AL型淀粉样变抗浆细胞治疗——免疫调节剂

limingxin1969 2023-11-20 发布于上海

展开全文

本文介绍AL型淀粉样变抗浆细胞治疗药物中的免疫调节剂（immunomodulatory drugs，IMiDs）。

一、上市药物介绍

免疫调节剂（IMiDs）可以调节细胞免疫和体液免疫，对免疫反应具有激活或抑制作用，能够改善免疫功能紊乱引起的症状。常用IMiDs有三种类型：免疫促进剂、免疫抑制剂和免疫双向调节剂。

目前，批准上市的IMiDs包括沙利度胺（thalidomide）、来那度胺（lenalidomide）和泊马度胺（pomalidomide）三种。

1.沙利度胺（俗称“反应停”）：是第一代iMiD。

最早于1954年在德国上市，但是，1961年因与婴儿出生缺陷（俗称“海豹儿”）退市。

1998年7月，沙利度胺获得美国FDA批准再次上市（英文商品名为Thalomid）用于治疗急性麻风结节性红斑。

2006年，美国FDA批准了沙利度胺用于治疗MM患者。

1999年，首次报道沙利度胺治疗MM的临床研究[1]。

2003年，报道沙利度胺治疗AL型淀粉样变的耐受性和有效性[2-3]，AL型淀粉样变患者对高剂量沙利度胺的耐受性差。

目前，沙利度胺治疗AL型淀粉样变的方案包括沙利度胺地塞米松（TD）方案[4]、环磷酰胺沙利度胺地塞米松（CTD）方案[5]及美法仑沙利度胺地塞米松（MTD）方案[6]。

沙利度胺的常用剂量为100~200mg/d。

由于沙利度胺具有严重的致畸性，用药前必须确保女性患者避孕依从性并且排除妊娠。

沙利度胺的不良反应主要有周围神经病变，以及增加血栓栓塞症风险。

2. 来那度胺（CC-5013）：是第二代iMiD。

2005年12月通过美国FDA批准上市用于治疗MM患者（由美国新基生物制药公司Celgene研发，2019年被美国的百时美施贵宝公司Bristol-Myers Squibb，BMS收购，英文商品名为Revlimid®）。

2013年6月，来那度胺获得我国国家食品药品监督管理总局，China Food and Drug Administration，CFDA）（2013年2月~2018年8月）批准上市（中文商品名为瑞复美®）用于治疗MM患者。

2006年，首次报道来那度胺单药或联合地塞米松（LD或RD方案）治疗MM患者（75例）和AL型淀粉样变患者（23例）的结果[7]。

之后，相关的临床研究报道逐渐增多[8-21]，涉及的治疗方案包括来那度胺单药、来那度胺地塞米松（LD或RD）方案、环磷酰胺来那度胺地塞米松（CLD或CRd或RdC）方案、美法仑来那度胺地塞米松（MLD）方案等。

来那度胺也可与硼替佐米地塞米松联合（BRD或PRD或VRD）方案[22]，与伊沙佐米地塞米松联合（IRD）方案[23]，与DARA 地塞米松联合（Dara-RD）方案[24]。

来那度胺的常用剂量为25mg/d。

与沙利度胺相比，来那度胺治疗MM更有效，更安全，而且毒性和不良反应也更少。

3.泊马度胺：是第三代iMiD。

2013年2月获得美国FDA批准上市（由美国塞尔基因公司研发，英文商品名为Pomalyst®）用于治疗MM。

目前，泊马度胺原研药尚未在国内上市。

2020年11月，由正大天晴公司研制的仿制药——泊马度胺胶囊（安跃®）正式获得我国国家药品监督管理局，National Medical Products Administration， NMPA）（2018年8月之后）批准上市治疗MM，成为早于原研药在中国上市的首个泊马度胺。

2012年，首次报道泊马度胺治疗AL型淀粉样变患者的活性[25]，之后陆续也有研究报道[26-29]。

目前，治疗方案只有泊马度胺地塞米松（PD）方案，也可以联合艾沙妥昔单抗地塞米松（IPD）方案治疗MM。

泊马度胺的常用剂量为4mg/d。

与沙利度胺和来那度胺比较，泊马度胺具有更小的剂量，更强的作用，同时具有更小的不良反应。

二、作用机制

主要包括以下三个方面：

1. 通过抑制肿瘤坏死因子-α（tumor necrosis factor-α，TNF-α）发挥抗炎作用。

2. 通过刺激白细胞介素-2（interleukin-2，IL-2）发挥免疫调节作用。

3. 通过抑制血管内皮生长因子（vascular endothelial growth factor，VEGF）发挥抗血管生成作用。

参考文献

1.Singhal S, Mehta J, Desikan R, et al. Antitumor activity of thalidomide in refractory multiple myeloma [J]. N Engl J Med, 1999, 341 (21): 1565-1571.

2.Seldin DC, Choufani EB, Dember LM, et al. Tolerability and efficacy of thalidomide for the treatment of patients with light chain-associated (AL) amyloidosis [J]. Clin Lymphoma, 2003, 3 (4): 241-246.

3.Dispenzieri A, Lacy MQ, Rajkumar SV, et al. Poor tolerance to high doses of thalidomide in patients with primary systemic amyloidosis [J]. Amyloid, 2003, 10 (4): 257-261.

4.Palladini G, Perfetti V, Perlini S, et al. The combination of thalidomide and intermediate-dose dexamethasone is an effective but toxic treatment for patients with primary amyloidosis (AL) [J]. Blood, 2005, 105 (7): 2949-2951.

5.Wechalekar AD, Goodman HJ, Lachmann HJ, et al. Safety and efficacy of risk-adapted cyclophosphamide, thalidomide, and dexamethasone in systemic AL amyloidosis [J]. Blood, 2007, 109 (2): 457-464.

6.Palladini G, Russo P, Lavatelli F, et al. Treatment of patients with advanced cardiac AL amyloidosis with oral melphalan, dexamethasone, and thalidomide [J]. Ann Hematol, 2009, 88 (4): 347-350.

7.Sviggum HP, Davis MD, Rajkumar SV, et al. Dermatologic adverse effects of lenalidomide therapy for amyloidosis and multiple myeloma [J].Arch Dermatol, 2006, 142 (10): 1298-1302.

8.Sanchorawala V, Wright DG, Rosenzweig M, et al. Lenalidomide and dexamethasone in the treatment of AL amyloidosis: results of a phase 2 trial [J]. Blood, 2007, 109 (2): 492-496.

9.Dispenzieri A, Lacy MQ, Zeldenrust SR, et al. The activity of lenalidomide with or without dexamethasone in patients with primary systemic amyloidosis [J]. Blood, 2007, 109 (2): 465-470.

10.Moreau P, Jaccard A, Benboubker L, et al. Lenalidomide in combination with melphalan and dexamethasone in patients with newly diagnosed AL amyloidosis: a multicenter phase 1/2 dose-escalation study [J]. Blood, 2010, 116 (23): 4777-4782.

11.Palladini G, Russo P, Foli A, et al. Salvage therapy with lenalidomide and dexamethasone in patients with advanced AL amyloidosis refractory to melphalan, bortezomib, and thalidomide [J]. Ann Hematol, 2012, 91 (1): 89-92.

12.Kumar SK, Hayman SR, Buadi FK, et al. Lenalidomide, cyclophosphamide, and dexamethasone (CRd) for light-chain amyloidosis: long-term results from a phase 2 trial [J]. Blood, 2012, 119 (21): 4860-4867.

13.Kastritis E, Terpos E, Roussou M, et al. A phase 1/2 study of lenalidomide with low-dose oral cyclophosphamide and low-dose dexamethasone (RdC) in AL amyloidosis [J]. Blood, 2012, 119 (23): 5384-5390.

14.Palladini G, Russo P, Milani P, et al. A phase II trial of cyclophosphamide, lenalidomide and dexamethasone in previously treated patients with AL amyloidosis [J]. Haematologica, 2013, 98 (3): 433-436.

15.Sanchorawala V, Patel JM, Sloan JM, et al. Melphalan, lenalidomide and dexamethasone for the treatment of immunoglobulin light chain amyloidosis: results of a phase II trial [J]. Haematologica, 2013, 98 (5): 789-792.

16.Dinner S, Witteles W, Afghahi A, et al. Lenalidomide, melphalan and dexamethasone in a population of patients with immunoglobulin light chain amyloidosis with high rates of advanced cardiac involvement [J]. Haematologica, 2013, 98 (10): 1593-1599.

17.Mahmood S, Venner CP, Sachchithanantham S, et al. Lenalidomide and dexamethasone for systemic AL amyloidosis following prior treatment with thalidomide or bortezomib regimens [J]. Br J Haematol, 2014, 166 (6): 842-848.

18.Cibeira MT, Oriol A, Lahuerta JJ, et al. PETHEMA cooperative study group. A phase II trial of lenalidomide, dexamethasone and cyclophosphamide for newly diagnosed patients with systemic immunoglobulin light chain amyloidosis [J]. Br J Haematol, 2015, 170 (6): 804-813.

19.Hegenbart U, Bochtler T, Benner A, et al. Lenalidomide/melphalan/ dexamethasone in newly diagnosed patients with immunoglobulin light chain amyloidosis: resutls of a prospective phase 2 study with long-term follow-up [J]. Haematologica, 2017, 102 (8): 1424-1431.

20.Kastritis E, Gavriatopoulou M, Roussou M, et al. Efficacy of lenalidomide as salvage therapy for patients with AL amyloidosis [J]. Amyloid, 2018, 25 (4): 234-241.

21.Basset M, Kimmich CR, Schreck N, et al. Lenalidomide and dexamethasone in relapsed/refractory immunoglobulin light chain (AL) amyloidosis: results from a large cohort of patients with long follow-up [J]. Br J Haematol, 2021, 195 (2): 230-243.

22.Kastritis E, Dialoupi I, Gavriatopoulou M, et al. Primary treatment of light-chain amyloidosis with bortezomib, lenalidomide, and dexamethasone [J]. Blood Adv, 2019, 3 (20): 3002-3009.

23.Cohen OC, Sharpley F, Gillmore JD, et al. Use of ixazomib, lenalidomide and dexamethasone in patients with relapsed amyloid light-chain amyloidosis [J]. Br J Haematol, 2020, 189 (4): 643-649.

24.Kimmich CR, Terzer T, Benner A, et al. Daratumumab, lenalidomide, and dexamethasone in systemic light-chain amyloidosis: high efficacy, relevant toxicity and main adverse effect of gain 1q21 [J]. Am J Hematol, 2021, 96 (7): E253-E257.

25.Dispenzieri A, Buadi F, Laumann K, et al. Activity of pomalidomide in patients with immunoglobulin light-chain amyloidosis [J]. Blood, 2012, 119 (23): 5397-404.

26.Sanchorawala V, Shelton AC, Lo S, et al. Pomalidomide and dexamethasone in the treatment of AL amyloidosis: results of a phase 1 and 2 trial [J]. Blood, 2016, 128 (8): 1059-1062.

27.Palladini G, Milani P, Foli A, et al. A phase 2 trial of pomalidomide and dexamethasone rescue treatment in patients with AL amyloidosis [J]. Blood, 2017, 129 (15): 2120-2123.

28.Sharpley FA, Manwani R, Mahmood S, et al. Real world outcomes of pomalidomide for treatment of relapsed light chain amyloidosis [J]. Br J Haematol, 2018, 183 (4): 557-563.

29.Milani P, Sharpley F, Schönland SO, et al. Pomalidomide and dexamethasone grant rapid haematologic responses in patients with relapsed and refractory AL amyloidosis: a European retrospective series of 153 patients [J]. Amyloid, 2020, 27 (4): 231-236.