Brentuximab Vedotin

点击蓝字 关注我们 原发性皮肤间变性大细胞淋巴瘤（PC-ALCL）是一种起源于皮肤的罕见外周T细胞淋巴瘤（PTCL）类型。标准治疗方法包括针对孤立性病变的手术切除或放射治疗，而多发性病变则考虑系统性化疗。尽管复发率较高，但由于病变通常局限于皮肤，其长期预后通常较为乐观。英国血液学会官方期刊《eJHaem》近日发表报道了一例PC-ALCL中枢神经系统（CNS）复发的病例，该患者接受了系统性化疗及自体外周血干细胞移植（ASCT）治疗。 一名63岁男性患者因左手第五指及左下肢感觉异常就诊。10个月前，患者左肋区出现一暗红色皮肤结节（图1A），病理诊断为ALCL（图1B–I）。正电子发射断层扫描/计算机断层扫描（PET/CT）及骨髓检查未发现其他病变。患者被诊断为PC-ALCL，并接受了局部放射治疗（40 Gy）。4个月前，患者左膝皮肤出现PC-ALCL复发，接受了手术切除。 图1.初诊时左肋区皮肤结节性病变 头部磁共振成像（MRI）显示右侧岛叶及左侧脑室旁白质存在肿块（图1A，B）。右侧岛叶肿块活检的病理分析显示，大脑组织中存在大量异型淋巴细胞浸润（图2A）。免疫组化结果显示，这些异型淋巴细胞CD3、CD4、CD30阳性，而CD8、CD20、ALK、EMA阴性（图2B–H）。这些发现与左肋区和左膝活检标本的结果一致。因此，诊断为PC-ALCL中枢神经系统复发。脑脊液中未发现淋巴瘤细胞浸润。皮肤病变仍处于缓解状态，且无其他系统性病变。 图2.钆增强T1加权MRI显示右侧岛叶（A，红色箭头）和左侧脑室旁白质（B，红色箭头）存在肿块病变 图3.对右侧岛叶肿块活检组织进行HE染色，结果显示存在大量具有非典型核的大细胞密集增生（A）。免疫组织化学染色显示，这些细胞对CD3（B）、CD4（C）和CD30（D）呈阳性反应。它们对CD8（E）、CD20（F）、间变性淋巴瘤激酶（G）和上皮膜抗原（H）呈阴性反应 患者接受了甲氨蝶呤、丙卡巴肼(Procarbazine)和长春新碱（MPV）化疗方案，包括第1天静脉注射甲氨蝶呤（MTX）3.5 g/m²，第1天静脉注射长春新碱1.4 mg/m²（最大剂量2.0 mg），以及第2至8天口服丙卡巴肼100 mg/m²（奇数周期）。MPV化疗开始后3周，患者静脉注射维布妥昔单抗（BV；1.8 mg/kg），并随访1周。该治疗方案定义为BV-MPV（一个疗程4周），共重复三次。 第一个疗程后，MRI显示中枢神经系统病变部分缓解。第二个疗程后，进行了自体外周血干细胞采集。移植前，患者达到完全缓解。随后，使用塞替派联合白消安（BuTT）预处理方案进行了ASCT，包括第-8至-5天静脉注射白消安（Bu，3.2 mg/kg）和第-4及-3天静脉注射塞替派（TT，5 mg/kg）。在细胞最低点阶段，患者出现严重发热性中性粒细胞减少症，但随着中性粒细胞植入而缓解。 移植后18天出院，计划使用BV进行维持治疗。然而，在第一个疗程前，放疗部位附近出现一红斑丘疹（图4A）。此外，左背部也出现一类似丘疹（图4B）。两处活检均显示PC-ALCL复发（图4C–J），发生在移植后5周。头部MRI显示中枢神经系统病变未复发。患者再次接受左肋区局部放射治疗（45 Gy），并使用BV进行挽救治疗，随后每3周进行一次BV维持治疗。两处病变对治疗有积极反应，皮肤和中枢神经系统病变在移植后1年内均保持完全缓解。 图4.移植后左侧肋骨区域和左侧背部出现红斑丘疹 — 讨 论 — PC-ALCL在诊断时通常仅表现为皮肤病变或区域淋巴结受累。然而，复发时可能发生系统性受累。Benner等人报道复发率约为54%，其中约10%的患者在区域淋巴结以外出现系统性病变。PC-ALCL中枢神经系统受累更为罕见，通过文献回顾，仅发现三例报道病例。其中2例与本例相似，均在皮肤病变缓解期间出现中枢神经系统复发。与其他淋巴瘤一样，系统性病变的状态和进展不一定与中枢神经系统受累相关。 由于疾病罕见性，对于PTCL（包括PC-ALCL）患者中枢神经系统受累尚无标准治疗。因此，参考了其他侵袭性淋巴瘤的治疗方法。在原发性中枢神经系统淋巴瘤（PCNSL）和继发性中枢神经系统淋巴瘤（SCNSL）患者中，放射治疗、鞘内治疗和系统性化疗仅显示出部分有效性。因此，对于身体状况良好的患者，建议使用系统性化疗进行诱导治疗，随后使用大剂量化疗联合ASCT进行巩固治疗。Omuro等人报道，使用R-MPV方案（利妥昔单抗+甲氨蝶呤+丙卡巴肼+长春新碱）进行诱导治疗，并结合大剂量化疗（塞替派、白消安和环磷酰胺）联合ASCT进行巩固治疗，对PCNSL有良好的疾病控制效果，2年无进展生存率为75%，2年总生存率为81%。 在本例中，使用BV-MPV化疗方案进行诱导治疗，因CD30阳性而用BV替代利妥昔单抗。在巩固治疗方面，大剂量化疗方案采用了塞替派和白消安。尽管皮肤病变早期复发，但中枢神经系统病变得到缓解并维持超过1年。同样，既往病例中也有采用基于大剂量MTX的诱导方案和基于塞替派的巩固方案，同样实现了长期缓解。BV能否穿透血脑屏障尚无明确证据，但鉴于孤立性CNS淋巴瘤仅局部治疗易致系统复发，建议将其作为系统病灶维持治疗。未来需进一步探索BV在脑脊液中的分布特性以优化治疗策略。 综上，PC-ALCL存在CNS复发风险，即使皮肤病灶缓解仍需长期随访。含大剂量MTX的全身化疗联合塞替派预处理ASCT或可为CNS受累患者提供有效治疗选择。 （来源：《肿瘤瞭望–血液时讯》编辑部） 声 明 凡署名原创的文章版权属《肿瘤瞭望》所有，欢迎分享、转载。本文仅供医疗卫生专业人士了解最新医药资讯参考使用，不代表本平台观点。该等信息不能以任何方式取代专业的医疗指导，也不应被视为诊疗建议，如果该信息被用于资讯以外的目的，本站及作者不承担相关责任。

Approval based on results of Phase 3 CheckMate -9DW clinical trial demonstrating a statistically significant and clinically meaningful improvement in overall survival with Opdivo plus Yervoy compared to investigator’s choice of lenvatinib or sorafenib PRINCETON, NJ, USA I March 07, 2025 I Bristol Myers Squibb (NYSE: BMY) today announced that the European Commission (EC) has approved Opdivo ® (nivolumab) plus Yervoy ® (ipilimumab) for the first-line treatment of adult patients with unresectable or advanced hepatocellular carcinoma (HCC). “The European Commission’s approval for Opdivo plus Yervoy adds to the growing body of evidence demonstrating the value of dual immunotherapy and represents an important new treatment option that may extend survival for patients with hepatocellular carcinoma,” said Dana Walker, M.D., M.S.C.E., vice president, Opdivo global program lead, Bristol Myers Squibb. “This approval marks a critical milestone in our commitment to improving outcomes for patients with liver cancer. We look forward to bringing this new first-line treatment option to patients in the European Union.” The decision is based on results from the CheckMate -9DW study, which were presented at the 2024 American Society of Oncology (ASCO ® ) Annual Meeting , the 2024 European Society for Medical Oncology Congress and the 2025 ASCO Gastrointestinal Cancers Symposium. Results showed that dual immunotherapy treatment with Opdivo plus Yervoy led to a statistically significant and clinically meaningful improvement in overall survival (OS), the clinical trial’s primary endpoint. In the trial, 85% of patients in the comparator arm were treated with lenvatinib and 15% were treated with sorafenib. The median OS was 23.7 months (95% CI: 18.8–29.4) for Opdivo plus Yervoy compared to 20.6 months (95% CI: 17.5–22.5) with the investigator’s choice of lenvatinib or sorafenib (HR: 0.79 (0.65–0.96); p=0.018). The OS benefit was observed across clinically relevant patient subgroups. The trial also showed an overall response rate (ORR) of 36.1% (95% CI: 31-41.5) compared to 13.2% (95% CI: 9.8-17.3; P<0.0001) of patients treated with lenvatinib or sorafenib and a deeper response with Opdivo plus Yervoy . The safety profile for the combination of Opdivo plus Yervoy remained consistent with previously reported data and was manageable with established protocols, with no new safety signals identified. This approval by the EC for Opdivo plus Yervoy for the first-line treatment of adult patients with unresectable or advanced HCC is valid in all 27 member states of the European Union (EU), as well as Iceland, Liechtenstein and Norway. In addition to approval in HCC, Opdivo- based options are also approved for treatment of multiple tumor types in the EU. In August 2024, the U.S. FDA also accepted the Company’s supplemental Biologics License Application (sBLA) for Opdivo plus Yervoy as a potential first-line treatment option for adult patients with unresectable HCC and assigned a Prescription Drug User Fee Act (PDUFA) goal date of April 21, 2025. The combination of Opdivo plus Yervoy was granted accelerated approval as a second-line treatment for patients with advanced HCC by the U.S. FDA in 2020 based on results from the Phase 2 CheckMate -040 trial. Bristol Myers Squibb thanks the patients and investigators for their important contributions to the Phase 3 CheckMate -9DW clinical trial. About CheckMate -9DW CheckMate -9DW is a Phase 3 randomized, open-label clinical trial evaluating the combination of Opdivo plus Yervoy compared to investigator’s choice of lenvatinib or sorafenib monotherapy in adult patients with unresectable or advanced hepatocellular carcinoma who have not received prior systemic therapy. A total of 668 patients were randomized to receive Opdivo plus Yervoy ( Opdivo 1mg/kg plus Yervoy 3mg/kg Q3W for up to four doses, followed by Opdivo monotherapy 480mg Q4W) infusion, or single agent lenvatinib or sorafenib taken orally in the control arm. 85% of patients in the comparator arm were treated with lenvatinib and 15% were treated with sorafenib. The primary endpoint of the trial is overall survival (OS) and secondary endpoints include objective response rate (ORR) and time to symptom deterioration. The study was not designed to independently compare Opdivo plus Yervoy vs. lenvatinib or Opdivo plus Yervoy vs. sorafenib. About Hepatocellular Carcinoma Liver cancer is the third most frequent cause of cancer death worldwide. Hepatocellular carcinoma (HCC) is the most common type of liver cancer, accounting for 90% of global cases. HCC is often diagnosed at an advanced stage, where effective treatment options are limited and are usually associated with poor outcomes. Up to 70% of patients experience recurrence within five years, particularly those still considered to be at high risk after surgery or ablation. While most cases of HCC are caused by hepatitis B virus or hepatitis C virus infections, metabolic syndrome and nonalcoholic steatohepatitis are rising in prevalence and expected to contribute to increased rates of HCC. About Opdivo Opdivo is a programmed death-1 (PD-1) immune checkpoint inhibitor that is designed to uniquely harness the body’s own immune system to help restore anti-tumor immune response. By harnessing the body’s own immune system to fight cancer, Opdivo has become an important treatment option across multiple cancers. Opdivo ’s leading global development program is based on Bristol Myers Squibb’s scientific expertise in the field of Immuno-Oncology and includes a broad range of clinical trials across all phases, including Phase 3, in a variety of tumor types. To date, the Opdivo clinical development program has treated more than 35,000 patients. The Opdivo trials have contributed to gaining a deeper understanding of the potential role of biomarkers in patient care, particularly regarding how patients may benefit from Opdivo across the continuum of PD-L1 expression. In July 2014, Opdivo was the first PD-1 immune checkpoint inhibitor to receive regulatory approval anywhere in the world. Opdivo is currently approved in more than 65 countries, including the United States, the European Union, Japan and China. In October 2015, the Company’s Opdivo and Yervoy combination regimen was the first Immuno-Oncology combination to receive regulatory approval for the treatment of metastatic melanoma and is currently approved in more than 50 countries, including the United States and the European Union. About Yervoy Yervoy is a recombinant, human monoclonal antibody that binds to the cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4). CTLA-4 is a negative regulator of T-cell activity. Yervoy binds to CTLA-4 and blocks the interaction of CTLA-4 with its ligands, CD80/CD86. Blockade of CTLA-4 has been shown to augment T-cell activation and proliferation, including the activation and proliferation of tumor infiltrating T-effector cells. Inhibition of CTLA-4 signaling can also reduce T-regulatory cell function, which may contribute to a general increase in T-cell responsiveness, including the anti-tumor immune response. On March 25, 2011, the U.S. Food and Drug Administration (FDA) approved Yervoy 3 mg/kg monotherapy for patients with unresectable or metastatic melanoma. Yervoy is approved for unresectable or metastatic melanoma in more than 50 countries. There is a broad, ongoing development program in place for Yervoy spanning multiple tumor types. INDICATIONS OPDIVO® (nivolumab), as a single agent, is indicated for the treatment of adult and pediatric patients 12 years and older with unresectable or metastatic melanoma. OPDIVO® (nivolumab), in combination with YERVOY® (ipilimumab), is indicated for the treatment of adult and pediatric patients 12 years and older with unresectable or metastatic melanoma. OPDIVO® is indicated for the adjuvant treatment of adult and pediatric patients 12 years and older with completely resected Stage IIB, Stage IIC, Stage III, or Stage IV melanoma. OPDIVO® (nivolumab), in combination with platinum-doublet chemotherapy, is indicated as neoadjuvant treatment of adult patients with resectable (tumors ≥4 cm or node positive) non-small cell lung cancer (NSCLC). OPDIVO® (nivolumab) in combination with platinum-doublet chemotherapy, is indicated for neoadjuvant treatment of adult patients with resectable (tumors ≥4 cm or node positive) non-small cell lung cancer (NSCLC) and no known epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) rearrangements, followed by single-agent OPDIVO® as adjuvant treatment after surgery. OPDIVO® (nivolumab), in combination with YERVOY® (ipilimumab), is indicated for the first-line treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors express PD-L1 (≥1%) as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations. OPDIVO® (nivolumab), in combination with YERVOY® (ipilimumab) and 2 cycles of platinum-doublet chemotherapy, is indicated for the first-line treatment of adult patients with metastatic or recurrent non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations. OPDIVO® (nivolumab) is indicated for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving OPDIVO. OPDIVO® (nivolumab), in combination with YERVOY® (ipilimumab), is indicated for the first-line treatment of adult patients with unresectable malignant pleural mesothelioma (MPM). OPDIVO® (nivolumab), in combination with YERVOY® (ipilimumab), is indicated for the first-line treatment of adult patients with intermediate or poor risk advanced renal cell carcinoma (RCC). OPDIVO® (nivolumab), in combination with cabozantinib, is indicated for the first-line treatment of adult patients with advanced renal cell carcinoma (RCC). OPDIVO® (nivolumab) is indicated for the treatment of adult patients with advanced renal cell carcinoma (RCC) who have received prior anti-angiogenic therapy. OPDIVO® (nivolumab) is indicated for the treatment of adult patients with classical Hodgkin lymphoma (cHL) that has relapsed or progressed after autologous hematopoietic stem cell transplantation (HSCT) and brentuximab vedotin or after 3 or more lines of systemic therapy that includes autologous HSCT. This indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. OPDIVO® (nivolumab) is indicated for the treatment of adult patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) with disease progression on or after platinum-based therapy. OPDIVO® (nivolumab) is indicated for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. OPDIVO® (nivolumab), as a single agent, is indicated for the adjuvant treatment of adult patients with urothelial carcinoma (UC) who are at high risk of recurrence after undergoing radical resection of UC. OPDIVO® (nivolumab), in combination with cisplatin and gemcitabine, is indicated as first-line treatment for adult patients with unresectable or metastatic urothelial carcinoma. OPDIVO® (nivolumab), as a single agent, is indicated for the treatment of adult and pediatric (12 years and older) patients with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC) that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. OPDIVO® (nivolumab), in combination with YERVOY® (ipilimumab), is indicated for the treatment of adult and pediatric patients 12 years and older with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC) that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. OPDIVO® (nivolumab), in combination with YERVOY® (ipilimumab), is indicated for the treatment of adult patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. OPDIVO® (nivolumab) is indicated for the treatment of adult patients with unresectable advanced, recurrent or metastatic esophageal squamous cell carcinoma (ESCC) after prior fluoropyrimidine- and platinum-based chemotherapy. OPDIVO® (nivolumab) is indicated for the adjuvant treatment of completely resected esophageal or gastroesophageal junction cancer with residual pathologic disease in adult patients who have received neoadjuvant chemoradiotherapy (CRT). OPDIVO® (nivolumab), in combination with fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the first-line treatment of adult patients with unresectable advanced or metastatic esophageal squamous cell carcinoma (ESCC). OPDIVO® (nivolumab), in combination with YERVOY® (ipilimumab), is indicated for the first-line treatment of adult patients with unresectable advanced or metastatic esophageal squamous cell carcinoma (ESCC). OPDIVO® (nivolumab), in combination with fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the treatment of adult patients with advanced or metastatic gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma. Please see U.S. Full Prescribing Information for OPDIVO and YERVOY . Clinical Trials and Patient Populations Checkmate 227-previously untreated metastatic non-small cell lung cancer, in combination with YERVOY; Checkmate 9LA–previously untreated recurrent or metastatic non-small cell lung cancer in combination with YERVOY and 2 cycles of platinum-doublet chemotherapy by histology; Checkmate 649–previously untreated advanced or metastatic gastric cancer, gastroesophageal junction and esophageal adenocarcinoma; Checkmate 577–adjuvant treatment of esophageal or gastroesophageal junction cancer; Checkmate 238–adjuvant treatment of patients with completely resected Stage III or Stage IV melanoma; Checkmate 76K–adjuvant treatment of patients 12 years of age and older with completely resected Stage IIB or Stage IIC melanoma; Checkmate 274–adjuvant treatment of urothelial carcinoma; Checkmate 275–previously treated advanced or metastatic urothelial carcinoma; Checkmate 142–MSI-H or dMMR metastatic colorectal cancer, as a single agent or in combination with YERVOY; Checkmate 142–MSI-H or dMMR metastatic colorectal cancer, as a single agent or in combination with YERVOY; Attraction-3–esophageal squamous cell carcinoma; Checkmate 648-previously untreated, unresectable advanced recurrent or metastatic esophageal squamous cell carcinoma in combination with chemotherapy; Checkmate 648-previously untreated, unresectable advanced recurrent or metastatic esophageal squamous cell carcinoma combination with YERVOY; Checkmate 040–hepatocellular carcinoma, in combination with YERVOY; Checkmate 743–previously untreated unresectable malignant pleural mesothelioma, in combination with YERVOY; Checkmate 037–previously treated metastatic melanoma; Checkmate 066–previously untreated metastatic melanoma; Checkmate 067–previously untreated metastatic melanoma, as a single agent or in combination with YERVOY; Checkmate 017–second-line treatment of metastatic squamous non-small cell lung cancer; Checkmate 057–second-line treatment of metastatic non-squamous non-small cell lung cancer; Checkmate 816–neoadjuvant non-small cell lung cancer, in combination with platinum-doublet chemotherapy; Checkmate 77T–Neoadjuvant treatment with platinum-doublet chemotherapy for non-small cell lung cancer followed by single-agent OPDIVO as adjuvant treatment after surgery; Checkmate 901–Adult patients with unresectable or metastatic urothelial carcinoma; Checkmate 141–recurrent or metastatic squamous cell carcinoma of the head and neck; Checkmate 025–previously treated renal cell carcinoma; Checkmate 214–previously untreated renal cell carcinoma, in combination with YERVOY; Checkmate 9ER–previously untreated renal cell carcinoma, in combination with cabozantinib; Checkmate 205/039–classical Hodgkin lymphoma. Bristol Myers Squibb: Creating a Better Future for People with Cancer Bristol Myers Squibb is inspired by a single vision — transforming patients’ lives through science. The goal of the company’s cancer research is to deliver medicines that offer each patient a better, healthier life and to make cure a possibility. Building on a legacy across a broad range of cancers that have changed survival expectations for many, Bristol Myers Squibb researchers are exploring new frontiers in personalized medicine and, through innovative digital platforms, are turning data into insights that sharpen their focus. Deep understanding of causal human biology, cutting-edge capabilities and differentiated research programs uniquely position the company to approach cancer from every angle. Cancer can have a relentless grasp on many parts of a patient’s life, and Bristol Myers Squibb is committed to taking actions to address all aspects of care, from diagnosis to survivorship. As a leader in cancer care, Bristol Myers Squibb is working to empower all people with cancer to have a better future. About the Bristol Myers Squibb and Ono Pharmaceutical Collaboration In 2011, through a collaboration agreement with Ono Pharmaceutical Co., Bristol Myers Squibb expanded its territorial rights to develop and commercialize Opdivo globally, except in Japan, South Korea and Taiwan, where Ono had retained all rights to the compound at the time. On July 23, 2014, Ono and Bristol Myers Squibb further expanded the companies’ strategic collaboration agreement to jointly develop and commercialize multiple immunotherapies – as single agents and combination regimens – for patients with cancer in Japan, South Korea and Taiwan. About Bristol Myers Squibb Bristol Myers Squibb is a global biopharmaceutical company whose mission is to discover, develop and deliver innovative medicines that help patients prevail over serious diseases. For more information about Bristol Myers Squibb, visit us at BMS.com or follow us on LinkedIn , X , YouTube , Facebook and Instagram . SOURCE: Bristol Myers Squibb