阿托珠单抗
与利妥昔单抗加标准化疗相比，阿托珠单抗加标准化疗处理未治疗的晚期滤泡性淋巴瘤已显示可提供更长的无进展生存期（3年随访）。[123]Marcus R, Davies A, Ando K, et al. Obinutuzumab for the first-line treatment of follicular lymphoma. N Engl J Med. 2017 Oct 5;377(14):1331-44.http://www.ncbi.nlm.nih.gov/pubmed/28976863?tool=bestpractice.com 美国食品药品监督管理局（FDA）和欧洲药品管理局正在审查将阿托珠单抗用于晚期滤泡性淋巴瘤的一线治疗。
贝伦妥单抗-维多汀
本妥昔单抗是一种抗体-药物偶联物，特异性靶向作用于表达CD30 的癌细胞。根据一项3期和2项2期临床试验的阳性结果，FDA已批准其在既往经过治疗的CD30 +蕈样肉芽肿或原发性皮肤间变性大细胞淋巴瘤成人患者中的应用。[124]Prince HM, Kim YH, Horwitz SM, et al. Brentuximab vedotin or physician's choice in CD30-positive cutaneous T-cell lymphoma (ALCANZA): an international, open-label, randomised, phase 3, multicentre trial. Lancet. 2017 Aug 5;390(10094):555-66.http://www.ncbi.nlm.nih.gov/pubmed/28600132?tool=bestpractice.com[125]Duvic M, Tetzlaff MT, Gangar P et al. Results of a phase II trial of brentuximab vedotin for CD30+ cutaneous T-cell lymphoma and lymphomatoid papulosis. J Clin Oncol. 2015 Nov 10;33(32):3759-65.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4737859/http://www.ncbi.nlm.nih.gov/pubmed/26261247?tool=bestpractice.com[126]Kim YH, Tavallaee M, Sundram U et al. Phase II investigator-initiated study of brentuximab vedotin in mycosis fungoides and Sézary syndrome with variable CD30 expression level: a multi-institution collaborative project. J Clin Oncol. 2015 Nov 10;33(32):3750-8.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5089160/http://www.ncbi.nlm.nih.gov/pubmed/26195720?tool=bestpractice.com3期试验表明，与甲氨蝶呤或蓓萨罗丁相比，给予本妥昔单抗后，全球客观反应率显著上升持续至少4个月。[124]Prince HM, Kim YH, Horwitz SM, et al. Brentuximab vedotin or physician's choice in CD30-positive cutaneous T-cell lymphoma (ALCANZA): an international, open-label, randomised, phase 3, multicentre trial. Lancet. 2017 Aug 5;390(10094):555-66.http://www.ncbi.nlm.nih.gov/pubmed/28600132?tool=bestpractice.com
Axicabtagene ciloleucel
Axicabtagene ciloleucel 是一种嵌合抗原受体疗法，可引导 T 细胞杀灭表达 CD19 的癌细胞，CD19 是一种在B细胞淋巴瘤和白血病中发现的细胞表面蛋白。根据早期临床试验结果，FDA 批准其用于患有特定类型大 B 细胞淋巴瘤（例如，弥漫性大 B 细胞淋巴瘤[DLBCL]、原发性纵隔大 B 细胞淋巴瘤、高级别B细胞淋巴瘤和由滤泡性淋巴瘤引发的DLBCL） ，一线、二线治疗或之后处理失败的成人。[127]Neelapu SS, Locke FL, Bartlett NL et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med. 2017 Dec 28;377(26):2531-44.http://www.ncbi.nlm.nih.gov/pubmed/29226797?tool=bestpractice.com[128]Kochenderfer JN, Dudley ME, Kassim SH, et al. Chemotherapy-refractory diffuse large B-cell lymphoma and indolent B-cell malignancies can be effectively treated with autologous T cells expressing an anti-CD19 chimeric antigen receptor. J Clin Oncol. 2015 Feb 20;33(6):540-9.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4322257/http://www.ncbi.nlm.nih.gov/pubmed/25154820?tool=bestpractice.com[129]Kochenderfer J, Somerville R, Lu T, et al. Anti-CD19 chimeric antigen receptor T cells preceded by low-dose chemotherapy to induce remissions of advanced lymphoma. J Clin Oncol. 2016;34(18 suppl):abstract LBA3010.[130]Locke FL, Neelapu SS, Bartlett NL, et al. Phase 1 results of ZUMA-1: a multicenter study of KTE-C19 anti-CD19 CAR T cell therapy in refractory aggressive lymphoma. Mol Ther. 2017 Jan 4;25(1):285-95.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5363293/http://www.ncbi.nlm.nih.gov/pubmed/28129122?tool=bestpractice.com
免疫检查点抑制剂
检查点抑制剂，如抗 PD1 抗体（例如纳武单抗、利妥昔单抗和帕博利珠单抗)，可阻断引发肿瘤耐药的途径。这些药物在进行高强度预处理的B细胞和T细胞NHL，包括原发性纵隔 B 细胞淋巴瘤的患者中显示出客观反应。[131]Lesokhin AM, Ansell SM, Armand P, et al. Preliminary results of a phase I study of nivolumab (BMS-936558) in patients with relapsed or refractory lymphoid malignancies. Blood. 2014;124(21):291.[132]Chen R, Zinzani PL, Fanale MA, et al. Phase II study of the efficacy and safety of pembrolizumab for relapsed/refractory classic Hodgkin lymphoma. J Clin Oncol. 2017 Jul 1;35(19):2125-32.http://ascopubs.org/doi/full/10.1200/JCO.2016.72.1316http://www.ncbi.nlm.nih.gov/pubmed/28441111?tool=bestpractice.com
抗体药物偶联物（ADCs）
一种新型 ADC 将抗79B 单克隆抗体与微管抑制剂单甲基 auristatin E（MMAE）、polatuzumab vedotin进行偶联，已被证明在复发或难治性 NHL 和慢性淋巴细胞白血病（CLL）中具有效应。[133]Palanca-Wessels MC, Czuczman M, Salles G, et al. Safety and activity of the anti-CD79B antibody-drug conjugate polatuzumab vedotin in relapsed or refractory B-cell non-Hodgkin lymphoma and chronic lymphocytic leukaemia: a phase 1 study. Lancet Oncol. 2015 Jun;16(6):704-15.http://www.ncbi.nlm.nih.gov/pubmed/25925619?tool=bestpractice.com
布鲁顿激酶抑制剂
伊布替尼已被证明对复发或难治性 B 细胞恶性肿瘤患者具有显著活性。[134]Advani RH, Buggy JJ, Sharman JP, et al. Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765) has significant activity in patients with relapsed/refractory B-cell malignancies. J Clin Oncol. 2013 Jan 1;31(1):88-94.http://www.ncbi.nlm.nih.gov/pubmed/23045577?tool=bestpractice.com 目前它被批准用于治疗 CLL，套细胞淋巴瘤（MCL）和Waldenström巨球蛋白血症。根据2期临床试验结果，已获得 FDA 加速批准用于复发或难治性边缘区淋巴瘤（MZL）患者。[135]ClinicalTrials.org. Study of the Bruton's tyrosine kinase inhibitor in subjects with relapsed/refractory marginal zone lymphoma. Nov 2018 [internet publication].https://clinicaltrials.gov/ct2/show/NCT01980628 测试伊布替尼与利妥昔单抗加环磷酰胺、多柔比星、长春新碱、泼尼松龙（R-CHOP）联合应用于新诊断活化B细胞亚型 DLBCL 患者疗效的临床试验同样正在进行，并给出了富有希望的早期结果。阿卡替尼是第二代布鲁顿激酶抑制剂，根据2期临床试验的结果，已获得 FDA 加速批准用于既往经过治疗的 MCL 患者。[136]ClinicalTrials.gov. An open-label, phase 2 study of ACP-196 (acalabrutinib) in subjects with mantle cell lymphoma. Jan 2019 [internet publication].https://clinicaltrials.gov/ct2/show/NCT02213926
磷脂酰肌醇-3 激酶 （PI3K）δ 抑制剂
若干种不同的新型PI3K δ 抑制剂目前正在复发或难治性 NHL 患者中进行临床试验。Copanlisib是一种针对α和δ同种型的泛 I 类PI3K抑制剂，已在2期临床试验中显示，对复发或难治性惰性NHL患者（包括滤泡性淋巴瘤、MZL、小淋巴细胞淋巴瘤，和淋巴浆细胞样淋巴瘤/Waldenström巨球蛋白血症）的肿瘤客观反应率为59％ 。[137]Dreyling MH, Santoro A, Leppa S, et al. Copanlisib in patients with relapsed or refractory follicular lymphoma. J Clin Oncol. 2017 May;35(suppl 15):7535.http://ascopubs.org/doi/abs/10.1200/JCO.2017.35.15_suppl.7535 Copanlisib 已获得FDA 加速批准用于至少接受过两次全身治疗的复发性滤泡性淋巴瘤患者。
BCL2 抑制剂
Venetoclax是同类首个选择性口服 BCL2 抑制剂，已在各种复发或难治性 NHL 中呈现出显著的临床活性。[138]Davids MS, Seymour JF, Gerecitano JF, et al. Phase I study of ABT-199 (GDC-0199) in patients with relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL): responses observed in diffuse large B-cell (DLBCL) and follicular lymphoma (FL) at higher cohort doses. J Clin Oncol. 2014;32(suppl 5):abstract 8522. 其他 BLC2 靶向抑制剂（例如 PNT2258）在1期临床试验中也显示出显著活性。[139]Harb WA, Lakhani N, Logsdon A, et al. The BCL2 targeted deoxyribonucleic acid inhibitor (DNAi) PNT 2258 is active in patients with relapsed or refractory non-Hodgkin’s lymphoma. Blood. 2014;124(21);1716.http://www.bloodjournal.org/content/124/21/1716?sso-checked=true
复合抑制剂
CUDC-907 是一种复合的组蛋白去乙酰化酶和 PI3K 抑制剂，已被证实在复发或难治性 DLBCL 患者中有反应。[140]Younes A, Berdeja JG, Patel MR, et al. Safety, tolerability, and preliminary activity of CUDC-907, a first-in-class, oral, dual inhibitor of HDAC and PI3K, in patients with relapsed or refractory lymphoma or multiple myeloma: an open-label, dose-escalation, phase 1 trial. Lancet Oncol. 2016 May;17(5):622-31.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5494693/http://www.ncbi.nlm.nih.gov/pubmed/27049457?tool=bestpractice.com
Baltaleucel-T（CMD-003）
Baltaleucel-T 可改造患者免疫细胞，使其激活以杀伤表达与致癌Epstein-Barr病毒（EBV）相关抗原的恶性细胞。正在研究其对表达 EBV 淋巴瘤的影响，包括自然杀伤性 T 细胞淋巴瘤和移植后淋巴组织增生性疾病。[141]ClinicalTrials.gov. Cellular immunotherapy treatment antigen-directed for EBV lymphoma (CITADEL). Jan 2019 [internet publication].https://clinicaltrials.gov/ct2/show/NCT01948180
环磷酰胺、多柔比星、长春新碱、泼尼松龙（CHOP）加碘-131-托西莫单抗
在滤泡性淋巴瘤进行临床研究性应用[142]Press OW, Unger JM, LeBlanc ML, et al. A phase III randomized intergroup trial (S0016) comparing CHOP plus rituximab with CHOP plus iodine-131-tositumomab for front-line treatment of follicular lymphoma: results of subset analyses and a comparison of prognostic models. J Clin Oncol. 2012;30(suppl):abstr 8001.http://meetinglibrary.asco.org/content/95376-114
苯达莫司汀
在外周T细胞淋巴瘤进行临床研究性应用[143]Damaj G, Gressin R, Bouabdallah K, et al. Results from a prospective, open-label, phase II trial of bendamustine in refractory or relapsed T-cell lymphomas: the BENTLY trial. J Clin Oncol. 2013 Jan 1;31(1):104-10.http://www.ncbi.nlm.nih.gov/pubmed/23109692?tool=bestpractice.com
氟达拉滨
在皮下脂膜炎样外周T细胞淋巴瘤进行临床研究性应用
吉西他滨
在皮下脂膜炎样外周T细胞淋巴瘤进行临床研究性应用
多柔比星
在皮下脂膜炎样外周T细胞淋巴瘤进行临床研究性应用
喷司他丁
在皮下脂膜炎样外周T细胞淋巴瘤进行临床研究性应用
Mogamulizumab
在蕈样肉芽肿/Sézary 综合征中进行临床研究性应用。
贝利司他 (Belinostat)
在外周T细胞淋巴瘤进行临床研究性应用[144]O'Connor OA, Horwitz S, Masszi T, et al. Belinostat in patients with relapsed or refractory peripheral T-cell lymphoma: results of the pivotal phase II BELIEF (CLN-19) Study. J Clin Oncol. 2015 Aug 10;33(23):2492-9.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5087312/http://www.ncbi.nlm.nih.gov/pubmed/26101246?tool=bestpractice.com
Mocetinostat
在 DLBCL 中进行临床研究性应用。[145]Crump M, Andreadis C, Assouline SE, et al. A phase II study of single agent mocetinostat, an oral isotype-selective histone deacetylase (HDAC) inhibitor, in patients with diffuse large cell B-cell (DLBCL) and follicular (FL) lymphomas. J Clin Oncol 2013;31(suppl);abstract 8535.
西达本胺
在外周T细胞淋巴瘤进行临床研究性应用[146]Shi Y, Dong M, Hong X, et al. Results from a multicenter, open-label, pivotal phase II study of chidamide in relapsed or refractory peripheral T-cell lymphoma. Ann Oncol. 2015 Aug;26(8):1766-71.http://annonc.oxfordjournals.org/content/26/8/1766.longhttp://www.ncbi.nlm.nih.gov/pubmed/26105599?tool=bestpractice.com
