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在SWOG S1826入组的患者中，EBV状态和组织学对纳武那单抗与Bv-AVD治疗结果的影响

IF 3.9 4区医学 Q2 HEMATOLOGY

Hematological Oncology Pub Date : 2025-06-16 DOI:10.1002/hon.70093_20

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

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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.Methods: 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).Results: 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 (p < 0.0001). EBV+ pts had higher IPS scores but no statistical difference in stage or B symptoms.With median follow-up of 24 months, within EBV− group, PFS was longer with N-AVD (HR 0.54; p = 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; p = 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; p = 0.0144). In N-AVD arm, no PFS difference was seen between EBV+ and EBV− (95% versus 92%; p = 0.88) but in Bv-AVD arm EBV+ pts had poorer PFS (72% versus 85%; p = 0.03).102 pts had non-NS histology (N-AVD = 55; Bv-AVD = 47), median age 48 years versus 22 years for NS (p < 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; p = 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; p = 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, p = 0.11). In Bv-AVD arm, non-NS pts had inferior PFS (HR = 3.4, p < 0.0001), 2 years PFS 65% versus 87% in NS.Conclusions: 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 those with non-NS histologies compared with Bv-AVD. These results inform future correlative studies to understand the impact of checkpoint blockade in molecular clusters of cHL. 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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\":null,\"url\":null,\"abstract\":\"Introduction: 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.Methods: 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).Results: 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 (p < 0.0001). EBV+ pts had higher IPS scores but no statistical difference in stage or B symptoms.With median follow-up of 24 months, within EBV− group, PFS was longer with N-AVD (HR 0.54; p = 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; p = 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; p = 0.0144). In N-AVD arm, no PFS difference was seen between EBV+ and EBV− (95% versus 92%; p = 0.88) but in Bv-AVD arm EBV+ pts had poorer PFS (72% versus 85%; p = 0.03).102 pts had non-NS histology (N-AVD = 55; Bv-AVD = 47), median age 48 years versus 22 years for NS (p < 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; p = 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; p = 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, p = 0.11). 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引用次数: 0

摘要

从历史上看，eb病毒（EBV）阳性（+）经典霍奇金淋巴瘤（cHL）患者的生存率低于EBV -患者，部分原因是老年患者的发病率增加。EBV本身除了9p24.1染色体改变和肿瘤微环境外，还直接导致cHL中PD-L1表达增加。这项来自S1826试验的亚群分析评估了新诊断的晚期cHL的N-AVD与Bv-AVD，评估了EBV状态和组织学对治疗结果的影响。方法：符合条件的III-IV期cHL患者的组织学经中心病理检查证实（结节硬化（NS）与非NS亚型：混合细胞，淋巴细胞丰富/耗尽），并报告EBV状态（IHC或ISH）。患者按1:1至6个周期随机分为N-AVD或Bv-AVD。主要终点为无进展生存期（PFS）。结果：在入组的994名患者中，522名患者（53%）具有可用的EBV状态(EBV+ = 101；Ebv−= 421)。在随机分配到N-AVD的254名患者中，48名（19%）EBV+， 206名EBV-。在随机分配到Bv-AVD的268例患者中，53例（20%）为EBV+， 215例为EBV-。EBV+患者的中位年龄为42岁（范围12-83岁），EBV -患者的中位年龄为25岁（范围12-80岁）。0.0001)。EBV+患者IPS评分较高，但在B期和B期症状上无统计学差异。中位随访时间为24个月，EBV组N-AVD患者PFS更长(HR 0.54；P = 0.0306)；2年PFS为92% (95% CI: 87-95)，而Bv-AVD为85% （95% CI: 79-89）。在EBV+组，N-AVD显著改善PFS (HR 0.27；P = 0.0127)；N-AVD的2年PFS为95% (95% CI: 80-99)， Bv-AVD的2年PFS为72% （95% CI: 58-83）。在EBV+患者中，经年龄组调整后，N-AVD治疗效果仍然显著(HR = 0.25；P = 0.0144)。在N-AVD组，EBV+和EBV -之间无PFS差异(95% vs 92%；p = 0.88)，但在Bv-AVD组，EBV+患者的PFS较差(72%对85%；P = 0.03)。非ns组织学102例(N-AVD = 55；Bv-AVD = 47)，中位年龄为48岁，NS为22岁(p <；0.0001)， 30%非ns为>；60岁与4%的NS患者相比；60年。在非ns患者中，N-AVD导致PFS延长(HR 0.31；95% ci: 0.31-0.74；p = 0.005)， Bv-AVD的2年PFS为92% (95% CI: 79-97)，而Bv-AVD为65% （95% CI: 50-77）。N-AVD患者的PFS较长(HR 0.49；95% ci: 0.28-0.86；p = 0.01): 2年PFS分别为94% （95% CI: 90-96）和87% （95% CI: 83-91）。在N-AVD组中，非NS组2年的PFS无显著差异，分别为92%和94% （HR 2.01, p = 0.11）。在Bv-AVD组，非ns患者的PFS较差(HR = 3.4, p <；0.0001)， 2年PFS为65%，NS为87%。结论：尽管与EBV状态或组织学亚型无关，N-AVD改善了所有晚期cHL患者的预后，但与Bv-AVD相比，它基本上消除了EBV+ cHL患者和非ns组织学患者的历史不良预后。这些结果为未来的相关研究提供了信息，以了解检查点阻断对cHL分子簇的影响。N-AVD应被视为晚期cHL的标准治疗，特别是非ns和EBV+ cHL。研究经费声明：经费由美国国立卫生研究院国家癌症研究所U10CA180888、U10CA180819提供；部分原因是BMS。关键词:免疫治疗;霍奇金淋巴瘤（儿童、青少年和年轻人）；潜在的利益冲突来源：S。顾问或顾问角色：ADC therapeutics， KITE/Gilead， Genmab和BMS。其他报酬：来自Nektar、Merck、Xencor、Chimagen和Genmab、KITE/Gilead、Janssen、cariboua等机构的研究经费。F. herrerera顾问或顾问角色：Bristol Myers Squibb、Genentech、Merck、Seagen、AstraZeneca、ADC Therapeutics、武田、Genmab、辉瑞、Abbvie、Allogene Therapeutics其他报酬：研究经费-Bristol Myers Squibb、Genentech、Merck、Seagen、AstraZenecaS。顾问或顾问角色：Abbvie， ADC Therapeutics， BMS, Genmab, Incyte, Karyopharm, Kite，辉瑞/Seagen DSMB: KaryopharmOther薪酬：研究支持：Constellation， Genentech, KaryopharmB。顾问或顾问角色：BMSJ。顾问或顾问角色：Astra Zeneca， Beigene， BMS, Caribou, Eisai, Foresight, Genentech, Grail， Kyowa麒麟，Novartis, Ono, Pfizer, Regeneron, Sail Bio, Teva, Treeline

本文章由计算机程序翻译，如有差异，请以英文原文为准。

IMPACT OF EBV STATUS AND HISTOLOGY ON OUTCOMES WITH NIVOLUMAB-AVD VERSUS Bv-AVD IN PATIENTS ENROLLED ON SWOG S1826

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IMPACT OF EBV STATUS AND HISTOLOGY ON OUTCOMES WITH NIVOLUMAB-AVD VERSUS Bv-AVD IN PATIENTS ENROLLED ON SWOG S1826

Introduction: 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.

Methods: 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).

Results: 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 (p < 0.0001). EBV+ pts had higher IPS scores but no statistical difference in stage or B symptoms.

With median follow-up of 24 months, within EBV− group, PFS was longer with N-AVD (HR 0.54; p = 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; p = 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; p = 0.0144). In N-AVD arm, no PFS difference was seen between EBV+ and EBV− (95% versus 92%; p = 0.88) but in Bv-AVD arm EBV+ pts had poorer PFS (72% versus 85%; p = 0.03).

102 pts had non-NS histology (N-AVD = 55; Bv-AVD = 47), median age 48 years versus 22 years for NS (p < 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; p = 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; p = 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, p = 0.11). In Bv-AVD arm, non-NS pts had inferior PFS (HR = 3.4, p < 0.0001), 2 years PFS 65% versus 87% in NS.

Conclusions: 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 those with non-NS histologies compared with Bv-AVD. These results inform future correlative studies to understand the impact of checkpoint blockade in molecular clusters of cHL. N-AVD should be considered a standard of care for advanced-stage cHL, particularly non-NS and EBV+ cHL.

Research funding declaration: Funding provided by the National Cancer Institute of the National Institutes of Health U10CA180888, U10CA180819; and in part by BMS.

Keywords: immunotherapy; Hodgkin lymphoma (pediatric, adolescent, and young adult); targeting the tumor microenvironment

Potential sources of conflict of interest:

S. Ahmed

Consultant or advisory role: ADC therapeutics, KITE/Gilead, Genmab and BMS.

Other remuneration: Research funding to institution from Nektar, Merck, Xencor, Chimagen and Genmab, KITE/Gilead, Janssen, Caribou.

A. F. Herrera

Consultant or advisory role: Bristol Myers Squibb, Genentech, Merck, Seagen, AstraZeneca, ADC Therapeutics, Takeda, Genmab, Pfizer, Abbvie, Allogene Therapeutics

Other remuneration: Research funding -Bristol Myers Squibb, Genentech, Merck, Seagen, AstraZeneca

S. C. Rutherford

Consultant or advisory role: Abbvie, ADC Therapeutics, BMS, Genmab, Incyte, Karyopharm, Kite, Pfizer/Seagen DSMB: Karyopharm

Other remuneration: Research support: Constellation, Genentech, Karyopharm

B. Kahl

Consultant or advisory role: BMS

J. P. Leonard

Consultant or advisory role: Astra Zeneca, Beigene, BMS, Caribou, Eisai, Foresight, Genentech, Grail, Kyowa Kirin, Novartis, Ono, Pfizer, Regeneron, Sail Bio, Teva, Treeline

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来源期刊

Hematological Oncology 医学-血液学

CiteScore

4.20

自引率

6.10%

发文量

147

审稿时长

>12 weeks

期刊介绍： Hematological Oncology considers for publication articles dealing with experimental and clinical aspects of neoplastic diseases of the hemopoietic and lymphoid systems and relevant related matters. Translational studies applying basic science to clinical issues are particularly welcomed. Manuscripts dealing with the following areas are encouraged: -Clinical practice and management of hematological neoplasia, including: acute and chronic leukemias, malignant lymphomas, myeloproliferative disorders -Diagnostic investigations, including imaging and laboratory assays -Epidemiology, pathology and pathobiology of hematological neoplasia of hematological diseases -Therapeutic issues including Phase 1, 2 or 3 trials as well as allogeneic and autologous stem cell transplantation studies -Aspects of the cell biology, molecular biology, molecular genetics and cytogenetics of normal or diseased hematopoeisis and lymphopoiesis, including stem cells and cytokines and other regulatory systems. Concise, topical review material is welcomed, especially if it makes new concepts and ideas accessible to a wider community. Proposals for review material may be discussed with the Editor-in-Chief. Collections of case material and case reports will be considered only if they have broader scientific or clinical relevance.