Progress of novel therapy in the treatment of chronic lymphocytic leukemia transforming Richter syndrome
-
摘要: Richter综合征是一种在慢性淋巴细胞白血病/小细胞淋巴瘤(chronic lymphocytic leukemia/small lymphocytic lymphoma，CLL/SLL)基础上发展的侵袭性淋巴瘤。目前大部分转化患者预后极差，特别是与CLL/SLL存在克隆相关的转化患者对传统化学免疫治疗疗效不理想。通过联合应用新型靶向药物以及细胞免疫治疗等手段，在一定程度上可以改善这部分患者的疗效；同时也为年龄适合的患者创造了获得移植的机会。本文我们主要阐述了CLL/SLL转化为Richter综合征的治疗进展。
-
关键词:
- Richter综合征 /
- 靶向药物 /
- 免疫治疗 /
- 移植 /
- 治疗进展
Abstract: Richter syndrome refers to an aggressive lymphoma that develops based on chronic lymphocytic leukemia/small lymphocytic lymphoma(CLL/SLL). The majority of transformed patients currently have an inferior prognosis, and in particular, conventional chemoimmunotherapy showed poor efficacy in clonal related patients. This group of patients may benefit from combinations of novel targeted agents and/or cellular immunotherapy. These new strategies also offer opportunities for patients who are age-appropriate for transplantation. In this review, we focus on current advances related to the therapeutic strategies available for this disease.-
Key words:
- Richter syndrome /
- targeted agents /
- immunotherapy /
- transplantation /
- therapeutic progress
-
-
表 1 既往RS患者化疗相关报道
研究方案 参考文献 研究类型 研究对象 研究人数/RS人数 RS-ORR/% RS-CR/% 中位PFS/月 中位OS/月 HyperCVXD Dabaja et al(2001) Ⅱ期 RS 29/29 44 38 未获得 10 FACPGM Tsimberidou et al(2002) Ⅱ期 RS、PLL、非霍奇金淋巴瘤 22/15 5 5 未获得 2.2 R-hyper-CVXD-R-MA Tsimberidou et al(2003) Ⅱ期 RS 30/30 41 38 未获得 10 OFAR1 Tsimberidou et al(2008) Ⅰ~Ⅱ期 FR-CLL、RS 50/20 50 20 未获得 6、59% OFAR2 Tsimberidou et al(2013) Ⅰ~Ⅱ期 难治复发CLL、RS 102/35 39 6.5 未获得 6.6 R-CHOP Langerbeins et al(2014) Ⅱ期 难治复发CLL、RS 60/15 67 7 10 21 OCHOP Eyre et al(2016) Ⅱ期 RS 37/37 46 27 6.2 11.4 R-EPOCH Rogers et al(2018) 回顾性 RS 46/46 39 未获得 3.5 5.9 HyperCVXD：环磷酰胺、长春新碱、柔红霉素脂质体(柔红霉素)和地塞米松；FACPGM：氟达拉滨、阿糖胞苷、环磷酰胺、顺铂和粒细胞-巨噬细胞集落刺激因子；R-hyper-CVXD-R-MA：环磷酰胺、长春新碱、柔红霉素脂质体、地塞米松联合利妥昔单抗与甲氨蝶呤、阿糖胞苷联合利妥昔单抗交替；OFAR1：奥沙利铂(25 mg/m2)、氟达拉滨、阿糖胞苷和利妥昔单抗；OFAR2：奥沙利铂(30 mg/m2)、氟达拉滨、阿糖胞苷和利妥昔单抗；R-CHOP：利妥昔单抗、环磷酰胺、多柔比星、长春新碱、泼尼松；OCHOP：奥法木单抗、环磷酰胺、多柔比星、长春新碱、泼尼松；R-EPOCH：利妥昔单抗、依托泊苷、泼尼松、长春新碱、环磷酰胺、多柔比星；PLL：幼淋细胞白血病；FR-CLL：氟达拉滨耐药的慢性淋巴细胞白血病。 
下载: 导出CSV
表 2 既往RS患者经移植治疗的相关报道
参考文献 研究类型 患者例数 移植类型 ORR/% PFS OS 非复发死亡率 复发率 粒细胞缺乏持续时间(≤0.5×109/L)/d 血小板减少持续时间(≤0.5×109/L)/d 急性移植物抗宿主病 慢性移植物抗宿主病 Cwynarski et al，2012 回顾性分析(n=59) auto-HSCT：34 auto-HSCT vs allo-HSCT 82 3年PFS：45% 预估3年OS：59% 3年：12% 3年：43% 12 (7~52) 18 (11~95) 未获得 未获得 allo-HSCT：25 60 3年PFS：27% 预估3年OS：36% 3年：26% 3年：47% 13.5(8~39) 15(10~60) 2~4级：7个月28% 未获得 Herrera et al，2021 回顾性分析(n=171) auto-HSCT：53 auto-HSCT vs allo-HSCT 64 3年PFS：48% 3年OS：57% 1年：10% 1年：29% 100 d恢复率：98% 100 d恢复率：96% 未获得 未获得 allo-HSCT：118 77 3年PFS：43% 3年OS：52% 1年：23% 1年：23% 100 d恢复率：96% 100 d恢复率：93% ≥3级：6个月13% 2年：41% Kim et al，2021 回顾性分析(n=28) 28 allo-HSCT 93 4年PFS：39% 4年OS：53% 4年：29% 4年：32% 未获得 未获得 2~4级：6个月36% 2年：52% Lahoud et al，2021 回顾性分析(n=23) 23 allo-HSCT 83 5年PFS：40% 5年OS：58% 1年：12% 35% 未获得 未获得 22% 35%
下载: 导出CSV
-
[1] Smyth E, Eyre TA, Cheah CY. Emerging Therapies for the Management of Richter Transformation[J]. J Clin Oncol, 2022, 41(2): 395-409.
[2] Parry EM, ten Hacken E, Wu CJ. Richter syndrome: Novel insights into the biology of transformation[J]. Blood, 2023, 142(1): 11-22.
[3] Thompson PA, Siddiqi T. Treatment of Richter's syndrome[J]. Hematology, 2022, 2022(1): 329-336. doi: 10.1182/hematology.2022000345
[4] Rogers KA, Huang Y, Ruppert AS, et al. A single-institution retrospective cohort study of first-line R-EPOCH chemoimmunotherapy for Richter syndrome demonstrating complex chronic lymphocytic leukaemia karyotype as an adverse prognostic factor[J]. Br J Haematol, 2018, 180(2): 259-266. doi: 10.1111/bjh.15035
[5] Rayan Ramadan, Alaa Alzak, Heather Leitch, et al. Ibrutinib reduces the risk of Richter's transformation in previously treated CLL patients: a population-based study in British columbia[C]. European Hematology Association, 2022, 06/10/22, PB1881.
[6] 沈晖, 朱华渊, 李建勇. BCL-2抑制剂在慢性淋巴细胞白血病中的研究进展[J]. 临床血液学杂志, 2022, 35(1): 77-81. doi: 10.13201/j.issn.1004-2806.2022.01.015
[7] Mouhssine S, Gaidano G. Richter Syndrome: From Molecular Pathogenesis to Druggable Targets[J]. Cancers(Basel), 2022, 14(19): 4644.
[8] Davids MS, Roberts AW, Seymour JF, et al. Phase Ⅰ First-in-Human Study of Venetoclax in Patients With Relapsed or Refractory Non-Hodgkin Lymphoma[J]. J Clin Oncol, 2017, 35(8): 826-833. doi: 10.1200/JCO.2016.70.4320
[9] Davids MS, Rogers KA, Tyekucheva S, et al. Venetoclax plus dose-adjusted R-EPOCH for Richter syndrome[J]. Blood, 2022, 139(5): 686-689. doi: 10.1182/blood.2021011386
[10] Iannello A, Vitale N, Coma S, et al. Synergistic efficacy of the dual PI3K-δ/γ inhibitor duvelisib with the Bcl-2 inhibitor venetoclax in Richter syndrome PDX models[J]. Blood, 2021, 137(24): 3378-3389. doi: 10.1182/blood.2020010187
[11] Jain N, Ferrajoli A, Thompson PA, et al. Venetoclax, Obinutuzumab and Atezolizumab(PD-L1 Checkpoint Inhibitor)for Treatment for Patients with Richter Transformation[J]. Blood, 2021, 138(Supplement 1): 1550-1550. doi: 10.1182/blood-2021-154279
[12] Mato AR, Shah NN, Jurczak W, et al. Pirtobrutinib in relapsed or refractory B-cell malignancies(BRUIN): a phase 1/2 study[J]. Lancet, 2021, 397(10277): 892-901. doi: 10.1016/S0140-6736(21)00224-5
[13] Mato AR, Schuster SJ, Foss FM, et al. A Once Daily, Oral, Triple Combination of BTK Inhibitor, mTOR Inhibitor and IMiD for Treatment of Relapsed/Refractory Richter's Transformation and De Novo Diffuse Large B-Cell Lymphoma[J]. Blood, 2020, 136(Supplement 1): 21-22.
[14] 付方方, 陈欣, 邢璐宇. 嵌合抗原受体T细胞治疗心肌病理性纤维化研究进展[J]. 临床心血管病杂志, 2023, 39(9): 734-737. doi: 10.13201/j.issn.1001-1439.2023.09.014
[15] 茆诗源, 马瑞聪, 聂山林, 等. CART细胞治疗患者住院期间心血管不良事件发生的危险因素分析[J]. 临床心血管病杂志, 2021, 37(12): 1106-1111. doi: 10.13201/j.issn.1001-1439.2021.12.008
[16] Benjamini O, Shimoni A, Besser M, et al. Safety and Efficacy of CD19-CAR T Cells in Richter's Transformation after Targeted Therapy for Chronic Lymphocytic Leukemia[J]. Blood, 2020, 136(Supplement 1): 40-40.
[17] Kittai AS, Bond DA, William B, et al. Clinical activity of axicabtagene ciloleucel in adult patients with Richter syndrome[J]. Blood Adv, 2020, 4(19): 4648-4652. doi: 10.1182/bloodadvances.2020002783
[18] Guieze R, Ysebaert L, Roos-Weil D, et al. Blinatumomab for Patients with Richter's Syndrome: A Multicenter Phase 2 Trial from the Filo Group[J]. Blood, 2021, 138(Supplement 1): 3570-3570. doi: 10.1182/blood-2021-147467
[19] Thompson PA, Jiang X, Banerjee P, et al. A phase two study of high dose blinatumomab in Richter's syndrome[J]. Leukemia, 2022, 36(9): 2228-2232. doi: 10.1038/s41375-022-01649-3
[20] Alderuccio JP, Mackrides N, Chapman JR, et al. Rapid complete response to blinatumomab as a successful bridge to allogeneic stem cell transplantation in a case of refractory Richter syndrome[J]. Leuk Lymphoma, 2019, 60(1): 230-233. doi: 10.1080/10428194.2018.1461862
[21] Vaisitti T, Braggio E, Allan JN, et al. Novel Richter Syndrome Xenograft Models to Study Genetic Architecture, Biology, and Therapy Responses[J]. Cancer Res, 2018, 78(13): 3413-3420. doi: 10.1158/0008-5472.CAN-17-4004
[22] Vaisitti T, Vitale N, Micillo M, et al. Anti-CD37 α-amanitin-conjugated antibodies as potential therapeutic weapons for Richter syndrome[J]. Blood, 2022, 140(13): 1565-1569. doi: 10.1182/blood.2022016211
[23] Vaisitti T, Arruga F, Vitale N, et al. ROR1 targeting with the antibody-drug conjugate VLS-101 is effective in Richter syndrome patient-derived xenograft mouse models[J]. Blood, 2021, 137(24): 3365-3377. doi: 10.1182/blood.2020008404
[24] Michael Wang, Matthew Mei, Paul M Barr, et al. Zilovertamab vedotin(MK-2140) for the treatment of non-hodgkin lymphoma: the phase 1 dose escalation and cohort expansion waveline-001 study of an anti-ROR1 antibody drug conjugate[C]. European Hematology Association, 2022, 06/10/22, PB1231.
[25] Aulakh S, Reljic T, Yassine F, et al. Allogeneic hematopoietic cell transplantation is an effective treatment for patients with Richter syndrome: A systematic review and meta-analysis[J]. Hematol Oncol Stem Cell Ther, 2021, 14(1): 33-40. doi: 10.1016/j.hemonc.2020.05.002
[26] Herrera AF, Ahn KW, Litovich C, et al. Autologous and allogeneic hematopoietic cell transplantation for diffuse large B-cell lymphoma-type Richter syndrome[J]. Blood Adv, 2021, 5(18): 3528-3539. doi: 10.1182/bloodadvances.2021004865
[27] Al-Sawaf O, Robrecht S, Bahlo J, et al. Richter transformation in chronic lymphocytic leukemia(CLL)-a pooled analysis of German CLL Study Group(GCLLSG)front line treatment trials[J]. Leukemia, 2021, 35(1): 169-176. doi: 10.1038/s41375-020-0797-x
[28] Ghosh N, Ahmed S, Ahn KW, et al. Association of Reduced-Intensity Conditioning Regimens With Overall Survival Among Patients With Non-Hodgkin Lymphoma Undergoing Allogeneic Transplant[J]. JAMA Oncol, 2020, 6(7): 1011-1018. doi: 10.1001/jamaoncol.2020.1278
[29] Lahoud OB, Devlin SM, Maloy MA, et al. Reduced-intensity conditioning hematopoietic stem cell transplantation for chronic lymphocytic leukemia and Richter's transformation[J]. Blood Adv, 2021, 5(14): 2879-2889. doi: 10.1182/bloodadvances.2020003726
-