组蛋白去乙酰化酶抑制剂在非霍奇金淋巴瘤中的临床应用

doi:10.3760/cma.j.cn371439-20220408-00096

摘要/Abstract

摘要：

近几十年来淋巴瘤的治疗取得了长足的进步,但复发或难治性淋巴瘤患者的预后往往令人失望。研究发现非霍奇金淋巴瘤的发病机制与组蛋白乙酰化改变有关。组蛋白去乙酰化酶抑制剂可提高淋巴瘤细胞组蛋白乙酰化水平,通过细胞周期抑制、诱导凋亡及免疫调节等机制发挥抗淋巴瘤作用。然而单用组蛋白去乙酰化酶抑制剂取得的治疗效果有限,与其他抗肿瘤药物联合使用治疗复发难治的非霍奇金淋巴瘤表现出很好的疗效。对含组蛋白去乙酰化酶抑制剂治疗方案的基础研究和临床试验进行总结可为淋巴瘤的治疗提供思路。

关键词: 淋巴瘤, 表观遗传, 组蛋白去乙酰化酶抑制剂, 联合用药

Abstract:

Great progress has been made in the treatment of lymphoma in recent decades, but the prognosis for patients with relapsed or refractory lymphoma is often disappointing. Studies have found that the pathogenesis of non-Hodgkin lymphoma is associated with changes in histone acetylation. Histone deacetylase inhibitors can increase the level of histone acetylation in lymphoma cells, and exert anti-lymphoma effects through mechanisms such as cell cycle inhibition, induction of apoptosis, and immunomodulation. However, histone deacetylase inhibitors alone have limited therapeutic effects, and the combination with other antineoplastic drugs for the treatment of relapsing and refractory non-Hodgkin lymphoma has shown good efficacy. Summarizing basic research and clinical trials of histone deacetylase inhibitor containing regimens provides ideas for the treatment of lymphoma.

Key words: Lymphoma, Epigenetic, Histone deacetylase inhibitor, Combination therapy

殷运燕, 李慧, 李雨晨, 惠慧, 许景艳. 组蛋白去乙酰化酶抑制剂在非霍奇金淋巴瘤中的临床应用[J]. 国际肿瘤学杂志, 2022, 49(8): 499-504.

Yin Yunyan, Li Hui, Li Yuchen, Hui Hui, Xu Jingyan. Clinical application of histone deacetylase inhibitors in non-Hodgkin lymphoma[J]. Journal of International Oncology, 2022, 49(8): 499-504.

参考文献 51

[1]	Xargay-Torrent S, López-Guerra M, Saborit-Villarroya I, et al. Vorinostat-induced apoptosis in mantle cell lymphoma is mediated by acetylation of proapoptotic BH3-only gene promoters[J]. Clin Cancer Res, 2011, 17(12): 3956-3968. DOI: 10.1158/1078-0432.CCR-10-3412. doi: 10.1158/1078-0432.CCR-10-3412 pmid: 21652541
[2]	Xue K, Gu JJ, Zhang Q, et al. Vorinostat, a histone deacetylase (HDAC) inhibitor, promotes cell cycle arrest and re-sensitizes rituximab- and chemo-resistant lymphoma cells to chemotherapy agents[J]. J Cancer Res Clin Oncol, 2016, 142(2): 379-387. DOI: 10.1007/s00432-015-2026-y. doi: 10.1007/s00432-015-2026-y
[3]	Mondello P, Tadros S, Teater M, et al. Selective inhibition of HDAC3 targets synthetic vulnerabilities and activates immune surveillance in lymphoma[J]. Cancer Discov, 2020, 10(3): 440-459. DOI: 10.1158/2159-8290.CD-19-0116. doi: 10.1158/2159-8290.CD-19-0116
[4]	Guan XW, Wang HQ, Ban WW, et al. Novel HDAC inhibitor chidamide synergizes with Rituximab to inhibit diffuse large B-cell lymphoma tumour growth by upregulating CD20[J]. Cell Death Dis, 2020, 11(1): 20. DOI: 10.1038/s41419-019-2210-0. doi: 10.1038/s41419-019-2210-0
[5]	Frys S, Simons Z, Hu Q, et al. Entinostat, a novel histone deacetylase inhibitor is active in B-cell lymphoma and enhances the anti-tumour activity of rituximab and chemotherapy agents[J]. Br J Haematol, 2015, 169(4): 506-519. DOI: 10.1111/bjh.13318. doi: 10.1111/bjh.13318
[6]	Olsen EA, Kim YH, Kuzel TM, et al. Phase Ⅱb multicenter trial of vorinostat in patients with persistent, progressive, or treatment refractory cutaneous T-cell lymphoma[J]. J Clin Oncol, 2007, 25(21): 3109-3115. DOI: 10.1200/JCO.2006.10.2434. doi: 10.1200/JCO.2006.10.2434
[7]	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]. J Clin Oncol, 2015, 33(23): 2492-2499. DOI: 10.1200/JCO.2014.59.2782. doi: 10.1200/JCO.2014.59.2782 pmid: 26101246
[8]	Whittaker SJ, Demierre MF, Kim EJ, et al. Final results from a multicenter, international, pivotal study of romidepsin in refractory cutaneous T-cell lymphoma[J]. J Clin Oncol, 2010, 28(29): 4485-4491. DOI: 10.1200/JCO.2010.28.9066. doi: 10.1200/JCO.2010.28.9066 pmid: 20697094
[9]	San-Miguel JF, Hungria VT, Yoon SS, et al. Panobinostat plus bor-tezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: a multicentre, randomised, double-blind phase 3 trial[J]. Lancet Oncol, 2014, 15(11): 1195-1206. DOI: 10.1016/S1470-2045(14)70440-1. doi: 10.1016/S1470-2045(14)70440-1 pmid: 25242045
[10]	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[J]. Ann Oncol, 2015, 26(8): 1766-1771. DOI: 10.1093/annonc/mdv237. doi: 10.1093/annonc/mdv237 pmid: 26105599
[11]	Evens AM, Balasubramanian S, Vose JM, et al. A phase Ⅰ/Ⅱ multicenter, open-label study of the oral histone deacetylase inhibitor abexinostat in relapsed/refractory lymphoma[J]. Clin Cancer Res, 2016, 22(5): 1059-1066. DOI: 10.1158/1078-0432.CCR-15-0624. doi: 10.1158/1078-0432.CCR-15-0624
[12]	Landsburg DJ, Barta SK, Ramchandren R, et al. Fimepinostat (CUDC-907) in patients with relapsed/refractory diffuse large B cell and high-grade B-cell lymphoma: report of a phase 2 trial and exploratory biomarker analyses[J]. Br J Haematol, 2021, 195(2): 201-209. DOI: 10.1111/bjh.17730. doi: 10.1111/bjh.17730
[13]	Abouyabis AN, Shenoy PJ, Sinha R, et al. A systematic review and meta-analysis of front-line anthracycline-based chemotherapy regimens for peripheral T-cell lymphoma[J]. ISRN Hematol, 2011, 2011: 623924. DOI: 10.5402/2011/623924. doi: 10.5402/2011/623924
[14]	Dupuis J, Morschhauser F, Ghesquières H, et al. Combination of romidepsin with cyclophosphamide, doxorubicin, vincristine, and prednisone in previously untreated patients with peripheral T-cell lymphoma: a non-randomised, phase 1b/2 study[J]. Lancet Haematol, 2015, 2(4): e160-e165. DOI: 10.1016/S2352-3026(15)00023-X. doi: 10.1016/S2352-3026(15)00023-X
[15]	Bachy E, Camus V, Thieblemont C, et al. Romidepsin plus CHOP versus CHOP in patients with previously untreated peripheral T-cell lymphoma: results of the Ro-CHOP phase Ⅲ study (conducted by LYSA)[J]. J Clin Oncol, 2022, 40(3): 242-251. DOI: 10.1200/JCO.21.01815. doi: 10.1200/JCO.21.01815
[16]	Zhang W, Su L, Liu L, et al. The combination of chidamide with the CHOEP regimen in previously untreated patients with peri-pheral T-cell lymphoma: a prospective, multicenter, single arm, phase 1b/2 study[J]. Cancer Biol Med, 2021, 18(3): 841-848. DOI: 10.20892/j.issn.2095-3941.2020.0413. doi: 10.20892/j.issn.2095-3941.2020.0413
[17]	Johnston PB, Cashen AF, Nikolinakos PG, et al. Belinostat in combination with standard cyclophosphamide, doxorubicin, vincristine and prednisone as first-line treatment for patients with newly diagnosed peripheral T-cell lymphoma[J]. Exp Hematol Oncol, 2021, 10(1): 15. DOI: 10.1186/s40164-021-00203-8. doi: 10.1186/s40164-021-00203-8 pmid: 33602316
[18]	Shi Y, Jia B, Xu W, et al. Chidamide in relapsed or refractory peripheral T cell lymphoma: a multicenter real-world study in China[J]. J Hematol Oncol, 2017, 10(1): 69. DOI: 10.1186/s13045-017-0439-6. doi: 10.1186/s13045-017-0439-6
[19]	Strati P, Chihara D, Oki Y, et al. A phase Ⅰ study of romidepsin and ifosfamide, carboplatin, etoposide for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma[J]. Haematologica, 2018, 103(9): e416-e418. DOI: 10.3324/haematol.2018.187617. doi: 10.3324/haematol.2018.187617
[20]	Marchi E, Zullo KM, Amengual JE, et al. The combination of hypomethylating agents and histone deacetylase inhibitors produce marked synergy in preclinical models of T-cell lymphoma[J]. Br J Haematol, 2015, 171(2): 215-226. DOI: 10.1111/bjh.13566. doi: 10.1111/bjh.13566
[21]	Falchi L, Ma H, Klein S, et al. Combined oral 5-azacytidine and romidepsin are highly effective in patients with PTCL: a multicenter phase 2 study[J]. Blood, 2021, 137(16): 2161-2170. DOI: 10.1182/blood.2020009004. doi: 10.1182/blood.2020009004
[22]	O'Connor OA, Falchi L, Lue JK, et al. Oral 5-azacytidine and romidepsin exhibit marked activity in patients with PTCL: a multicenter phase 1 study[J]. Blood, 2019, 134(17): 1395-1405. DOI: 10.1182/blood.2019001285. doi: 10.1182/blood.2019001285 pmid: 31471376
[23]	Zhang H, Dong L, Chen Q, et al. Synergistic antitumor effect of histone deacetylase inhibitor and doxorubicin in peripheral T-cell lymphoma[J]. Leuk Res, 2017, 56: 29-35. DOI: 10.1016/j.leukres.2017.01.025. doi: 10.1016/j.leukres.2017.01.025
[24]	Jain S, Jirau-Serrano X, Zullo KM, et al. Preclinical pharmacologic evaluation of pralatrexate and romidepsin confirms potent synergy of the combination in a murine model of human T-cell lymphoma[J]. Clin Cancer Res, 2015, 21(9): 2096-2106. DOI: 10.1158/1078-0432.CCR-14-2249. doi: 10.1158/1078-0432.CCR-14-2249
[25]	Vu K, Wu CH, Yang CY, et al. Romidepsin plus liposomal doxorubicin is safe and effective in patients with relapsed or refractory T-cell lymphoma: results of a phase Ⅰ dose-escalation study[J]. Clin Cancer Res, 2020, 26(5): 1000-1008. DOI: 10.1158/1078-0432.CCR-19-2152. doi: 10.1158/1078-0432.CCR-19-2152
[26]	Passero FC Jr, Ravi D, McDonald JT, et al. Combinatorial ixazomib and belinostat therapy induces NFE2L2-dependent apoptosis in Hodgkin and T-cell lymphoma[J]. Br J Haematol, 2020, 188(2): 295-308. DOI: 10.1111/bjh.16160. doi: 10.1111/bjh.16160
[27]	Briere D, Sudhakar N, Woods DM, et al. The class Ⅰ/Ⅳ HDAC inhibitor mocetinostat increases tumor antigen presentation, decreases immune suppressive cell types and augments checkpoint inhibitor therapy[J]. Cancer Immunol Immunother, 2018, 67(3): 381-392. DOI: 10.1007/s00262-017-2091-y. doi: 10.1007/s00262-017-2091-y pmid: 29124315
[28]	Wei C, Hu S, Luo M, et al. A novel mechanism of action of histone deacetylase inhibitor chidamide: enhancing the chemotaxis function of circulating PD-1(+) cells from patients with PTCL[J]. Front Oncol, 2021, 11: 682436. DOI: 10.3389/fonc.2021.682436. doi: 10.3389/fonc.2021.682436
[29]	Yan Z, Yao S, Liu Y, et al. Durable response to sintilimab and chidamide in a patient with pegaspargase- and immunotherapy-resistant NK/T-cell lymphoma: case report and literature review[J]. Front Oncol, 2020, 10: 608304. DOI: 10.3389/fonc.2020.608304. doi: 10.3389/fonc.2020.608304
[30]	Zaja F, Salvi F, Rossi M, et al. Single-agent panobinostat for relapsed/refractory diffuse large B-cell lymphoma: clinical outcome and correlation with genomic data. A phase 2 study of the Fonda-zione Italiana Linfomi[J]. Leuk Lymphoma, 2018, 59(12): 2904-2910. DOI: 10.1080/10428194.2018.1452208. doi: 10.1080/10428194.2018.1452208
[31]	Chu Y, Yahr A, Huang B, et al. Romidepsin alone or in combination with anti-CD20 chimeric antigen receptor expanded natural killer cells targeting Burkitt lymphoma in vitro and in immunodeficient mice[J]. Oncoimmunology, 2017, 6(9): e1341031. DOI: 10.1080/2162402X.2017.1341031. doi: 10.1080/2162402X.2017.1341031
[32]	Chen R, Frankel P, Popplewell L, et al. A phase Ⅱ study of vorinostat and rituximab for treatment of newly diagnosed and relapsed/refractory indolent non-Hodgkin lymphoma[J]. Haematologica, 2015, 100(3): 357-362. DOI: 10.3324/haematol.2014.117473. doi: 10.3324/haematol.2014.117473
[33]	Barnes JA, Redd R, Fisher DC, et al. Panobinostat in combination with rituximab in heavily pretreated diffuse large B-cell lymphoma: results of a phase Ⅱ study[J]. Hematol Oncol, 2018, 36(4): 633-637. DOI: 10.1002/hon.2515. doi: 10.1002/hon.2515
[34]	Assouline SE, Nielsen TH, Yu S, et al. Phase 2 study of panobinostat with or without rituximab in relapsed diffuse large B-cell lymphoma[J]. Blood, 2016, 128(2): 185-194. DOI: 10.1182/blood-2016-02-699520. doi: 10.1182/blood-2016-02-699520 pmid: 27166360
[35]	Oki Y, Kelly KR, Flinn I, et al. CUDC-907 in relapsed/refractory diffuse large B-cell lymphoma, including patients with MYC-alterations: results from an expanded phase Ⅰ trial[J]. Haematologica, 2017, 102(11): 1923-1930. DOI: 10.3324/haematol.2017.172882. doi: 10.3324/haematol.2017.172882
[36]	Zhang MC, Fang Y, Wang L, et al. Clinical efficacy and molecular biomarkers in a phase Ⅱ study of tucidinostat plus R-CHOP in elderly patients with newly diagnosed diffuse large B-cell lymphoma[J]. Clin Epigenetics, 2020, 12(1): 160. DOI: 10.1186/s13148-020-00948-9. doi: 10.1186/s13148-020-00948-9
[37]	Persky DO, Li H, Rimsza LM, et al. A phase Ⅰ/Ⅱ trial of vorinostat (SAHA) in combination with rituximab-CHOP in patients with newly diagnosed advanced stage diffuse large B-cell lymphoma (DLBCL): SWOG S0806[J]. Am J Hematol, 2018, 93(4): 486-493. DOI: 10.1002/ajh.25010. doi: 10.1002/ajh.25010
[38]	乔薇, 宋腾, 陈馨蕊, 等. PI3K信号通路过度激活对非霍奇金淋巴瘤患者预后的影响及其靶向药物疗效[J]. 国际肿瘤学杂志, 2021, 48(2): 121-124. DOI: 10.3760/cma.j.cn371439-20200615-00024. doi: 10.3760/cma.j.cn371439-20200615-00024
[39]	Sun K, Atoyan R, Borek MA, et al. Dual HDAC and PI3K inhibitor CUDC-907 downregulates MYC and suppresses growth of MYC-dependent cancers[J]. Mol Cancer Ther, 2017, 16(2): 285-299. DOI: 10.1158/1535-7163.MCT-16-0390. doi: 10.1158/1535-7163.MCT-16-0390
[40]	Kirschbaum M, Frankel P, Popplewell L, et al. Phase Ⅱ study of vorinostat for treatment of relapsed or refractory indolent non-Hodgkin's lymphoma and mantle cell lymphoma[J]. J Clin Oncol, 2011, 29(9): 1198-1203. DOI: 10.1200/JCO.2010.32.1398. doi: 10.1200/JCO.2010.32.1398 pmid: 21300924
[41]	Carbone A, Roulland S, Gloghini A, et al. Follicular lymphoma[J]. Nat Rev Dis Primers, 2019, 5(1): 83. DOI: 10.1038/s41572-019-0132-x. doi: 10.1038/s41572-019-0132-x
[42]	Paoluzzi L, Scotto L, Marchi E, et al. Romidepsin and belinostat synergize the antineoplastic effect of bortezomib in mantle cell lymphoma[J]. Clin Cancer Res, 2010, 16(2): 554-565. DOI: 10.1158/1078-0432.CCR-09-1937. doi: 10.1158/1078-0432.CCR-09-1937 pmid: 20068080
[43]	Yazbeck V, Shafer D, Perkins EB, et al. A phase Ⅱ trial of bor-tezomib and vorinostat in mantle cell lymphoma and diffuse large B-cell lymphoma[J]. Clin Lymphoma Myeloma Leuk, 2018, 18(9): 569-575.e1. DOI: 10.1016/j.clml.2018.05.023. doi: S2152-2650(18)30236-2 pmid: 30122201
[44]	Holkova B, Kmieciak M, Bose P, et al. Phase 1 trial of carfilzomib (PR-171) in combination with vorinostat (SAHA) in patients with relapsed or refractory B-cell lymphomas[J]. Leuk Lymphoma, 2016, 57(3): 635-643. DOI: 10.3109/10428194.2015.1075019. doi: 10.3109/10428194.2015.1075019
[45]	Spurgeon SE, Sharma K, Claxton DF, et al. Phase 1-2 study of vorinostat (SAHA), cladribine and rituximab (SCR) in relapsed B-cell non-Hodgkin lymphoma and previously untreated mantle cell lymphoma[J]. Br J Haematol, 2019, 186(6): 845-854. DOI: 10.1111/bjh.16008. doi: 10.1111/bjh.16008
[46]	Meyer SN, Scuoppo C, Vlasevska S, et al. Unique and shared epigenetic programs of the CREBBP and EP300 acetyltransferases in germinal center B cells reveal targetable dependencies in lymphoma[J]. Immunity, 2019, 51(3): 535-547.e9. DOI: 10.1016/j.immuni.2019.08.006. doi: 10.1016/j.immuni.2019.08.006
[47]	Pasqualucci L, Dominguez-Sola D, Chiarenza A, et al. Inactiva-ting mutations of acetyltransferase genes in B-cell lymphoma[J]. Nature, 2011, 471(7337): 189-195. DOI: 10.1038/nature09730. doi: 10.1038/nature09730
[48]	Gu W, Roeder RG. Activation of p53 sequence-specific DNA bin-ding by acetylation of the p53 C-terminal domain[J]. Cell, 1997, 90(4): 595-606. DOI: 10.1016/s0092-8674(00)80521-8. doi: 10.1016/s0092-8674(00)80521-8 pmid: 9288740
[49]	Bereshchenko OR, Gu W, Dalla-Favera R. Acetylation inactivates the transcriptional repressor BCL6[J]. Nat Genet, 2002, 32(4): 606-613. DOI: 10.1038/ng1018. doi: 10.1038/ng1018 pmid: 12402037
[50]	Juskevicius D, Jucker D, Klingbiel D, et al. Mutations of CREBBP and SOCS1 are Independent prognostic factors in diffuse large B cell lymphoma: mutational analysis of the SAKK 38/07 prospective clinical trial cohort[J]. J Hematol Oncol, 2017, 10(1): 70. DOI: 10.1186/s13045-017-0438-7. doi: 10.1186/s13045-017-0438-7
[51]	Sun Y, Gao Y, Chen J, et al. CREBBP cooperates with the cell cycle machinery to attenuate chidamide sensitivity in relapsed/refractory diffuse large B-cell lymphoma[J]. Cancer Lett, 2021, 521: 268-280. DOI: 10.1016/j.canlet.2021.09.002. doi: 10.1016/j.canlet.2021.09.002