Primary Central Nervous System Lymphoma

*仅供医学专业人士阅读参考3月19日，国家药品监督管理局（NMPA）批准恒瑞医药的塞替派（Thiotepa）（商品名：瑞航®）用于儿童（<18周岁）重型β-地中海贫血异基因造血干细胞移植（allo-HSCT）前预处理适应症。这是国内首款获批造血干细胞移植预处理相关适应症，且唯一视同通过仿制药一致性评价的塞替派，填补了这一领域的长期空白。诞生于上个世纪50年代的化疗药物塞替派和氮芥一样，同属烷化剂，可以通过抑制DNA的合成而产生强大的抗癌活性。上世纪90年代，塞替派已经在多个国家被批准用于乳腺癌、卵巢癌等实体瘤治疗，我国也在2018年批准了塞替派的实体瘤适应症。作为一个老牌化疗药物，塞替派在诞生半个世纪之后，重新燃起了科学界兴趣。研究发现，大剂量塞替派具有十分强劲的清髓和免疫抑制功效；同时，塞替派具有极高的血脑屏障穿透能力，在脑脊液中的浓度接近血浆浓度。两种特性叠加，让塞替派成为中枢神经系统淋巴瘤诱导治疗，以及造血干细胞移植前预处理的潜在主力军。2007年，美国FDA就批准了塞替派用于β-地中海贫血allo-HSCT预处理的适应症，欧洲药品管理局（EMA）也在不久后批准了塞替派用于儿童或成人血液病HSCT预处理的适应症。2018年，恒瑞医药的塞替派获美国FDA简略新药申请（ANDA，即美国仿制药申请）批准，成功打入国际市场，目前在美国及欧盟市场均有广泛使用。低调的化疗实力派作为一种经典的化疗药物，塞替派在乳腺癌，膀胱癌，卵巢癌等实体瘤，以及癌性胸腔积液治疗中都有长期的临床使用经验。在乳腺癌治疗领域，塞替派强劲的入脑能力，使其在中枢神经转移性乳腺癌领域具有巨大的潜力。一项回顾性研究评估了长春瑞滨联合塞替派治疗转移性乳腺癌的疗效和安全性[1]。研究纳入了144名患者，其中45位患者具有脑转移，前序治疗中位数为2轮，所有入组患者都曾接受过紫杉醇和/或蒽环类药物治疗。研究显示，长春瑞滨联合塞替派治疗中位无进展生存期为4.4个月，中枢神经系统转移人群为3.6个月。在整体人群中，中位总生存期为12.7个月。图片来源：DALL·E在膀胱癌治疗领域，塞替派可以作为内膀胱疗法的有效治疗选择。一项荟萃分析纳入了39项试验，评估了辅助内膀胱疗法对比单独使用尿道膀胱肿瘤切除术对于疾病复发风险的影响[2]。研究发现，包括塞替派在内的多种辅助内膀胱疗法均与降低疾病复发风险相关。当然，让塞替派从一众化疗药物中脱颖而出的，还是其出色的入脑能力。原发性中枢神经系统淋巴瘤 （PCNSL）是一种独特的非霍奇金淋巴瘤亚型，仅累及中枢神经系统，诱导化疗之后续接巩固治疗是标准治疗方案。塞替派与甲氨蝶呤、阿糖胞苷等多种具有良好血脑屏障通透性的药物组成的MATRix方案在PCNSL的诱导治疗中显示出良好的抗肿瘤效果。图片来源：DALL·E一项来自国际结外淋巴瘤研究组（IELSG）的随机临床对照研究评估了MA方案（甲氨蝶呤、阿糖胞苷）、R-MA方案（利妥昔单抗、甲氨蝶呤、阿糖胞苷）及MATRix方案（甲氨蝶呤、阿糖胞苷、塞替派、利妥昔单抗）的疗效[3]。研究纳入了27例初治PCNSL患者，研究结果发现，MATRix方案具有明显的疗效优势，治疗完全缓解率为49%（MA方案：23%，R-MA方案：30%）；2年总生存率高达69%（MA方案：42%，R-MA方案：56%）。近年来，随着塞替派在国内的重新上市以及实体瘤适应症的获批，相信这款化疗经典药物会勃发出更大生机。造血干细胞移植前预处理的王牌军塞替派强劲的清髓和免疫抑制功效，使其成为造血干细胞移植前预处理的王牌军，在急性白血病、原发性中枢神经系统淋巴瘤、神经母细胞瘤以及β-地中海贫血等疾病的造血干细胞移植前预处理中大展身手。在急性白血病移植前预处理方面，大剂量白消安联合环磷酰胺和全身放疗（TBI）是最常用的预处理方案，但患者成功植入率仍不尽人意。很多研究探索了包含塞替派的预处理方案，其中TBF（塞替派、白消安、氟达拉滨）方案是目前较为常用的预处理方案。2019年的一项全球多中心回顾性研究评估了TBF预处理方案在急性髓系白血病（AML）allo-HSCT中使用的临床结局[4]，患者2年无进展生存率和总生存率分别达到67%和71% 。图片来源：DALL·E另一项研究评估了白消安联合氟达拉滨（BF）及BF基础上添加塞替派的TBF方案，在253例进行allo-HSCT的AML患者中的应用[5]。研究结果显示，相比于BF方案，采用TBF预处理方案可以显著降低5年累计复发率（15% vs 30%, P=0.004），并提高5年生存率（68% vs 51%, P=0.002）。除此之外，研究显示，TBI联合塞替派及环磷酰胺预处理在儿童ALL患者治疗中，3年无病生存率可达65%[6]。一项来自欧洲血液和骨髓移植协会（EBMT）的回顾性研究，也评估了塞替派 vs 环磷酰胺+TBI在成人ALL预处理中的应用[7]。研究发现，以塞替派为基础的预处理方案在疗效方面不劣于传统大剂量环磷酰胺联合TBI方案。除了急性白血病之外，塞替派也是PCNSL自体造血干细胞移植（auto-HSCT）前预处理的首选用药。PCNSL在诱导化疗缓解后，常序贯含有塞替派作为预处理方案的auto-HSCT或全脑放疗进行巩固治疗。2017年，一项来自欧洲的大型随机对照研究IELSG32纳入118例经化疗获得缓解的PCNSL[8]，随机分为全脑放疗组和auto-HSCT组（卡莫司汀+塞替派作为预处理方案）。研究结果显示，两组在生存率方面无统计学差异，但auto-HSCT组神经系统不良反应发生率更低。2019年发表的一项随机对照研究，探索了使用TBC预处理方案（塞替派+白消安+环磷酰胺）的auto-HSCT对比放疗的患者生存情况[9]。结果显示，auto-HSCT组的2年无进展生存率高达87%，优于放疗组的63%（P=0.005）。同时，auto-HSCT组患者的认知功能未受损或有不同程度提高，但放疗组患者的认知能力明显下降。这项研究的8年随访结果显示[10]，auto-HSCT组和放疗组8年无事件生存率分别为67%和39%（P=0.03），auto-HSCT组复发风险显著降低（风险比，0.13；P<0.001）。在随访期间，与auto-HSCT相比，放疗组治疗后患者的平衡能力（52% vs 10%，P ≤ 0.001）和神经认知（64% vs 13%，P <0.001）显著恶化。图片来源：DALL·E除了上述我们提到的急性白血病和PCNSL之外，塞替派在神经母细胞瘤auto-HSCT方面也发挥着重要的作用。神经母细胞瘤是儿童最常见的颅外实体瘤，中高危患者预后较差，常用的治疗手段包括化疗、手术、放疗和造血干细胞移植等。研究显示，含有塞替派和白消安-美法仑的移植预处理方案对于高危神经母细胞瘤具有较好的疗效和安全性[11]。另一种使用包含塞替派的预处理方案TMT（苏消安+美法仑+塞替派）的auto-HSCT在原发耐药患者中也具有良好的疗效[12]。作为移植前预处理的王牌军，塞替派在儿童重型β-地中海贫血移植前预处理中具有独特的价值。β-地中海贫血是最常见的遗传性贫血，allo-HSCT是目前重型β-地中海贫血最主要的治疗手段，90%以上的儿童患者可以通过allo-HSCT获得治愈。白消安联合环磷酰胺（BuCy）作为传统的预处理方案在临床中有广泛的应用，但仍具有一定的植入失败率风险。在1985~2007年间，意大利佩萨罗医院为中位年龄7岁的515名卢卡雷利（Lucarelli）1度和2度患者进行了骨髓移植。由于观察到4岁以下的患者排斥率较高，医院自2003年开始，为这部分患者的BuCy预处理方案中增加了塞替派，这种治疗方式也被称为佩萨罗方案[13]。图片来源：DALL·E2004~2007年间，罗马一项研究为37名卢卡雷利（Lucarelli）1度和2度患者进行了骨髓移植，年龄＜4岁的患者接受了BuCy联合塞替派方案，而年龄≥4岁的患者接受了BuCy方案。研究结果显示，年龄不到17岁的1度和2度患者患者总生存率高达97%，植入失败率仅为8%。罗马经验验证了佩萨罗方案的可复制性，表明塞替派在特定患者群体的预处理方案中有独特的价值[13]。对于Lucarelli 3度患者，由于其移植死亡率和排斥率都较高，以往有研究探索了减低剂量预处理移植（reduced intensity transplantation，RIT），研究发现，包含塞替派的RIT方案可以降低急性移植物抗宿主病的发生率[14]。2012年，我国学者的一项研究，报告了82例重度β-地中海贫血患者采用NF-08-TM（白消安+氟达拉滨+环磷酰胺+塞替派）的预处理方案，植入失败率仅为1.9%，3年生存率高达92.3%[15]。《造血干细胞移植治疗重型β地中海贫血儿科专家共识》（2018版）将含塞替派的NF-08-TM方案和NF-14-TM方案作为移植前预处理的重要选择。从以上研究不难发现，塞替派作为一款老牌经典化疗药物，在肿瘤药物百花齐放的今天，仍然发挥着独特的价值，国内众多指南共识也将塞替派作为特定肿瘤化疗和各类移植前预处理的重要选择。此次，恒瑞医药注射用塞替派（瑞航®）在儿童（<18周岁）重型β-地中海贫血allo-HSCT前预处理适应症的获批也为中国患儿提供了全新的选择。值得一提的是，瑞航®具有15mg和100mg两种规格，可灵活满足临床不同场景的应用。作为国内首个视同通过一致性评价的塞替派，瑞航®将以更经济的价格惠及更多中国患者。参考文献：【1】 Loison R, Abbar B, et al. Vinorelbine thiotepa in metastatic breast cancer: a large real-life retrospective study. Acta Oncol. 2023 Dec;62(12):1961-1966. doi: 10.1080/0284186X.2023.2260943. Epub 2023 Nov 25. PMID: 37750392.【2】 Chou R, Selph S, et al. Intravesical Therapy for the Treatment of Nonmuscle Invasive Bladder Cancer: A Systematic Review and Meta-Analysis. J Urol. 2017 May;197(5):1189-1199. doi: 10.1016/j.juro.2016.12.090. Epub 2016 Dec 24. PMID: 28027868.【3】 Ferreri AJ, Cwynarski K, et al. Chemoimmunotherapy with methotrexate, cytarabine, thiotepa, and rituximab (MATRix regimen) in patients with primary CNS lymphoma: results of the first randomisation of the International Extranodal Lymphoma Study Group-32 (IELSG32) phase 2 trial. Lancet Haematol. 2016 May;3(5):e217-27. doi: 10.1016/S2352-3026(16)00036-3. Epub 2016 Apr 6. PMID: 27132696.【4】 Pagliardini T, Castagna L, et al. Thiotepa, Fludarabine, and Busulfan Conditioning Regimen before T Cell-Replete Haploidentical Transplantation with Post-Transplant Cyclophosphamide for Acute Myeloid Leukemia: A Bicentric Experience of 100 Patients. Biol Blood Marrow Transplant. 2019 Sep;25(9):1803-1809. doi: 10.1016/j.bbmt.2019.05.014. Epub 2019 May 22. PMID: 31128325.【5】 Sora F, Grazia CD, et al. Allogeneic Hemopoietic Stem Cell Transplants in Patients with Acute Myeloid Leukemia (AML) Prepared with Busulfan and Fludarabine (BUFLU) or Thiotepa, Busulfan, and Fludarabine (TBF): A Retrospective Study. Biol Blood Marrow Transplant. 2020 Apr;26(4):698-703. doi: 10.1016/j.bbmt.2019.12.725. Epub 2019 Dec 23. PMID: 31875522.【6】 Zecca M, Pession A, et al. Total body irradiation, thiotepa, and cyclophosphamide as a conditioning regimen for children with acute lymphoblastic leukemia in first or second remission undergoing bone marrow transplantation with HLA-identical siblings. J Clin Oncol. 1999 Jun;17(6):1838-46. doi: 10.1200/JCO.1999.17.6.1838. PMID: 10561223.【7】 Eder S, Canaani J, et al. Thiotepa-based conditioning versus total body irradiation as myeloablative conditioning prior to allogeneic stem cell transplantation for acute lymphoblastic leukemia: A matched-pair analysis from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation. Am J Hematol. 2017 Oct;92(10):997-1003. doi: 10.1002/ajh.24823. Epub 2017 Jul 19. PMID: 28614903.【8】 Ferreri AJM, Cwynarski K, et al. Whole-brain radiotherapy or autologous stem-cell transplantation as consolidation strategies after high-dose methotrexate-based chemoimmunotherapy in patients with primary CNS lymphoma: results of the second randomisation of the International Extranodal Lymphoma Study Group-32 phase 2 trial. Lancet Haematol. 2017 Nov;4(11):e510-e523. doi: 10.1016/S2352-3026(17)30174-6. Epub 2017 Oct 17. PMID: 29054815.【9】 Houillier C, Taillandier L, et al. Radiotherapy or Autologous Stem-Cell Transplantation for Primary CNS Lymphoma in Patients 60 Years of Age and Younger: Results of the Intergroup ANOCEF-GOELAMS Randomized Phase II PRECIS Study. J Clin Oncol. 2019 Apr 1;37(10):823-833. doi: 10.1200/JCO.18.00306.【10】 Houillier C, Dureau S, et al. Radiotherapy or Autologous Stem-Cell Transplantation for Primary CNS Lymphoma in Patients Age 60 Years and Younger: Long-Term Results of the Randomized Phase II PRECIS Study. J Clin Oncol. 2022 Nov 10;40(32):3692-3698. doi: 10.1200/JCO.22.00491. Epub 2022 Jul 14. PMID: 35834762.【11】 Pasqualini C, Dufour C, et al. Tandem high-dose chemotherapy with thiotepa and busulfan-melphalan and autologous stem cell transplantation in very high-risk neuroblastoma patients. Bone Marrow Transplant. 2016 Feb;51(2):227-31. doi: 10.1038/bmt.2015.264. Epub 2015 Nov 2. PMID: 26524264.【12】 Wawrzyniak-Dzierżek E, Gajek K, et al. Feasibility and Safety of Treosulfan, Melphalan, and Thiotepa-Based Megachemotherapy with Autologous or Allogeneic Stem Cell Transplantation in Heavily Pretreated Children with Relapsed or Refractory Neuroblastoma. Biol Blood Marrow Transplant. 2019 Sep;25(9):1792-1797. doi: 10.1016/j.bbmt.2019.05.006. Epub 2019 May 11. PMID: 31085306.【13】 Isgrò A, Gaziev J, Sodani P, Lucarelli G. Progress in hematopoietic stem cell transplantation as allogeneic cellular gene therapy in thalassemia. Ann N Y Acad Sci. 2010 Aug;1202:149-54. doi: 10.1111/j.1749-6632.2010.05543.x. PMID: 20712786.【14】 Hongeng S, Pakakasama S, et al. Reduced intensity stem cell transplantation for treatment of class 3 Lucarelli severe thalassemia patients. Am J Hematol. 2007 Dec;82(12):1095-8. doi: 10.1002/ajh.21002. PMID: 17674372.【15】 Li C, Wu X, et al. A novel conditioning regimen improves outcomes in β-thalassemia major patients using unrelated donor peripheral blood stem cell transplantation. 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SYDNEY, March 21, 2024 /PRNewswire/ -- Kazia Therapeutics Limited (NASDAQ: KZIA), a biotechnology company specialising in oncology, is pleased to announce that it has entered into an exclusive licensing agreement with Sovargen Co., Ltd, a biotechnology company specializing in central nervous system (CNS) diseases, to develop, manufacture and commercialise paxalisib as a potential treatment of intractable epilepsy in focal cortical dysplasia type 2 (FCD T2) and tuberous sclerosis complex (TSC) disease. The underlying cause of FCD T2 and TSC can be traced back to somatic mutations in the PI3K/Akt/mTOR pathway or mutations in the TSC1 or TSC2 genes, which lead to the overactivation of the mTOR pathway. Paxalisib is an oral dual inhibitor targeting both PI3K and mTOR within this pathway, and it is distinguished by its ability to penetrate the brain. Although FCD T2 and TSC are rare orphan diseases, they represent a high medical unmet need with significant market opportunity. There are currently no approved drugs for patients with FCD T2. Under the agreement, Kazia will receive an upfront payment of US$1.5 million, potential milestone payments of up to US$19 million upon the achievement of development and regulatory milestones, and a percentage of sub-licensing revenues and royalties on net sales of products incorporating paxalisib. The licensing agreement includes all countries worldwide, excluding mainland China, Hong Kong, Macao and Taiwan, which Kazia retains. Kazia CEO Dr. John Friend said: "We are pleased to announce we have exclusively licensed the development, manufacture and commercialization of paxalisib to Sovargen for its potential use in select CNS diseases that are associated with mTORopathy. Kazia's primary focus of paxalisib continues to be oncology, with multiple studies ongoing. Our license with Sovargen provides us the ability to explore the impact of paxalisib outside of our area of expertise where there is substantial patient need and market opportunity. We are enthusiastic about seeing paxalisib's potential explored in these patient populations." Sovargen CEO Cheolwon Park shared his excitement about the collaboration: "The dual inhibition mechanism of paxalisib, coupled with its observed safety pro previous oncology studies, positions us to anticipate initiation of a Phase 2 clinical trial for patients with FCD T2 and TSC in the latter half of 2024. Sovargen has played a pioneering role in identifying the critical link between mTOR hyperactivation due to mTORopathy somatic mutations and epileptic seizures in FCD T2 patients and we have an unwavering dedication to developing effective treatments for these patients." About Kazia Therapeutics Limited Kazia Therapeutics Limited (NASDAQ: KZIA) is an oncology-focused drug development company, based in Sydney, Australia. Our lead program is paxalisib, an investigational brain-penetrant inhibitor of the PI3K / Akt / mTOR pathway, which is being developed to treat multiple forms of brain cancer. Licensed from Genentech in late 2016, paxalisib is or has been the subject of ten clinical trials in this disease. A completed Phase 2 study in glioblastoma reported early signals of clinical activity in 2021, and a pivotal study in glioblastoma, GBM AGILE, is ongoing, with final data expected in 1H2024. Other clinical trials are ongoing in brain metastases, diffuse midline gliomas, and primary CNS lymphoma, with several of these having reported encouraging interim data. Paxalisib was granted Orphan Drug Designation for glioblastoma by the FDA in February 2018, and FTD for glioblastoma by the FDA in August 2020. Paxalisib was also granted FTD in July 2023 for the treatment of solid tumour brain metastases harboring PI3K pathway mutations in combination with radiation therapy. In addition, paxalisib was granted Rare Pediatric Disease Designation and Orphan Drug Designation by the FDA for diffuse intrinsic pontine glioma in August 2020, and for atypical teratoid / rhabdoid tumours in June 2022 and July 2022, respectively. Kazia is also developing EVT801, a small-molecule inhibitor of VEGFR3, which was licensed from Evotec SE in April 2021. Preclinical data has shown EVT801 to be active against a broad range of tumour types and has provided evidence of synergy with immuno-oncology agents. A Phase I study is ongoing and preliminary data is anticipated in CY2024. For more information, please visit or follow us on Twitter @KaziaTx. About Sovargen Sovargen Co., Ltd. is a biotechnology company focused on the discovery and development of drugs to treat rare and incurable neurological disorders that are caused by brain somatic mosaicism. Sovargen's platform technology is associated with ASO (Antisense Oligonucleotide) development for undruggable targets in CNS disease including technology for target discovery (SovarIN™), ASO drug discovery & optimization (SovarON™), and target validation & efficacy evaluation platform using disease-specific animal model and human organoid system (SovarUP™). For more information, please visit Forward-Looking Statements This announcement may contain forward-looking statements, which can generally be identified as such by the use of words such as "may," "will," "estimate," "future," "forward," "anticipate," or other similar words. Any statement describing Kazia's future plans, strategies, intentions, expectations, objectives, goals or prospects, and other statements that are not historical facts, are also forward-looking statements, including, but not limited to, statements regarding: expansion of paxalisib into other indications including intractable epilepsy in focal cortical dysplasia type 2 (FCD T2) and tuberous sclerosis complex (TSC) disease, expectations regarding whether milestones will be met, expectations on market opportunities for paxalisib in FCD T2 and TSC, plans to initiate clinical trials for paxalisib in FCD T2 and TSC, the timing for results and data related to Kazia's clinical and preclinical trials and investigator-initiated trials of Kazia's product candidates, and Kazia's strategy and plans with respect to its programs, including paxalisib and EVT801. Such statements are based on Kazia's current expectations and projections about future events and future trends affecting its business and are subject to certain risks and uncertainties that could cause actual results to differ materially from those anticipated in the forward-looking statements, including risks and uncertainties: associated with clinical and preclinical trials and product development, related to regulatory approvals, and related to the impact of global economic conditions. These and other risks and uncertainties are described more fully in Kazia's Annual Report, filed on form 20-F with the United States Securities and Exchange Commission (SEC), and in subsequent filings with the SEC. Kazia undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events, or otherwise, except as required under applicable law. You should not place undue reliance on these forward-looking statements, which apply only as of the date of this announcement. This announcement was authorized for release by Dr John Friend, CEO. Company Codes: NASDAQ-SMALL:KZIA

Breyanzi offers a personalized treatment option delivered as a one-time infusion that provides deep and durable responses for patients with relapsed or refractory CLL or SLL who have historically had no standard of care In TRANSCEND CLL 004, the first pivotal multicenter trial to evaluate a CAR T cell therapy in patients with relapsed or refractory CLL or SLL, 20% of patients treated with Breyanzi achieved a complete response (CR) with median duration of CR not reached, along with an established safety pro > Breyanzi is now FDA approved for relapsed or refractory large B-cell lymphoma and CLL or SLL, bringing this differentiated CD19-directed CAR T cell therapy to more patients PRINCETON, N.J.--(BUSINESS WIRE)-- Bristol Myers Squibb (NYSE: BMY) today announced the U.S. Food and Drug Administration (FDA) has granted accelerated approval of Breyanzi® (lisocabtagene maraleucel; liso-cel), a CD19-directed chimeric antigen receptor (CAR) T cell therapy, for the treatment of adult patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who have received at least two prior lines of therapy, including a Bruton tyrosine kinase (BTK) inhibitor and a B-cell lymphoma 2 (BCL-2) inhibitor. This indication is approved under accelerated approval based on response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s). In R/R CLL or SLL, Breyanzi is delivered through a treatment process which culminates in a one-time infusion* with a single dose containing 90 to 110 x 106 CAR-positive viable T cells. Please see the Important Safety Information section below, including Boxed WARNINGS for Breyanzi regarding Cytokine Release Syndrome (CRS), Neurologic Toxicities, and Secondary Hematological Malignancies. This press release features multimedia. View the full release here: Product image for download (Photo: Bristol Myers Squibb) “CAR T cell therapies represent a transformative treatment option for patients with certain types of blood cancers,” said Bryan Campbell, senior vice president, Head of Commercial, Cell Therapy, Bristol Myers Squibb. “For years, attempts to bring other CAR T cell therapies to patients with relapsed or refractory CLL or SLL met challenges and found little success. With the approval of Breyanzi as the first CAR T for relapsed or refractory CLL or SLL, we are now able to offer these patients a personalized option, while further expanding access across the broadest array of B-cell malignancies, to address this critical unmet need.” CLL and SLL are among the most common types of B-cell lymphoma. Treatments for people living with CLL or SLL primarily consist of targeted therapies including BTK- and BCL-2 inhibitors. However, patients often experience relapse or become refractory following early-line treatment with these therapies and there is no established standard of care for patients with double-class exposed CLL or SLL. After relapsing or becoming refractory to these therapies, patients have few options and poor outcomes, including lack of durable complete responses. The Phase 1/2 open-label, single-arm TRANSCEND CLL 004 study was the first pivotal multicenter trial to evaluate a CAR T cell therapy in patients with relapsed or refractory CLL or SLL. The CR rate associated with Breyanzi treatment was 20% (95% CI: 11.1-31.8). Among patients who achieved a CR, median duration of response was not reached (95% CI: 15 months-NR) at the time of data cutoff. Among all responders (ORR = 45%; 95% CI: 32.3-57.5), median duration of response was 35.3 months (95% CI: 12.4-NR). High rates of minimal residual disease (MRD) negative status were observed across patients treated with Breyanzi who achieved a CR, with an MRD-negativity rate of 100% in the blood (95% CI: 75.3-100) and 92.3% in the bone marrow (95% CI: 64-99.8). “CLL and SLL are currently considered incurable diseases with few treatment options in the relapsed setting that can confer complete responses, something that has historically been associated with improved long-term outcomes,” said Tanya Siddiqi, M.D., lead investigator and Associate Professor, Division of Lymphoma, City of Hope National Medical Center. “The FDA approval of liso-cel in relapsed or refractory CLL and SLL after treatment with prior BTKi and BCL2i is a remarkable breakthrough, shifting the treatment paradigm from continuous therapy with sequential regimens to overcome drug resistance, to a one-time personalized T-cell based approach that has the potential to offer patients complete and lasting remission.” Among 89 patients in the study treated with Breyanzi, occurrences of cytokine release syndrome (CRS) and neurologic events (NEs) were mostly low grade. Any grade CRS occurred in 83% of patients, with Grade 3 CRS occurring in 9% of patients. No Grade 4/5 CRS events were reported. Any grade NEs were reported in 46% of patients, with Grade 3 NEs reported in 20% of patients and one case of Grade 4 NE reported. No Grade 5 NEs were reported. “For people struggling with relapsed or refractory CLL or SLL, current treatment choices are limited,” said Dr. Brian Koffman, physician, CLL patient and cofounder, executive vice president and chief medical officer of CLL Society. “The approval of Breyanzi as the first CAR T cell therapy available for relapsed or refractory CLL or SLL brings new hope to these patients with the potential for durable responses after a single CAR T infusion. We are grateful to the patients and their families who enter the trials and to all the researchers involved in making possible this important new treatment option in CLL and SLL.” Bristol Myers Squibb offers various programs and resources to address the needs of patients and caregivers, and provides support that allows for access to therapies, including Breyanzi. Bristol Myers Squibb also supports the patient and physician treatment experience by providing Cell Therapy 360, a digital service platform, which optimizes access to relevant information, manufacturing updates, and patient and caregiver support. About TRANSCEND CLL 004 TRANSCEND CLL 004 (NCT03331198) is a Phase 1/2 open-label, single-arm, multicenter study evaluating Breyanzi in patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma. The Phase 1 dose escalation portion of the study assessed the safety and recommended dose for the subsequent Phase 2 expansion cohort. The Phase 2 portion of the study is evaluating Breyanzi at the recommended dose from the Phase 1 monotherapy arm. The primary endpoint of the Phase 2 portion of the study is complete response rate, including complete remission with incomplete bone marrow recovery, based on independent review committee according to the International Workshop on Chronic Lymphocytic Leukemia (iwCLL) 2018 guidelines. About CLL and SLL Chronic lymphocytic leukemia (CLL) is one of the most common types of leukemia in adults. In CLL, too many blood stem cells in the bone marrow become abnormal lymphocytes, and these abnormal cells have difficulty fighting infections. As the number of abnormal cells grows, there is less room for healthy white blood cells, red blood cells and platelets. Small lymphocytic lymphoma (SLL) also affects the lymphocytes, with cancer cells found mostly in the lymph nodes. While there are several treatments available for CLL and SLL, there is a need for additional effective therapies as there is no standard of care for relapsed or refractory CLL or SLL after prior therapy with targeted agents, such as Bruton tyrosine kinase (BTK) and B-cell lymphoma 2 (BCL-2) inhibitors. Patients with relapsed or refractory disease have limited treatment options and generally experience shorter periods of response with each subsequent treatment. About Breyanzi Breyanzi is a CD19-directed CAR T cell therapy with a 4-1BB costimulatory domain, which enhances the expansion and persistence of the CAR T cells. Breyanzi is made from a patient’s own T cells, which are collected and genetically reengineered to become CAR T cells that are then delivered via infusion as a one-time treatment. Breyanzi is approved in the U.S., Japan and Europe for the second-line treatment of relapsed or refractory LBCL, and in Japan, Europe, Switzerland, and Canada for relapsed and refractory LBCL after two or more lines of systemic therapy. Bristol Myers Squibb’s clinical development program for Breyanzi includes clinical studies in other types of lymphoma. For more information, visit clinicaltrials.gov. * Treatment process includes leukapheresis, manufacturing, administration, and adverse event monitoring. Indication BREYANZI is a CD19-directed genetically modified autologous T cell immunotherapy indicated for the treatment of: adult patients with large B-cell lymphoma (LBCL), including diffuse large B-cell lymphoma (DLBCL) not otherwise specified (including DLBCL arising from indolent lymphoma), high-grade B cell lymphoma, primary mediastinal large B-cell lymphoma, and follicular lymphoma grade 3B, who have: refractory disease to first-line chemoimmunotherapy or relapse within 12 months of first-line chemoimmunotherapy; or refractory disease to first-line chemoimmunotherapy or relapse after first-line chemoimmunotherapy and are not eligible for hematopoietic stem cell transplantation (HSCT) due to comorbidities or age; or relapsed or refractory disease after two or more lines of systemic therapy. Limitations of Use: BREYANZI is not indicated for the treatment of patients with primary central nervous system lymphoma. adult patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who have received at least 2 prior lines of therapy, including a Bruton tyrosine kinase (BTK) inhibitor and a B-cell lymphoma 2 (BCL-2) inhibitor. This indication is approved under accelerated approval based on response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s). Important Safety Information WARNING: CYTOKINE RELEASE SYNDROME, NEUROLOGIC TOXICITIES, AND SECONDARY HEMATOLOGICAL MALIGNANCIES Cytokine Release Syndrome (CRS), including fatal or life-threatening reactions, occurred in patients receiving BREYANZI. Do not administer BREYANZI to patients with active infection or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab with or without corticosteroids. Neurologic toxicities, including fatal or life-threatening reactions, occurred in patients receiving BREYANZI, including concurrently with CRS, after CRS resolution or in the absence of CRS. Monitor for neurologic events after treatment with BREYANZI. Provide supportive care and/or corticosteroids as needed. T cell malignancies have occurred following treatment of hematologic malignancies with BCMA- and CD19-directed genetically modified autologous T cell immunotherapies, including BREYANZI. BREYANZI is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the BREYANZI REMS. Cytokine Release Syndrome Cytokine release syndrome (CRS), including fatal or life-threatening reactions, occurred following treatment with BREYANZI. Among patients receiving BREYANZI for LBCL (N=418), CRS occurred in 46% (190/418), including ≥ Grade 3 CRS in 3.1% of patients. In patients receiving BREYANZI after two or more lines of therapy for LBCL, CRS occurred in 46% (122/268), including ≥ Grade 3 CRS in 4.1% of patients. One patient had fatal CRS and 2 had ongoing CRS at time of death. The median time to onset was 5 days (range: 1 to 15 days). CRS resolved in 98% with a median duration of 5 days (range: 1 to 17 days). In patients receiving BREYANZI after one line of therapy for LBCL, CRS occurred in 45% (68/150), including Grade 3 CRS in 1.3% of patients. The median time to onset was 4 days (range: 1 to 63 days). CRS resolved in all patients with a median duration of 4 days (range: 1 to 16 days). Among patients receiving BREYANZI for CLL/SLL, CRS occurred in 83% (74/89), including Grade 3 CRS in 9% of patients. The median time to onset was 4 days (range: 1 to 18 days). CRS resolved in 97% with a median duration of 6 days (range: 2 to 37 days). The most common manifestations of CRS (≥ 10% in LBCL or CLL/SLL) included fever (94% LBCL; 97% CLL/SLL), hypotension (42% LBCL; 46% CLL/SLL), tachycardia (28% LBCL), chills (23% LBCL; 43% CLL/SLL), hypoxia (16% LBCL; 35% CLL/SLL), sinus tachycardia (22% CLL/SLL), and headache (12% LBCL; 18% CLL/SLL). Serious events that may be associated with CRS include cardiac arrhythmias (including atrial fibrillation and ventricular tachycardia), cardiac arrest, cardiac failure, diffuse alveolar damage, renal insufficiency, capillary leak syndrome, hypotension, hypoxia, and hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS). Ensure that 2 doses of tocilizumab are available prior to infusion of BREYANZI. Of the patients who received BREYANZI for LBCL (n=418) and CLL/SLL (n=89), 23% (LBCL) and 64% (CLL/SLL) received tocilizumab and/or a corticosteroid for CRS, including 10% (LBCL) and 33% (CLL/SLL) who received tocilizumab only and 2.2% (LBCL) and 2.2% (CLL/SLL) who received corticosteroids only. Neurologic Toxicities Neurologic toxicities that were fatal or life-threatening, including immune effector cell-associated neurotoxicity syndrome (ICANS), occurred following treatment with BREYANZI. Serious events including cerebral edema and seizures occurred with BREYANZI. Fatal and serious cases of leukoencephalopathy, some attributable to fludarabine, also occurred. In patients receiving BREYANZI after two or more lines of therapy for LBCL, CAR T cell-associated neurologic toxicities occurred in 35% (95/268), including ≥ Grade 3 cases in 12% of patients. Three patients had fatal neurologic toxicity and 7 had ongoing neurologic toxicity at time of death. The median time to onset of neurotoxicity was 8 days (range: 1 to 46 days). Neurologic toxicities resolved in 85% of patients with a median duration of 12 days (range: 1 to 87 days). In patients receiving BREYANZI after one line of therapy for LBCL, CAR T cell-associated neurologic toxicities occurred in 27% (41/150) of patients, including Grade 3 cases in 7% of patients. The median time to onset of neurologic toxicity was 8 days (range: 1 to 63 days). The median duration of neurologic toxicity was 6 days (range: 1 to 119 days). In all patients combined receiving BREYANZI for LBCL, CAR T cell-associated neurologic toxicities occurred in 33% (136/418), including ≥ Grade 3 cases in 10% of patients. The median time to onset was 8 days (range: 1 to 63), with 87% of cases developing by 16 days. Neurologic toxicities resolved in 85% of patients with a median duration of 11 days (range: 1 to 119 days). Of patients developing neurotoxicity, 77% (105/136) also developed CRS. In patients receiving BREYANZI for CLL/SLL, CAR T cell-associated neurologic toxicities occurred in 46% (41/89), including Grade 3 cases in 20% of patients and a single Grade 4 case. The median time to onset of neurotoxicity was 7 days (range: 1 to 21 days), with 95% of cases developing by 16 days. Neurologic toxicities resolved in 85% with a median duration of 7 days (range: 1 to 83 days). Of patients developing neurotoxicity, 95% (39/41) also developed CRS. The most common neurologic toxicities (≥ 5% in LBCL or CLL) included encephalopathy (20% LBCL; 36% CLL/SLL), tremor (13% LBCL; 14% CLL/SLL), aphasia (8% LBCL; 8% CLL/SLL), headache (6% LBCL; 9% CLL/SLL), dizziness (6% LBCL), and delirium (5% LBCL; 12% CLL/SLL). CRS and Neurologic Toxicities Monitoring Monitor patients daily for at least 7 days following BREYANZI infusion at a REMS-certified healthcare facility for signs and symptoms of CRS and neurologic toxicities and assess for other causes of neurological symptoms. Monitor patients for signs and symptoms of CRS and neurologic toxicities for at least 4 weeks after infusion and treat promptly. At the first sign of CRS, institute treatment with supportive care, tocilizumab, or tocilizumab and corticosteroids as indicated. Manage neurologic toxicity with supportive care and/or corticosteroid as needed. Counsel patients to seek immediate medical attention should signs or symptoms of CRS or neurologic toxicity occur at any time. BREYANZI REMS Because of the risk of CRS and neurologic toxicities, BREYANZI is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the BREYANZI REMS. The required components of the BREYANZI REMS are: Healthcare facilities that dispense and administer BREYANZI must be enrolled and comply with the REMS requirements. Certified healthcare facilities must have on-site, immediate access to tocilizumab. Ensure that a minimum of 2 doses of tocilizumab are available for each patient for infusion within 2 hours after BREYANZI infusion, if needed for treatment of CRS. Further information is available at , or contact Bristol-Myers Squibb at 1-866-340-7332. Hypersensitivity Reactions Allergic reactions may occur with the infusion of BREYANZI. Serious hypersensitivity reactions, including anaphylaxis, may be due to dimethyl sulfoxide (DMSO). Serious Infections Severe infections, including life-threatening or fatal infections, have occurred in patients after BREYANZI infusion. In patients receiving BREYANZI, infections of any grade occurred in 36% (LBCL) and 35% (CLL/SLL), with Grade 3 or higher infections occurring in 12% (LBCL) and 16% (CLL/SLL) of all patients. Grade 3 or higher infections with an unspecified pathogen occurred in 7% (LBCL) and 10% (CLL/SLL), bacterial infections in 4.3% (LBCL) and 2.2% (CLL/SLL), viral infections in 1.9% (LBCL) and 1.1% (CLL/SLL), and fungal infections in 0.5% (LBCL) and 2.2% (CLL/SLL). Febrile neutropenia developed after BREYANZI infusion in 8% (LBCL) and 12% (CLL/SLL) of patients. Febrile neutropenia may be concurrent with CRS. In the event of febrile neutropenia, evaluate for infection and manage with broad spectrum antibiotics, fluids, and other supportive care as medically indicated. Monitor patients for signs and symptoms of infection before and after BREYANZI administration and treat appropriately. Administer prophylactic antimicrobials according to standard institutional guidelines. Avoid administration of BREYANZI in patients with clinically significant, active systemic infections. Viral reactivation: Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients treated with drugs directed against B cells. In patients who received BREYANZI, 15 of 16 LBCL patients, and all 9 CLL/SLL patients with a prior history of HBV were treated with concurrent antiviral suppressive therapy. Perform screening for HBV, HCV, and HIV in accordance with clinical guidelines before collection of cells for manufacturing. In patients with prior history of HBV, consider concurrent antiviral suppressive therapy to prevent HBV reactivation per standard guidelines. Prolonged Cytopenias Patients may exhibit cytopenias not resolved for several weeks following lymphodepleting chemotherapy and BREYANZI infusion. Grade 3 or higher cytopenias persisted at Day 29 following BREYANZI infusion in 36% (LBCL) and 45% (CLL/SLL) of patients, and included thrombocytopenia in 28% (LBCL) and 23% (CLL/SLL), neutropenia in 21% (LBCL) and 35% (CLL/SLL), and anemia in 6% (LBCL) and 12% (CLL/SLL). Monitor complete blood counts prior to and after BREYANZI administration. Hypogammaglobulinemia B-cell aplasia and hypogammaglobulinemia can occur in patients receiving BREYANZI. In patients receiving BREYANZI, hypogammaglobulinemia was reported as an adverse reaction in 11% (LBCL) and 14% (CLL/SLL) of patients. Hypogammaglobulinemia, either as an adverse reaction or laboratory IgG level below 500 mg/dL after infusion, was reported in 28% (LBCL) and 37% (CLL/SLL) of patients. Monitor immunoglobulin levels after treatment with BREYANZI and manage using infection precautions, antibiotic prophylaxis, and immunoglobulin replacement as clinically indicated. Live vaccines: The safety of immunization with live viral vaccines during or following BREYANZI treatment has not been studied. Vaccination with live virus vaccines is not recommended for at least 6 weeks prior to the start of lymphodepleting chemotherapy, during BREYANZI treatment, and until immune recovery following treatment with BREYANZI. Secondary Malignancies Patients treated with BREYANZI may develop secondary malignancies. T cell malignancies have occurred following treatment of hematologic malignancies with BCMA- and CD19-directed genetically modified autologous T cell immunotherapies, including BREYANZI. Mature T cell malignancies, including CAR-positive tumors, may present as soon as weeks following infusion, and may include fatal outcomes. Monitor lifelong for secondary malignancies. In the event that a secondary malignancy occurs, contact Bristol-Myers Squibb at 1- 888-805-4555 for reporting and to obtain instructions on collection of patient samples for testing. Effects on Ability to Drive and Use Machines Due to the potential for neurologic events, including altered mental status or seizures, patients receiving BREYANZI are at risk for developing altered or decreased consciousness or impaired coordination in the 8 weeks following BREYANZI administration. Advise patients to refrain from driving and engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery, for at least 8 weeks. Immune Effector Cell-Associated Hemophagocytic Lymphohistiocytosis-Like Syndrome (IEC-HS) Immune Effector Cell-Associated Hemophagocytic Lymphohistiocytosis-Like Syndrome (IEC-HS), including fatal or life-threatening reactions, occurred following treatment with BREYANZI. Three of 89 (3%) safety evaluable patients with R/R CLL/SLL developed IEC-HS. Time to onset of IEC-HS ranged from 7 to 18 days. Two of the 3 patients developed IEC-HS in the setting of ongoing CRS and 1 in the setting of ongoing neurotoxicity. IEC-HS was fatal in 2 of 3 patients. One patient had fatal IEC-HS and one had ongoing IEC-HS at time of death. IEC-HS is a life-threatening condition with a high mortality rate if not recognized and treated early. Treatment of IEC-HS should be administered per current practice guidelines. Adverse Reactions The most common nonlaboratory adverse reactions (incidence ≥ 30%) in: LBCL are fever, cytokine release syndrome, fatigue, musculoskeletal pain, and nausea. The most common Grade 3-4 laboratory abnormalities (≥ 30%) include lymphocyte count decrease, neutrophil count decrease, platelet count decrease, and hemoglobin decrease. CLL/SLL are cytokine release syndrome, encephalopathy, fatigue, musculoskeletal pain, nausea, and diarrhea. The most common Grade 3-4 laboratory abnormalities (≥ 30%) in CLL/SLL include neutrophil count decrease, white blood cell decrease, hemoglobin decrease, platelet count decrease, and lymphocyte count decrease. Please see full Prescribing Information, including Boxed WARNINGS and Medication Guide. 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 platforms 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 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, Twitter, YouTube, Facebook and Instagram. Cautionary Statement Regarding Forward-Looking Statements This press release contains “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995 regarding, among other things, the research, development and commercialization of pharmaceutical products. All statements that are not statements of historical facts are, or may be deemed to be, forward-looking statements. Such forward-looking statements are based on current expectations and projections about our future financial results, goals, plans and objectives and involve inherent risks, assumptions and uncertainties, including internal or external factors that could delay, divert or change any of them in the next several years, that are difficult to predict, may be beyond our control and could cause our future financial results, goals, plans and objectives to differ materially from those expressed in, or implied by, the statements. These risks, assumptions, uncertainties and other factors include, among others, whether Breyanzi (lisocabtagene maraleucel) for such additional indication described in this release will be commercially successful, that any marketing approvals, if granted, may have significant limitations on their use, and that continued approval of such product candidate for such additional indication described in this release may be contingent upon verification and description of clinical benefit in confirmatory trial(s). No forward-looking statement can be guaranteed. Forward-looking statements in this press release should be evaluated together with the many risks and uncertainties that affect Bristol Myers Squibb’s business and market, particularly those identified in the cautionary statement and risk factors discussion in Bristol Myers Squibb’s Annual Report on Form 10-K for the year ended December 31, 2023, as updated by our subsequent Quarterly Reports on Form 10-Q, Current Reports on Form 8-K and other filings with the Securities and Exchange Commission. The forward-looking statements included in this document are made only as of the date of this document and except as otherwise required by applicable law, Bristol Myers Squibb undertakes no obligation to publicly update or revise any forward-looking statement, whether as a result of new information, future events, changed circumstances or otherwise. corporatefinancial-news