Journal of Shandong University (Health Sciences) ›› 2019, Vol. 57 ›› Issue (7): 21-30.doi: 10.6040/j.issn.1671-7554.0.2019.477

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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

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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

CLC Number: 

  • 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.
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