A. Marouf, S. Grassmann, J. Rahman, N. Ganesan, P. Berning, Y. Lin, P. Torka, A. Kumar, O. Eren, T. Zhou, A. Dogan, J. Sun, M. Lim, K. Elenitoba-Johnson, A. Zelenetz, S. Horwitz, G. Salles, A. Moskowitz, S. A. Vardhana
<p><b>Introduction:</b> Large granular lymphocytic (LGL) leukemia is a clonal T- or NK-cell disorder frequently associated with cytopenias. Standard treatments rely on immunosuppressive therapies with limited efficacy and toxicity concerns. Given that up to 40% of LGL cases harbor activating STAT3 mutations, JAK/STAT oncogenic dependence has emerged as a potential therapeutic target.</p><p><b>Methods:</b> We recently completed a multicenter investigator-initiated phase II clinical trial that evaluated ruxolitinib (20 mg PO twice daily) in LGL patients, with treatment continuing until progression (Moskowitz et al., <i>Blood</i> 2021 and <i>ASH</i> 2023). Peripheral blood samples collected before and during treatment were analyzed using single-cell Combined Indexing of Transcriptome and Epitopes (CITE-seq) and plasma proteomic profiling to elucidate Ruxolitinib mechanism of action. Functional experiments, including confocal microscopy, Cut&Run, and western blot analyses, were conducted in STAT3-wild type (WT) and STAT3-mutant Jurkat cells to validate key findings (Figure 1A).</p><p><b>Results:</b> Among 22 evaluable patients, ruxolitinib achieved a 68% clinical benefit rate and a 45% overall response rate. Single-cell analysis revealed that Ruxolitinib efficacy stems not only from direct targeting of LGL cells but also from reducing JAK/STAT-driven myeloid inflammation. Specifically, ruxolitinib suppressed IL6/JAK/STAT3 target gene expression in WT but not in STAT3-mutant LGL cells, consistent with these mutations conferring kinase-independent activity. Further analysis indicated that non-malignant circulating myeloid cells, which showed high JAK/STAT target gene enrichment at baseline, exhibit significant downregulation of JAK/STAT activity on-treatment in responding patients. SCENIC analysis was performed to investigate the heightened inflammatory signaling in STAT3-mutant cells, revealing increased STAT1 and IRF8 expression before ruxolitinib exposure. Functional assays confirmed increased nuclear translocation of STAT1 and stronger binding to IFNg-responsive genes in STAT3 mutant Jurkat cells (Figure 1B,C). This suggested that STAT3 gain-of-function mutations stabilize STAT3 homodimers, enhancing STAT1 signaling and interferon-gamma (IFNg) production (Figure 1D). Among IFNg-stimulated genes, we identified macrophage migration inhibitory factor (MIF) as an LGL-derived factor linked to treatment response. Further functional studies demonstrated that MIF enhances monocyte-induced inflammation by specific activation of JAK/STAT in these myeloid cells.</p><p><b>Conclusion:</b> These findings establish a previously unrecognized STAT3-STAT1 interplay in LGL, where STAT3 mutations enhance STAT1 signaling, promoting IFNg-mediated MIF secretion. Finally, STAT3 and STAT1 cooperatively induce myeloid-driven inflammation and cytopenia in patients with STAT3-mutant LGL, this loop being a key therapeutic target of ruxolitinib.</p><p><b>Research</b> <b>fun
大颗粒淋巴细胞白血病（LGL）是一种克隆性T细胞或nk细胞疾病，通常与细胞减少症相关。标准治疗依赖免疫抑制疗法，疗效有限，且存在毒性问题。考虑到高达40%的LGL病例携带激活STAT3突变，JAK/STAT致癌依赖性已成为潜在的治疗靶点。方法：我们最近完成了一项多中心研究者发起的II期临床试验，该试验评估了ruxolitinib （20mg PO，每日两次）在LGL患者中的应用，持续治疗直至进展（Moskowitz等人，Blood 2021和ASH 2023）。采用单细胞转录组和表位联合索引（CITE-seq）和血浆蛋白质组学分析方法分析治疗前和治疗期间收集的外周血样本，以阐明Ruxolitinib的作用机制。功能实验，包括共聚焦显微镜、Cut&；Run和western blot分析，在stat3野生型（WT）和stat3突变型Jurkat细胞中进行，以验证关键发现（图1A）。结果：在22例可评估患者中，ruxolitinib获得68%的临床获益率和45%的总缓解率。单细胞分析显示，Ruxolitinib的疗效不仅源于直接靶向LGL细胞，还源于减少JAK/ stat驱动的髓系炎症。具体来说，ruxolitinib在WT中抑制了IL6/JAK/STAT3靶基因的表达，而在STAT3突变的LGL细胞中则没有，这与这些突变赋予激酶非依赖性活性相一致。进一步的分析表明，在基线时表现出高JAK/STAT靶基因富集的非恶性循环骨髓细胞在治疗后表现出JAK/STAT活性的显著下调。通过SCENIC分析研究stat3突变细胞中炎症信号的升高，发现暴露于ruxolitinib前STAT1和IRF8的表达升高。功能分析证实STAT3突变Jurkat细胞中STAT1核易位增加，与ifng应答基因结合更强（图1B，C）。这表明STAT3功能获得突变稳定了STAT3同型二聚体，增强了STAT1信号传导和干扰素γ (IFNg)的产生（图1D）。在ifng刺激的基因中，我们发现巨噬细胞迁移抑制因子（MIF）是与治疗反应相关的lgl衍生因子。进一步的功能研究表明，MIF通过在这些髓细胞中特异性激活JAK/STAT来增强单核细胞诱导的炎症。结论：这些发现在LGL中建立了先前未被认识的STAT3-STAT1相互作用，其中STAT3突变增强STAT1信号传导，促进ifng介导的MIF分泌。最后，STAT3和STAT1在STAT3突变的LGL患者中共同诱导髓细胞驱动的炎症和细胞减少，这一环是ruxolitinib的关键治疗靶点。研究资金声明：S.A.V.由Steven a . Greenberg淋巴瘤研究基金和Joshua and Lisa Bernstein的慷慨捐赠支持。关键词：其他淋巴细胞癌；其他基础科学和转化科学；分子靶向治疗没有潜在的利益冲突来源。
{"title":"RUXOLITINIB TARGETS STAT1-STAT3 COOPERATIVELY IN LARGE GRANULAR LYMPHOCYTIC LEUKEMIA","authors":"A. Marouf, S. Grassmann, J. Rahman, N. Ganesan, P. Berning, Y. Lin, P. Torka, A. Kumar, O. Eren, T. Zhou, A. Dogan, J. Sun, M. Lim, K. Elenitoba-Johnson, A. Zelenetz, S. Horwitz, G. Salles, A. Moskowitz, S. A. Vardhana","doi":"10.1002/hon.70094_394","DOIUrl":"https://doi.org/10.1002/hon.70094_394","url":null,"abstract":"<p><b>Introduction:</b> Large granular lymphocytic (LGL) leukemia is a clonal T- or NK-cell disorder frequently associated with cytopenias. Standard treatments rely on immunosuppressive therapies with limited efficacy and toxicity concerns. Given that up to 40% of LGL cases harbor activating STAT3 mutations, JAK/STAT oncogenic dependence has emerged as a potential therapeutic target.</p><p><b>Methods:</b> We recently completed a multicenter investigator-initiated phase II clinical trial that evaluated ruxolitinib (20 mg PO twice daily) in LGL patients, with treatment continuing until progression (Moskowitz et al., <i>Blood</i> 2021 and <i>ASH</i> 2023). Peripheral blood samples collected before and during treatment were analyzed using single-cell Combined Indexing of Transcriptome and Epitopes (CITE-seq) and plasma proteomic profiling to elucidate Ruxolitinib mechanism of action. Functional experiments, including confocal microscopy, Cut&Run, and western blot analyses, were conducted in STAT3-wild type (WT) and STAT3-mutant Jurkat cells to validate key findings (Figure 1A).</p><p><b>Results:</b> Among 22 evaluable patients, ruxolitinib achieved a 68% clinical benefit rate and a 45% overall response rate. Single-cell analysis revealed that Ruxolitinib efficacy stems not only from direct targeting of LGL cells but also from reducing JAK/STAT-driven myeloid inflammation. Specifically, ruxolitinib suppressed IL6/JAK/STAT3 target gene expression in WT but not in STAT3-mutant LGL cells, consistent with these mutations conferring kinase-independent activity. Further analysis indicated that non-malignant circulating myeloid cells, which showed high JAK/STAT target gene enrichment at baseline, exhibit significant downregulation of JAK/STAT activity on-treatment in responding patients. SCENIC analysis was performed to investigate the heightened inflammatory signaling in STAT3-mutant cells, revealing increased STAT1 and IRF8 expression before ruxolitinib exposure. Functional assays confirmed increased nuclear translocation of STAT1 and stronger binding to IFNg-responsive genes in STAT3 mutant Jurkat cells (Figure 1B,C). This suggested that STAT3 gain-of-function mutations stabilize STAT3 homodimers, enhancing STAT1 signaling and interferon-gamma (IFNg) production (Figure 1D). Among IFNg-stimulated genes, we identified macrophage migration inhibitory factor (MIF) as an LGL-derived factor linked to treatment response. Further functional studies demonstrated that MIF enhances monocyte-induced inflammation by specific activation of JAK/STAT in these myeloid cells.</p><p><b>Conclusion:</b> These findings establish a previously unrecognized STAT3-STAT1 interplay in LGL, where STAT3 mutations enhance STAT1 signaling, promoting IFNg-mediated MIF secretion. Finally, STAT3 and STAT1 cooperatively induce myeloid-driven inflammation and cytopenia in patients with STAT3-mutant LGL, this loop being a key therapeutic target of ruxolitinib.</p><p><b>Research</b> <b>fun","PeriodicalId":12882,"journal":{"name":"Hematological Oncology","volume":"43 S3","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hon.70094_394","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144299987","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Epigenetic therapy has been an active area of investigation since epigenetic dysregulation has been shown to be involved in the pathogenesis of hematological malignancies. Inhibitors of histone deacetylases (HDACi) were the first being recognized as a potentially effective treatment approach for lymphoma and entered clinical practice in cutaneous and peripheral T-cell lymphomas with three FDA approved compounds. In mature lymphoid malignancies, single agent trials of agents who proved beneficial in myeloid malignancies such as inhibitors of DNA methyltransferases (DNMTi), bromodomain and extra-terminal domain proteins (BETi) or isocitrate dehydrogenases (IDHi) have been disappointing. Overall, In B-cell lymphoma, the initial enthusiasm has been tempered by the limited efficacy in monotherapy or the suboptimal benefit-risk ratio compared to other emerging therapeutic classes, notably bispecific antibodies and CARTs. This research has found a second wind with the design of new agents targeting enhancer of zeste homologue 2 (EZH2) in follicular lymphoma, EZH1–2 in ATLL/PTCL, protein arginine N-methyltransferases (PRMTs), mainly PRMT5 in Hodgkin and T-cell lymphoma and even BCL6, a master gene involved in B-cell lymphoma through perturbation of BCL6-regulated epigenetic programs
This review highlights the most recent findings with these agents and promising future directions of research in this area including their potential in overcoming epigenetically driven drug resistance mechanisms, in combination with chemotherapy especially when biomarker driven or with new immunotherapies in view of their ability to modify the tumor microenvironment.
{"title":"EPIGENETIC VULNERABILITIES: PRE-CLINICAL AND CLINICAL EVIDENCES","authors":"F. Morschhauser","doi":"10.1002/hon.70093_18","DOIUrl":"https://doi.org/10.1002/hon.70093_18","url":null,"abstract":"<p>Epigenetic therapy has been an active area of investigation since epigenetic dysregulation has been shown to be involved in the pathogenesis of hematological malignancies. Inhibitors of histone deacetylases (HDACi) were the first being recognized as a potentially effective treatment approach for lymphoma and entered clinical practice in cutaneous and peripheral T-cell lymphomas with three FDA approved compounds. In mature lymphoid malignancies, single agent trials of agents who proved beneficial in myeloid malignancies such as inhibitors of DNA methyltransferases (DNMTi), bromodomain and extra-terminal domain proteins (BETi) or isocitrate dehydrogenases (IDHi) have been disappointing. Overall, In B-cell lymphoma, the initial enthusiasm has been tempered by the limited efficacy in monotherapy or the suboptimal benefit-risk ratio compared to other emerging therapeutic classes, notably bispecific antibodies and CARTs. This research has found a second wind with the design of new agents targeting enhancer of zeste homologue 2 (EZH2) in follicular lymphoma, EZH1–2 in ATLL/PTCL, protein arginine N-methyltransferases (PRMTs), mainly PRMT5 in Hodgkin and T-cell lymphoma and even BCL6, a master gene involved in B-cell lymphoma through perturbation of BCL6-regulated epigenetic programs</p><p>This review highlights the most recent findings with these agents and promising future directions of research in this area including their potential in overcoming epigenetically driven drug resistance mechanisms, in combination with chemotherapy especially when biomarker driven or with new immunotherapies in view of their ability to modify the tumor microenvironment.</p><p><b>Keywords:</b> genomics, epigenomics, and other -omics</p><p>No potential sources of conflict of interest.</p>","PeriodicalId":12882,"journal":{"name":"Hematological Oncology","volume":"43 S3","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hon.70093_18","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144300095","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
S. Ahmed, H. Li, A. F Herrera, A. Perry, A. E Kovach, K. Davison, S. C Rutherford, S. Castellino, A. Evens, B. Kahl, N. Bartlett, J. P Leonard, M. A Shipp, S. M Smith, K. Kelly, M. LeBlanc, J. W Friedberg, J. Y Song
<p><b>Introduction:</b> Historically, survival rates in patients (pts) with Epstein-Barr virus (EBV)-positive (+) classic Hodgkin lymphoma (cHL) are lower than EBV− pts, in part due to increased frequency in older pts. EBV itself directly leads to increased PD-L1 expression in cHL, in addition to chromosome 9p24.1 alterations and the tumor microenvironment. This subset analysis from the S1826 trial which evaluated N-AVD versus Bv-AVD in newly diagnosed advanced-stage cHL assesses the impact of EBV status and histology on treatment outcomes.</p><p><b>Methods:</b> Eligible pts with stage III–IV cHL had histology confirmed by central pathology review (nodular sclerosis (NS) versus non-NS subtypes: mixed cellularity, lymphocyte-rich/depleted) and reported EBV status (IHC or ISH). Pts were randomized 1:1 to 6 cycles of N-AVD or Bv-AVD. The primary endpoint was progression-free survival (PFS).</p><p><b>Results:</b> Of 994 pts enrolled, 522 pts (53%) had available EBV status (EBV+ = 101; EBV− = 421). Among the 254 pts randomized to N-AVD, 48 (19%) were EBV+ and 206 were EBV-. Amongst 268 pts randomized to Bv-AVD, 53 (20%) were EBV+ and 215 were EBV-. Median age was 42 years (range 12–83) in EBV+ pts versus 25 years (range 12–80) in EBV− pts (<i>p</i> < 0.0001). EBV+ pts had higher IPS scores but no statistical difference in stage or B symptoms.</p><p>With median follow-up of 24 months, within EBV− group, PFS was longer with N-AVD (HR 0.54; <i>p</i> = 0.0306); 2-year PFS of 92% (95% CI: 87–95) versus 85% (95% CI: 79–89) for Bv-AVD. In the EBV+ group, PFS was dramatically improved with N-AVD (HR 0.27; <i>p</i> = 0.0127); 2-year PFS of 95% (95% CI: 80–99) in N-AVD and 72% (95% CI: 58–83) in Bv-AVD. Among EBV+ patients, the treatment effect with N-AVD remained significant after adjusting for age groups (HR = 0.25; <i>p</i> = 0.0144). In N-AVD arm, no PFS difference was seen between EBV+ and EBV− (95% versus 92%; <i>p</i> = 0.88) but in Bv-AVD arm EBV+ pts had poorer PFS (72% versus 85%; <i>p</i> = 0.03).</p><p>102 pts had non-NS histology (N-AVD = 55; Bv-AVD = 47), median age 48 years versus 22 years for NS (<i>p</i> < 0.0001), and 30% non-NS were > 60 years versus 4% of NS pts > 60 years. In non-NS pts, N-AVD resulted in longer PFS (HR 0.31; 95% CI: 0.31–0.74; <i>p</i> = 0.005), 2-year PFS of 92% (95% CI: 79–97) versus 65% (95% CI: 50–77) for Bv-AVD. NS pts had longer PFS with N-AVD (HR 0.49; 95% CI: 0.28–0.86; <i>p</i> = 0.01): 2-year PFS of 94% (95% CI: 90–96) versus 87% (95% CI: 83–91). In N-AVD arm, PFS was not significantly different in non-NS 2 years PFS 92% versus 94% in NS pts (HR 2.01, <i>p</i> = 0.11). In Bv-AVD arm, non-NS pts had inferior PFS (HR = 3.4, <i>p</i> < 0.0001), 2 years PFS 65% versus 87% in NS.</p><p><b>Conclusions:</b> While N-AVD improves outcomes for advanced stage cHL in all pts irrespective of EBV status or histologic subtype, it substantially abrogated the historically poor outcomes in pts with EBV+ cHL and thos
{"title":"IMPACT OF EBV STATUS AND HISTOLOGY ON OUTCOMES WITH NIVOLUMAB-AVD VERSUS Bv-AVD IN PATIENTS ENROLLED ON SWOG S1826","authors":"S. Ahmed, H. Li, A. F Herrera, A. Perry, A. E Kovach, K. Davison, S. C Rutherford, S. Castellino, A. Evens, B. Kahl, N. Bartlett, J. P Leonard, M. A Shipp, S. M Smith, K. Kelly, M. LeBlanc, J. W Friedberg, J. Y Song","doi":"10.1002/hon.70093_20","DOIUrl":"https://doi.org/10.1002/hon.70093_20","url":null,"abstract":"<p><b>Introduction:</b> Historically, survival rates in patients (pts) with Epstein-Barr virus (EBV)-positive (+) classic Hodgkin lymphoma (cHL) are lower than EBV− pts, in part due to increased frequency in older pts. EBV itself directly leads to increased PD-L1 expression in cHL, in addition to chromosome 9p24.1 alterations and the tumor microenvironment. This subset analysis from the S1826 trial which evaluated N-AVD versus Bv-AVD in newly diagnosed advanced-stage cHL assesses the impact of EBV status and histology on treatment outcomes.</p><p><b>Methods:</b> Eligible pts with stage III–IV cHL had histology confirmed by central pathology review (nodular sclerosis (NS) versus non-NS subtypes: mixed cellularity, lymphocyte-rich/depleted) and reported EBV status (IHC or ISH). Pts were randomized 1:1 to 6 cycles of N-AVD or Bv-AVD. The primary endpoint was progression-free survival (PFS).</p><p><b>Results:</b> Of 994 pts enrolled, 522 pts (53%) had available EBV status (EBV+ = 101; EBV− = 421). Among the 254 pts randomized to N-AVD, 48 (19%) were EBV+ and 206 were EBV-. Amongst 268 pts randomized to Bv-AVD, 53 (20%) were EBV+ and 215 were EBV-. Median age was 42 years (range 12–83) in EBV+ pts versus 25 years (range 12–80) in EBV− pts (<i>p</i> < 0.0001). EBV+ pts had higher IPS scores but no statistical difference in stage or B symptoms.</p><p>With median follow-up of 24 months, within EBV− group, PFS was longer with N-AVD (HR 0.54; <i>p</i> = 0.0306); 2-year PFS of 92% (95% CI: 87–95) versus 85% (95% CI: 79–89) for Bv-AVD. In the EBV+ group, PFS was dramatically improved with N-AVD (HR 0.27; <i>p</i> = 0.0127); 2-year PFS of 95% (95% CI: 80–99) in N-AVD and 72% (95% CI: 58–83) in Bv-AVD. Among EBV+ patients, the treatment effect with N-AVD remained significant after adjusting for age groups (HR = 0.25; <i>p</i> = 0.0144). In N-AVD arm, no PFS difference was seen between EBV+ and EBV− (95% versus 92%; <i>p</i> = 0.88) but in Bv-AVD arm EBV+ pts had poorer PFS (72% versus 85%; <i>p</i> = 0.03).</p><p>102 pts had non-NS histology (N-AVD = 55; Bv-AVD = 47), median age 48 years versus 22 years for NS (<i>p</i> < 0.0001), and 30% non-NS were > 60 years versus 4% of NS pts > 60 years. In non-NS pts, N-AVD resulted in longer PFS (HR 0.31; 95% CI: 0.31–0.74; <i>p</i> = 0.005), 2-year PFS of 92% (95% CI: 79–97) versus 65% (95% CI: 50–77) for Bv-AVD. NS pts had longer PFS with N-AVD (HR 0.49; 95% CI: 0.28–0.86; <i>p</i> = 0.01): 2-year PFS of 94% (95% CI: 90–96) versus 87% (95% CI: 83–91). In N-AVD arm, PFS was not significantly different in non-NS 2 years PFS 92% versus 94% in NS pts (HR 2.01, <i>p</i> = 0.11). In Bv-AVD arm, non-NS pts had inferior PFS (HR = 3.4, <i>p</i> < 0.0001), 2 years PFS 65% versus 87% in NS.</p><p><b>Conclusions:</b> While N-AVD improves outcomes for advanced stage cHL in all pts irrespective of EBV status or histologic subtype, it substantially abrogated the historically poor outcomes in pts with EBV+ cHL and thos","PeriodicalId":12882,"journal":{"name":"Hematological Oncology","volume":"43 S3","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hon.70093_20","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144300096","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
P. L. Zinzani, S. Spurgeon, M. Pavlovsky, C. Y. Cheah, D. Villa, S. Luminari, V. Otero, G. De Jesus, R. Lesley, M. L. Wang
<p><b>Introduction:</b> The combination of acalabrutinib with bendamustine-rituximab (ABR) significantly improved progression-free survival (PFS) versus placebo with BR (PBR) in the phase 3 ECHO trial (NCT02972840) in older patients (pts) with previously untreated mantle cell lymphoma (MCL) (Wang M, et al. <i>EHA</i> 2024. Abstract #LB3439). Minimal residual disease (MRD) has been shown to be an impactful prognostic factor for outcomes in MCL. Previously presented data from the trial showed that a lower percentage of pts receiving ABR had molecular relapse during the maintenance period than pts receiving PBR (Dreyling M, et al. <i>Blood</i>. 2024;144(Suppl 1):1626). Herein, we examine the association between MRD status and clinical outcomes in the ECHO trial.</p><p><b>Methods:</b> Pts aged ≥ 65 years with previously untreated MCL and Eastern Cooperative Oncology Group performance status ≤ 2 were randomly assigned 1:1 to receive ABR or PBR. BR was given for 6 cycles (induction) followed by rituximab maintenance for 2 years in pts achieving a partial or complete response (CR). Acalabrutinib (100 mg twice daily) or placebo was administered until disease progression or unacceptable toxicity. Crossover to acalabrutinib was permitted at disease progression. The primary endpoint was PFS per independent review committee. MRD (10<sup>−5</sup>) was assessed in peripheral blood every 24 weeks and at CR or progressive disease using the ClonoSEQ assay (Adaptive Biotechnologies).</p><p><b>Results:</b> At the February 15, 2024 data cutoff, 266 pts in the ABR arm and 252 pts in the PBR arm were evaluable for MRD (89.0% and 84.3%, respectively). Pts who did not achieve MRD negativity at any time had a median PFS and overall survival (OS) of 13.8 and 22.8 months, respectively, while pts achieving MRD negativity had a median PFS of 66.7 months (hazard ratio [HR] 0.22; <i>p</i> < 0.0001) and median OS was not reached (HR: 0.31; <i>p</i> = 0.00015); pts who did not achieve MRD negativity were 4.5 times more likely to experience disease progression. Pts who became MRD negative at any time also had better outcomes with or without clinical complete response versus those who remained MRD positive (Figure). The probability of maintaining MRD negativity after induction was 2.3-fold greater for pts in the ABR arm (HR: 0.44; <i>p</i> = 0.022). Among all pts, those who maintained MRD negativity after 24 weeks had improved outcomes (median PFS 70.2 months) versus those who converted from MRD negative at 24 weeks to MRD positive during the maintenance period (median PFS 44.2 months; HR: 1.96; <i>p</i> < 0.0001).</p><p><b>Conclusions:</b> In the phase 3 ECHO trial, achieving MRD negativity was associated with improved PFS. MRD was a stronger prognostic factor for outcome than clinical response. Continuous therapy with acalabrutinib increased the probability of maintaining MRD negativity after induction, and sustained MRD negativity was associated with improved PFS, suggest
{"title":"MINIMAL RESIDUAL DISEASE WITH BENDAMUSTINE-RITUXIMAB WITH OR WITHOUT ACALABRUTINIB IN PATIENTS WITH PREVIOUSLY UNTREATED MANTLE CELL LYMPHOMA: RESULTS FROM THE ECHO TRIAL","authors":"P. L. Zinzani, S. Spurgeon, M. Pavlovsky, C. Y. Cheah, D. Villa, S. Luminari, V. Otero, G. De Jesus, R. Lesley, M. L. Wang","doi":"10.1002/hon.70093_136","DOIUrl":"https://doi.org/10.1002/hon.70093_136","url":null,"abstract":"<p><b>Introduction:</b> The combination of acalabrutinib with bendamustine-rituximab (ABR) significantly improved progression-free survival (PFS) versus placebo with BR (PBR) in the phase 3 ECHO trial (NCT02972840) in older patients (pts) with previously untreated mantle cell lymphoma (MCL) (Wang M, et al. <i>EHA</i> 2024. Abstract #LB3439). Minimal residual disease (MRD) has been shown to be an impactful prognostic factor for outcomes in MCL. Previously presented data from the trial showed that a lower percentage of pts receiving ABR had molecular relapse during the maintenance period than pts receiving PBR (Dreyling M, et al. <i>Blood</i>. 2024;144(Suppl 1):1626). Herein, we examine the association between MRD status and clinical outcomes in the ECHO trial.</p><p><b>Methods:</b> Pts aged ≥ 65 years with previously untreated MCL and Eastern Cooperative Oncology Group performance status ≤ 2 were randomly assigned 1:1 to receive ABR or PBR. BR was given for 6 cycles (induction) followed by rituximab maintenance for 2 years in pts achieving a partial or complete response (CR). Acalabrutinib (100 mg twice daily) or placebo was administered until disease progression or unacceptable toxicity. Crossover to acalabrutinib was permitted at disease progression. The primary endpoint was PFS per independent review committee. MRD (10<sup>−5</sup>) was assessed in peripheral blood every 24 weeks and at CR or progressive disease using the ClonoSEQ assay (Adaptive Biotechnologies).</p><p><b>Results:</b> At the February 15, 2024 data cutoff, 266 pts in the ABR arm and 252 pts in the PBR arm were evaluable for MRD (89.0% and 84.3%, respectively). Pts who did not achieve MRD negativity at any time had a median PFS and overall survival (OS) of 13.8 and 22.8 months, respectively, while pts achieving MRD negativity had a median PFS of 66.7 months (hazard ratio [HR] 0.22; <i>p</i> < 0.0001) and median OS was not reached (HR: 0.31; <i>p</i> = 0.00015); pts who did not achieve MRD negativity were 4.5 times more likely to experience disease progression. Pts who became MRD negative at any time also had better outcomes with or without clinical complete response versus those who remained MRD positive (Figure). The probability of maintaining MRD negativity after induction was 2.3-fold greater for pts in the ABR arm (HR: 0.44; <i>p</i> = 0.022). Among all pts, those who maintained MRD negativity after 24 weeks had improved outcomes (median PFS 70.2 months) versus those who converted from MRD negative at 24 weeks to MRD positive during the maintenance period (median PFS 44.2 months; HR: 1.96; <i>p</i> < 0.0001).</p><p><b>Conclusions:</b> In the phase 3 ECHO trial, achieving MRD negativity was associated with improved PFS. MRD was a stronger prognostic factor for outcome than clinical response. Continuous therapy with acalabrutinib increased the probability of maintaining MRD negativity after induction, and sustained MRD negativity was associated with improved PFS, suggest","PeriodicalId":12882,"journal":{"name":"Hematological Oncology","volume":"43 S3","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hon.70093_136","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144300207","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
S. Huerga-Domínguez, B. Ariceta, P. Aguirre-Ruiz, P. San Martín-Uriz, S. Sarvide, Á. López-Janeiro, D. Alignani, E. Muiños-Lopez, M. Abengozar-Muela, S. Browne, R. Figueroa, C. Grande, A. López-López, J. R. Rodríguez-Madoz, A. Vilas-Zornoza, S. Roa, F. Prósper, M. Canales
<p>B. Ariceta equally contributing author.</p><p><b>Introduction:</b> The diversity of germinal centers has a significant role in the transformation of follicular lymphoma (FL). This heterogeneity in FL is driven by a combination of genetic and epigenetic modifications, and interactions with the tumor microenvironment (TME). Understanding how these mechanisms lead disease progression is crucial for identifying therapeutic targets and prognostic markers.</p><p><b>Methods:</b> We performed single-cell DNA sequencing (scDNA-seq) (Mission Bio Tapestri Platform), single-cell RNA sequencing (scRNA-seq), and spatial transcriptomics (10X Genomics) analysis on 5 lymph node samples at diagnosis: 3 DLBCL (1 GCB, 2 ABC) and 2 FL (1 transformed—tFL- and 1 non-transformed—ntFL-).</p><p><b>Results:</b> In the scRNA-seq analysis, malignant B cells clustered into 6 clusters. Light-zone (LZ) cells were specific to ntF, whereas tFL and GCB were enriched in dark zone/light zone (DZ/LZ) cells. Pre-memory B (pre-M) and pre-plasma cells predominated in ABC (Figure 1a). Differential expression analysis identified BCR activation (DZ-LZ), cytokine signaling (LZ), and pro-tumor pathways activation, including NF-kB (pre-M). Transcriptional similarities between tFL and GCB suggest a common precursor driven by BCR activation. However, GCB revealed a dominant cell-cycle dysregulation signature, while tFL showed an immune-evasion one.</p><p>T cell subclusters varied significantly across patients. ntFL was enriched in naïve CD4<sup>−</sup>CD8<sup>−</sup> and CD8<sup>+</sup> central memory T cells, while tFL and GCB were enriched in CD4<sup>+</sup> T cells. CD4<sup>+</sup> and CD8<sup>+</sup>Teff cells were predominant in ABC samples. CD4<sup>+</sup> T cells promoted T cell tolerance (IL6/STAT3, PD-1), while CD8<sup>+</sup>Teff cells exhibited high exhaustion marker expression. CD8<sup>+</sup>Teff cells from DLBCL and tFL showed stronger exhaustion profiles than ntFL. CD4<sup>+</sup> Tfh cells expressed genes involved in adhesion with malignant B cells, with significantly higher expression in DLBCL and tFL (Figure 1b).</p><p>In the scDNA-seq analysis, patients harbored mutations in chromatin-modifying genes (<i>KMT2D</i> and <i>EZH2</i>) and oncogenic genes (<i>NOTCH2</i>). In GCB and tFL samples, <i>KMT2D</i> variants were identified as early events, while <i>EZH2</i> (tFL) and <i>ATM</i> (GCB) mutations emerged as secondary events. A nonsense mutation in <i>TET2</i> was detected in non-B cells, suggesting the presence of clonal hematopoiesis (CH). A second scDNA-seq analysis was performed to investigate CH further, focusing on CH-related variants in 3 samples. All harbored 2 or 3 mutations in epigenetic modifier genes (<i>TET2</i>, <i>ASXL1,</i> and <i>DNMT3A</i>).</p><p>In the spatial transcriptomics analysis, 28,387 spots were examined. Deconvolution using paired scRNA-seq data confirmed an adequate representation of all cell types.</p><p><b>Conclusions:</b> These findings pr
{"title":"GENOMIC AND TRANSCRIPTIONAL SINGLE-CELL HETEROGENEITY IN GERMINAL-CENTER LYMPHOMAS: INSIGHTS INTO FOLLICULAR LYMPHOMA TRANSFORMATION","authors":"S. Huerga-Domínguez, B. Ariceta, P. Aguirre-Ruiz, P. San Martín-Uriz, S. Sarvide, Á. López-Janeiro, D. Alignani, E. Muiños-Lopez, M. Abengozar-Muela, S. Browne, R. Figueroa, C. Grande, A. López-López, J. R. Rodríguez-Madoz, A. Vilas-Zornoza, S. Roa, F. Prósper, M. Canales","doi":"10.1002/hon.70094_179","DOIUrl":"https://doi.org/10.1002/hon.70094_179","url":null,"abstract":"<p>B. Ariceta equally contributing author.</p><p><b>Introduction:</b> The diversity of germinal centers has a significant role in the transformation of follicular lymphoma (FL). This heterogeneity in FL is driven by a combination of genetic and epigenetic modifications, and interactions with the tumor microenvironment (TME). Understanding how these mechanisms lead disease progression is crucial for identifying therapeutic targets and prognostic markers.</p><p><b>Methods:</b> We performed single-cell DNA sequencing (scDNA-seq) (Mission Bio Tapestri Platform), single-cell RNA sequencing (scRNA-seq), and spatial transcriptomics (10X Genomics) analysis on 5 lymph node samples at diagnosis: 3 DLBCL (1 GCB, 2 ABC) and 2 FL (1 transformed—tFL- and 1 non-transformed—ntFL-).</p><p><b>Results:</b> In the scRNA-seq analysis, malignant B cells clustered into 6 clusters. Light-zone (LZ) cells were specific to ntF, whereas tFL and GCB were enriched in dark zone/light zone (DZ/LZ) cells. Pre-memory B (pre-M) and pre-plasma cells predominated in ABC (Figure 1a). Differential expression analysis identified BCR activation (DZ-LZ), cytokine signaling (LZ), and pro-tumor pathways activation, including NF-kB (pre-M). Transcriptional similarities between tFL and GCB suggest a common precursor driven by BCR activation. However, GCB revealed a dominant cell-cycle dysregulation signature, while tFL showed an immune-evasion one.</p><p>T cell subclusters varied significantly across patients. ntFL was enriched in naïve CD4<sup>−</sup>CD8<sup>−</sup> and CD8<sup>+</sup> central memory T cells, while tFL and GCB were enriched in CD4<sup>+</sup> T cells. CD4<sup>+</sup> and CD8<sup>+</sup>Teff cells were predominant in ABC samples. CD4<sup>+</sup> T cells promoted T cell tolerance (IL6/STAT3, PD-1), while CD8<sup>+</sup>Teff cells exhibited high exhaustion marker expression. CD8<sup>+</sup>Teff cells from DLBCL and tFL showed stronger exhaustion profiles than ntFL. CD4<sup>+</sup> Tfh cells expressed genes involved in adhesion with malignant B cells, with significantly higher expression in DLBCL and tFL (Figure 1b).</p><p>In the scDNA-seq analysis, patients harbored mutations in chromatin-modifying genes (<i>KMT2D</i> and <i>EZH2</i>) and oncogenic genes (<i>NOTCH2</i>). In GCB and tFL samples, <i>KMT2D</i> variants were identified as early events, while <i>EZH2</i> (tFL) and <i>ATM</i> (GCB) mutations emerged as secondary events. A nonsense mutation in <i>TET2</i> was detected in non-B cells, suggesting the presence of clonal hematopoiesis (CH). A second scDNA-seq analysis was performed to investigate CH further, focusing on CH-related variants in 3 samples. All harbored 2 or 3 mutations in epigenetic modifier genes (<i>TET2</i>, <i>ASXL1,</i> and <i>DNMT3A</i>).</p><p>In the spatial transcriptomics analysis, 28,387 spots were examined. Deconvolution using paired scRNA-seq data confirmed an adequate representation of all cell types.</p><p><b>Conclusions:</b> These findings pr","PeriodicalId":12882,"journal":{"name":"Hematological Oncology","volume":"43 S3","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hon.70094_179","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144292040","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
<p>T-cell redirecting therapies, have revolutionized the management of diverse malignancies, especially B-cell non-Hodgkin lymphomas. Currently approved such therapies include T-cells that are engineered to express chimeric antigen receptors (CAR-T cells) and bispecific antibodies that bridge T-cells to diverse tumor antigens. Yet despite their remarkable efficacy and curative potential, resistance and relapse to these therapies remain significant hurdles, and unfortunately, still observed in most patients today. This presentation will explore the tumor-intrinsic mechanisms that contribute to such resistance in mature B-cell neoplasms, while also considering the roles of T-cell dysfunction and the tumor microenvironment (TME) in resistance phenotypes.</p><p>I will review data from several studies that have highlighted key mechanisms and pathways underlying such tumor intrinsic resistance. In one key study by Sworder et al. (<i>Cancer Cell</i>, 2023) a comprehensive simultaneous tumor and effector profiling (STEP) approach has been described to investigate resistance determinants in large B-cell lymphomas treated with anti-CD19 CAR T-cells. In addition to genetic and epigenetic mechanisms known to hamper target antigen expression of key tumor markers (such as CD19, CD20, CD22, and BCMA), these studies have revealed that genetic alterations in B cell identity genes like PAX5 and IRF8 may lead to lineage switch or loss of target antigens. Separately, these studies show how somatic gains driving upregulation of key immune checkpoints like PD-L1 upregulation can help tumors evade T-cell attacks. For bispecific antibodies, similar mechanisms, such as antigen loss, are also observed, suggesting shared challenges across therapies.</p><p>When considering non-tumor intrinsic mechanisms of resistance, the TME is also known to play a crucial role, with research indicating that immune-suppressed TME profiles correlate with poorer outcomes, likely by hindering T-cell function through axes such as PD-1, TIM-3, suppressive actions of Tregs, MDSCs, inhibitory cytokines, and others. T-cell exhaustion, driven by chronic antigen exposure and TME immunosuppression, is known to reduce effector functions and persistence, impacting both CAR-T and bispecific antibody efficacy. Conversely, TMEs with high B cell proliferation may predict better CAR-T responses, an unexpected feature that could also guide therapy selection.</p><p>I will highlight how such approaches to integrative genomic profiling, TME analysis, and T-cell functional assessments can enhance outcome prediction and personalize T-cell therapies. In addition to defining key gaps in our current knowledge, I will describe strategies to help bridge these gaps, toward optimizing existing therapies and developing next-generation interventions to overcome resistance, potentially improving long-term outcomes for patients with lymphomas and other tumors.</p><p><b>Keywords:</b> aggressive B-cell non-Hodgkin lymphoma</p
t细胞重定向疗法已经彻底改变了各种恶性肿瘤的治疗，特别是b细胞非霍奇金淋巴瘤。目前批准的治疗方法包括t细胞修饰表达嵌合抗原受体（CAR-T细胞）和双特异性抗体，将t细胞与多种肿瘤抗原连接起来。然而，尽管这些疗法具有显著的疗效和治疗潜力，但耐药性和复发仍然是重大障碍，不幸的是，今天在大多数患者中仍然观察到这些障碍。本报告将探讨成熟b细胞肿瘤产生这种耐药的肿瘤内在机制，同时也考虑t细胞功能障碍和肿瘤微环境（TME）在耐药表型中的作用。我将回顾几项研究的数据，这些研究强调了肿瘤内在抗性的关键机制和途径。在Sworder等人（Cancer Cell, 2023）的一项关键研究中，描述了一种综合的同步肿瘤和效应分析（STEP）方法来研究抗cd19 CAR - t细胞治疗的大b细胞淋巴瘤的耐药决定因素。除了已知的阻碍关键肿瘤标志物（如CD19、CD20、CD22和BCMA）靶抗原表达的遗传和表观遗传机制外，这些研究还揭示了B细胞识别基因（如PAX5和IRF8）的遗传改变可能导致谱系切换或靶抗原的丢失。另外，这些研究表明，体细胞增益如何驱动关键免疫检查点（如PD-L1上调）的上调，从而帮助肿瘤逃避t细胞的攻击。对于双特异性抗体，也观察到类似的机制，如抗原丢失，这表明各种治疗方法都存在共同的挑战。当考虑到非肿瘤的内在耐药机制时，TME也被认为起着至关重要的作用，研究表明免疫抑制的TME谱与较差的结果相关，可能是通过PD-1、TIM-3、Tregs、MDSCs、抑制性细胞因子等轴阻碍t细胞功能。已知由慢性抗原暴露和TME免疫抑制驱动的t细胞衰竭会降低效应剂的功能和持久性，影响CAR-T和双特异性抗体的功效。相反，具有高B细胞增殖的TMEs可能预测更好的CAR-T反应，这是一个意想不到的特征，也可以指导治疗选择。我将重点介绍这些整合基因组分析、TME分析和t细胞功能评估的方法如何提高结果预测和个性化t细胞治疗。除了定义我们目前知识中的关键差距之外，我还将描述帮助弥合这些差距的策略，以优化现有疗法和开发下一代干预措施来克服耐药性，潜在地改善淋巴瘤和其他肿瘤患者的长期预后。关键词：侵袭性b细胞非霍奇金淋巴瘤潜在利益冲突来源
{"title":"MECHANISMS OF RESISTANCE TO T-CELL REDIRECTING THERAPIES","authors":"A. A. Alizadeh","doi":"10.1002/hon.70093_68","DOIUrl":"https://doi.org/10.1002/hon.70093_68","url":null,"abstract":"<p>T-cell redirecting therapies, have revolutionized the management of diverse malignancies, especially B-cell non-Hodgkin lymphomas. Currently approved such therapies include T-cells that are engineered to express chimeric antigen receptors (CAR-T cells) and bispecific antibodies that bridge T-cells to diverse tumor antigens. Yet despite their remarkable efficacy and curative potential, resistance and relapse to these therapies remain significant hurdles, and unfortunately, still observed in most patients today. This presentation will explore the tumor-intrinsic mechanisms that contribute to such resistance in mature B-cell neoplasms, while also considering the roles of T-cell dysfunction and the tumor microenvironment (TME) in resistance phenotypes.</p><p>I will review data from several studies that have highlighted key mechanisms and pathways underlying such tumor intrinsic resistance. In one key study by Sworder et al. (<i>Cancer Cell</i>, 2023) a comprehensive simultaneous tumor and effector profiling (STEP) approach has been described to investigate resistance determinants in large B-cell lymphomas treated with anti-CD19 CAR T-cells. In addition to genetic and epigenetic mechanisms known to hamper target antigen expression of key tumor markers (such as CD19, CD20, CD22, and BCMA), these studies have revealed that genetic alterations in B cell identity genes like PAX5 and IRF8 may lead to lineage switch or loss of target antigens. Separately, these studies show how somatic gains driving upregulation of key immune checkpoints like PD-L1 upregulation can help tumors evade T-cell attacks. For bispecific antibodies, similar mechanisms, such as antigen loss, are also observed, suggesting shared challenges across therapies.</p><p>When considering non-tumor intrinsic mechanisms of resistance, the TME is also known to play a crucial role, with research indicating that immune-suppressed TME profiles correlate with poorer outcomes, likely by hindering T-cell function through axes such as PD-1, TIM-3, suppressive actions of Tregs, MDSCs, inhibitory cytokines, and others. T-cell exhaustion, driven by chronic antigen exposure and TME immunosuppression, is known to reduce effector functions and persistence, impacting both CAR-T and bispecific antibody efficacy. Conversely, TMEs with high B cell proliferation may predict better CAR-T responses, an unexpected feature that could also guide therapy selection.</p><p>I will highlight how such approaches to integrative genomic profiling, TME analysis, and T-cell functional assessments can enhance outcome prediction and personalize T-cell therapies. In addition to defining key gaps in our current knowledge, I will describe strategies to help bridge these gaps, toward optimizing existing therapies and developing next-generation interventions to overcome resistance, potentially improving long-term outcomes for patients with lymphomas and other tumors.</p><p><b>Keywords:</b> aggressive B-cell non-Hodgkin lymphoma</p","PeriodicalId":12882,"journal":{"name":"Hematological Oncology","volume":"43 S3","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hon.70093_68","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144292218","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
J. S. Abramson, M. Ku, M. Hertzberg, C. P. Fox, C. Herbaux, H. Huang, D. H. Yoon, W. S. Kim, H. Zhang, H. Abdulhaq, W. Townsend, E. Mulvihill, V. Orellana-Noia, R. Ta, H. Huang, M. J. Kallemeijn, A. Belousov, A. Bottos, L. Lundberg, G. P. Gregory
<p><b>Introduction:</b> Glofitamab, a CD20:CD3 bispecific antibody, has shown durable responses as fixed duration monotherapy in R/R DLBCL after ≥ 2 prior lines of therapy (LOT; Dickinson et al. NEJM 2022). In the Phase 3 STARGLO trial, Glofit-GemOx demonstrated overall survival (OS) and progression-free survival (PFS) benefits over rituximab (R)-GemOx in autologous stem cell transplant (ASCT)-ineligible R/R DLBCL (Abramson et al. Lancet 2024). Here, we present updated efficacy and safety from the STARGLO trial (NCT04408638), including landmark analyses of patients (pts) in complete remission (CR).</p><p><b>Methods:</b> Pts were randomized 2:1 to receive Glofit-GemOx (8 cycles plus 4 cycles glofitamab monotherapy) or R-GemOx (8 cycles) and stratified by number of prior LOT (1 vs. ≥ 2) and refractoriness to their last therapy. After obinutuzumab pretreatment, glofitamab was given in Cycle (C) 1 as weekly step-up doses (2.5/10 mg) then 30 mg target dose every 21 days from C2 Day 1. Pts with only 1 prior LOT must have been ASCT-ineligible. Primary endpoint was OS. Secondary endpoints included independent review committee (IRC)-assessed PFS and CR rate. A landmark analysis of pts in CR at end of treatment (EOT) was performed.</p><p><b>Results:</b> Of 274 pts (Glofit-GemOx, <i>n</i> = 183; R-GemOx, <i>n</i> = 91), 172 (62.8%) had 1 prior LOT, 102 (37.2%) had ≥ 2 prior LOT, 153 (55.8%) were primary refractory, and 166 (60.6%) were refractory to their last therapy. Baseline characteristics were unchanged compared with the primary analysis and well balanced across arms.</p><p>With 2 years (yrs) of follow-up (data cut off: June 17, 2024; median follow-up: 24.7 months [mo]), Glofit-GemOx continued to confer superior OS (median: not evaluable [NE] vs. 13.5 mo; hazard ratio [HR] 0.60, 95% confidence interval [CI]: 0.42–0.85), median IRC-assessed PFS (13.8 vs. 3.6 mo; HR 0.41, 95% CI: 0.29–0.58), and CR rate (58.5 vs. 25.3%) versus R-GemOx. For Glofit-GemOx-treated pts in CR (<i>n</i> = 107), median duration of CR was not reached (95% CI: 27.2–NE; median CR follow-up, 18.2 mo [range: 15.2–19.3]). In pts with a CR at EOT (<i>n</i> = 82), the OS and PFS rates 1 yr after EOT were 89.3% and 82.4%, respectively.</p><p>The Glofit-GemOx safety profile was unchanged. Cytokine release syndrome (CRS) was the most common adverse event in glofitamab-exposed pts (Grade [Gr] 1, 32.0%; Gr 2, 10.5%; Gr 3, 2.3%). Events consistent with immune effector cell-associated neurotoxicity syndrome occurred in 4 pts (all concurrent with CRS; most Gr 1–2 [<i>n</i> = 3]). Exploratory biomarker and immune recovery data will be presented.</p><p><b>Conclusions:</b> With 2 yrs of follow-up, Glofit-GemOx sustained a clinically meaningful benefit in OS and PFS versus R-GemOx in ASCT-ineligible pts with R/R DLBCL, with most (82%) pts in CR at EOT still in remission. The safety profile was consistent with known risks of each drug. The updated analyses demonstrate durable remissions and maintain
{"title":"GLOFITAMAB PLUS GEMCITABINE AND OXALIPLATIN (Glofit-GemOx) IN PATIENTS WITH RELAPSED/REFRACTORY (R/R) DIFFUSE LARGE B-CELL LYMPHOMA (DLBCL): 2-YEAR FOLLOW-UP OF STARGLO","authors":"J. S. Abramson, M. Ku, M. Hertzberg, C. P. Fox, C. Herbaux, H. Huang, D. H. Yoon, W. S. Kim, H. Zhang, H. Abdulhaq, W. Townsend, E. Mulvihill, V. Orellana-Noia, R. Ta, H. Huang, M. J. Kallemeijn, A. Belousov, A. Bottos, L. Lundberg, G. P. Gregory","doi":"10.1002/hon.70093_76","DOIUrl":"https://doi.org/10.1002/hon.70093_76","url":null,"abstract":"<p><b>Introduction:</b> Glofitamab, a CD20:CD3 bispecific antibody, has shown durable responses as fixed duration monotherapy in R/R DLBCL after ≥ 2 prior lines of therapy (LOT; Dickinson et al. NEJM 2022). In the Phase 3 STARGLO trial, Glofit-GemOx demonstrated overall survival (OS) and progression-free survival (PFS) benefits over rituximab (R)-GemOx in autologous stem cell transplant (ASCT)-ineligible R/R DLBCL (Abramson et al. Lancet 2024). Here, we present updated efficacy and safety from the STARGLO trial (NCT04408638), including landmark analyses of patients (pts) in complete remission (CR).</p><p><b>Methods:</b> Pts were randomized 2:1 to receive Glofit-GemOx (8 cycles plus 4 cycles glofitamab monotherapy) or R-GemOx (8 cycles) and stratified by number of prior LOT (1 vs. ≥ 2) and refractoriness to their last therapy. After obinutuzumab pretreatment, glofitamab was given in Cycle (C) 1 as weekly step-up doses (2.5/10 mg) then 30 mg target dose every 21 days from C2 Day 1. Pts with only 1 prior LOT must have been ASCT-ineligible. Primary endpoint was OS. Secondary endpoints included independent review committee (IRC)-assessed PFS and CR rate. A landmark analysis of pts in CR at end of treatment (EOT) was performed.</p><p><b>Results:</b> Of 274 pts (Glofit-GemOx, <i>n</i> = 183; R-GemOx, <i>n</i> = 91), 172 (62.8%) had 1 prior LOT, 102 (37.2%) had ≥ 2 prior LOT, 153 (55.8%) were primary refractory, and 166 (60.6%) were refractory to their last therapy. Baseline characteristics were unchanged compared with the primary analysis and well balanced across arms.</p><p>With 2 years (yrs) of follow-up (data cut off: June 17, 2024; median follow-up: 24.7 months [mo]), Glofit-GemOx continued to confer superior OS (median: not evaluable [NE] vs. 13.5 mo; hazard ratio [HR] 0.60, 95% confidence interval [CI]: 0.42–0.85), median IRC-assessed PFS (13.8 vs. 3.6 mo; HR 0.41, 95% CI: 0.29–0.58), and CR rate (58.5 vs. 25.3%) versus R-GemOx. For Glofit-GemOx-treated pts in CR (<i>n</i> = 107), median duration of CR was not reached (95% CI: 27.2–NE; median CR follow-up, 18.2 mo [range: 15.2–19.3]). In pts with a CR at EOT (<i>n</i> = 82), the OS and PFS rates 1 yr after EOT were 89.3% and 82.4%, respectively.</p><p>The Glofit-GemOx safety profile was unchanged. Cytokine release syndrome (CRS) was the most common adverse event in glofitamab-exposed pts (Grade [Gr] 1, 32.0%; Gr 2, 10.5%; Gr 3, 2.3%). Events consistent with immune effector cell-associated neurotoxicity syndrome occurred in 4 pts (all concurrent with CRS; most Gr 1–2 [<i>n</i> = 3]). Exploratory biomarker and immune recovery data will be presented.</p><p><b>Conclusions:</b> With 2 yrs of follow-up, Glofit-GemOx sustained a clinically meaningful benefit in OS and PFS versus R-GemOx in ASCT-ineligible pts with R/R DLBCL, with most (82%) pts in CR at EOT still in remission. The safety profile was consistent with known risks of each drug. The updated analyses demonstrate durable remissions and maintain","PeriodicalId":12882,"journal":{"name":"Hematological Oncology","volume":"43 S3","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hon.70093_76","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144292221","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
C. Querfeld, L. Chen, X. Wu, Z. Han, C. Su, Y. Yuan, M. Banez, J. Quach, T. Barnhizer, L. Crisan, S. T. Rosen, J. Zain
<p><b>Introduction:</b> Advanced stages of cutaneous T cell lymphoma (CTCL) have an unfavorable prognosis. We have shown that CTCL escapes immune surveillance via immune checkpoint signaling such as the PD-1/PD-L1 axis. Selective targeting of the functionally exhausted malignant T cells in cutaneous T-cell lymphoma (CTCL) and distinct cells within the tumor microenvironment (TME) via PD1/PD-L1 blockade (durvalumab) may restore an anti-tumor immune response. We initiated the randomized Phase 2 portion to compare single agent durvalumab to durvalumab plus lenalidomide in relapsed/advanced CTCL (NCT03011814). The primary end point was objective response rate (ORR) using the global composite response (based on skin, blood, nodes, and viscera) according to consensus guidelines. Secondary end points included duration of response, progression-free survival, and toxicity. Relationships between gene expression profile, tumor-microenvironment (TME), and antitumor activity were exploratory end points.</p><p><b>Methods:</b> Adult patients with histologically confirmed MF or SS, who had failed ≥ 2 systemic therapies were enrolled and randomized 1:1 to single agent durvalumab (1500 mg (day 1 of 28-day cycle) or durvalumab (same dose) & lenalidomide (10 mg for cycle 1, 15 mg for cycle 2, then 20 mg for subsequent cycles daily for 21 days of each 28-day cycle). The study used a “pick a winner” design based on ORR. Serial skin and blood samples were collected to assess the impact on the TME and anti-tumor activity.</p><p><b>Results:</b> Among 25 patients [12 durvalumab; 13 durvalumab/lenalidomide; stage IB, 2 (17%) vs. 4 (31%); stage IIB, 5 (42%) vs. 3 (23%); stage III/IV, 5 (42%) vs. 6 (46%); large cell transformation 3 (25%) vs. 5 (38%)], the combination showed superior clinical activity, with an ORR of 75% versus 42% and a 12-month PFS of 73% (95% CI: 38%–91%) versus 36% (95% CI: 11%–63%) (Figure 1). Median PFS was 6.2 months for durvalumab and not reached for the combination. The most common treatment-emergent adverse events were more frequent in the durvalumab/lenalidomide arm versus durvalumab arm and included fatigue (<i>n</i> = 10), diarrhea (<i>n</i> = 6), anemia (5), decreased platelets (<i>n</i> = 5), leukopenia & neutropenia (<i>n</i> = 4), constipation (<i>n</i> = 4), and leg edema (<i>n</i> = 4). The majority of AEs with both treatment arms were mild to moderate in severity (grade I/II, 92%; grade III, 8 %). One grade IV neutropenia on combo arm was observed.</p><p><b>Conclusions:</b> This randomized phase 2 trial of durvalumab +/− lenalidomide evaluating anti-tumor activity demonstrated superior clinical activity of combinatorial durvalumab/lenalidomide versus single-agent durvalumab in refractory/advanced CTCL. Responses were durable and ongoing, and treatment was well tolerated. Our correlative results from sequential skin biopsies demonstrated immune signatures for enhanced anti-tumor responses that may be predictive of response to check
{"title":"DURVALUMAB AND LENALIDOMIDE SHOWS SUPERIOR EFFICACY OVER SINGLE-AGENT DURVALUMAB IN REFRACTORY/ADVANCED CUTANEOUS T CELL LYMPHOMA: RESULTS FROM A RANDOMIZED PHASE 2 TRIAL","authors":"C. Querfeld, L. Chen, X. Wu, Z. Han, C. Su, Y. Yuan, M. Banez, J. Quach, T. Barnhizer, L. Crisan, S. T. Rosen, J. Zain","doi":"10.1002/hon.70094_399","DOIUrl":"https://doi.org/10.1002/hon.70094_399","url":null,"abstract":"<p><b>Introduction:</b> Advanced stages of cutaneous T cell lymphoma (CTCL) have an unfavorable prognosis. We have shown that CTCL escapes immune surveillance via immune checkpoint signaling such as the PD-1/PD-L1 axis. Selective targeting of the functionally exhausted malignant T cells in cutaneous T-cell lymphoma (CTCL) and distinct cells within the tumor microenvironment (TME) via PD1/PD-L1 blockade (durvalumab) may restore an anti-tumor immune response. We initiated the randomized Phase 2 portion to compare single agent durvalumab to durvalumab plus lenalidomide in relapsed/advanced CTCL (NCT03011814). The primary end point was objective response rate (ORR) using the global composite response (based on skin, blood, nodes, and viscera) according to consensus guidelines. Secondary end points included duration of response, progression-free survival, and toxicity. Relationships between gene expression profile, tumor-microenvironment (TME), and antitumor activity were exploratory end points.</p><p><b>Methods:</b> Adult patients with histologically confirmed MF or SS, who had failed ≥ 2 systemic therapies were enrolled and randomized 1:1 to single agent durvalumab (1500 mg (day 1 of 28-day cycle) or durvalumab (same dose) & lenalidomide (10 mg for cycle 1, 15 mg for cycle 2, then 20 mg for subsequent cycles daily for 21 days of each 28-day cycle). The study used a “pick a winner” design based on ORR. Serial skin and blood samples were collected to assess the impact on the TME and anti-tumor activity.</p><p><b>Results:</b> Among 25 patients [12 durvalumab; 13 durvalumab/lenalidomide; stage IB, 2 (17%) vs. 4 (31%); stage IIB, 5 (42%) vs. 3 (23%); stage III/IV, 5 (42%) vs. 6 (46%); large cell transformation 3 (25%) vs. 5 (38%)], the combination showed superior clinical activity, with an ORR of 75% versus 42% and a 12-month PFS of 73% (95% CI: 38%–91%) versus 36% (95% CI: 11%–63%) (Figure 1). Median PFS was 6.2 months for durvalumab and not reached for the combination. The most common treatment-emergent adverse events were more frequent in the durvalumab/lenalidomide arm versus durvalumab arm and included fatigue (<i>n</i> = 10), diarrhea (<i>n</i> = 6), anemia (5), decreased platelets (<i>n</i> = 5), leukopenia & neutropenia (<i>n</i> = 4), constipation (<i>n</i> = 4), and leg edema (<i>n</i> = 4). The majority of AEs with both treatment arms were mild to moderate in severity (grade I/II, 92%; grade III, 8 %). One grade IV neutropenia on combo arm was observed.</p><p><b>Conclusions:</b> This randomized phase 2 trial of durvalumab +/− lenalidomide evaluating anti-tumor activity demonstrated superior clinical activity of combinatorial durvalumab/lenalidomide versus single-agent durvalumab in refractory/advanced CTCL. Responses were durable and ongoing, and treatment was well tolerated. Our correlative results from sequential skin biopsies demonstrated immune signatures for enhanced anti-tumor responses that may be predictive of response to check","PeriodicalId":12882,"journal":{"name":"Hematological Oncology","volume":"43 S3","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hon.70094_399","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144292473","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
J. Kuruvilla, P. Armand, A. F. Herrera, V. Ribrag, C. Thieblemont, B. von Tresckow, S. Thompson, K. E. Ryland, R. Z. Yusuf, P. L. Zinzani
<p><b>Introduction:</b> Allogeneic stem cell transplant (allo-SCT) carries a relevant risk of transplantation-related mortality (TRM), especially from graft-versus-host disease (GVHD), particularly in patients previously treated with checkpoint inhibitors. Final safety results in participants (pts) with hematologic malignancies who received allo-SCT after pembrolizumab (pembro) therapy across a variety of pembro clinical studies are presented.</p><p><b>Methods:</b> Data were pooled from 10 phase 1–3 studies (KEYNOTE-A33 [NCT04317066], KEYNOTE-013 [NCT01953692], KEYNOTE-155 [NCT02684617], KEYNOTE-051 [NCT02332668], KEYNOTE-B68 [NCT04875195], KEYNOTE-087 [NCT02453594], KEYNOTE-170 [NCT02576990], KEYNOTE-183 [NCT02576977], KEYNOTE-204 [NCT02684292], and MK4280-003 [NCT03598608]). Outcomes of interest included acute and chronic GVHD, incidence of allo-SCT–related adverse events, overall survival (OS), and TRM.</p><p><b>Results:</b> A total of 112 pts were reported to have received allo-SCT, 14 were not included in the analysis (13 received allo-SCT > 2 years after last dose of pembro and 1 had a missing date of allo-SCT). Median duration on study treatment was 5.6 months (range, 0.03–29.7), and median time from last dose of pembro to first allo-SCT was 4.9 months (range, 1–20). Of 98 evaluable pts, 67 pts (68%) received intervening therapy between pembro and allo-SCT. At time of transplant, 47 pts (48%) had active disease, 39 pts (40%) were in remission, and 12 (12%) had unknown disease status. A total of 91 pts (93%) received allo-SCT only; 7 (7%) received autologous SCT followed by allo-SCT. Among 63 pts (64%) who developed GVHD, 52 (53%) experienced acute events (Glucksberg II-IV [<i>n</i> = 34] and Glucksberg III-IV [<i>n</i> = 19]) and 24 (25%) experienced chronic events (mild [<i>n</i> = 11], moderate [<i>n</i> = 8], and severe [<i>n</i> = 5]). The most common sites for chronic GVHD were skin (<i>n</i> = 15), oral mucosa (<i>n</i> = 12), and liver (<i>n</i> = 9). Other predetermined non-GVHD events of clinical interest occurred in 42 pts (43%), categorized as critical illness (30%), febrile syndrome treated with corticosteroids (1%), immune-mediated adverse events (10%), pulmonary complications (14%), and venoocclusive liver disease (3%). The most common predetermined events of clinical interest (≥ 5%) were febrile neutropenia and pneumonia (6% each). The most common of the other adverse events not included in the 5 categories above (≥ 2%) were grade ≤ 2 pyrexia (5%) and rash (2%). Median OS was not reached (NR; 95% CI: NR-NR) post–allo-SCT, with 100-day, 24-month, and 48-month OS rates of 94%, 70%, and 68%, respectively. Estimated TRM rates at 100 days, 24 months, and 48 months were 5%, 21%, and 21%, respectively.</p><p><b>Conclusion:</b> The inclusion of additional pts in this analysis revealed comparable rates of acute and chronic GVHD, OS, and TRM compared to previous studies and historical benchmarks, thus, reinforcing the role of allo-
{"title":"FINAL SAFETY ANALYSIS IN PARTICIPANTS WITH HEMATOLOGIC MALIGNANCIES WHO RECEIVED ALLOGENEIC STEM CELL TRANSPLANT AFTER PEMBROLIZUMAB THERAPY","authors":"J. Kuruvilla, P. Armand, A. F. Herrera, V. Ribrag, C. Thieblemont, B. von Tresckow, S. Thompson, K. E. Ryland, R. Z. Yusuf, P. L. Zinzani","doi":"10.1002/hon.70094_351","DOIUrl":"https://doi.org/10.1002/hon.70094_351","url":null,"abstract":"<p><b>Introduction:</b> Allogeneic stem cell transplant (allo-SCT) carries a relevant risk of transplantation-related mortality (TRM), especially from graft-versus-host disease (GVHD), particularly in patients previously treated with checkpoint inhibitors. Final safety results in participants (pts) with hematologic malignancies who received allo-SCT after pembrolizumab (pembro) therapy across a variety of pembro clinical studies are presented.</p><p><b>Methods:</b> Data were pooled from 10 phase 1–3 studies (KEYNOTE-A33 [NCT04317066], KEYNOTE-013 [NCT01953692], KEYNOTE-155 [NCT02684617], KEYNOTE-051 [NCT02332668], KEYNOTE-B68 [NCT04875195], KEYNOTE-087 [NCT02453594], KEYNOTE-170 [NCT02576990], KEYNOTE-183 [NCT02576977], KEYNOTE-204 [NCT02684292], and MK4280-003 [NCT03598608]). Outcomes of interest included acute and chronic GVHD, incidence of allo-SCT–related adverse events, overall survival (OS), and TRM.</p><p><b>Results:</b> A total of 112 pts were reported to have received allo-SCT, 14 were not included in the analysis (13 received allo-SCT > 2 years after last dose of pembro and 1 had a missing date of allo-SCT). Median duration on study treatment was 5.6 months (range, 0.03–29.7), and median time from last dose of pembro to first allo-SCT was 4.9 months (range, 1–20). Of 98 evaluable pts, 67 pts (68%) received intervening therapy between pembro and allo-SCT. At time of transplant, 47 pts (48%) had active disease, 39 pts (40%) were in remission, and 12 (12%) had unknown disease status. A total of 91 pts (93%) received allo-SCT only; 7 (7%) received autologous SCT followed by allo-SCT. Among 63 pts (64%) who developed GVHD, 52 (53%) experienced acute events (Glucksberg II-IV [<i>n</i> = 34] and Glucksberg III-IV [<i>n</i> = 19]) and 24 (25%) experienced chronic events (mild [<i>n</i> = 11], moderate [<i>n</i> = 8], and severe [<i>n</i> = 5]). The most common sites for chronic GVHD were skin (<i>n</i> = 15), oral mucosa (<i>n</i> = 12), and liver (<i>n</i> = 9). Other predetermined non-GVHD events of clinical interest occurred in 42 pts (43%), categorized as critical illness (30%), febrile syndrome treated with corticosteroids (1%), immune-mediated adverse events (10%), pulmonary complications (14%), and venoocclusive liver disease (3%). The most common predetermined events of clinical interest (≥ 5%) were febrile neutropenia and pneumonia (6% each). The most common of the other adverse events not included in the 5 categories above (≥ 2%) were grade ≤ 2 pyrexia (5%) and rash (2%). Median OS was not reached (NR; 95% CI: NR-NR) post–allo-SCT, with 100-day, 24-month, and 48-month OS rates of 94%, 70%, and 68%, respectively. Estimated TRM rates at 100 days, 24 months, and 48 months were 5%, 21%, and 21%, respectively.</p><p><b>Conclusion:</b> The inclusion of additional pts in this analysis revealed comparable rates of acute and chronic GVHD, OS, and TRM compared to previous studies and historical benchmarks, thus, reinforcing the role of allo-","PeriodicalId":12882,"journal":{"name":"Hematological Oncology","volume":"43 S3","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hon.70094_351","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144292664","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
E. Corvilain, R. Di blasi, C. Thieblemont, M. Cheminant, B. Guffroy, J. Decroocq, A. Campidelli, M. Rubio, F. Claves, S. Carras, M. Mothy, V. Dupont, R. Houot, S. Choquet
<p><b>Introduction:</b> Post-transplant lymphoproliferative disorder (PTLD) is a rare but severe complication of solid organ transplantation (SOT). First-line treatment typically involves reducing immunosuppressive drugs (ID) alongside Rituximab, followed by maintenance for partial responders (PR) or immunochemotherapy for progression disease (PD). The management of refractory/relapsed (R/R) remains uncertain. The role of CD19 CAR-T cells is not established, though case reports and a series of 22 patients have been published.</p><p><b>Methods:</b> We conducted a retrospective analysis of the multicenter French DESCAR-T registry (NCT04328298) to identify patients treated by CD19 CAR-T cells for SOT-related PTLD. The study period spanned from July 2019 to September 2024. Survival analyses were performed using Kaplan-Meier models.</p><p><b>Results:</b> We identified 12 patients (5 males) treated by CD19 CAR-T cells. Prior SOTs included kidneys (<i>n =</i> 10), liver (<i>n =</i> 1) and lungs (<i>n =</i> 1). In all but one patient, lymphoproliferation occurred more than one year after SOT. All PTLD were classified as diffuse large B cell lymphoma (EBV-associated in 10/11, 1 not available (NA)), except one diagnosed as transformed marginal zone lymphoma. CAR-T cells were administered as second line treatment in 3 patients, and beyond second line in 9 patients. The median age at infusion was 41 years (IQR: 22–62). At diagnosis, performance status was 0-1 in 11/12, Ann-Arbor stage was III-IV in 8/12 and aaIPI score was 1-2 in 11/12 patients. The median lymphocyte rate at apheresis was 0.6G/L (IQR:0-3.4). CAR-T products used included axicabtagene ciloleucel (<i>n =</i> 9) and tisagenlecleucel (<i>n =</i> 3). Ten patients received cyclophosphamide-fludarabine as conditioning regimen (2 NA). ID was modified in all patients at diagnosis then before apheresis. At CAR-T infusion, patients were receiving corticosteroids alone (<i>n</i> = 8), m-TOR inhibitor (<i>n</i> = 1), corticosteroids and calcineurin inhibitor (<i>n =</i> 1), or no ID (<i>n =</i> 2). Cytokine-release-syndrome occurred in all patients with grade 3–4 in 2 cases. Immune-effector-cell associated neurotoxicity (ICANS) was observed in 7 patients with grade 3–4 in 2 cases. Hypogammaglobulinemia (< 5 g/L) was reported in 70% of patients (7/10) without need of immunoglobulins replacement. The best ORR was 82%, including 64% complete response, 18% PR and 18% PD. With a median follow-up of 12.9 months (mo) (95% CI: 4.5-(-)), median progression-free-survival and overall survival were both 16.6 mo (95% CI: 1.1-(-) and 2-(-), respectively) (Figure). Six patients died among which three due to PD and 2 from high grade ICANS (one acute, one late) (1 NA). Among the six surviving patients, one experienced kidney rejection requiring a return to dialysis.</p><p><b>Conclusion:</b> This is the second reported series of patients with R/R SOT-related PTLD treated with CD19 CAR-T cells. Our findings suggest that
{"title":"CD19 CAR-T CELL THERAPY IN RELAPSED/REFRACTORY SOLID ORGAN TRANSPLANT-RELATED LYMPHOPROLIFERATION: A LYSA ANALYSIS OF THE FRENCH COHORT DESCAR-T","authors":"E. Corvilain, R. Di blasi, C. Thieblemont, M. Cheminant, B. Guffroy, J. Decroocq, A. Campidelli, M. Rubio, F. Claves, S. Carras, M. Mothy, V. Dupont, R. Houot, S. Choquet","doi":"10.1002/hon.70094_381","DOIUrl":"https://doi.org/10.1002/hon.70094_381","url":null,"abstract":"<p><b>Introduction:</b> Post-transplant lymphoproliferative disorder (PTLD) is a rare but severe complication of solid organ transplantation (SOT). First-line treatment typically involves reducing immunosuppressive drugs (ID) alongside Rituximab, followed by maintenance for partial responders (PR) or immunochemotherapy for progression disease (PD). The management of refractory/relapsed (R/R) remains uncertain. The role of CD19 CAR-T cells is not established, though case reports and a series of 22 patients have been published.</p><p><b>Methods:</b> We conducted a retrospective analysis of the multicenter French DESCAR-T registry (NCT04328298) to identify patients treated by CD19 CAR-T cells for SOT-related PTLD. The study period spanned from July 2019 to September 2024. Survival analyses were performed using Kaplan-Meier models.</p><p><b>Results:</b> We identified 12 patients (5 males) treated by CD19 CAR-T cells. Prior SOTs included kidneys (<i>n =</i> 10), liver (<i>n =</i> 1) and lungs (<i>n =</i> 1). In all but one patient, lymphoproliferation occurred more than one year after SOT. All PTLD were classified as diffuse large B cell lymphoma (EBV-associated in 10/11, 1 not available (NA)), except one diagnosed as transformed marginal zone lymphoma. CAR-T cells were administered as second line treatment in 3 patients, and beyond second line in 9 patients. The median age at infusion was 41 years (IQR: 22–62). At diagnosis, performance status was 0-1 in 11/12, Ann-Arbor stage was III-IV in 8/12 and aaIPI score was 1-2 in 11/12 patients. The median lymphocyte rate at apheresis was 0.6G/L (IQR:0-3.4). CAR-T products used included axicabtagene ciloleucel (<i>n =</i> 9) and tisagenlecleucel (<i>n =</i> 3). Ten patients received cyclophosphamide-fludarabine as conditioning regimen (2 NA). ID was modified in all patients at diagnosis then before apheresis. At CAR-T infusion, patients were receiving corticosteroids alone (<i>n</i> = 8), m-TOR inhibitor (<i>n</i> = 1), corticosteroids and calcineurin inhibitor (<i>n =</i> 1), or no ID (<i>n =</i> 2). Cytokine-release-syndrome occurred in all patients with grade 3–4 in 2 cases. Immune-effector-cell associated neurotoxicity (ICANS) was observed in 7 patients with grade 3–4 in 2 cases. Hypogammaglobulinemia (< 5 g/L) was reported in 70% of patients (7/10) without need of immunoglobulins replacement. The best ORR was 82%, including 64% complete response, 18% PR and 18% PD. With a median follow-up of 12.9 months (mo) (95% CI: 4.5-(-)), median progression-free-survival and overall survival were both 16.6 mo (95% CI: 1.1-(-) and 2-(-), respectively) (Figure). Six patients died among which three due to PD and 2 from high grade ICANS (one acute, one late) (1 NA). Among the six surviving patients, one experienced kidney rejection requiring a return to dialysis.</p><p><b>Conclusion:</b> This is the second reported series of patients with R/R SOT-related PTLD treated with CD19 CAR-T cells. Our findings suggest that ","PeriodicalId":12882,"journal":{"name":"Hematological Oncology","volume":"43 S3","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hon.70094_381","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144292685","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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