Hematological Oncology最新文献

{"title":"STABILIZED MYCT58A BYPASSES T-CELL HELP TO FUEL GERMINAL CENTER B-CELL LYMPHOMAGENESIS","authors":"B. Chen, A. Q. Xu, M. S. Hung, A. Toboso-Navasa, I. Rodriguez-Hernandez, P. Chakravarty, D. P. Calado","doi":"10.1002/hon.70094_171","DOIUrl":"https://doi.org/10.1002/hon.70094_171","url":null,"abstract":"<p>B. Chen and A. Q. Xu equally contributing author.</p><p><b>Introduction:</b> Constitutive MYC overexpression is a hallmark of germinal center (GC) B-cell-derived lymphomas. Stabilizing mutations in MYC, such as T58A, are frequently found in highly aggressive subtypes, including Burkitt’s lymphoma and Double-Hit lymphomas. Under physiological conditions, MYC is transiently upregulated in positively selected GC B-cells within the light zone (LZ) following T-cell help (TCH). However, the precise mechanisms by which aberrant MYC expression drives GC B-cell lymphomagenesis remain unclear. Here, we propose that aberrant MYC levels diminish GC B-cell dependence on TCH, thereby promoting lymphomagenesis.</p><p><b>Methods:</b> We generated novel mouse models in which either wildtype MYC (MYC<sup>WT</sup>) or MYC stabilizing mutant (MYC<sup>T58A</sup>) was overexpressed in GC B-cells using the Cɣ1-Cre system. To assess the phenotypic and functional consequences, we performed flow cytometry and immunohistochemistry. To investigate MYC-driven alterations in GC dynamics and metabolism, we conducted CITE-seq analysis on MYC<sup>WT</sup>, MYC<sup>T58A</sup>, and control GC B-cells. Additionally, we modulated TCH and its downstream mTOR signaling pathway in GC B-cells using CD40L blockade and rapamycin treatment.</p><p><b>Results:</b> MYC<sup>WT</sup> overexpression induced GC B-cell hyperplasia and promoted the expansion of a dark zone (DZ)-like phenotype. This was accompanied by increased cell cycle entry and progression in the LZ, albeit with a concurrent rise in apoptosis. CITE-seq analysis revealed that MYC<sup>WT</sup> overexpression led to a reduction in activation signatures in positively selected LZ GC B-cells, suggesting that these cells become less dependent on TCH. Functionally, MYC<sup>WT</sup> overexpression conferred an advantage under conditions of limited TCH. However, MYC<sup>WT</sup>-overexpressing GC B-cells remained sensitive to sustained CD40L blockade or mTOR inhibition, indicating that MYC<sup>WT</sup> activity is still regulated by TCH in a premalignant state.</p><p>In contrast, MYC<sup>T58A</sup> overexpression did not induce short-term GC hyperplasia but instead prolonged GC B-cell retention and exacerbated lymphomagenesis. CITE-seq analysis revealed that MYC<sup>T58A</sup> GC B-cells not only exhibited a consistent reduction in activation signatures but also enriched for an intermediate LZ/DZ \"Grey Zone\" phenotype characterized by a metabolic profile resembling lymphoma. Functionally, MYC<sup>T58A</sup> overexpression conferred GC B-cells with the ability to survive even under inhibition of key TCH-dependent signaling pathways, most notably mTOR signaling.</p><p><b>Conclusion:</b> These findings suggest thatMYC overexpression, particularly MYC<sup>T58A</sup>, reprograms GC B-cells to bypass TCH dependency, supporting their transition toward a lymphomagenic state. This work provides mechanistic insights into how MYC mutations drive ","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_171","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144299858","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}

{"title":"ASSESSING THE EFFICACY AND TOXICITY OF CNS PROPHYLAXIS IN DIFFUSE LARGE B-CELL LYMPHOMA (CLSG-CNS-01): A RANDOMIZED, MULTICENTER, PROSPECTIVE PHASE 3 TRIAL","authors":"H. Mocikova, L. Gaherova, T. Jancarkova, A. Suri, A. Janikova, K. Steinerova, D. Belada, R. Pytlik, J. Duras, M. Trnkova, P. Blahovcova, T. Kozak, M. Trneny","doi":"10.1002/hon.70094_278","DOIUrl":"https://doi.org/10.1002/hon.70094_278","url":null,"abstract":"<p><b>Introduction:</b> CNS relapse occurs in around 5% of patients with systemic diffuse large B-cell lymphoma (DLBCL) and its prognosis is poor. The optimal strategy for CNS prophylaxis is not established. The CLSG-CNS-01 trial compared CNS prophylaxis with high doses of intravenous (i.v.) methotrexate (MTX) and intrathecal (i.t.) MTX in systemic DLBCL.</p><p><b>Methods:</b> This randomized, multicenter, prospective phase 3 trial was registered at ClinicalTrials.gov (NCT02777736). Patients with systemic DLBCL aged between 18 and 72 years were treated with 6 cycles of R-CHOP+2xR or DA EPOCH-R+2xR. Patients with intermediate (2–3 risk factors) and high risk (4–6 risk factors) for CNS relapse were randomly assigned (1:1) to CNS prophylaxis with either 2 doses of MTX 3g/m<sup>2</sup> i.v. (arm A) or 6 doses of MTX 12 mg i.t. (arm B). Low risk patients (0–1 risk factor) for CNS relapse were not randomized and did not receive CNS prophylaxis (arm C). Primary objective was to compare cumulative incidence of CNS relapse between arms A and B. Major secondary objectives included: overall response rate (ORR), progression-free and overall survivals (PFS, OS) and treatment toxicity.</p><p><b>Results:</b> Overall 100 patients were enrolled between 2015 and 2024: 30 were randomly assigned to arm A and 31 to arm B; 39 patients did not receive prophylaxis (arm C). Median age of patients was 61 years (range 27–72) and 54% were male. CNS relapses occurred in 3 (3%) patients (arm A 1, arm B 2) during the median follow-up of 54.9 months. CNS relapse after MTX i.v. occurred later (5.2 years after the initiation of treatment). Comparison of 5year cumulative incidence of CNS relapse between randomized arms A and B did not reach statistical significance (0% vs. 8.7%, HR 1.521, <i>p</i> = 0.72). ORR was not significant among arms A, B, C (83.3% vs. 83.8% vs. 94.8%, <i>p</i> = 0.20). The 5year PFS was comparable in arms A and B (45.3% and 57.4%), HR 0.66, <i>p</i> = 0.20. CNS prophylaxis (i.v. and i.t.) significantly increased neutropenia grade ≥ 3 (12.61% vs. 18.48 % vs. 3.59 %, <i>p</i> < 0.0001) with the highest rate of infections grade ≥ 3 in arm A (4.95% vs. 0.95% vs. 0.80%, <i>p</i> = 0.0046). Other toxicities grade ≥ 3 occurred most frequently in arm A (<i>p</i> = 0.0039). Overall 29 patients died (arm A 16, arm B 10, arm C 3). Infections (arm A 5 vs. arm B 2) and unknown causes (arm A 4 vs. arm B 2) indicated the major difference between randomized arms. This observation resulted in significantly worse 5year OS in arm A versus B (47.2% vs. 72.4%, HR 0.46, <i>p</i> = 0.04).</p><p><b>Conclusions:</b> CNS prophylaxis with MTX i.v. or i.t. did not eliminate CNS relapse, but MTX i.v. delayed its occurrence. Cumulative incidence of CNS relapse did not differ significantly between i.v. and i.t. MTX prophylaxis, however, the number of randomized patients was low. MTX i.v. was significantly associated with worse OS, probably due to the toxicity.</p><p><b>Research</b> <","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_278","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144299949","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}

{"title":"IMPACT OF RITUXIMAB EARLY ADMINISTRATION ON OUTCOMES IN ADVANCED STAGE LOW TUMOR BURDEN FOLLICULAR LYMPHOMA: SUBGROUP ANALYSIS OF PHASE III JCOG1411/FLORA STUDY","authors":"D. Maruyama, N. Fukuhara, K. Ishizawa, Y. Sano, R. Machida, S. Makita, W. Munakata, S. Ota, M. Ichikawa, E. Negoro, T. Murayama, R. Suzuki, I. Yoshida, H. Morimoto, M. Tokunaga, K. Ohmachi, H. Takahashi, Y. Suehiro, S. Yoshida, K. Nosaka, T. Kawakita, Y. Sekiguchi, K. Kataoka, S. Murakami, M. Maruta, K. Takase, J. Makiyama, K. Ishitsuka, K. Tsukasaki, H. Nagai","doi":"10.1002/hon.70094_231","DOIUrl":"https://doi.org/10.1002/hon.70094_231","url":null,"abstract":"<p><b>Introduction:</b> We conducted a randomized phase III study to confirm the superiority of rituximab early administration over watchful waiting (WW) in untreated advanced stage low tumor burden (LTB) follicular lymphoma (FL) (JCOG1411/FLORA study, UMIN000025187). The primary analysis demonstrated that rituximab early administration significantly improved event-free survival (EFS) as a primary endpoint vs. WW (Fukuhara et al. <i>ASH</i>, 2024). Here, we present subgroup analysis results.</p><p><b>Methods:</b> In this study, LTB-FL by Groupe d’Etude des Lymphomes Folliculaires criteria were divided into two groups; very LTB (the largest mass < 5 cm, two or less nodal sites [each ≥ 3 cm], no effusion), and intermediate tumor burden (one or more of the followings: the largest mass 5 cm or more but less than 7 cm, three nodal sites [each ≥ 3 cm], no serious effusion) which is defined as to be compatible with criteria for rituximab administration. Patients (pts) aged 20–80 years with previously untreated and advanced stage very LTB-FL (grade 1–3A) were randomized to the WW arm or the rituximab arm (days 1, 8, 15, and 22). Rituximab was administered repeatedly in both arms when the tumor burden reached intermediate.</p><p><b>Results:</b> A total of 292 pts were randomized to the WW arm (148 pts) and the rituximab arm (144 pts). Baseline characteristics were well balanced in terms of age, sex, stage, histologic grade, FLIPI/FLIPI2 risk between the two arms. With a median follow-up of 2.5 years (range: 0-6.9), the EFS was significantly better in the rituximab arm than that in the WW arm (hazard ratio [HR], 0.625; 95% confidence interval [CI], 0.425-0.918; one-sided log-rank <i>p</i> = 0.0078 < 0.0123, alpha adjusted for multiplicity). In the pre-planned subgroup analyses, male (HR, 0.531; 95% CI: 0.302–0.935), histologic grade of 3A (HR, 0.437; 95% CI: 0.224–0.852), intermediate/high risk of FLIPI (HR, 0.665; 95% CI: 0.456–0.970) and FLIPI2 (HR, 0.655; 95% CI: 0.444–0.965) had lower HR of EFS in the rituximab arm (Figure 1), and similar trend was observed in cytotoxic therapy-free survival. In a post-hoc analysis, the subgroup of the interval from diagnosis to enrollment > 91 days favored of EFS in the rituximab arm (HR, 0.490; 95% CI: 0.264–0.909). On the other hand, no subgroups with clear benefit in terms of progression-free and overall survivals were identified. Median rituximab doses were 0 (range, 0–12) in the WW arm and 4 (range, 0–16) in the rituximab arm, respectively. There was a slight imbalance in histologic transformation (HT) events (19 pts in the WW arm vs. 12 pts in the rituximab arm) and lymphoma deaths were occurred only in the WW arm, with 4 out of the 5 deaths having HT.</p><p><b>Conclusions:</b> Rituximab early administration has been confirmed to delay disease progression to high tumor burden and initiation of cytotoxic chemotherapy in patients with untreated advanced stage LTB-FL, including those with specific subgroup","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_231","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144299911","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}

{"title":"CHARACTERIZATION AND CLINICAL IMPACT OF THE CIRCULATING IMMUNE CELL PROFILE IN PATIENTS WITH FOLLICULAR LYMPHOMA","authors":"A. Rivero, D. Moreno, P. Mozas, A. Moreno, I. Tena, F. Araujo, L. Alserawan, J. Correa, G. Frigola, J. Delgado, M. Osuna, M. Bashiri, A. I. Perez-Valencia, M. Gomez, I. Lopez, I. Hernandez, H. Brillembourg, P. Perez-Galan, E. Giné, E. Matutes, N. Villamor, A. Lopez-Guilermo, L. Magnano","doi":"10.1002/hon.70094_203","DOIUrl":"https://doi.org/10.1002/hon.70094_203","url":null,"abstract":"<p>L. Magnano equally contributing author.</p><p><b>Introduction:</b> FL is characterized by a heterogeneous clinical course. Although the importance of the microenvironment in its pathogenesis is well established, detailed information on the immune profile in peripheral blood (PB) has not been previously investigated. The aim of this study was to characterize immune profile in PB of FL patients (pts) at diagnosis (dxFL) and at relapse (rFL) and compare it with that of healthy controls (HC). Correlation with baseline clinical features was also explored.</p><p><b>Methods:</b> We prospectively collected PB samples from FL pts (median age: 61 y; 41M/33F) at dxFL (<i>n</i> = 42) and at rFL (<i>n</i> = 40), as well as from 10 HC (median age: 51 y; 4M/6F) from 2019 to 2024. The identification of the main subsets of T-cells, B-cells, NK-cells, monocytes, neutrophils, dendritic cells (DC) and myeloid suppressor cells was performed by multiparameter flow cytometry. At least 150.000 events were acquired and analysed using Infinicyt software. A Cox regression was performed to identify immune biomarkers that had an impact on time to first treatment (> / < 6 months). In 18 dxFL pts, RNA expression was measured in PB with the nCounter technology.</p><p><b>Results:</b> Compared with HC, dxFL pts exhibited a lower CD4<sup>+</sup>/CD8<sup>+</sup> ratio due to depletion of CD4<sup>+</sup> cells with an increase in CD8<sup>+</sup> lymphocytes. Furthermore, dxFL pts were characterized by a decrease in naïve CD4<sup>+</sup> and CD8<sup>+</sup> (<i>p</i> < 0.0001), along with an increase in effector (E) and effector memory (EM) lymphocytes (<i>p</i> < 0.05), both CD4<sup>+</sup> and CD8<sup>+</sup>. Of note, total regulatory T lymphocytes (Treg) and Th1 cells were increased in FL pts, while NK-cells were decreased, likely indicating an immunosuppressive environment. FL pts showed a decrease in total DC, but with an increase in myeloid DC subset (<i>p</i> = 0.015). These differences remained and became more marked in the relapse setting (Figure 1a). Subsequently, these data were correlated with the main clinical features. Pts with high tumour burden according GELF criteria at diagnosis were enriched in EM (<i>p</i> = 0.001) and activated CD8<sup>+</sup> cells (<i>p</i> = 0.031), but a significantly decrease in Th1 (<i>p</i> = 0.042). Of note, pts with high-risk features as bulky disease (> 7 cm), higher LDH and int/high FLIPI showed an expansion in Treg <b>(</b>Figure 1b<b>)</b>. Genes involved in Treg expression (<i>CCL17, FOXP3, SOCS1, NFKBIA</i> and <i>DUSP4</i>) and T EM phenotype (<i>CCL3, CD70</i>) were upregulated in high tumour burden pts. In dxFL pts, immune predictive variables for early treatment initiation (< 6 m) were lower CD3<sup>+</sup>, E CD4<sup>+</sup> and myeloid DC; and higher EM CD4<sup>+</sup> and activated CD8<sup>+</sup>. Multivariate analysis showed that higher EM CD4<sup>+</sup> lymphocytes was the most important variable to","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_203","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144299923","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}

{"title":"MOLECULAR SUBTYPE-GUIDED R-MINE+X REGIMEN IN RELAPSED/REFRACTORY DIFFUSE LARGE B-CELL LYMPHOMA: A SINGLE-ARM, OPEN-LABEL, MULTICENTER PHASE II STUDY","authors":"J. Liang, H. Shen, H. Yin, J. Wu, Y. Li, L. Bi, W. Qin, L. Su, J. Liu, L. Wang, J. Li, W. Xu","doi":"10.1002/hon.70094_317","DOIUrl":"https://doi.org/10.1002/hon.70094_317","url":null,"abstract":"<p>W. Xu equally contributing author.</p><p><b>Background:</b> The genetic heterogeneity of diffuse large B-cell lymphoma (DLBCL) significant influences prognosis and treatment response. Recent advances in molecular profiling have facilitated the identification of driver mutations (Zhang et al. 2023). Nevertheless, data on relapsed/refractory (R/R) DLBCL remain limited. Salvage chemotherapy R-MINE (rituximab, mitoxantrone, ifosfamide, etoposide) remains the therapeutic mainstay, yet suboptimal survival persists. To address this, we explored R-MINE by replacing conventional mitoxantrone with mitoxantrone hydrochloride liposome (Lipo-MIT) and incorporated molecular subtype-guided targeted agents (X) into the R-MINE+X regimen for R/R DLBCL.</p><p><b>Methods:</b> This multicenter, single-arm, open-label, phase II study enrolled adult patients (pts) with R/R DLBCL. Following the first R-MINE cycle, pts received subtype-stratified targeted therapy (X) in combination with R-MINE. The R-MINE+X regimen (rituximab 375 mg/m<sup>2</sup>, d0; Lipo-MIT 12‒20 mg/m<sup>2</sup>, d1; ifosfamide 1.33 g/m<sup>2</sup>, d1‒3; etoposide 65 mg/m<sup>2</sup>, d1‒3) was administered for up to 3 cycles (each cycle lasting 21 days). Targeted combinations: MCD/BN2 (BTK inhibitors), EZB (chidamide), TP53 mutation (PD-1 monoclonal antibody), other subtypes (lenalidomide/investigator's choice). The primary endpoint was objective response rate (ORR). This study is registered (NCT05784987) at www.clinicaltrials.gov.</p><p><b>Results:</b> From April 2022 to March 2025, sixty R/R DLBCL pts were enrolled (median age 62 [range 24–79]; 58.3% male). Among them, 45 (75.0%) pts had advanced-stage disease with stage III‒IV, and 28 (46.7%) pts had IPI scores of 3‒5. Forty (66.7%) pts were refractory to the last-line therapy, and 31 pts (51.7%) were primary refractory.</p><p>As of the date cutoff, a total of 49 pts had undergone at least once efficacy assessment, with the ORR of 75.5% (37/49) and complete response (CR) rate of 51.0% (25/49). With <i>EZB</i> group (<i>n</i> = 3), 2 pts achieved CR and 1 patient achieved partial response (PR). The <i>MCD/BN2</i> group (<i>n</i> = 18) showed an ORR of 77.8% (14/18) and a CR rate of 55.6% (10/18). Among the <i>TP53 mutation</i> group (<i>n</i> = 2), 1 patient achieved PR. The ORR and CR rate of the <i>other</i> group (<i>n</i> = 24) were 75.0% (18/24) and 50.0% (12/24), respectively. Preliminary efficacy was demonstrated in advanced-stage disease, non-germinal center B cell like (non-GCB) and double expressor lymphoma (DEL) (Table 1). These results suggest particular therapeutic potential in populations with unfavorable prognostic features. With a median follow-up of only 3.1 months (95% CI: 2.2–4.0), the survival requires longer observation. The most common grade 3/4 treatment-related adverse events were neutropenia (35.0%), leucopenia (31.7%), anemia (25.0%), thrombocytopenia (15.0%), and hypokalemia (11.7%). No cardiac-related adverse events","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_317","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144299985","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}

{"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}

{"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}

{"title":"IMPACT OF EBV STATUS AND HISTOLOGY ON OUTCOMES WITH NIVOLUMAB-AVD VERSUS Bv-AVD IN PATIENTS ENROLLED ON SWOG S1826","authors":"S. Ahmed,&nbsp;H. Li,&nbsp;A. F Herrera,&nbsp;A. Perry,&nbsp;A. E Kovach,&nbsp;K. Davison,&nbsp;S. C Rutherford,&nbsp;S. Castellino,&nbsp;A. Evens,&nbsp;B. Kahl,&nbsp;N. Bartlett,&nbsp;J. P Leonard,&nbsp;M. A Shipp,&nbsp;S. M Smith,&nbsp;K. Kelly,&nbsp;M. LeBlanc,&nbsp;J. W Friedberg,&nbsp;J. Y Song","doi":"10.1002/hon.70093_20","DOIUrl":"https://doi.org/10.1002/hon.70093_20","url":null,"abstract":"&lt;p&gt;&lt;b&gt;Introduction:&lt;/b&gt; 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.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Methods:&lt;/b&gt; 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).&lt;/p&gt;&lt;p&gt;&lt;b&gt;Results:&lt;/b&gt; 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 (&lt;i&gt;p&lt;/i&gt; &lt; 0.0001). EBV+ pts had higher IPS scores but no statistical difference in stage or B symptoms.&lt;/p&gt;&lt;p&gt;With median follow-up of 24 months, within EBV− group, PFS was longer with N-AVD (HR 0.54; &lt;i&gt;p&lt;/i&gt; = 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; &lt;i&gt;p&lt;/i&gt; = 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; &lt;i&gt;p&lt;/i&gt; = 0.0144). In N-AVD arm, no PFS difference was seen between EBV+ and EBV− (95% versus 92%; &lt;i&gt;p&lt;/i&gt; = 0.88) but in Bv-AVD arm EBV+ pts had poorer PFS (72% versus 85%; &lt;i&gt;p&lt;/i&gt; = 0.03).&lt;/p&gt;&lt;p&gt;102 pts had non-NS histology (N-AVD = 55; Bv-AVD = 47), median age 48 years versus 22 years for NS (&lt;i&gt;p&lt;/i&gt; &lt; 0.0001), and 30% non-NS were &gt; 60 years versus 4% of NS pts &gt; 60 years. In non-NS pts, N-AVD resulted in longer PFS (HR 0.31; 95% CI: 0.31–0.74; &lt;i&gt;p&lt;/i&gt; = 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; &lt;i&gt;p&lt;/i&gt; = 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, &lt;i&gt;p&lt;/i&gt; = 0.11). In Bv-AVD arm, non-NS pts had inferior PFS (HR = 3.4, &lt;i&gt;p&lt;/i&gt; &lt; 0.0001), 2 years PFS 65% versus 87% in NS.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Conclusions:&lt;/b&gt; 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}

{"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,&nbsp;S. Spurgeon,&nbsp;M. Pavlovsky,&nbsp;C. Y. Cheah,&nbsp;D. Villa,&nbsp;S. Luminari,&nbsp;V. Otero,&nbsp;G. De Jesus,&nbsp;R. Lesley,&nbsp;M. L. Wang","doi":"10.1002/hon.70093_136","DOIUrl":"https://doi.org/10.1002/hon.70093_136","url":null,"abstract":"&lt;p&gt;&lt;b&gt;Introduction:&lt;/b&gt; 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. &lt;i&gt;EHA&lt;/i&gt; 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. &lt;i&gt;Blood&lt;/i&gt;. 2024;144(Suppl 1):1626). Herein, we examine the association between MRD status and clinical outcomes in the ECHO trial.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Methods:&lt;/b&gt; 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&lt;sup&gt;−5&lt;/sup&gt;) was assessed in peripheral blood every 24 weeks and at CR or progressive disease using the ClonoSEQ assay (Adaptive Biotechnologies).&lt;/p&gt;&lt;p&gt;&lt;b&gt;Results:&lt;/b&gt; 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; &lt;i&gt;p&lt;/i&gt; &lt; 0.0001) and median OS was not reached (HR: 0.31; &lt;i&gt;p&lt;/i&gt; = 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; &lt;i&gt;p&lt;/i&gt; = 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; &lt;i&gt;p&lt;/i&gt; &lt; 0.0001).&lt;/p&gt;&lt;p&gt;&lt;b&gt;Conclusions:&lt;/b&gt; 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}

{"title":"GENOMIC AND TRANSCRIPTIONAL SINGLE-CELL HETEROGENEITY IN GERMINAL-CENTER LYMPHOMAS: INSIGHTS INTO FOLLICULAR LYMPHOMA TRANSFORMATION","authors":"S. Huerga-Domínguez,&nbsp;B. Ariceta,&nbsp;P. Aguirre-Ruiz,&nbsp;P. San Martín-Uriz,&nbsp;S. Sarvide,&nbsp;Á. López-Janeiro,&nbsp;D. Alignani,&nbsp;E. Muiños-Lopez,&nbsp;M. Abengozar-Muela,&nbsp;S. Browne,&nbsp;R. Figueroa,&nbsp;C. Grande,&nbsp;A. López-López,&nbsp;J. R. Rodríguez-Madoz,&nbsp;A. Vilas-Zornoza,&nbsp;S. Roa,&nbsp;F. Prósper,&nbsp;M. Canales","doi":"10.1002/hon.70094_179","DOIUrl":"https://doi.org/10.1002/hon.70094_179","url":null,"abstract":"&lt;p&gt;B. Ariceta equally contributing author.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Introduction:&lt;/b&gt; 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.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Methods:&lt;/b&gt; 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-).&lt;/p&gt;&lt;p&gt;&lt;b&gt;Results:&lt;/b&gt; 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.&lt;/p&gt;&lt;p&gt;T cell subclusters varied significantly across patients. ntFL was enriched in naïve CD4&lt;sup&gt;−&lt;/sup&gt;CD8&lt;sup&gt;−&lt;/sup&gt; and CD8&lt;sup&gt;+&lt;/sup&gt; central memory T cells, while tFL and GCB were enriched in CD4&lt;sup&gt;+&lt;/sup&gt; T cells. CD4&lt;sup&gt;+&lt;/sup&gt; and CD8&lt;sup&gt;+&lt;/sup&gt;Teff cells were predominant in ABC samples. CD4&lt;sup&gt;+&lt;/sup&gt; T cells promoted T cell tolerance (IL6/STAT3, PD-1), while CD8&lt;sup&gt;+&lt;/sup&gt;Teff cells exhibited high exhaustion marker expression. CD8&lt;sup&gt;+&lt;/sup&gt;Teff cells from DLBCL and tFL showed stronger exhaustion profiles than ntFL. CD4&lt;sup&gt;+&lt;/sup&gt; Tfh cells expressed genes involved in adhesion with malignant B cells, with significantly higher expression in DLBCL and tFL (Figure 1b).&lt;/p&gt;&lt;p&gt;In the scDNA-seq analysis, patients harbored mutations in chromatin-modifying genes (&lt;i&gt;KMT2D&lt;/i&gt; and &lt;i&gt;EZH2&lt;/i&gt;) and oncogenic genes (&lt;i&gt;NOTCH2&lt;/i&gt;). In GCB and tFL samples, &lt;i&gt;KMT2D&lt;/i&gt; variants were identified as early events, while &lt;i&gt;EZH2&lt;/i&gt; (tFL) and &lt;i&gt;ATM&lt;/i&gt; (GCB) mutations emerged as secondary events. A nonsense mutation in &lt;i&gt;TET2&lt;/i&gt; 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 (&lt;i&gt;TET2&lt;/i&gt;, &lt;i&gt;ASXL1,&lt;/i&gt; and &lt;i&gt;DNMT3A&lt;/i&gt;).&lt;/p&gt;&lt;p&gt;In the spatial transcriptomics analysis, 28,387 spots were examined. Deconvolution using paired scRNA-seq data confirmed an adequate representation of all cell types.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Conclusions:&lt;/b&gt; 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}