) achieving the exposure target (<strong>Figure 1</strong>). At a median follow-up of 7 mo (range 1-10), 11 patients have had day +100 restaging. Responses were CR (n=4, n=2 MRD-), VGPR (n=4), and PR (n=3). 5/11 patients had deepening of responses (VGPR to CR n=4, PR to VGPR, n=1) (<strong>Figure 2</strong>). Median time to neutrophil engraftment was 12 days (range 9–18). 3 patients experienced engraftment syndrome. Grade 3 adverse events included febrile neutropenia (n=5) and mucositis (n=2). No grade 4–5 toxicities were observed. There were no relapses or deaths at last follow-up.</div></div><div><h3>Conclusions</h3><div>In the lead-in of this first prospective study of its kind, pop PK-targeted melphalan dosing in combination with siltuximab was a feasible and safe treatment strategy for older MM patients undergoing AHCT. The primary objective was met with the majority of patients achieving the prespecified melphalan AUC target with an acceptable toxicity profile. The ongoing randomized phase II trial will test whether precision-dosing of melphalan paired with IL-6 blocka
{"title":"Precision Melphalan Dosing Using a Population Pharmacokinetic Model Combined with IL-6 Blockade (Siltuximab) in Older Adults with Multiple Myeloma Undergoing Autologous Hematopoietic Cell Transplantation: Phase II Lead-in Outcomes","authors":"Natalia Tijaro Ovalle MD , Andrew Lin PharmD, BCOP , Danielle Lutrario MS , Khayla Leiva BS , Joel Lamboy BS, MBA , Anjali Patel BS , Alyssa Kamrowski BS, MPH , Ryan Schofield MS , Hamza Hashmi MD , Hani Hassoun MD , Malin Hultcrantz MD, PhD , Neha Korde MD , Alexander M. Lesokhin MD , Kylee H. Maclachlan MBChB, PhD , Sham Mailankody MBBS , Sridevi Rajeeve MD , Urvi A. Shah MD , Carlyn Rose Tan MD , Saad Z. Usmani MD , David J. Chung MD, PhD , Gunjan L. Shah MD, MS","doi":"10.1016/j.jtct.2025.12.058","DOIUrl":"10.1016/j.jtct.2025.12.058","url":null,"abstract":"<div><h3>Introduction</h3><div>Conventional autologous hematopoietic cell transplantation (AHCT) using body surface area (BSA)-based melphalan dosing results in variable drug exposure among patients with multiple myeloma (MM), risking relapse in some and excessive toxicity in others, particularly in older adults. Building on our prior studies, we hypothesized that combining population pharmacokinetic (pop PK)-guided melphalan dosing with interleukin-6 (IL-6) blockade using siltuximab may improve therapeutic effectiveness and mitigate AHCT-associated symptom burden in this population.</div></div><div><h3>Objective</h3><div>1. Evaluate how PopPK-guided dosing of melphalan plus IL-6 blockade impacts efficacy and symptom burden of AHCT in older adults with MM.</div></div><div><h3>Methods</h3><div>In a single-center phase II lead-in (NCT06679829), patients ≥60 years with MM received melphalan 70 mg/m² on day -2, followed by individualized day -1 dosing using our validated pop PK model (Shah et al, <em>Clin Pharmacokinet</em>, 2022) to achieve a cumulative area under the curve (AUC) target of 13 ± 1.5 mg*h/L (InsightRx, Inc., San Francisco, CA). Siltuximab 11 mg/kg was administered on days -7 and +14. Co-primary lead-in objectives were safety and feasibility. Secondary endpoints included disease response, minimal residual disease (MRD) by next-generation flow cytometry, and engraftment kinetics.</div></div><div><h3>Results</h3><div>15 patients were treated (median age 68 [range 61–73], 53% female, 73% standard-risk cytogenetics) after receiving quadruplet induction (median 1 prior line of treatment, range 1-2). Before AHCT, disease status included complete response (CR) without MRD (MRD-) (n=2), very good partial response (VGPR) (n=7), partial response (PR) (n=5), and stable disease (SD) (n=1). The median melphalan AUC in the cohort was 13.1 mg*h/L (range 11.3–14.5), with 14/15 (93%) achieving the exposure target (<strong>Figure 1</strong>). At a median follow-up of 7 mo (range 1-10), 11 patients have had day +100 restaging. Responses were CR (n=4, n=2 MRD-), VGPR (n=4), and PR (n=3). 5/11 patients had deepening of responses (VGPR to CR n=4, PR to VGPR, n=1) (<strong>Figure 2</strong>). Median time to neutrophil engraftment was 12 days (range 9–18). 3 patients experienced engraftment syndrome. Grade 3 adverse events included febrile neutropenia (n=5) and mucositis (n=2). No grade 4–5 toxicities were observed. There were no relapses or deaths at last follow-up.</div></div><div><h3>Conclusions</h3><div>In the lead-in of this first prospective study of its kind, pop PK-targeted melphalan dosing in combination with siltuximab was a feasible and safe treatment strategy for older MM patients undergoing AHCT. The primary objective was met with the majority of patients achieving the prespecified melphalan AUC target with an acceptable toxicity profile. The ongoing randomized phase II trial will test whether precision-dosing of melphalan paired with IL-6 blocka","PeriodicalId":23283,"journal":{"name":"Transplantation and Cellular Therapy","volume":"32 2","pages":"Pages S35-S36"},"PeriodicalIF":4.4,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146098627","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.2025.12.076
Jason Westin MD, MS, FACP, FASCO , Julio C. Chavez MD , Stephen J. Schuster MD , Vladan Vučinić MD , Patricia A. Young MD , Patrick Connor Johnson MD , Stefania Bramanti MD , Alessandro Rambaldi MD , Javier Briones Meijide MD, PhD , Koji Kato MD, PhD , Juan-Manuel Sancho MD , Mi Kwon MD, PhD , Carlos Solano MD, PhD , Shaun Fleming MBBS (Hons), PhD, FRACP, FRCPA , Saurabh Dahiya MD, FACP , Alejandro Martin García-Sancho MD, PhD , Pedro Marques Ramos PhD , David Pearson PhD , Salif Diallo MSc , Aiesha Zia MSc , Pere Barba MD, PhD
<div><h3>Introduction</h3><div>Although ∼70% of patients (pts) with large B-cell lymphoma (LBCL) respond to frontline (1L) chemoimmunotherapy, outcomes are poor for high-risk (HR) disease and pts not achieving complete response (CR). Rapcabtagene autoleucel is an investigational CD19-directed CAR-T cell therapy rapidly manufactured in <2 d using the T-Charge™ platform. We report a descriptive interim analysis of the ongoing phase 2 trial of rapcabtagene autoleucel in pts with 1L HR LBCL (NCT03960840).</div></div><div><h3>Methods</h3><div>Pts had histologically confirmed LBCL, IPI score of 3-5, and/or <em>MYC</em> and <em>BCL2</em> and/or <em>BCL6</em> rearrangement (DHL per WHO 2016). After 2 cycles of 1L therapy, eligible pts had stable disease (SD) or partial response (PR) by PET scan. Pts with progressive disease or CR were not eligible. Lymphodepletion was followed by a single rapcabtagene autoleucel infusion (12.5 × 10<sup>6</sup> cells). The primary endpoint was CR rate (CRR), defined as best overall response of CR post infusion. Secondary endpoints included overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), event-free survival (EFS), overall survival (OS), adverse events (AEs), and cellular kinetics.</div></div><div><h3>Results</h3><div>As of January 22, 2025 (enrollment ongoing at data cutoff), 37 pts received rapcabtagene autoleucel (median follow-up: 4.2 mo). At diagnosis, 86% had an IPI score ≥3, 38% had DHL, 95% had stage III-IV disease, 51% had germinal center B-cell (GCB) LBCL, and 41% had non-GCB. In total, 57% had an IPI of 4-5 or DHL, and 43% had an IPI of 3 without DHL. After 2 cycles of 1L therapy, 86% had PR and 14% had SD. Among 31 infused pts with ≥1 mo post-infusion follow-up, CRR was 74% and ORR was 90%. AEs (any grade) occurred in 100% of infused pts. Cytokine release syndrome (CRS) occurred in 38% (all Gr 1), immune effector cell-associated neurotoxicity syndrome (ICANS) in 8% (all Gr ≤3), and infections in 49% (Gr ≥3, 8%). Median times to CRS onset and resolution were 9.5 d and 4 d, respectively. Among pts with CRS, 50% (7/14) received tocilizumab; none were admitted to the ICU. Median times to ICANS onset and resolution were 17 d and 19 d (1 case ongoing), respectively. One pt developed immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome (Gr 2), which resolved after tocilizumab and anakinra treatment. Among pts with Gr 3 or 4 cytopenias at 1 mo post infusion, the probability of resolution by mo 3 was 100% for neutropenia, leukopenia, and anemia, and 87% for thrombocytopenia. No deaths or secondary malignancies were reported. Robust in vivo expansion (median C<sub>max</sub>: 31,000 copies/µg DNA) was similar to that reported for 3L r/r DLBCL (median C<sub>max</sub>: 41,800 copies/µg DNA).</div></div><div><h3>Conclusions</h3><div>Single-dose rapcabtagene autoleucel showed promising initial efficacy and a manageable safety profile in pts with 1L HR LBC
{"title":"Phase II Interim Results for Rapcabtagene Autoleucel (YTB323) in Patients with First-Line, High-Risk Large B-cell Lymphoma","authors":"Jason Westin MD, MS, FACP, FASCO , Julio C. Chavez MD , Stephen J. Schuster MD , Vladan Vučinić MD , Patricia A. Young MD , Patrick Connor Johnson MD , Stefania Bramanti MD , Alessandro Rambaldi MD , Javier Briones Meijide MD, PhD , Koji Kato MD, PhD , Juan-Manuel Sancho MD , Mi Kwon MD, PhD , Carlos Solano MD, PhD , Shaun Fleming MBBS (Hons), PhD, FRACP, FRCPA , Saurabh Dahiya MD, FACP , Alejandro Martin García-Sancho MD, PhD , Pedro Marques Ramos PhD , David Pearson PhD , Salif Diallo MSc , Aiesha Zia MSc , Pere Barba MD, PhD","doi":"10.1016/j.jtct.2025.12.076","DOIUrl":"10.1016/j.jtct.2025.12.076","url":null,"abstract":"<div><h3>Introduction</h3><div>Although ∼70% of patients (pts) with large B-cell lymphoma (LBCL) respond to frontline (1L) chemoimmunotherapy, outcomes are poor for high-risk (HR) disease and pts not achieving complete response (CR). Rapcabtagene autoleucel is an investigational CD19-directed CAR-T cell therapy rapidly manufactured in <2 d using the T-Charge™ platform. We report a descriptive interim analysis of the ongoing phase 2 trial of rapcabtagene autoleucel in pts with 1L HR LBCL (NCT03960840).</div></div><div><h3>Methods</h3><div>Pts had histologically confirmed LBCL, IPI score of 3-5, and/or <em>MYC</em> and <em>BCL2</em> and/or <em>BCL6</em> rearrangement (DHL per WHO 2016). After 2 cycles of 1L therapy, eligible pts had stable disease (SD) or partial response (PR) by PET scan. Pts with progressive disease or CR were not eligible. Lymphodepletion was followed by a single rapcabtagene autoleucel infusion (12.5 × 10<sup>6</sup> cells). The primary endpoint was CR rate (CRR), defined as best overall response of CR post infusion. Secondary endpoints included overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), event-free survival (EFS), overall survival (OS), adverse events (AEs), and cellular kinetics.</div></div><div><h3>Results</h3><div>As of January 22, 2025 (enrollment ongoing at data cutoff), 37 pts received rapcabtagene autoleucel (median follow-up: 4.2 mo). At diagnosis, 86% had an IPI score ≥3, 38% had DHL, 95% had stage III-IV disease, 51% had germinal center B-cell (GCB) LBCL, and 41% had non-GCB. In total, 57% had an IPI of 4-5 or DHL, and 43% had an IPI of 3 without DHL. After 2 cycles of 1L therapy, 86% had PR and 14% had SD. Among 31 infused pts with ≥1 mo post-infusion follow-up, CRR was 74% and ORR was 90%. AEs (any grade) occurred in 100% of infused pts. Cytokine release syndrome (CRS) occurred in 38% (all Gr 1), immune effector cell-associated neurotoxicity syndrome (ICANS) in 8% (all Gr ≤3), and infections in 49% (Gr ≥3, 8%). Median times to CRS onset and resolution were 9.5 d and 4 d, respectively. Among pts with CRS, 50% (7/14) received tocilizumab; none were admitted to the ICU. Median times to ICANS onset and resolution were 17 d and 19 d (1 case ongoing), respectively. One pt developed immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome (Gr 2), which resolved after tocilizumab and anakinra treatment. Among pts with Gr 3 or 4 cytopenias at 1 mo post infusion, the probability of resolution by mo 3 was 100% for neutropenia, leukopenia, and anemia, and 87% for thrombocytopenia. No deaths or secondary malignancies were reported. Robust in vivo expansion (median C<sub>max</sub>: 31,000 copies/µg DNA) was similar to that reported for 3L r/r DLBCL (median C<sub>max</sub>: 41,800 copies/µg DNA).</div></div><div><h3>Conclusions</h3><div>Single-dose rapcabtagene autoleucel showed promising initial efficacy and a manageable safety profile in pts with 1L HR LBC","PeriodicalId":23283,"journal":{"name":"Transplantation and Cellular Therapy","volume":"32 2","pages":"Pages S48-S49"},"PeriodicalIF":4.4,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146098629","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.2025.12.059
Ciara L Freeman MD, PhD , Robert C Norberg MS , Dietrich Werner Idiaquez MD , K. Ruwani M Fernando PhD , Yoganand Balagurunathan PhD , Nicholas Figura MD , Daniel Deavila BS , Gabriel De Avila BS , Praneeth Sudalagunta PhD , Ariosto Silva PhD , Omar Castaneda Puglianini MD , Hien Liu MD , Brandon Blue MD , Rachid C Baz MD , Melissa Alsina MD , Taiga Nishihori MD , Rolf Petter Tonseth MD , Rachel Howard PhD , Ariel Grajales-Cruz MD , Frederick L Locke MD , Issam M El Naqa PhD
<div><h3>Introduction</h3><div>Early treatment failure (ETF) after BCMA-directed CAR-T remains common, with 1-year PFS ∼47–73% across contemporary series. Outcomes are shaped by tumor burden, T-cell fitness, and clinical factors.</div></div><div><h3>Objectives</h3><div>Develop and validate a real-world pre-LD multimodal model from standard-of-care (SOC) data—PET/CT MTV, AQUIOS lymphocyte subsets, and routine labs/cytogenetics—to biologically stratify ETF risk before therapy.</div></div><div><h3>Methods</h3><div>We assembled a real-world cohort of ide-cel/cilta-cel recipients with all predictors measured pre-LD. Thirty-five baseline variables included ferritin, CRP, β2-microglobulin, ISS, high-risk FISH and metabolic tumor volume (MTV) from pre-LD 18F-FDG PET/CT (Freeman <em>Blood</em> 2024). Lymphocyte subsets (T/B) were obtained on all patients using the AQUIOS BC (Beckman Coulter) with Tetra-1/2 reagents. Complete cases formed the modeling set. Cox Elastic Net and Random Survival Forest (RSF) were trained with patient-level 5-fold cross-validation (multiple random initializations). Harrell’s concordance index (C-index) with out-of-bag predictions quantified prognostic performance, further assessed using Brier Scores calibration at 1-year and feature contributions by permutation importance and SHAP. Model scores defined low/intermediate/high risk bands; cumulative risk was compared using Nelson–Aalen curves.</div></div><div><h3>Results</h3><div>The RSF achieved c-index 0.686 ± 0.058 and Brier 0.052 (95% CI 0.044–0.060), indicating accurate 1-year risk prediction. Stratification yielded distinct risk bands: 81% (high), 41% (intermediate), and 22% (low) 1-year ETF (log-rank high–low p=1.7×10⁻¹⁰; high–int p=1.4×10⁻⁵; int–low p=0.003; <strong>Figure 1</strong>). In practical terms, the model identified patients at nearly fourfold higher risk of early failure, enabling potential adjustment of bridging, manufacturing timing, or monitoring intensity.</div><div>The transparent baseline (Cox–Elastic Net) performed less well (c-index 0.624 ± 0.078; Brier 0.188 [95% CI 0.163–0.213]), confirming the added value of nonlinear interactions between tumor burden and immune composition. SHAP analysis reinforced biological plausibility: higher tumor burden (EMD, marrow plasma-cell %, MTV, β₂M, LDH), greater inflammatory load (ferritin, CRP), and lower host reserve (albumin) increased ETF risk, whereas a favorable immune balance (higher CD4:CD8 ratio, CD3, CD19) correlated with better outcomes.</div></div><div><h3>Conclusions</h3><div>Pre-LD multimodal model combining SOC PET/CT tumor burden, lymphocyte subsets, and routine labs yielded clinically actionable ETF risk bands and outperforms a transparent linear baseline. T-cell composition—especially the CD4:CD8 balance—emerged as a consistent predictor of outcome. These results support optimized apheresis timing, and targeted manufacturing strategies to enhance T-cell fitness. External and temporal validation are un
bcma定向CAR-T后的早期治疗失败（ETF）仍然很常见，在当代系列中，1年PFS为47-73%。结果受肿瘤负荷、t细胞适应性和临床因素的影响。目的：根据标准护理（SOC）数据（pet /CT MTV、AQUIOS淋巴细胞亚群和常规实验室/细胞遗传学），开发并验证真实世界的ld前多模式模型，以在治疗前对ETF风险进行生物学分层。方法：我们收集了一个真实世界的ide- cell /cilta- cell受体队列，所有预测指标均测量了ld前。35个基线变量包括铁蛋白、CRP、β2-微球蛋白、ISS、高风险FISH和代谢肿瘤体积（MTV），来自ld前18F-FDG PET/CT （Freeman Blood 2024）。所有患者的淋巴细胞亚群（T/B）均使用AQUIOS BC （Beckman Coulter）和Tetra-1/2试剂进行测定。完整的案例构成了建模集。Cox Elastic Net和随机生存森林（RSF）采用患者水平的5倍交叉验证（多次随机初始化）进行训练。Harrell 's与体外预测的一致性指数（C-index）量化了预后表现，并通过1年的Brier评分校准和排列重要性和SHAP的特征贡献进一步评估。模型得分定义了低/中/高风险等级；采用nelson - aallen曲线比较累积风险。结果RSF的c-index为0.686±0.058，Brier为0.052 (95% CI为0.044 ~ 0.060)，可准确预测1年风险。分层产生了明显的风险带：81%（高），41%（中）和22%（低）1年的ETF （log-rank高-低p=1.7×10⁻¹⁰；高- int p=1.4×10⁻¹；低- int p=0.003；图1）。在实际应用中，该模型识别出早期衰竭风险高出近四倍的患者，从而可以调整桥接、制造时间或监测强度。透明基线（Cox-Elastic Net）表现较差（c-index为0.624±0.078；Brier为0.188 [95% CI 0.163-0.213]），证实了肿瘤负荷与免疫组成之间非线性相互作用的附加价值。SHAP分析增强了生物学上的合理性：较高的肿瘤负荷（EMD、骨髓浆细胞%、MTV、β₂M、LDH）、较高的炎症负荷（铁蛋白、CRP）和较低的宿主储备（白蛋白）增加了ETF的风险，而良好的免疫平衡（较高的CD4:CD8比率、CD3、CD19）与较好的预后相关。结论spre - ld多模态模型结合了SOC PET/CT肿瘤负荷、淋巴细胞亚群和常规实验室，得出了临床可操作的ETF风险分级，优于透明线性基线。t细胞组成——尤其是CD4:CD8平衡——成为预测结果的一致因素。这些结果支持优化分离时间和有针对性的制造策略来增强t细胞适应性。外部和时间验证正在进行中。
{"title":"Multimodal Prediction of Early Treatment Failure after BCMA CAR-T Incorporating PET Derived Tumor Burden and Lymphocyte Subsets","authors":"Ciara L Freeman MD, PhD , Robert C Norberg MS , Dietrich Werner Idiaquez MD , K. Ruwani M Fernando PhD , Yoganand Balagurunathan PhD , Nicholas Figura MD , Daniel Deavila BS , Gabriel De Avila BS , Praneeth Sudalagunta PhD , Ariosto Silva PhD , Omar Castaneda Puglianini MD , Hien Liu MD , Brandon Blue MD , Rachid C Baz MD , Melissa Alsina MD , Taiga Nishihori MD , Rolf Petter Tonseth MD , Rachel Howard PhD , Ariel Grajales-Cruz MD , Frederick L Locke MD , Issam M El Naqa PhD","doi":"10.1016/j.jtct.2025.12.059","DOIUrl":"10.1016/j.jtct.2025.12.059","url":null,"abstract":"<div><h3>Introduction</h3><div>Early treatment failure (ETF) after BCMA-directed CAR-T remains common, with 1-year PFS ∼47–73% across contemporary series. Outcomes are shaped by tumor burden, T-cell fitness, and clinical factors.</div></div><div><h3>Objectives</h3><div>Develop and validate a real-world pre-LD multimodal model from standard-of-care (SOC) data—PET/CT MTV, AQUIOS lymphocyte subsets, and routine labs/cytogenetics—to biologically stratify ETF risk before therapy.</div></div><div><h3>Methods</h3><div>We assembled a real-world cohort of ide-cel/cilta-cel recipients with all predictors measured pre-LD. Thirty-five baseline variables included ferritin, CRP, β2-microglobulin, ISS, high-risk FISH and metabolic tumor volume (MTV) from pre-LD 18F-FDG PET/CT (Freeman <em>Blood</em> 2024). Lymphocyte subsets (T/B) were obtained on all patients using the AQUIOS BC (Beckman Coulter) with Tetra-1/2 reagents. Complete cases formed the modeling set. Cox Elastic Net and Random Survival Forest (RSF) were trained with patient-level 5-fold cross-validation (multiple random initializations). Harrell’s concordance index (C-index) with out-of-bag predictions quantified prognostic performance, further assessed using Brier Scores calibration at 1-year and feature contributions by permutation importance and SHAP. Model scores defined low/intermediate/high risk bands; cumulative risk was compared using Nelson–Aalen curves.</div></div><div><h3>Results</h3><div>The RSF achieved c-index 0.686 ± 0.058 and Brier 0.052 (95% CI 0.044–0.060), indicating accurate 1-year risk prediction. Stratification yielded distinct risk bands: 81% (high), 41% (intermediate), and 22% (low) 1-year ETF (log-rank high–low p=1.7×10⁻¹⁰; high–int p=1.4×10⁻⁵; int–low p=0.003; <strong>Figure 1</strong>). In practical terms, the model identified patients at nearly fourfold higher risk of early failure, enabling potential adjustment of bridging, manufacturing timing, or monitoring intensity.</div><div>The transparent baseline (Cox–Elastic Net) performed less well (c-index 0.624 ± 0.078; Brier 0.188 [95% CI 0.163–0.213]), confirming the added value of nonlinear interactions between tumor burden and immune composition. SHAP analysis reinforced biological plausibility: higher tumor burden (EMD, marrow plasma-cell %, MTV, β₂M, LDH), greater inflammatory load (ferritin, CRP), and lower host reserve (albumin) increased ETF risk, whereas a favorable immune balance (higher CD4:CD8 ratio, CD3, CD19) correlated with better outcomes.</div></div><div><h3>Conclusions</h3><div>Pre-LD multimodal model combining SOC PET/CT tumor burden, lymphocyte subsets, and routine labs yielded clinically actionable ETF risk bands and outperforms a transparent linear baseline. T-cell composition—especially the CD4:CD8 balance—emerged as a consistent predictor of outcome. These results support optimized apheresis timing, and targeted manufacturing strategies to enhance T-cell fitness. External and temporal validation are un","PeriodicalId":23283,"journal":{"name":"Transplantation and Cellular Therapy","volume":"32 2","pages":"Pages S36-S37"},"PeriodicalIF":4.4,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146098631","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}
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