C. D'Angelo, C. Enke, J. Vose, R. G. Bociek, S. Ananth, E. Lyden, F. Yu, M. Schissel, M. Lunning
<p><b>Introduction:</b> Low dose radiation therapy (RT), 4 Gray administered over 2 fractions (BOOM-BOOM), has demonstrated efficacy and low toxicity in B-cell lymphoma. Pre-clinical experiments demonstrate that BOOM-BOOM RT prior to CAR T-cell therapy successfully enhances CAR T-cell efficacy, suggesting engagement of immunotherapeutic mechanisms. We hypothesized that BOOM-BOOM radiation would be safe and effective as bridging therapy prior to liso-cel infusion.</p><p><b>Methods:</b> We performed an investigator-initiated study of BOOM-BOOM bridging RT prior to liso-cel. Eligible patients included adults with relapsed/refractory aggressive B-cell non-Hodgkin lymphoma at the University of Nebraska Medical Center. Subjects received BOOM-BOOM RT to disease sites 7–10 days prior to liso-cel. No other bridging therapy beyond steroids was allowed. The primary endpoint was feasibility, defined as the percentage of subjects enrolled who received BOOM-BOOM RT and liso-cel.</p><p><b>Results:</b> The trial has completed recruitment, and this is the first analysis of feasibility and efficacy for the whole cohort. The median follow-up is 146 days. Thirty-two subjects were enrolled and 30 subjects received BOOM-BOOM RT and liso-cel (30/32, 94%), meeting the prespecified feasibility threshold of > 70%. The median age was 70 (range 23–84), 22 (69%) subjects were male. Three subjects were diagnosed with high-grade B-cell lymphoma, 1 with grey zone lymphoma, 1 with Richter’s transformation, and 27 with DLBCL. Fourteen subjects (18/32, 56%) had a LDH above the upper limit of normal. Twenty-nine subjects (29/32, 91%) received liso-cel as second line therapy. Twenty-one subjects (21/32, 66%) had extranodal disease, 20/32 (63%) were advanced stage, and 16/32 (50%) were refractory to frontline therapy.</p><p>Twenty-nine subjects receiving per-protocol therapy were evaluable for response using Lugano criteria for PET/CT. Responses to BOOM-BOOM and liso-cel were observed in 25/29 (86%) subjects, and the complete response (CR) rate was 24/29 (83%). Two subjects had stable disease, and 2 subjects experienced progressive disease as best response. Progression-free survival (PFS) and overall survival (OS) curves are depicted in Figure 1. A landmark analysis by response at D30 for PFS and OS is depicted in Figure 1C/D and demonstrates a 200-day PFS and OS rate for patients obtaining a CR of 75% (95% CI: 46%–90%) and 89% (95% CI: 62%–97%), respectively.</p><p>Thirty subjects were evaluable for safety. CRS was observed in 15 subjects and was G1–2 in 14 and G5 in one. Immune effector cell-associated neurotoxicity was observed in 8 subjects and G3–4 in 5/8. Two subjects died, 1 due to intestinal perforation and 1 due to septic shock prior to D100.</p><p><b>Conclusion:</b> The combination of BOOM-BOOM RT and liso-cel met our primary endpoint of feasibility and produced a high CR rate of 83%. These data suggest that the use of low-dose RT as bridging therapy is safe, feasible, a
{"title":"BOOM-BOOM RADIATION PRIOR TO LISOCABTAGENE MARALEUCEL IS FEASIBLE AND CONTRIBUTES TO HIGH COMPLETE RESPONSE RATES FOR AGGRESSIVE B-CELL NON-HODGKIN LYMPHOMA","authors":"C. D'Angelo, C. Enke, J. Vose, R. G. Bociek, S. Ananth, E. Lyden, F. Yu, M. Schissel, M. Lunning","doi":"10.1002/hon.70093_111","DOIUrl":"https://doi.org/10.1002/hon.70093_111","url":null,"abstract":"<p><b>Introduction:</b> Low dose radiation therapy (RT), 4 Gray administered over 2 fractions (BOOM-BOOM), has demonstrated efficacy and low toxicity in B-cell lymphoma. Pre-clinical experiments demonstrate that BOOM-BOOM RT prior to CAR T-cell therapy successfully enhances CAR T-cell efficacy, suggesting engagement of immunotherapeutic mechanisms. We hypothesized that BOOM-BOOM radiation would be safe and effective as bridging therapy prior to liso-cel infusion.</p><p><b>Methods:</b> We performed an investigator-initiated study of BOOM-BOOM bridging RT prior to liso-cel. Eligible patients included adults with relapsed/refractory aggressive B-cell non-Hodgkin lymphoma at the University of Nebraska Medical Center. Subjects received BOOM-BOOM RT to disease sites 7–10 days prior to liso-cel. No other bridging therapy beyond steroids was allowed. The primary endpoint was feasibility, defined as the percentage of subjects enrolled who received BOOM-BOOM RT and liso-cel.</p><p><b>Results:</b> The trial has completed recruitment, and this is the first analysis of feasibility and efficacy for the whole cohort. The median follow-up is 146 days. Thirty-two subjects were enrolled and 30 subjects received BOOM-BOOM RT and liso-cel (30/32, 94%), meeting the prespecified feasibility threshold of > 70%. The median age was 70 (range 23–84), 22 (69%) subjects were male. Three subjects were diagnosed with high-grade B-cell lymphoma, 1 with grey zone lymphoma, 1 with Richter’s transformation, and 27 with DLBCL. Fourteen subjects (18/32, 56%) had a LDH above the upper limit of normal. Twenty-nine subjects (29/32, 91%) received liso-cel as second line therapy. Twenty-one subjects (21/32, 66%) had extranodal disease, 20/32 (63%) were advanced stage, and 16/32 (50%) were refractory to frontline therapy.</p><p>Twenty-nine subjects receiving per-protocol therapy were evaluable for response using Lugano criteria for PET/CT. Responses to BOOM-BOOM and liso-cel were observed in 25/29 (86%) subjects, and the complete response (CR) rate was 24/29 (83%). Two subjects had stable disease, and 2 subjects experienced progressive disease as best response. Progression-free survival (PFS) and overall survival (OS) curves are depicted in Figure 1. A landmark analysis by response at D30 for PFS and OS is depicted in Figure 1C/D and demonstrates a 200-day PFS and OS rate for patients obtaining a CR of 75% (95% CI: 46%–90%) and 89% (95% CI: 62%–97%), respectively.</p><p>Thirty subjects were evaluable for safety. CRS was observed in 15 subjects and was G1–2 in 14 and G5 in one. Immune effector cell-associated neurotoxicity was observed in 8 subjects and G3–4 in 5/8. Two subjects died, 1 due to intestinal perforation and 1 due to septic shock prior to D100.</p><p><b>Conclusion:</b> The combination of BOOM-BOOM RT and liso-cel met our primary endpoint of feasibility and produced a high CR rate of 83%. These data suggest that the use of low-dose RT as bridging therapy is safe, feasible, a","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_111","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144299760","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}
B. Chen, A. Q. Xu, M. S. Hung, A. Toboso-Navasa, I. Rodriguez-Hernandez, P. Chakravarty, D. P. Calado
<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
{"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}
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
<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> <
简介：系统性弥漫性大b细胞淋巴瘤（DLBCL）患者的中枢神经系统复发发生率约为5%，预后较差。预防中枢神经系统疾病的最佳策略尚未确定。CLSG-CNS-01试验比较了高剂量静脉注射（i.v.）甲氨蝶呤（MTX）和鞘内注射（i.t.）预防CNS的效果。MTX在系统性DLBCL中的应用。方法：该随机、多中心、前瞻性3期试验已在ClinicalTrials.gov注册（NCT02777736）。年龄在18 - 72岁之间的系统性DLBCL患者接受6个周期的R-CHOP+2xR或DA EPOCH-R+2xR治疗。具有中度（2 - 3个危险因素）和高危（4-6个危险因素）CNS复发的患者被随机（1:1）分配到CNS预防组，其中2剂MTX 3g/m2静脉注射（A组）或6剂MTX 12mg静脉注射（B组）。CNS复发的低风险患者（0-1危险因素）没有随机分组，也没有接受CNS预防治疗（C组）。主要目标是比较A组和b组CNS复发的累积发生率。次要目标包括：总缓解率（ORR）、无进展生存期和总生存期（PFS， OS）和治疗毒性。结果：2015年至2024年共入组100例患者：30例随机分配到A组，31例随机分配到B组；39例患者未接受预防治疗（C组）。患者中位年龄为61岁（27-72岁），54%为男性。在54.9个月的中位随访期间，有3例（3%）患者（a1组，b2组）出现中枢神经系统复发。甲氨喋呤静脉注射后中枢神经系统复发发生较晚（治疗开始后5.2年）。随机组A组与随机组B组5年累积中枢神经系统复发发生率比较无统计学意义（0% vs. 8.7%, HR 1.521, p = 0.72）。A、B、C组的ORR无统计学意义（83.3%比83.8%比94.8%,p = 0.20）。A组和B组5年PFS具有可比性（45.3%和57.4%），HR 0.66, p = 0.20。中枢神经系统预防（静脉注射和静脉注射）显著增加中性粒细胞减少症≥3级(12.61% vs. 18.48% vs. 3.59%, p <；0.0001)， A组感染率≥3级最高（4.95% vs. 0.95% vs. 0.80%, p = 0.0046）。其他≥3级的毒性最常见于A组（p = 0.0039）。共有29例患者死亡（A组16例，B组10例，C组3例）。感染（aa组5 vs B组2）和未知原因（aa组4 vs B组2）表明随机分组之间的主要差异。这一观察结果导致A组5年OS明显低于B组（47.2% vs. 72.4%, HR 0.46, p = 0.04）。结论：甲氨喋呤静脉滴注或静脉滴注并不能消除中枢神经系统的复发，但甲氨喋呤延缓了中枢神经系统复发的发生。CNS复发的累积发生率在静脉注射和静脉注射MTX预防之间没有显著差异，然而，随机患者的数量很低。MTX静脉注射与更差的OS显著相关，可能是由于毒性。研究经费声明：本工作得到捷克共和国卫生部AZV NU21-03-00411基金和合作项目的支持，研究领域为“肿瘤学和血液学”。关键词：化疗；侵袭性b细胞非霍奇金淋巴瘤没有潜在的利益冲突来源。
{"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}
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
<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
{"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}
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
<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
L. Magnano同等贡献作者。简介：FL的特点是具有异质性的临床病程。虽然微环境在其发病机制中的重要性已经确立，但有关外周血（PB）免疫谱的详细信息此前尚未研究过。本研究的目的是表征FL患者（pts）在诊断（dxFL）和复发（rFL）时的PB免疫特征，并将其与健康对照（HC）进行比较。还探讨了与基线临床特征的相关性。方法：前瞻性收集FL患者(中位年龄：61岁；41M/33F)在dxFL （n = 42）和rFL (n = 40)，以及10 HC(中位年龄：51岁；4M/6F)，从2019年到2024年。采用多参数流式细胞术对t细胞、b细胞、nk细胞、单核细胞、中性粒细胞、树突状细胞（DC）和骨髓抑制细胞等主要亚群进行鉴定。使用Infinicyt软件获得并分析了至少15万个事件。采用Cox回归来鉴定对首次治疗时间有影响的免疫生物标志物(>；/ & lt;6个月)。在18个dxFL病例中，用nCounter技术检测PB中RNA的表达。结果：与HC相比，dxFL患者CD4+/CD8+比值较低，这是由于CD4+细胞耗损，CD8+淋巴细胞增加所致。此外，dxFL患者的特点是naïve CD4+和CD8+降低(p <；0.0001)，效应淋巴细胞(E)和效应记忆淋巴细胞（EM）增加(p <；0.05)， CD4+和CD8+。值得注意的是，总调节性T淋巴细胞（Treg）和Th1细胞在FL中增加，而nk细胞减少，可能表明免疫抑制环境。FL患者总DC减少，但髓系DC亚群增加（p = 0.015）。这些差异仍然存在，并且在复发时变得更加明显（图1a）。随后，这些数据与主要临床特征相关联。根据GELF诊断标准，高肿瘤负担的患者在诊断时EM （p = 0.001）和活化的CD8+细胞（p = 0.031）中富集，但Th1显著降低（p = 0.042）。值得注意的是，具有高危特征的pts为大体积疾病(>；7cm)，较高的LDH和int/高FLIPI显示Treg的扩张（图1b）。参与Treg表达的基因（CCL17、FOXP3、SOCS1、NFKBIA和DUSP4）和tem表型（CCL3、CD70）在高肿瘤负担患者中上调。在dxFL患者中，早期治疗开始的免疫预测变量(<；6 m) CD3+、E CD4+和髓系DC降低；高EM CD4+和活化CD8+。多因素分析显示，较高的EM CD4+淋巴细胞是预测首次治疗时间的最重要变量（p = 0.03）。结论：FL在PB中显示的免疫特征与HC中观察到的明显不同，并且在复发时更为明显。了解这些免疫改变可以增强对FL行为的理解，并有助于在免疫治疗时代设计基于免疫谱的患者定制策略。研究经费声明：Fondo de Investigaciones Sanitarias， Instituto de Salud Carlos III （PI19/00925 to LM和PI23/01207 to LM）。Andrea Rivero得到了“Emili Letang-Josep Font”基金（巴塞罗那医院诊所）的资助。关键词:微环境;诊断和预后生物标志物；惰性非霍奇金淋巴瘤没有潜在的利益冲突来源。
{"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}
J. Liang, H. Shen, H. Yin, J. Wu, Y. Li, L. Bi, W. Qin, L. Su, J. Liu, L. Wang, J. Li, W. Xu
<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
{"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}
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}
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