C. S. Tam, P. Ghia, M. Shadman, T. Munir, S. S. Opat, P. A. Walker, M. Lasica, I. W. Flinn, T. Tian, S. Agresti, J. Hirata, J. R. Brown
<p><b>Introduction:</b> Zanubrutinib is a next-generation Bruton tyrosine kinase inhibitor that is approved for five indications, including CLL/SLL. Initial results from the SEQUOIA study (NCT03336333), at a median follow-up of 26.2 months, demonstrated superior progression-free survival (PFS) by independent review with zanubrutinib versus bendamustine + rituximab (arms A and B) in patients with treatment-naive CLL/SLL without del(17p) as well as high overall response rate (ORR) and PFS benefit in patients with del(17p) (arm C). Additionally, the 5-year follow-up in arm A demonstrated durable PFS benefit, with estimated 54- and 60-month PFS rates of 80% and 76%, respectively. Here we report updated results in SEQUOIA arm C, in patients with del(17p), after approximately 5 years of follow-up (data cutoff: Apr 30, 2024).</p><p><b>Methods:</b> Arm C is a nonrandomized cohort of SEQUOIA patients with del(17p) that received zanubrutinib monotherapy. Investigator-assessed PFS, overall survival (OS), ORR, and safety/tolerability were evaluated. Adverse events (AEs) were recorded until disease progression or start of next-line therapy.</p><p><b>Results:</b> Between Feb 2018 and Mar 2019, 111 treatment-naive patients with del(17p) were enrolled to receive zanubrutinib. The median age was 71 years (range, 42–87 years), 79 (71%) were male, 67 (60%) were IGHV unmutated, and 47 (42%) had both del(17p) and <i>TP53</i> mutation. At a median follow-up of 65.8 months (range, 5–75 months), median PFS was not reached. The estimated 60-month PFS rate was 72.2% (62.4%–79.8%) (Figure), or 73.0% (63.3%–80.6%) when adjusted for COVID-19. Median OS was also not reached. The estimated 60-month OS rate was 85.1% (76.9%–90.6%), or 87.0% (79.0%–92.1%) when adjusted for COVID-19. The ORR was 97.3%, and the complete response/complete response with incomplete hematologic recovery rate was 18.2%. Zanubrutinib treatment was ongoing in 62.2% of patients. The most common causes for treatment discontinuation were AEs and progressive disease (in 17.1% and 15.3%, respectively). Key AEs of interest (AEI) included any-grade infection (82%), bleeding (60%), neutropenia (19%), hypertension (18%), anemia (9%), thrombocytopenia (8%), and atrial fibrillation/flutter (7%). Grade ≥ 3 AEI included infection (33%), neutropenia (16%), hypertension (8%), bleeding (6%), atrial fibrillation/flutter (5%), and thrombocytopenia (2%).</p><p><b>Conclusions:</b> With this 5-year follow-up in SEQUOIA, the efficacy of zanubrutinib in treatment-naive higher-risk patients with del(17p) was maintained, and patients continue to demonstrate PFS benefits consistent with the randomized cohort of patients without del(17p) (arm A). Additionally, with longer-term follow-up, no new safety signals were identified. This update, in the largest cohort of uniformly treated patients with del(17p), suggests that zanubrutinib remains a valuable frontline treatment option for patients with or without del(17p) CLL/SLL.</p><p><b
{"title":"SEQUOIA 5-YEAR FOLLOW-UP IN ARM C: FRONTLINE ZANUBRUTINIB IN PATIENTS WITH DEL(17P) AND TREATMENT-NAIVE CHRONIC LYMPHOCYTIC LEUKEMIA/SMALL LYMPHOCYTIC LYMPHOMA (CLL/SLL)","authors":"C. S. Tam, P. Ghia, M. Shadman, T. Munir, S. S. Opat, P. A. Walker, M. Lasica, I. W. Flinn, T. Tian, S. Agresti, J. Hirata, J. R. Brown","doi":"10.1002/hon.70093_72","DOIUrl":"https://doi.org/10.1002/hon.70093_72","url":null,"abstract":"<p><b>Introduction:</b> Zanubrutinib is a next-generation Bruton tyrosine kinase inhibitor that is approved for five indications, including CLL/SLL. Initial results from the SEQUOIA study (NCT03336333), at a median follow-up of 26.2 months, demonstrated superior progression-free survival (PFS) by independent review with zanubrutinib versus bendamustine + rituximab (arms A and B) in patients with treatment-naive CLL/SLL without del(17p) as well as high overall response rate (ORR) and PFS benefit in patients with del(17p) (arm C). Additionally, the 5-year follow-up in arm A demonstrated durable PFS benefit, with estimated 54- and 60-month PFS rates of 80% and 76%, respectively. Here we report updated results in SEQUOIA arm C, in patients with del(17p), after approximately 5 years of follow-up (data cutoff: Apr 30, 2024).</p><p><b>Methods:</b> Arm C is a nonrandomized cohort of SEQUOIA patients with del(17p) that received zanubrutinib monotherapy. Investigator-assessed PFS, overall survival (OS), ORR, and safety/tolerability were evaluated. Adverse events (AEs) were recorded until disease progression or start of next-line therapy.</p><p><b>Results:</b> Between Feb 2018 and Mar 2019, 111 treatment-naive patients with del(17p) were enrolled to receive zanubrutinib. The median age was 71 years (range, 42–87 years), 79 (71%) were male, 67 (60%) were IGHV unmutated, and 47 (42%) had both del(17p) and <i>TP53</i> mutation. At a median follow-up of 65.8 months (range, 5–75 months), median PFS was not reached. The estimated 60-month PFS rate was 72.2% (62.4%–79.8%) (Figure), or 73.0% (63.3%–80.6%) when adjusted for COVID-19. Median OS was also not reached. The estimated 60-month OS rate was 85.1% (76.9%–90.6%), or 87.0% (79.0%–92.1%) when adjusted for COVID-19. The ORR was 97.3%, and the complete response/complete response with incomplete hematologic recovery rate was 18.2%. Zanubrutinib treatment was ongoing in 62.2% of patients. The most common causes for treatment discontinuation were AEs and progressive disease (in 17.1% and 15.3%, respectively). Key AEs of interest (AEI) included any-grade infection (82%), bleeding (60%), neutropenia (19%), hypertension (18%), anemia (9%), thrombocytopenia (8%), and atrial fibrillation/flutter (7%). Grade ≥ 3 AEI included infection (33%), neutropenia (16%), hypertension (8%), bleeding (6%), atrial fibrillation/flutter (5%), and thrombocytopenia (2%).</p><p><b>Conclusions:</b> With this 5-year follow-up in SEQUOIA, the efficacy of zanubrutinib in treatment-naive higher-risk patients with del(17p) was maintained, and patients continue to demonstrate PFS benefits consistent with the randomized cohort of patients without del(17p) (arm A). Additionally, with longer-term follow-up, no new safety signals were identified. This update, in the largest cohort of uniformly treated patients with del(17p), suggests that zanubrutinib remains a valuable frontline treatment option for patients with or without del(17p) CLL/SLL.</p><p><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.70093_72","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144299720","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. M. Kahn, J. M. Unger, H. Li, S. M. Castellino, H. Dillon, T. Hernandez, S. C. Rutherford, A. Punnett, M. LeBlanc, J. Y. Song, S. M. Smith, A. M. Evens, K. M. Kelly, J. W. Friedberg, A. Herrera
<p>J. M. Unger, H. Li, S. M. Castellino, H. Dillon, T. Hernandez, S. C. Rutherford, A. Punnett, M. LeBlanc, J. Y. Song, S. M. Smith, A. M. Evens, K. M. Kelly, J. W. Friedberg, and A. Herrera equally contributing author.</p><p><b>Background</b>: The phase 3 randomized trial S1826 showed that among patients with advanced-stage classic Hodgkin lymphoma (cHL), nivolumab plus doxorubicin, vinblastine, and dacarbazine (N+AVD) resulted in longer progression-free survival (PFS) compared to brentuximab vedotin plus AVD (BV+AVD). We assessed whether the treatment benefits of N+AVD applied to potentially socioeconomically vulnerable populations.</p><p><b>Methods:</b> S1826 was a multicenter trial for patients ≥ 12 years old with stage III or IV newly diagnosed cHL. The trial was stopped early at its pre-specified second interim analysis due to efficacy of the N+AVD arm (hazard ratio [HR] for progression or death, 0.48; 95% confidence interval [CI], 0.27–0.87, <i>p</i> = 0.001). We assessed whether there was any evidence of differential benefit of N+AVD with respect to PFS according to categories of race/ethnicity (Black race and/or Hispanic ethnicity vs. others), rural versus urban residence, area-level socioeconomic deprivation (Area Deprivation Index [ADI] above median, yes vs. no), and insurance status (Medicaid or no insurance vs. others) using interaction tests. Analyses were conducted using Cox regression adjusting for the study-specified stratification variables including age (12 –17 vs. 18–60 vs. > 60 years), the international prognostic score (IPS; 0–3 vs. 4–7), and intent to use radiation (yes vs. no). An overall Type I error rate of alpha = 0.10 was used; multiplicity was accounted for by specifying each individual test at the two-sided alpha = 0.025 level using Bonferroni. If no interaction was found, the marginal association of socioeconomic variables and PFS using multivariable Cox regression was examined.</p><p><b>Results:</b> Of N = 970 eligible patients, 90% were < 60 years, and 56% were male; 11.8% were Black, 12.7% were Hispanic, and 32% had IPS 4–7. Among socioeconomic variables, the combined Black and/or Hispanic patients comprised 24.5%, 13.3% were from rural areas, 50% lived in areas above the median ADI level, and 23.2% had Medicaid or no insurance. In survival analyses, there was no statistically significant evidence that the effect of treatment on PFS differed between levels of the socioeconomic variables (Table). For instance, the PFS HR was 0.52 for Black and/or Hispanic patients and 0.41 for other patients (interaction <i>p</i>-value = 0.60). Across all patients, there was no statistically significant association of Black and/or Hispanic race/ethnicity (HR = 1.10, 95% CI: 0.72–1.69, <i>p</i> = 0.65), rural geography (HR = 1.11, 95% CI: 0.67–1.85, <i>p</i> = 0.67), high ADI (HR = 1.30, 95% CI: 0.89–1.88, <i>p</i> = 0.17), or Medicaid/no insurance (HR = 1.01, 95% CI: 0.63–1.60, <i>p</i> = 0.98) with PFS.</p><p><b>Conclusion:
J. M.昂格，H.李，S. M.卡斯特利诺，H.狄龙，T.埃尔南德斯，S. C.卢瑟福，A.庞尼特，M. LeBlanc， J. Y.宋，S. M.史密斯，A. M.埃文斯，K. M.凯利，J. W.弗里德伯格和A.埃雷拉都是同样贡献的作者。背景：3期随机试验S1826显示，在晚期经典霍奇金淋巴瘤（cHL）患者中，纳武单抗联合阿霉素、长春花碱和达卡巴嗪（N+AVD）比布伦妥昔单抗联合AVD （BV+AVD）可获得更长的无进展生存期（PFS）。我们评估了N+AVD的治疗益处是否适用于潜在的社会经济弱势群体。方法：S1826是一项针对≥12岁的III期或IV期新诊断cHL患者的多中心试验。由于N+AVD组的疗效，该试验在预先指定的第二次中期分析中提前停止(进展或死亡的风险比[HR]为0.48；95%可信区间[CI]， 0.27-0.87, p = 0.001)。根据种族/民族（黑人和/或西班牙裔与其他种族）、农村与城市居住、区域层面的社会经济剥夺（区域剥夺指数高于中位数，是与否）和保险状况（医疗补助或无保险与其他），我们使用相互作用测试评估了是否有任何证据表明N+AVD对PFS有不同的益处。使用Cox回归对研究指定的分层变量进行分析，包括年龄(12 -17岁vs. 18-60岁vs. >；60岁)，国际预后评分(IPS；0-3 vs. 4-7)，以及使用辐射的意图（是vs.否）。总体I型错误率为alpha = 0.10；多重性是通过使用Bonferroni在双侧alpha = 0.025水平上指定每个个体检验来解释的。如果没有发现相互作用，则使用多变量Cox回归检查社会经济变量与PFS的边际关联。结果：在970例符合条件的患者中，90%为<；60岁，男性占56%；11.8%为黑人，12.7%为西班牙裔，32%为IPS 4-7。在社会经济变量中，黑人和/或西班牙裔患者占24.5%，13.3%来自农村地区，50%生活在高于ADI中位数水平的地区，23.2%有医疗补助或没有保险。在生存分析中，没有统计学上显著的证据表明治疗对PFS的影响在不同的社会经济变量水平之间存在差异（表）。例如，黑人和/或西班牙裔患者的PFS HR为0.52，其他患者为0.41（相互作用p值= 0.60）。在所有患者中，黑人和/或西班牙裔人种/民族（HR = 1.10, 95% CI: 0.72-1.69, p = 0.65）、农村地理（HR = 1.11, 95% CI: 0.67 - 1.85, p = 0.67）、高ADI （HR = 1.30, 95% CI: 0.89-1.88, p = 0.17）或医疗补助/无保险（HR = 1.01, 95% CI: 0.63-1.60, p = 0.98）与PFS没有统计学意义的关联。结论：在S1826纳入的晚期cHL患者中，我们没有发现证据表明，与BV+AVD相比，N+AVD的PFS获益会因社会不利因素而显著减弱。这表明N+AVD广泛适用于不同社会经济背景的患者。总体生存分析正在进行中。科研经费声明：美国国立卫生研究院国家癌症研究所U10CA180888、U10CA180819；部分由BMS实现；埃米特,托尼斯蒂芬森白血病淋巴瘤学会（LLS）学者奖；拉里&；丹尼斯·梅森临床学者职业发展奖；V基金会劳埃德家庭临床研究者基金；LLS临床研究学者奖。关键词：癌症健康差异无潜在利益冲突来源
{"title":"THE ASSOCIATION OF SOCIAL DISADVANTAGE WITH OUTCOMES IN PATIENTS WITH ADVANCED-STAGE, CLASSIC HODGKIN LYMPHOMA ENROLLED IN THE PHASE 3 INTERGROUP TRIAL S1826","authors":"J. M. Kahn, J. M. Unger, H. Li, S. M. Castellino, H. Dillon, T. Hernandez, S. C. Rutherford, A. Punnett, M. LeBlanc, J. Y. Song, S. M. Smith, A. M. Evens, K. M. Kelly, J. W. Friedberg, A. Herrera","doi":"10.1002/hon.70094_368","DOIUrl":"https://doi.org/10.1002/hon.70094_368","url":null,"abstract":"<p>J. M. Unger, H. Li, S. M. Castellino, H. Dillon, T. Hernandez, S. C. Rutherford, A. Punnett, M. LeBlanc, J. Y. Song, S. M. Smith, A. M. Evens, K. M. Kelly, J. W. Friedberg, and A. Herrera equally contributing author.</p><p><b>Background</b>: The phase 3 randomized trial S1826 showed that among patients with advanced-stage classic Hodgkin lymphoma (cHL), nivolumab plus doxorubicin, vinblastine, and dacarbazine (N+AVD) resulted in longer progression-free survival (PFS) compared to brentuximab vedotin plus AVD (BV+AVD). We assessed whether the treatment benefits of N+AVD applied to potentially socioeconomically vulnerable populations.</p><p><b>Methods:</b> S1826 was a multicenter trial for patients ≥ 12 years old with stage III or IV newly diagnosed cHL. The trial was stopped early at its pre-specified second interim analysis due to efficacy of the N+AVD arm (hazard ratio [HR] for progression or death, 0.48; 95% confidence interval [CI], 0.27–0.87, <i>p</i> = 0.001). We assessed whether there was any evidence of differential benefit of N+AVD with respect to PFS according to categories of race/ethnicity (Black race and/or Hispanic ethnicity vs. others), rural versus urban residence, area-level socioeconomic deprivation (Area Deprivation Index [ADI] above median, yes vs. no), and insurance status (Medicaid or no insurance vs. others) using interaction tests. Analyses were conducted using Cox regression adjusting for the study-specified stratification variables including age (12 –17 vs. 18–60 vs. > 60 years), the international prognostic score (IPS; 0–3 vs. 4–7), and intent to use radiation (yes vs. no). An overall Type I error rate of alpha = 0.10 was used; multiplicity was accounted for by specifying each individual test at the two-sided alpha = 0.025 level using Bonferroni. If no interaction was found, the marginal association of socioeconomic variables and PFS using multivariable Cox regression was examined.</p><p><b>Results:</b> Of N = 970 eligible patients, 90% were < 60 years, and 56% were male; 11.8% were Black, 12.7% were Hispanic, and 32% had IPS 4–7. Among socioeconomic variables, the combined Black and/or Hispanic patients comprised 24.5%, 13.3% were from rural areas, 50% lived in areas above the median ADI level, and 23.2% had Medicaid or no insurance. In survival analyses, there was no statistically significant evidence that the effect of treatment on PFS differed between levels of the socioeconomic variables (Table). For instance, the PFS HR was 0.52 for Black and/or Hispanic patients and 0.41 for other patients (interaction <i>p</i>-value = 0.60). Across all patients, there was no statistically significant association of Black and/or Hispanic race/ethnicity (HR = 1.10, 95% CI: 0.72–1.69, <i>p</i> = 0.65), rural geography (HR = 1.11, 95% CI: 0.67–1.85, <i>p</i> = 0.67), high ADI (HR = 1.30, 95% CI: 0.89–1.88, <i>p</i> = 0.17), or Medicaid/no insurance (HR = 1.01, 95% CI: 0.63–1.60, <i>p</i> = 0.98) with PFS.</p><p><b>Conclusion:","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_368","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144299664","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
E. Pettersson, K. Vemuri, M. Berglund, J. Collin, M. Herre, R. Amini, D. Molin, A. Olsson, G. Enblad
<p><b>Introduction:</b> Neutrophil extracellular traps (NETs) are complexes of decondensed chromatin and granule proteins that can be released from activated neutrophils during infections or in inflammatory conditions, including cancer. Accumulation of NETs in tissues and blood can contribute to increased inflammation, thrombosis and organ damage. In several types of solid cancers, NETs have been shown to facilitate metastasis and tumour growth, leading to a worse prognosis. However, little is known about the role of NETs in malignant lymphomas.</p><p><b>Methods:</b> The concentration of NETs was analysed in plasma samples taken at diagnosis from patients with diffuse large B-cell lymphoma (DLBCL, <i>n</i> = 227) and classical Hodgkin lymphoma (cHL, <i>n</i> = 117) in the Uppsala Umeå Comprehensive Cancer Consortium (U-CAN) biobank. Plasma from blood donors (<i>n</i> = 54) were used as healthy controls. NETs were measured using a commercial enzyme-linked immunosorbent assay (ELISA) targeting complexes of citrullinated histones and extracellular DNA, a biomarker with high specificity for NETs. Clinical data, including blood counts at diagnosis and treatment outcome, was extracted from patient records and analysed in relation to the plasma concentrations of NETs.</p><p><b>Results:</b> Higher concentrations of NETs were seen in plasma from DLBCL patients (range 0.62 to 200 ng/ml) compared to cHL patients (<i>p</i> < 0.01, range 0.58 to 62 ng/ml) and healthy controls (<i>p</i> < 0.001, range 1.0 to 37 ng/ml). The level of NETs in cHL was not significantly higher than in control samples. In both DLBCL and cHL, a poorer overall survival was seen in patients with concentrations of NETs above median (7.4 and 5.6 ng/ml respectively, <i>p</i> < 0.05). There was no significant correlation between progression free survival and NETs. In cHL, there was a positive correlation between elevated levels of NETs and age above 45 years (<i>p</i> < 0.05), but no correlation to age was shown in DLBCL. The NET levels did not significantly differ between the sexes. A trend, although not significant, could be seen with increased NET levels in higher stages of both DLBCL and cHL. The plasma concentration of NETs in both lymphoma diseases showed a positive correlation with the neutrophil count in blood (<i>p</i> < 0.05), as well as erythrocyte sedimentation rate (ESR) above 50 mmHg (<i>p</i> < 0.01) at diagnosis.</p><p><b>Conclusions:</b> In line with previous studies on NETs in cancer, we show that high levels of NETs in plasma correlates with worse survival for both DLBCL and cHL patients. However, plasma concentrations were only significantly increased in DLBCL compared to healthy controls, with no correlation to age or sex. Based on the results, NETs could be a possible prognostic marker to further investigate in malignant lymphoma. In both DLBCL and cHL, higher levels of NETs were seen in patients with elevated neutrophil count and high ESR, a sign of
{"title":"INVESTIGATING NEUTROPHIL EXTRACELLULAR TRAPS AS A POSSIBLE PROGNOSTIC MARKER IN DIFFUSE LARGE B-CELL LYMPHOMA AND CLASSICAL HODGKIN LYMPHOMA","authors":"E. Pettersson, K. Vemuri, M. Berglund, J. Collin, M. Herre, R. Amini, D. Molin, A. Olsson, G. Enblad","doi":"10.1002/hon.70094_205","DOIUrl":"https://doi.org/10.1002/hon.70094_205","url":null,"abstract":"<p><b>Introduction:</b> Neutrophil extracellular traps (NETs) are complexes of decondensed chromatin and granule proteins that can be released from activated neutrophils during infections or in inflammatory conditions, including cancer. Accumulation of NETs in tissues and blood can contribute to increased inflammation, thrombosis and organ damage. In several types of solid cancers, NETs have been shown to facilitate metastasis and tumour growth, leading to a worse prognosis. However, little is known about the role of NETs in malignant lymphomas.</p><p><b>Methods:</b> The concentration of NETs was analysed in plasma samples taken at diagnosis from patients with diffuse large B-cell lymphoma (DLBCL, <i>n</i> = 227) and classical Hodgkin lymphoma (cHL, <i>n</i> = 117) in the Uppsala Umeå Comprehensive Cancer Consortium (U-CAN) biobank. Plasma from blood donors (<i>n</i> = 54) were used as healthy controls. NETs were measured using a commercial enzyme-linked immunosorbent assay (ELISA) targeting complexes of citrullinated histones and extracellular DNA, a biomarker with high specificity for NETs. Clinical data, including blood counts at diagnosis and treatment outcome, was extracted from patient records and analysed in relation to the plasma concentrations of NETs.</p><p><b>Results:</b> Higher concentrations of NETs were seen in plasma from DLBCL patients (range 0.62 to 200 ng/ml) compared to cHL patients (<i>p</i> < 0.01, range 0.58 to 62 ng/ml) and healthy controls (<i>p</i> < 0.001, range 1.0 to 37 ng/ml). The level of NETs in cHL was not significantly higher than in control samples. In both DLBCL and cHL, a poorer overall survival was seen in patients with concentrations of NETs above median (7.4 and 5.6 ng/ml respectively, <i>p</i> < 0.05). There was no significant correlation between progression free survival and NETs. In cHL, there was a positive correlation between elevated levels of NETs and age above 45 years (<i>p</i> < 0.05), but no correlation to age was shown in DLBCL. The NET levels did not significantly differ between the sexes. A trend, although not significant, could be seen with increased NET levels in higher stages of both DLBCL and cHL. The plasma concentration of NETs in both lymphoma diseases showed a positive correlation with the neutrophil count in blood (<i>p</i> < 0.05), as well as erythrocyte sedimentation rate (ESR) above 50 mmHg (<i>p</i> < 0.01) at diagnosis.</p><p><b>Conclusions:</b> In line with previous studies on NETs in cancer, we show that high levels of NETs in plasma correlates with worse survival for both DLBCL and cHL patients. However, plasma concentrations were only significantly increased in DLBCL compared to healthy controls, with no correlation to age or sex. Based on the results, NETs could be a possible prognostic marker to further investigate in malignant lymphoma. In both DLBCL and cHL, higher levels of NETs were seen in patients with elevated neutrophil count and high ESR, a sign of","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_205","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144299850","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. D. Dreyfuss, N. Ganesan, B. S. Imber, M. LaRiviere, D. Isrow, J. Plastaras, J. Svoboda, J. Yahalom, C. H. Moskowitz, A. Moskowitz
<p><b>Background:</b> Chemotherapy (chemo) followed by stem cell transplant (SCT) is standard of care for relapsed/refractory (RR) Hodgkin Lymphoma (HL). In a phase II study, we evaluated pembrolizumab (pembro) with involved site radiation therapy (ISRT) as an alternative salvage approach for localized favorable relapse.</p><p><b>Methods:</b> Patients with RR stage IA/IIA, non-bulky (< 10cm) HL after one line of therapy had a PETCT simulation followed by pembro 200 mg IV q 21d for 4 cycles and PETCT simulation 3 wks later. Patients then received ISRT per response as follows: (1) 20 Gy for complete metabolic response (CMR) defined by Deauville Score (DS) 1–3; (2) 30 Gy for partial metabolic response (PMR) or stable disease (SD) (DS 4–5) and negative biopsy; or (3) 36–40 Gy for PMR/SD and positive biopsy. Patients who progressed (PD) were taken off study. PETCT response was documented 4–6 weeks after ISRT. The primary endpoint was CMR rate after pembro-RT. Secondary endpoints were response to single agent pembro, 2-year progression free survival (PFS), and toxicity.</p><p><b>Results:</b> 22 of planned 22 patients enrolled with median age of 36 (range 22–66) and 10 (45%) males. 3 (14%) had stage I, 18 (82%) stage II, and 1 had an unspecified limited stage at initial diagnosis. Frontline therapy was chemotherapy alone in 19 (86%) and combined modality in 3 (14%). 21 (95%) received adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD), 17 (81%) with < 6 cycles. 14 (64%) had relapsed and 8 (36%) had refractory disease.</p><p>7 (32%) had CMR after pembro, 3 (14%) had PMR/SD with negative biopsy, 6 (27%) had PMR with positive biopsy, 1 (5%) had PMR without biopsy, and 5 (23%) had PD. 17 patients proceeded to ISRT, of whom 7 (41%) with CMR received 20 Gy, 3 (18%) with PMR/SD and negative biopsy received 30 Gy, and 7 (41%) with PMR/SD and positive/no biopsy received 36–40 Gy. Of the 14 with post-RT PET, 12 (86% of these patients, 67% overall) achieved CMR. After median follow up of 34 months (6–79), 2-year PFS was 65% (95% CI: 47–91).</p><p>Five patients progressed on pembro and three relapsed after a median of 12 months (range 7–70) from completion of pembro-RT. Among the patients with PD during or after pembro-RT, three are currently in remission, one is currently undergoing therapy, and the status for the others are unknown. Subsequent treatments included pembro plus gemcitabine/vinorelbine/liposomal doxorubicin followed by ASCT (<i>n</i> = 2), brentuximab vedotin (BV) plus nivolumab followed by ASCT (<i>n</i> = 1) and 2 doses of BV followed by additional RT (<i>n</i> = 1).</p><p>Immune-related toxicities were 3 (14%) grade 1 rash, and 3 (14%) grade 2 hypo/hyperthyroidism. Grade > 2 toxicities were 1 (5%) grade 3 headache, 1 (5%) grade 3 urinary tract infection, 1 (5%) grade 3 encephalopathy, and 1 (5%) grade 4 lipase elevation.</p><p><b>Conclusion:</b> Pembro-RT yielded excellent CMR rates and minimal toxicity. These data suggest pembro-R
{"title":"PEMBROLIZUMAB AND RADIATION THERAPY ALONE AS AN ALTERNATIVE TO TRANSPLANT FOR LOCALIZED FAILURE AFTER CHEMOTHERAPY IN HODGKIN LYMPHOMA: A MULTICENTER PHASE II STUDY","authors":"A. D. Dreyfuss, N. Ganesan, B. S. Imber, M. LaRiviere, D. Isrow, J. Plastaras, J. Svoboda, J. Yahalom, C. H. Moskowitz, A. Moskowitz","doi":"10.1002/hon.70093_129","DOIUrl":"https://doi.org/10.1002/hon.70093_129","url":null,"abstract":"<p><b>Background:</b> Chemotherapy (chemo) followed by stem cell transplant (SCT) is standard of care for relapsed/refractory (RR) Hodgkin Lymphoma (HL). In a phase II study, we evaluated pembrolizumab (pembro) with involved site radiation therapy (ISRT) as an alternative salvage approach for localized favorable relapse.</p><p><b>Methods:</b> Patients with RR stage IA/IIA, non-bulky (< 10cm) HL after one line of therapy had a PETCT simulation followed by pembro 200 mg IV q 21d for 4 cycles and PETCT simulation 3 wks later. Patients then received ISRT per response as follows: (1) 20 Gy for complete metabolic response (CMR) defined by Deauville Score (DS) 1–3; (2) 30 Gy for partial metabolic response (PMR) or stable disease (SD) (DS 4–5) and negative biopsy; or (3) 36–40 Gy for PMR/SD and positive biopsy. Patients who progressed (PD) were taken off study. PETCT response was documented 4–6 weeks after ISRT. The primary endpoint was CMR rate after pembro-RT. Secondary endpoints were response to single agent pembro, 2-year progression free survival (PFS), and toxicity.</p><p><b>Results:</b> 22 of planned 22 patients enrolled with median age of 36 (range 22–66) and 10 (45%) males. 3 (14%) had stage I, 18 (82%) stage II, and 1 had an unspecified limited stage at initial diagnosis. Frontline therapy was chemotherapy alone in 19 (86%) and combined modality in 3 (14%). 21 (95%) received adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD), 17 (81%) with < 6 cycles. 14 (64%) had relapsed and 8 (36%) had refractory disease.</p><p>7 (32%) had CMR after pembro, 3 (14%) had PMR/SD with negative biopsy, 6 (27%) had PMR with positive biopsy, 1 (5%) had PMR without biopsy, and 5 (23%) had PD. 17 patients proceeded to ISRT, of whom 7 (41%) with CMR received 20 Gy, 3 (18%) with PMR/SD and negative biopsy received 30 Gy, and 7 (41%) with PMR/SD and positive/no biopsy received 36–40 Gy. Of the 14 with post-RT PET, 12 (86% of these patients, 67% overall) achieved CMR. After median follow up of 34 months (6–79), 2-year PFS was 65% (95% CI: 47–91).</p><p>Five patients progressed on pembro and three relapsed after a median of 12 months (range 7–70) from completion of pembro-RT. Among the patients with PD during or after pembro-RT, three are currently in remission, one is currently undergoing therapy, and the status for the others are unknown. Subsequent treatments included pembro plus gemcitabine/vinorelbine/liposomal doxorubicin followed by ASCT (<i>n</i> = 2), brentuximab vedotin (BV) plus nivolumab followed by ASCT (<i>n</i> = 1) and 2 doses of BV followed by additional RT (<i>n</i> = 1).</p><p>Immune-related toxicities were 3 (14%) grade 1 rash, and 3 (14%) grade 2 hypo/hyperthyroidism. Grade > 2 toxicities were 1 (5%) grade 3 headache, 1 (5%) grade 3 urinary tract infection, 1 (5%) grade 3 encephalopathy, and 1 (5%) grade 4 lipase elevation.</p><p><b>Conclusion:</b> Pembro-RT yielded excellent CMR rates and minimal toxicity. These data suggest pembro-R","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_129","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144299797","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}
K. D. Hofer, S. Scheinost, L. Ben-Taarit, J. Hüllein, T. Walther, K. Putzker, L. Sellner, M. W. Kühn, T. Kindler, F. Nguyen-Khac, M. Crespo Maull, F. Bosch, A. Theocharides, M. G. Manz, J. Bourquin, B. Bornhauser, S. Dietrich, J. Lewis, W. Huber, J. Lu, T. Zenz
K. D. Hofer and S. Scheinost equally contributing author.
Ex vivo drug screening may leverage the cellular response to drugs for disease understanding, identification of new targets and improved treatment. Precise stratification of patients with hematologic malignancies based on molecular profiling can improve treatment selection and outcome.
Here, we perform a large-scale drug screen across a range of hematologic malignancies to link drug response to diseases and subgroups, identify pathway dependencies and define determinants of drug response. We analyze sequential samples to assess the dynamics of drug response phenotypes over time and compare ex vivo results to clinical outcomes.
For 722 patient samples from 17 blood cancers we assessed drug response to 63 different compounds. The analysis of 143,640 data points shows that drug response is strongly linked to disease entities. We link functional pathway dependencies to individual blood cancers and genetic subgroups. In CLL, trisomy(12) confers susceptibility to inhibition of MEK/ERK and PI3K-AKT-mTOR pathways. DDX3X mutations are associated with increased sensitivity to BTK and SYK inhibition. Longitudinal assessment shows stable drug response over time in untreated patients. Patients receiving BCR signaling inhibitors acquire sensitivities to BET and dual MCL-1/BCL-2 inhibition.
We have generated an accessible resource of ex vivo drug profiling across different hematologic malignancies that can be leveraged for functional analyses and biomarker-stratified treatment strategies.
Researchfunding declaration: Jacques and Gloria Gossweiler Foundation, Swiss Academy of Medical Sciences, University Hospital Zurich
Keywords: bioinformatics; computational and systems biology; tumor biology and heterogeneity
No potential sources of conflict of interest.
K. D. Hofer和S. Scheinost是同样有贡献的作者。体外药物筛选可以利用细胞对药物的反应来了解疾病，确定新的靶点和改善治疗。基于分子谱的血液恶性肿瘤患者的精确分层可以改善治疗选择和结果。在这里，我们在一系列血液恶性肿瘤中进行了大规模的药物筛选，以将药物反应与疾病和亚群联系起来，确定途径依赖性并定义药物反应的决定因素。我们分析了连续的样本，以评估药物反应表型随时间的动态，并将离体结果与临床结果进行比较。对于来自17种血癌的722例患者样本，我们评估了对63种不同化合物的药物反应。对143,640个数据点的分析表明，药物反应与疾病实体密切相关。我们将功能通路依赖与个体血癌和遗传亚群联系起来。在CLL中，三体（12）对MEK/ERK和PI3K-AKT-mTOR通路的抑制具有易感性。DDX3X突变与BTK和SYK抑制敏感性增加有关。纵向评估显示，未经治疗的患者随着时间的推移，药物反应稳定。接受BCR信号抑制剂治疗的患者对BET和MCL-1/BCL-2双重抑制具有敏感性。我们已经创建了一个可访问的跨不同血液恶性肿瘤的体外药物分析资源，可以用于功能分析和生物标志物分层治疗策略。研究经费声明：Jacques and Gloria Gossweiler基金会，瑞士医学科学院，苏黎世大学医院计算与系统生物学；肿瘤生物学和异质性无潜在的利益冲突来源。
{"title":"SYSTEMATIC INVESTIGATION OF DISEASE- AND GENOTYPE-SPECIFIC VULNERABILITIES IN PRIMARY BLOOD CANCER USING HIGH-THROUGHPUT EX VIVO DRUG SCREENING","authors":"K. D. Hofer, S. Scheinost, L. Ben-Taarit, J. Hüllein, T. Walther, K. Putzker, L. Sellner, M. W. Kühn, T. Kindler, F. Nguyen-Khac, M. Crespo Maull, F. Bosch, A. Theocharides, M. G. Manz, J. Bourquin, B. Bornhauser, S. Dietrich, J. Lewis, W. Huber, J. Lu, T. Zenz","doi":"10.1002/hon.70093_114","DOIUrl":"https://doi.org/10.1002/hon.70093_114","url":null,"abstract":"<p>K. D. Hofer and S. Scheinost equally contributing author.</p><p>Ex vivo drug screening may leverage the cellular response to drugs for disease understanding, identification of new targets and improved treatment. Precise stratification of patients with hematologic malignancies based on molecular profiling can improve treatment selection and outcome.</p><p>Here, we perform a large-scale drug screen across a range of hematologic malignancies to link drug response to diseases and subgroups, identify pathway dependencies and define determinants of drug response. We analyze sequential samples to assess the dynamics of drug response phenotypes over time and compare ex vivo results to clinical outcomes.</p><p>For 722 patient samples from 17 blood cancers we assessed drug response to 63 different compounds. The analysis of 143,640 data points shows that drug response is strongly linked to disease entities. We link functional pathway dependencies to individual blood cancers and genetic subgroups. In CLL, trisomy(12) confers susceptibility to inhibition of MEK/ERK and PI3K-AKT-mTOR pathways. DDX3X mutations are associated with increased sensitivity to BTK and SYK inhibition. Longitudinal assessment shows stable drug response over time in untreated patients. Patients receiving BCR signaling inhibitors acquire sensitivities to BET and dual MCL-1/BCL-2 inhibition.</p><p>We have generated an accessible resource of ex vivo drug profiling across different hematologic malignancies that can be leveraged for functional analyses and biomarker-stratified treatment strategies.</p><p><b>Research</b> <b>funding declaration:</b> Jacques and Gloria Gossweiler Foundation, Swiss Academy of Medical Sciences, University Hospital Zurich</p><p><b>Keywords:</b> bioinformatics; computational and systems biology; tumor biology and heterogeneity</p><p><b>No potential sources of conflict of interest.</b></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_114","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144299758","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
C. 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}
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