高剂量化疗联合自体造血干细胞移植治疗新诊断的原发性中枢神经系统淋巴瘤：一项前瞻性、单臂、2期试验。
High-dose chemotherapy with autologous haemopoietic stem cell transplantation for newly diagnosed primary CNS lymphoma: a prospective, single-arm, phase 2 trial.
作者信息
Illerhaus Gerald, Kasenda Benjamin, Ihorst Gabriele, Egerer Gerlinde, Lamprecht Monika, Keller Ulrich, Wolf Hans-Heinrich, Hirt Carsten, Stilgenbauer Stephan, Binder Mascha, Hau Peter, Edinger Matthias, Frickhofen Norbert, Bentz Martin, Möhle Robert, Röth Alexander, Pfreundschuh Michael, von Baumgarten Louisa, Deckert Martina, Hader Claudia, Fricker Heidi, Valk Elke, Schorb Elisabeth, Fritsch Kristina, Finke Jürgen
机构信息
Department of Haematology/Oncology and Palliative Care, Klinikum Stuttgart, Stuttgart, Germany; Department of Hematology, Oncology, and Stem-Cell Transplantation, University Medical Hospital and Faculty of Medicine, Albert-Ludwigs University, Freiburg, Germany.
Department of Haematology/Oncology and Palliative Care, Klinikum Stuttgart, Stuttgart, Germany; Department of Medicine, Royal Marsden Hospital, London, UK.
出版信息
Lancet Haematol. 2016 Aug;3(8):e388-97. doi: 10.1016/S2352-3026(16)30050-3. Epub 2016 Jul 13.
BACKGROUND
High-dose methotrexate-based chemotherapy is standard for primary CNS lymphoma, but most patients relapse. High-dose chemotherapy with autologous stem cell transplantation (HCT-ASCT) is supposed to overcome the blood-brain barrier and eliminate residual disease in the CNS. We aimed to investigate the safety and efficacy of HCT-ASCT in patients with newly diagnosed primary CNS lymphoma.
METHODS
In this prospective, single-arm, phase 2 trial, we recruited patients aged 18-65 years with newly diagnosed primary CNS lymphoma and immunocompetence, with no limitation on clinical performance status, from 15 hospitals in Germany. Patients received five courses of intravenous rituximab 375 mg/m(2) (7 days before first high-dose methotrexate course and then every 10 days) and four courses of intravenous high-dose methotrexate 8000 mg/m(2) (every 10 days) and then two courses of intravenous rituximab 375 mg/m(2) (day 1), cytarabine 3 g/m(2) (days 2 and 3), and thiotepa 40 mg/m(2) (day 3). 3 weeks after the last course, patients commenced intravenous HCT-ASCT (rituximab 375 mg/m(2) [day 1], carmustine 400 mg/m(2) [day 2], thiotepa 2 × 5 mg/kg [days 3 and 4], and infusion of stem cells [day 7]), irrespective of response status after induction. We restricted radiotherapy to patients without complete response after HCT-ASCT. The primary endpoint was complete response at day 30 after HCT-ASCT in all registered eligible patients who received at least 1 day of study treatment. This trial is registered at ClinicalTrials.gov, number NCT00647049.
FINDINGS
Between Jan 18, 2007, and May 23, 2011, we recruited 81 patients, of whom two (2%) were excluded, therefore we included 79 (98%) patients in the analysis. All patients started induction treatment; 73 (92%) commenced HCT-ASCT. 61 (77·2% [95% CI 66·1-86·6]) patients achieved a complete response. During induction treatment, the most common grade 3 toxicity was anaemia (37 [47%]) and the most common grade 4 toxicity was thrombocytopenia (50 [63%]). During HCT-ASCT, the most common grade 3 toxicity was fever (50 [68%] of 73) and the most common grade 4 toxicity was leucopenia (68 [93%] of 73). We recorded four (5%) treatment-related deaths (three [4%] during induction and one [1%] 4 weeks after HCT-ASCT).
INTERPRETATION
HCT-ASCT with thiotepa and carmustine is an effective treatment option in young patients with newly diagnosed primary CNS lymphoma, but further comparative studies are needed.
FUNDING
University Hospital Freiburg and Amgen.
背景
基于大剂量甲氨蝶呤的化疗是原发性中枢神经系统淋巴瘤的标准治疗方法，但大多数患者会复发。大剂量化疗联合自体干细胞移植（HCT-ASCT）被认为可以克服血脑屏障并消除中枢神经系统中的残留病灶。我们旨在研究HCT-ASCT在新诊断的原发性中枢神经系统淋巴瘤患者中的安全性和疗效。
方法
在这项前瞻性、单臂、2期试验中，我们从德国的15家医院招募了年龄在18至65岁之间、新诊断为原发性中枢神经系统淋巴瘤且免疫功能正常的患者，对临床性能状态没有限制。患者接受5个疗程的静脉注射利妥昔单抗375 mg/m²（在第一个大剂量甲氨蝶呤疗程前7天，然后每10天一次）和4个疗程的静脉注射大剂量甲氨蝶呤8000 mg/m²（每10天一次），然后是2个疗程的静脉注射利妥昔单抗375 mg/m²（第1天）、阿糖胞苷3 g/m²（第2天和第3天）和噻替派40 mg/m²（第3天）。在最后一个疗程后3周，患者开始静脉注射HCT-ASCT（利妥昔单抗375 mg/m²[第1天]、卡莫司汀400 mg/m²[第2天]、噻替派2×5 mg/kg[第3天和第4天]以及干细胞输注[第7天]），无论诱导后的反应状态如何。我们将放疗限制在HCT-ASCT后未完全缓解的患者中。主要终点是在接受至少1天研究治疗的所有登记合格患者中，HCT-ASCT后30天的完全缓解。该试验已在ClinicalTrials.gov注册，编号为NCT00647049。
研究结果
在2007年1月18日至2011年5月23日期间，我们招募了81名患者，其中两名（2%）被排除，因此我们将79名（98%）患者纳入分析。所有患者均开始诱导治疗；73名（92%）开始进行HCT-ASCT。61名（77.2%[95%CI 66.1-86.6]）患者实现了完全缓解。在诱导治疗期间，最常见的3级毒性是贫血（37名[47%]），最常见的4级毒性是血小板减少（50名[63%]）。在HCT-ASCT期间，最常见的3级毒性是发热（73名中的50名[68%]），最常见的4级毒性是白细胞减少（73名中的68名[93%]）。我们记录了4例（5%）与治疗相关的死亡（诱导期间3例[4%]，HCT-ASCT后4周1例[1%]）。
解读
使用噻替派和卡莫司汀的HCT-ASCT是新诊断的原发性中枢神经系统淋巴瘤年轻患者的一种有效治疗选择，但需要进一步的比较研究。
资助
弗莱堡大学医院和安进公司。
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