您的位置:山东大学 -> 科技期刊社 -> 《山东大学学报(医学版)》

山东大学学报 (医学版) ›› 2019, Vol. 57 ›› Issue (7): 21-30.doi: 10.6040/j.issn.1671-7554.0.2019.477

• • 上一篇    下一篇

新药时代慢性淋巴细胞白血病的治疗选择

李建勇,夏奕, 徐卫   

  1. 南京医科大学第一附属医院血液科 江苏省人民医院血液科, 江苏 南京 210029
  • 发布日期:2022-09-27
  • 通讯作者: 李建勇. E-mail:lijianyonglm@126.com
  • 基金资助:
    国家自然科学基金(81700193,81600130,81770166,817200108002)

Selecting therapy for chronic lymphocytic leukemia in the era of novel agents

LI Jianyong, XIA Yi, XU Wei   

  1. Department of Hematology, First Affiliated Hospital of Nanjing Medical University;
    Department of Hematology, Jiangsu Province Hospital, Nanjing 210029, Jiangsu, China
  • Published:2022-09-27

摘要: 慢性淋巴细胞白血病(CLL)是欧美国家最常见的成人白血病。我国CLL发病率虽偏低,但呈上涨趋势。既往CLL治疗以免疫化学治疗为主。近年来,布鲁顿氏酪氨酸激酶(BTK)抑制剂伊布替尼和acalabrutinib、3-磷脂酰肌醇激酶(PI3K)抑制剂idelalisib和duvelisib、B淋巴细胞瘤-2(BCL2)抑制剂venetoclax的上市使得CLL治疗获得了突破性进展,同时包括嵌合性抗原受体T淋巴细胞(CART)在内的细胞免疫治疗也初显成效。在众多治疗选择中,如何为临床特征迥异的CLL患者选择合适的个体化治疗方案,是临床医生面临的挑战。

关键词: 慢性淋巴细胞白血病, 治疗, 伊布替尼, idelalisib, venetoclax

Abstract: Chronic lymphocytic leukemia(CLL)is the most common type of adult leukemia in Caucasian population. Although CLL is less common in Chinese, an increasing incidence of new cases is observed. Before 2010s, the standard 山 东 大 学 学 报 (医 学 版)57卷7期 -李建勇,等.新药时代慢性淋巴细胞白血病的治疗选择 \=-therapy for CLL was chemoimmunotherapy. In recent years, Brutons tyrosine kinase(BTK)inhibitors ibrutinib and acalabrutinib, phosphatidylinositol 3-kinase(PI3K)inhibitors idelalisib and duvelisib, and BCL2 antagonist venetoclax have led to remarkable improvement in the survival of CLL patients. Novel cellular immunotherapy, including chimeric antigen receptor-engineered T(CART), has also shown promising efficacy in the treatment of CLL. How to choose individualized therapeutic regimen from the various approaches is now posing challenges upon clinicians.

Key words: Chronic lymphocytic leukemia, Treatment, Ibrutinib, Idelalisib, Venetoclax

中图分类号: 

  • R733.7
[1] Slager SL, Benavente Y, Blair A, et al. Medical history, lifestyle, family history, and occupational risk factors for chronic lymphocytic leukemia/small lymphocytic lymphoma: the InterLymph Non-Hodgkin Lymphoma Subtypes Project [J]. J Natl Cancer Inst Monogr, 2014, 2014(48): 41-51.
[2] Yang SM, Li JY, Gale RP, et al. The mystery of chronic lymphocytic leukemia(CLL): Why is it absent in Asians and what does this tell us about etiology, pathogenesis and biology? [J]. Blood Rev, 2015, 29(3): 205-213.
[3] Yang S, Gale RP, Shi H, et al. Is there an epidemic of chronic lymphocytic leukaemia(CLL)in China? [J]. Leuk Res, 2018, 73: 16-20. doi: 10.1016/j.leukres.
[4] Hallek M, Cheson BD, Catovsky D, et al. iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL [J]. Blood, 2018, 131(25): 2745-2760.
[5] Dighiero G, Maloum K, Desablens B, et al. Chlorambucil in indolent chronic lymphocytic leukemia. French cooperative group on chronic lymphocytic leukemia [J]. N Engl J Med, 1998, 338(21): 1506-1514.
[6] Hoechstetter MA, Busch R, Eichhorst B, et al. Early, risk-adapted treatment with fludarabine in Binet stage A chronic lymphocytic leukemia patients: results of the CLL1 trial of the German CLL study group [J]. Leukemia, 2017, 31(12): 2833-2837.
[7] Langerbeins P, Bahlo J, Rhein C, et al. The CLL12 trial protocol: a placebo-controlled double-blind Phase III study of ibrutinib in the treatment of early-stage chronic lymphocytic leukemia patients with risk of early disease progression [J]. Future Oncol, 2015, 11(13): 1895-1903.
[8] Fischer K, Bahlo J, Fink AM, et al. Long-term remissions after FCR chemoimmunotherapy in previously untreated patients with CLL: updated results of the CLL8 trial [J]. Blood, 2016, 127(2): 208-215.
[9] Thompson PA, Tam CS, O'Brien SM, et al. Fludarabine, cyclophosphamide, and rituximab treatment achieves long-term disease-free survival in IGHV-mutated chronic lymphocytic leukemia [J]. Blood, 2016, 127(3): 303-309.
[10] Rossi D, Terzi-di-Bergamo L, De Paoli L, et al. Molecular prediction of durable remission after first-line fludarabine-cyclophosphamide-rituximab in chronic lymphocytic leukemia [J]. Blood, 2015, 126(16): 1921-1924.
[11] Hallek M, Fischer K, Fingerle-Rowson G, et al. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial [J]. Lancet, 2010, 376(9747): 1164-1174.
[12] Benjamini O, Jain P, Trinh L, et al. Second cancers in patients with chronic lymphocytic leukemia who received frontline fludarabine, cyclophosphamide and rituximab therapy: distribution and clinical outcomes [J]. Leuk Lymphoma, 2015, 56(6): 1643-1650.
[13] Eichhorst B, Fink AM, Bahlo J, et al. First-line chemoimmunotherapy with bendamustine and rituximab versus fludarabine, cyclophosphamide, and rituximab in patients with advanced chronic lymphocytic leukaemia(CLL10): an international, open-label, randomised, phase 3, non-inferiority trial [J]. Lancet Oncol, 2016, 17(7): 928-942.
[14] Goede V, Fischer K, Engelke A, et al. Obinutuzumab as frontline treatment of chronic lymphocytic leukemia: updated results of the CLL11 study [J]. Leukemia, 2015, 29(7): 1602-1604.
[15] Burger JA, Tedeschi A, Barr PM, et al. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia [J]. N Engl J Med, 2015, 373(25): 2425-2437.
[16] Woyach JA, Ruppert AS, Heerema NA, et al. Ibrutinib regimens versus chemoimmunotherapy in older patients with untreated CLL [J]. N Engl J Med, 2018, 379(26): 2517-2528.
[17] Moreno C, Greil R, Demirkan F, et al. Ibrutinib + obinutuzumab versus chlorambucil + obinutuzumab as first-line treatment in patients with chronic lymphocytic leukemia or small lymphocytic lymphoma(cll/sll): results from phase 3 illuminate [J]. Blood, 2018, 132: 691.
[18] Shanafelt TD, Wang V, Kay NE et al. A randomized phase III study of ibrutinib(PCI-32765)-based therapy vs. standard fludarabine, cyclophosphamide, and rituximab(FCR)chemoimmunotherapy in untreated younger patients with chronic lymphocytic leukemia(CLL): a trial of the ECOG-ACRIN cancer research group(E1912)[J]. Blood, 2018, 132: 4.
[19] Jain N, Thompson PA, Burger JA, et al. Ibrutinib, fludarabine, cyclophosphamide, and obinutuzumab(iFCG)for firstline treatment of patients with CLL with mutated IGHV and without TP53 aberrations [J]. Blood, 2018, 132: 185.
[20] Ahn IE, Farooqui MZH, Tian X, et al. Depth and durability of response to ibrutinib in CLL: 5-year follow-up of a phase 2 study [J]. Blood, 2018, 131(21): 2357-2366.
[21] Jain N, Keating MJ, Thompson PA, et al. Ibrutinib and Venetoclax for First-Line of CLL [J]. N Engl J Med, 2019, 380(22): 2095-2103.
[22] Byrd JC, Brown JR, O'Brien S, et al. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia [J]. N Engl J Med, 2014, 371(3): 213-223.
[23] Brown JR, Hillmen P, O'Brien S, et al. Extended follow-up and impact of high-risk prognostic factors from the phase 3 RESONATE study in patients with previously treated CLL/SLL [J]. Leukemia, 2018, 32(1): 83-91.
[24] Jones J, Coutre S, Byrd J, et al. Evaluation of 243 patients with deletion 17p chronic lymphocytic leukemia treated with ibrutinib: a cross-study analysis of treatment outcomes [J]. Haematologica, 2016, 101(Suppl 1): 150.
[25] Burger J, Sivina M, Ferrajoli A, et al. Randomized trial of ibrutinib versus ibrutinib plus rituximab(Ib1R)in patients with chronic lymphocytic leukemia(CLL)[J]. Blood, 2017, 130(Suppl 1): 427.
[26] Davids M, Kim H, Savell A, et al. Initial results of a phase Ib study of ibrutinib in combination with obinutuzumab in patients with relapsed or refractory chronic lymphocytic leukemia [J]. Blood, 2017, 130(Suppl 1): 4317.
[27] Woyach J, Awan F, Jianfar M, et al. Acalabrutinib with obinutuzumab in relapsed/refractory and treatment-naive patients with chronic lymphocytic leukemia: the phase 1b/2 ACE-CL-003 study [J]. Blood, 2017, 130(Suppl 1): 432.
[28] Sharman J, Brander D, Mato A, et al. Ublituximab and ibrutinib for previously treated genetically high-risk chronic lymphocytic leukemia: results of the GENUINE phase 3 study [J]. Hematol Oncol, 2017, 35(Suppl 2): 111-112.
[29] Chanan-Khan A, Cramer P, Demirkan F, et al. Ibrutinib combined with bendamustine and rituximab compared with placebo, bendamustine, and rituximab for previously treated chronic lymphocytic leukaemia or small lymphocytic lymphoma(HELIOS): a randomised, double-blind, phase 3 study [J]. Lancet Oncol, 2016, 17(2): 200-211.
[30] Fraser G, Cramer P, Demirkan F, et al. Updated results from the phase 3 HELIOS study of ibrutinib, bendamustine, and rituximab in relapsed chronic lymphocytic leukemia/small lymphocytic lymphoma [J]. Leukemia, 2019, 33(4): 969-980.
[31] Roberts AW, Davids MS, Pagel JM, et al. Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia [J]. N Engl J Med, 2016, 374(4): 311-322.
[32] Stilgenbauer S, Eichhorst B, Schetelig J, et al. Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion: a multicentre, open-label, phase 2 study [J]. Lancet Oncol, 2016, 17(6): 768-778.
[33] Kater AP, Hillmen P, Eichhorst B, et al. First prospective data on impact of minimal residual disease on long-term clinical outcomes after venetoclax plus rituximab versus bendamustine plus rituximab: phase III Murano study [J]. Blood, 2018, 132: 695.
[34] Seymour JF, Kipps TJ, Eichhorst B, et al. Venetoclax-Rituximab in Relapsed or Refractory Chronic Lymphocytic Leukemia [J]. N Engl J Med, 2018, 378(12): 1107-1120.
[35] Flinn IW, Brunvand M, Choi M, et al. Safety and efcacy of a combination of venetoclax(GDC-0199/ABT-199)and obinutuzumab in patients with relapsed/refractory or previously untreated chronic lymphocytic leukemia-results from a phase 1b study(GP28331)[J]. Blood, 2015, 126: 494.
[36] Hillmen P, Rawstron A, Brock K, et al. Ibrutinib Plus venetoclax in Relapsed/Refractory CLL: results of the bloodwise TAP clarity study [J]. Blood, 2018, 132: 182.
[37] Furman RR, Sharman JP, Coutre SE, et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia [J]. N Engl J Med, 2014, 370(11): 997-1007.
[38] Jones JA, Robak T, Brown JR, et al. Efficacy and safety of idelalisib in combination with ofatumumab for previously treated chronic lymphocytic leukaemia: an open-label, randomised phase 3 trial [J]. Lancet Haematol, 2017, 4(3): 114-126.
[39] Zelenetz AD, Barrientos JC, Brown JR, et al. Idelalisib or placebo in combination with bendamustine and rituximab in patients with relapsed or refractory chronic lymphocytic leukaemia: interim results from a phase 3, randomised, double-blind, placebo-controlled trial [J]. Lancet Oncol, 2017, 18(3): 297-311.
[40] Flinn IW, Hillmen P, Montillo M, et al. The phase 3 DUO trial: duvelisib vs ofatumumab in relapsed and refractory CLL/SLL [J]. Blood, 2018, 132(23): 2446-2455.
[41] Lampson BL, Kasar SN, Matos TR, et al. Idelalisib given front-line for treatment of chronic lymphocytic leukemia causes frequent immune-mediated hepatotoxicity [J]. Blood, 2016, 128(2): 195-203.
[42] Woyach JA, Ruppert AS, Guinn D, et al. BTK(C481S)-mediated resistance to ibrutinib in chronic lymphocytic leukemia [J]. J Clin Oncol, 2017, 35(13): 1437-1443.
[43] Mato A, Wierda W, Davids M, et al. Analysis of PET-CT to identify Richter's transformation in 167 patients with disease progression following kinase inhibitor therapy [J]. Blood, 2017, 130(Suppl 1): 834.
[44] Jones JA, Mato AR, Wierda WG, et al. Venetoclax for chronic lymphocytic leukaemia progressing after ibrutinib: an interim analysis of a multicentre, open-label, phase 2 trial [J]. Lancet Oncol, 2018, 19(1): 65-75.
[45] Mato AR, Hill BT, Lamanna N, et al. Optimal sequencing of ibrutinib, idelalisib, and venetoclax in chronic lymphocytic leukemia: results from a multicenter study of 683 patients [J]. Ann Oncol, 2017, 28(5): 1050-1056.
[46] Brown JR. Relapsed CLL: sequencing, combinations, and novel agents [J]. Hematology Am Soc Hematol Educ Program, 2018, 2018(1): 248-255.
[47] Mato AR, Nabhan C, Thompson MC, et al. Toxicities and outcomes of 616 ibrutinib-treated patients in the United States: a real-world analysis [J]. Haematologica, 2018, 103(5): 874-879.
[48] Kramer I, Stilgenbauer S, Dietrich S, et al. Allogeneic hematopoietic cell transplantation for high-risk CLL: 10-year follow-up of the GCLLSG CLL3X trial [J]. Blood, 2017, 130(12): 1477-1480.
[49] Hahn M, Bottcher S, Dietrich S, et al. Allogeneic hematopoietic stem cell transplantation for poor-risk CLL: dissecting immune-modulating strategies for disease eradication and treatment of relapse [J]. Bone Marrow Transplant, 2015, 50(10): 1279-1285.
[50] Dreger P, Schnaiter A, Zenz T, et al. TP53, SF3B1, and NOTCH1 mutations and outcome of allotransplantation for chronic lymphocytic leukemia: six-year follow-up of the GCLLSG CLL3X trial [J]. Blood, 2013, 121(16): 3284-3288.
[51] Sorror ML, Storer BE, Sandmaier BM, et al. Five-year follow-up of patients with advanced chronic lymphocytic leukemia treated with allogeneic hematopoietic cell transplantation after nonmyeloablative conditioning [J]. J Clin Oncol, 2008, 26(30): 4912-4920.
[52] Brown JR, Kim HT, Armand P, et al. Long-term follow-up of reduced-intensity allogeneic stem cell transplantation for chronic lymphocytic leukemia: prognostic model to predict outcome [J]. Leukemia, 2013, 27(2): 362-369.
[53] Michallet M, Socie G, Mohty M, et al. Rituximab, fludarabine, and total body irradiation as conditioning regimen before allogeneic hematopoietic stem cell transplantation for advanced chronic lymphocytic leukemia: long-term prospective multicenter study [J]. Exp Hematol, 2013, 41(2): 127-133.
[54] van Gelder M, de Wreede LC, Bornhauser M, et al. Long-term survival of patients with CLL after allogeneic transplantation: a report from the european society for blood and marrow transplantation [J]. Bone Marrow Transplant, 2017, 52(3): 372-380.
[55] Schetelig J, de Wreede LC, van Gelder M, et al. Risk factors for treatment failure after allogeneic transplantation of patients with CLL: a report from the european society for blood and marrow transplantation [J]. Bone Marrow Transplant, 2017, 52(4): 552-560.
[56] Dreger P, Dohner H, Ritgen M, et al. Allogeneic stem cell transplantation provides durable disease control in poor-risk chronic lymphocytic leukemia: long-term clinical and MRD results of the german CLL study group CLL3X trial [J]. Blood, 2010, 116(14): 2438-2447.
[57] Porter DL, Hwang WT, Frey NV, et al. Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia [J]. Sci Transl Med, 2015, 7(303): 303.
[58] Turtle CJ, Hay KA, Hanafi LA, et al. Durable molecular remissions in chronic lymphocytic leukemia treated with CD19-specific chimeric antigen receptor-modified T Cells after failure of ibrutinib [J]. J Clin Oncol, 2017, 35(26): 3010-3020.
[1] 巩性军,吴树明,张供,李守先,庞昕焱. 无顶冠状静脉窦综合征的诊断和外科治疗[J]. 山东大学学报(医学版), 2209, 47(6): 129-.
[2] 孙红林,管玉强,于培儒,李磊,杜庆霞,丁浩. 支架植入治疗儿童主动脉缩窄并高血压的可行性及近中期疗效[J]. 山东大学学报 (医学版), 2026, 64(4): 58-62.
[3] 林明霞,刘桂斌,马燕花,连曌昱,任洋洋. ATP酶铜转运蛋白α介导的铜死亡途径及在肿瘤治疗中的价值[J]. 山东大学学报 (医学版), 2026, 64(4): 117-124.
[4] 樊呈敏,宋静雨,于书彦,毛雪琴. 舒肝解郁胶囊治疗青少年抑郁障碍的研究进展[J]. 山东大学学报 (医学版), 2026, 64(3): 17-23.
[5] 李雪凯,孙淋涵,刘端瑞,倪阳. 乳酸化修饰在肿瘤炎癌进程中的功能与机制研究进展[J]. 山东大学学报 (医学版), 2025, 63(9): 65-76.
[6] 国科,陈绪军,郑宝石,施超,黄克力,曹勇,陈军,吴东凯,张晓慎,罗俊辉,申林,莫绪明,杨岷,王晓武,雷印胜,田茂州,王振东,孟自力,孙忠东,李有金,陆辉辉,孟春营,高峰,陈黔苏,郭能瑞,柳德斌,张楠,林宇,陈文生,宋保国,方智,王海晨,廖晓波,徐朝军. 快通道拔管在全动脉冠脉旁路移植术的多中心临床效果[J]. 山东大学学报 (医学版), 2025, 63(5): 26-32.
[7] 赵芸慕兰,高海燕. 中、高危分化型甲状腺癌患者术后 131I治疗反应及预后的影响因素[J]. 山东大学学报 (医学版), 2025, 63(2): 21-28.
[8] 韩馨玮,牛月,魏代敏. 激素替代方案准备内膜的冻胚移植前雌激素治疗时间对新生儿体质量的影响[J]. 山东大学学报 (医学版), 2025, 63(11): 46-52.
[9] 黄艳,周应芳,彭超. 青少年子宫内膜异位症的管理要点和策略[J]. 山东大学学报 (医学版), 2025, 63(10): 8-12.
[10] 薛铭,梁静,凌斌. 各种类型子宫内膜异位症疼痛特点及治疗研究进展[J]. 山东大学学报 (医学版), 2025, 63(10): 13-19.
[11] 山东省医学会乳腺疾病多学科联合委员会. 乳腺癌多学科协作诊疗山东共识(2024年版)[J]. 山东大学学报 (医学版), 2025, 63(1): 10-16.
[12] 宋雅雯,郭联涛,孔德光,孙圣荣. VTCN1导致HR+乳腺癌预后不良及内分泌治疗耐药[J]. 山东大学学报 (医学版), 2025, 63(1): 43-59.
[13] 刘晶晶,庞婧,赵晓丹,林昕,付敏,陈静静. 基于乳腺X线摄影及DCE-MRI机器学习模型预测乳腺癌新辅助治疗后病理完全缓解:双中心研究[J]. 山东大学学报 (医学版), 2025, 63(1): 60-72.
[14] 陈忠,王盛. 主动脉疾病治疗现状及思考[J]. 山东大学学报 (医学版), 2024, 62(9): 1-6.
[15] 范立彬,张鸿坤. 腹主动脉瘤腔内修复术后Ⅱ型内漏的预防及治疗进展[J]. 山东大学学报 (医学版), 2024, 62(9): 55-60.
Viewed
Full text


Abstract

Cited

  Shared   
  Discussed   
No Suggested Reading articles found!