Blood Res.  2020 Jul;55(S1):S72-S82. 10.5045/br.2020.S012.

Recent advances in chronic lymphocytic leukemia therapy

• Uhm J

• KMID: 2504746
• DOI: http://doi.org/10.5045/br.2020.S012

Abstract

Chronic lymphocytic leukemia is a genetically heterogeneous disease, and a complex set of genetic alterations is associated with its pathogenesis. CLL is the most common leukemia in the western countries, whereas it is rare in Asia, including Korea. The prognostic models integrate the traditional staging systems developed by Rai et al. and Binet et al. with biochemical and genetic markers. With the advent of molecular biology, a variety of targeted agents, including anti-CD20 antibodies, inhibitors of BCR signaling pathway, and BCL-2 inhibitors, have been introduced, which has changed the landscape of CLL treatment greatly. This review will focus on the risk stratification and the management of CLL in the era of novel small molecules.

Keyword

Chronic lymphocytic leukemia; Prognostic models; Immunochemotherapy TP53

Reference

1. Landgren O, Albitar M, Ma W, et al. 2009; B-cell clones as early markers for chronic lymphocytic leukemia. N Engl J Med. 360:659–67. DOI: 10.1056/NEJMoa0806122. PMID: 19213679. PMCID: PMC7015348.

2. Rozman C, Montserrat E. 1995; Chronic lymphocytic leukemia. N Engl J Med. 333:1052–7. DOI: 10.1056/NEJM199510193331606. PMID: 7675049.

3. Swerdlow SH, Campo E, Pileri SA, et al. 2016; The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 127:2375–90. DOI: 10.1182/blood-2016-01-643569. PMID: 26980727. PMCID: PMC4874220.

4. Siegel RL, Miller KD, Jemal A. 2015; Cancer statistics, 2015. CA Cancer J Clin. 65:5–29. DOI: 10.3322/caac.21254. PMID: 25559415.

5. Lee H, Park HJ, Park EH, et al. 2018; Nationwide statistical analysis of lymphoid malignancies in Korea. Cancer Res Treat. 50:222–38. DOI: 10.4143/crt.2017.093. PMID: 28361523. PMCID: PMC5784621.

6. Rai KR, Sawitsky A, Cronkite EP, Chanana AD, Levy RN, Pasternack BS. 1975; Clinical staging of chronic lymphocytic leukemia. Blood. 46:219–34. DOI: 10.1182/blood.V46.2.219.219. PMID: 1139039.

7. Binet JL, Auquier A, Dighiero G, et al. 1981; A new prognostic classification of chronic lymphocytic leukemia derived from a multivariate survival analysis. Cancer. 48:198–206. DOI: 10.1002/1097-0142(19810701)48:1<198::AID-CNCR2820480131>3.0.CO;2-V. PMID: 7237385.

8. Rozman C, Bosch F, Montserrat E. 1997; Chronic lymphocytic leukemia: a changing natural history? Leukemia. 11:775–8. DOI: 10.1038/sj.leu.2400679. PMID: 9177426.

9. Chiorazzi N, Rai KR, Ferrarini M. 2005; Chronic lymphocytic leukemia. N Engl J Med. 352:804–15. DOI: 10.1056/NEJMra041720. PMID: 15728813.

10. Hallek M, Cheson BD, Catovsky D, et al. 2018; iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL. Blood. 131:2745–60. DOI: 10.1182/blood-2017-09-806398. PMID: 29540348.

11. Shanafelt TD. 2009; Predicting clinical outcome in CLL: how and why. Hematology Am Soc Hematol Educ Program. 421–9. DOI: 10.1182/asheducation-2009.1.421. PMID: 20008228.

12. Eichhorst B, Hallek M. 2016; Prognostication of chronic lymphocytic leukemia in the era of new agents. Hematology Am Soc Hematol Educ Program. 2016:149–55. DOI: 10.1182/asheducation-2016.1.149. PMID: 27913474. PMCID: PMC6142472.

13. International CLL-IPI Working Group. 2016; An international prognostic index for patients with chronic lymphocytic leukaemia (CLL-IPI): a meta-analysis of individual patient data. Lancet Oncol. 17:779–90. DOI: 10.1016/S1470-2045(16)30029-8. PMID: 27185642.

14. Hallek M, Shanafelt TD, Eichhorst B. 2018; Chronic lymphocytic leukaemia. Lancet. 391:1524–37. DOI: 10.1016/S0140-6736(18)30422-7. PMID: 29477250.

15. Hanahan D, Weinberg RA. 2000; The hallmarks of cancer. Cell. 100:57–70. DOI: 10.1016/S0092-8674(00)81683-9. PMID: 10647931.

16. Kikushige Y, Ishikawa F, Miyamoto T, et al. 2011; Self-renewing hematopoietic stem cell is the primary target in pathogenesis of human chronic lymphocytic leukemia. Cancer Cell. 20:246–59. DOI: 10.1016/j.ccr.2011.06.029. PMID: 21840488.

17. Rossi DJ, Jamieson CH, Weissman IL. 2008; Stems cells and the pathways to aging and cancer. Cell. 132:681–96. DOI: 10.1016/j.cell.2008.01.036. PMID: 18295583.

18. Huntly BJ, Shigematsu H, Deguchi K, et al. 2004; MOZ-TIF2, but not BCR-ABL, confers properties of leukemic stem cells to committed murine hematopoietic progenitors. Cancer Cell. 6:587–96. DOI: 10.1016/j.ccr.2004.10.015. PMID: 15607963.

19. So CW, Karsunky H, Passegué E, Cozzio A, Weissman IL, Cleary ML. 2003; MLL-GAS7 transforms multipotent hematopoietic progenitors and induces mixed lineage leukemias in mice. Cancer Cell. 3:161–71. DOI: 10.1016/S1535-6108(03)00019-9. PMID: 12620410.

20. Bosch F, Dalla-Favera R. 2019; Chronic lymphocytic leukaemia: from genetics to treatment. Nat Rev Clin Oncol. 16:684–701. DOI: 10.1038/s41571-019-0239-8. PMID: 31278397.

21. Kelsoe G. 1994; B cell diversification and differentiation in the periphery. J Exp Med. 180:5–6. DOI: 10.1084/jem.180.1.5. PMID: 8006600. PMCID: PMC2191559.

22. Deaglio S, Morra M, Mallone R, et al. 1998; Human CD38 (ADP-ribosyl cyclase) is a counter-receptor of CD31, an Ig superfamily member. J Immunol. 160:395–402.

23. Zupo S, Massara R, Dono M, et al. 2000; Apoptosis or plasma cell differentiation of CD38-positive B-chronic lymphocytic leukemia cells induced by cross-linking of surface IgM or IgD. Blood. 95:1199–206. DOI: 10.1182/blood.V95.4.1199.004k21_1199_1206. PMID: 10666191.

24. Klein U, Tu Y, Stolovitzky GA, et al. 2001; Gene expression profiling of B cell chronic lymphocytic leukemia reveals a homogeneous phenotype related to memory B cells. J Exp Med. 194:1625–38. DOI: 10.1084/jem.194.11.1625. PMID: 11733577. PMCID: PMC2193527.

25. Seifert M, Sellmann L, Bloehdorn J, et al. 2012; Cellular origin and pathophysiology of chronic lymphocytic leukemia. J Exp Med. 209:2183–98. DOI: 10.1084/jem.20120833. PMID: 23091163. PMCID: PMC3501361.

26. Damle RN, Wasil T, Fais F, et al. 1999; Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia. Blood. 94:1840–7. DOI: 10.1182/blood.V94.6.1840. PMID: 10477712.

27. Hamblin TJ, Davis Z, Gardiner A, Oscier DG, Stevenson FK. 1999; Unmutated Ig V(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood. 94:1848–54. DOI: 10.1182/blood.V94.6.1848. PMID: 10477713.

28. Crombie J, Davids MS. 2017; IGHV mutational status testing in chronic lymphocytic leukemia. Am J Hematol. 92:1393–7. DOI: 10.1002/ajh.24808. PMID: 28589701. PMCID: PMC5675754.

29. Ghia P, Stamatopoulos K, Belessi C, et al. 2007; ERIC recommendations on IGHV gene mutational status analysis in chronic lymphocytic leukemia. Leukemia. 21:1–3. DOI: 10.1038/sj.leu.2404457. PMID: 17167526.

30. Rosenquist R, Ghia P, Hadzidimitriou A, et al. 2017; Immunoglobulin gene sequence analysis in chronic lymphocytic leukemia: updated ERIC recommendations. Leukemia. 31:1477–81. DOI: 10.1038/leu.2017.125. PMID: 28439111. PMCID: PMC5508071.

31. Crespo M, Bosch F, Villamor N, et al. 2003; ZAP-70 expression as a surrogate for immunoglobulin-variable-region mutations in chronic lymphocytic leukemia. N Engl J Med. 348:1764–75. DOI: 10.1056/NEJMoa023143. PMID: 12724482.

32. Rassenti LZ, Huynh L, Toy TL, et al. 2004; ZAP-70 compared with immunoglobulin heavy-chain gene mutation status as a predictor of disease progression in chronic lymphocytic leukemia. N Engl J Med. 351:893–901. DOI: 10.1056/NEJMoa040857. PMID: 15329427.

33. Chan AC, Iwashima M, Turck CW, Weiss A. 1992; ZAP-70: a 70 kd protein-tyrosine kinase that associates with the TCR zeta chain. Cell. 71:649–62. DOI: 10.1016/0092-8674(92)90598-7.

34. Kong GH, Bu JY, Kurosaki T, Shaw AS, Chan AC. 1995; Reconstitution of Syk function by the ZAP-70 protein tyrosine kinase. Immunity. 2:485–92. DOI: 10.1016/1074-7613(95)90029-2.

35. Wierda WG, O'Brien S, Wang X, et al. 2011; Multivariable model for time to first treatment in patients with chronic lymphocytic leukemia. J Clin Oncol. 29:4088–95. DOI: 10.1200/JCO.2010.33.9002. PMID: 21969505. PMCID: PMC4876352.

36. Rossi D, Rasi S, Spina V, et al. 2013; Integrated mutational and cytogenetic analysis identifies new prognostic subgroups in chronic lymphocytic leukemia. Blood. 121:1403–12. DOI: 10.1182/blood-2012-09-458265. PMID: 23243274. PMCID: PMC3578955.

37. Bergmann MA, Busch R, Eichhorst B, et al. 2013; Overall survival in early stage chronic lymphocytic leukemia patients with treatment indication due to disease progression: follow-up data of the CLL1 trial of the German CLL Study Group (GCLLSG). Blood. 122:4127. DOI: 10.1182/blood.V122.21.4127.4127.

38. Hallek M, Fischer K, Fingerle-Rowson G, et al. 2010; Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet. 376:1164–74. DOI: 10.1016/S0140-6736(10)61381-5. PMID: 20888994.

39. Fischer K, Bahlo J, Fink AM, et al. 2016; Long-term remissions after FCR chemoimmunotherapy in previously untreated patients with CLL: updated results of the CLL8 trial. Blood. 127:208–15. DOI: 10.1182/blood-2015-06-651125. PMID: 26486789.

40. Tam CS, O'Brien S, Wierda W, et al. 2008; Long-term results of the fludarabine, cyclophosphamide, and rituximab regimen as initial therapy of chronic lymphocytic leukemia. Blood. 112:975–80. DOI: 10.1182/blood-2008-02-140582. PMID: 18411418. PMCID: PMC3952498.

41. Fischer K, Cramer P, Busch R, et al. 2012; Bendamustine in combination with rituximab for previously untreated patients with chronic lymphocytic leukemia: a multicenter phase II trial of the German Chronic Lymphocytic Leukemia Study Group. J Clin Oncol. 30:3209–16. DOI: 10.1200/JCO.2011.39.2688. PMID: 22869884.

42. Eichhorst B, Fink AM, Bahlo J, et al. 2016; 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. Lancet Oncol. 17:928–42. DOI: 10.1016/S1470-2045(16)30051-1. PMID: 27216274.

43. Hillmen P, Robak T, Janssens A, et al. 2015; Chlorambucil plus ofatumumab versus chlorambucil alone in previously untreated patients with chronic lymphocytic leukaemia (COMPLEMENT 1): a randomised, multicentre, open-label phase 3 trial. Lancet. 385:1873–83. DOI: 10.1016/S0140-6736(15)60027-7. PMID: 25882396.

44. Goede V, Fischer K, Busch R, et al. 2014; Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med. 370:1101–10. DOI: 10.1056/NEJMoa1313984. PMID: 24401022.

45. Stilgenbauer S. 2015; Prognostic markers and standard management of chronic lymphocytic leukemia. Hematology Am Soc Hematol Educ Program. 2015:368–77. DOI: 10.1182/asheducation-2015.1.368. PMID: 26637745.

46. Stilgenbauer S, Schnaiter A, Paschka P, et al. 2014; Gene mutations and treatment outcome in chronic lymphocytic leukemia: results from the CLL8 trial. Blood. 123:3247–54. DOI: 10.1182/blood-2014-01-546150. PMID: 24652989.

47. Mohamed AJ, Yu L, Bäckesjö CM, et al. 2009; Bruton's tyrosine kinase (Btk): function, regulation, and transformation with special emphasis on the PH domain. Immunol Rev. 228:58–73. DOI: 10.1111/j.1600-065X.2008.00741.x. PMID: 19290921.

48. Pal Singh S, Dammeijer F, Hendriks RW. 2018; Role of Bruton's tyrosine kinase in B cells and malignancies. Mol Cancer. 17:57. DOI: 10.1186/s12943-018-0779-z. PMID: 29455639. PMCID: PMC5817726.

49. Byrd JC, Furman RR, Coutre SE, et al. 2013; Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 369:32–42. DOI: 10.1056/NEJMoa1215637. PMID: 23782158. PMCID: PMC3772525.

50. Herman SE, Gordon AL, Hertlein E, et al. 2011; Bruton tyrosine kinase represents a promising therapeutic target for treatment of chronic lymphocytic leukemia and is effectively targeted by PCI-32765. Blood. 117:6287–96. DOI: 10.1182/blood-2011-01-328484. PMID: 21422473. PMCID: PMC3122947.

51. Honigberg LA, Smith AM, Sirisawad M, et al. 2010; The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy. Proc Natl Acad Sci U S A. 107:13075–80. DOI: 10.1073/pnas.1004594107. PMID: 20615965. PMCID: PMC2919935.

52. Ponader S, Chen SS, Buggy JJ, et al. 2012; The Bruton tyrosine kinase inhibitor PCI-32765 thwarts chronic lymphocytic leukemia cell survival and tissue homing in vitro and in vivo. Blood. 119:1182–9. DOI: 10.1182/blood-2011-10-386417. PMID: 22180443. PMCID: PMC4916557.

53. Byrd JC, Brown JR, O'Brien S, et al. 2014; Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med. 371:213–23. DOI: 10.1056/NEJMoa1400376. PMID: 24881631. PMCID: PMC4134521.

54. Burger JA, Tedeschi A, Barr PM, et al. 2015; Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med. 373:2425–37. DOI: 10.1056/NEJMoa1509388. PMID: 26639149. PMCID: PMC4722809.

55. Byrd JC, Furman RR, Coutre SE, et al. 2015; Three-year follow-up of treatment-naive and previously treated patients with CLL and SLL receiving single-agent ibrutinib. Blood. 125:2497–506. DOI: 10.1182/blood-2014-10-606038. PMID: 25700432. PMCID: PMC4400288.

56. Barr PM, Robak T, Owen C, et al. 2018; Sustained efficacy and detailed clinical follow-up of first-line ibrutinib treatment in older patients with chronic lymphocytic leukemia: extended phase 3 results from RESONATE-2. Haematologica. 103:1502–10. DOI: 10.3324/haematol.2018.192328. PMID: 29880603. PMCID: PMC6119145.

57. Byrd JC, Harrington B, O'Brien S, et al. 2016; Acalabrutinib (ACP-196) in relapsed chronic lymphocytic leukemia. N Engl J Med. 374:323–32. DOI: 10.1056/NEJMoa1509981. PMID: 26641137. PMCID: PMC4862586.

58. Awan FT, Schuh A, Brown JR, et al. 2019; Acalabrutinib monotherapy in patients with chronic lymphocytic leukemia who are intolerant to ibrutinib. Blood Adv. 3:1553–62. DOI: 10.1182/bloodadvances.2018030007. PMID: 31088809. PMCID: PMC6517672.

59. Hoellenriegel J, Meadows SA, Sivina M, et al. 2011; The phosphoinositide 3'-kinase delta inhibitor, CAL-101, inhibits B-cell receptor signaling and chemokine networks in chronic lymphocytic leukemia. Blood. 118:3603–12. DOI: 10.1182/blood-2011-05-352492. PMID: 21803855. PMCID: PMC4916562.

60. Lannutti BJ, Meadows SA, Herman SE, et al. 2011; CAL-101, a p110delta selective phosphatidylinositol-3-kinase inhibitor for the treatment of B-cell malignancies, inhibits PI3K signaling and cellular viability. Blood. 117:591–4. DOI: 10.1182/blood-2010-03-275305. PMID: 20959606. PMCID: PMC3694505.

61. Sharman JP, Coutre SE, Furman RR, et al. 2019; Final results of a randomized, phase III study of rituximab with or without idelalisib followed by open-label idelalisib in patients with relapsed chronic lymphocytic leukemia. J Clin Oncol. 37:1391–402. DOI: 10.1200/JCO.18.01460. PMID: 30995176.

62. Raedler LA. 2015; Zydelig (Idelalisib): first-in-class PI3 kinase inhibitor approved for the treatment of 3 hematologic malignancies. Am Health Drug Benefits. 8:157–62.

63. Furman RR, Sharman JP, Coutre SE, et al. 2014; Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med. 370:997–1007. DOI: 10.1056/NEJMoa1315226. PMID: 24450857. PMCID: PMC4161365.

64. Jones JA, Robak T, Brown JR, et al. 2017; Efficacy and safety of idelalisib in combination with ofatumumab for previously treated chronic lymphocytic leukaemia: an open-label, randomised phase 3 trial. Lancet Haematol. 4:e114–e26. DOI: 10.1016/S2352-3026(17)30019-4. PMID: 28257752.

65. Ahn IE, Underbayev C, Albitar A, et al. 2017; Clonal evolution leading to ibrutinib resistance in chronic lymphocytic leukemia. Blood. 129:1469–79. DOI: 10.1182/blood-2016-06-719294. PMID: 28049639. PMCID: PMC5356450.

66. Maddocks KJ, Ruppert AS, Lozanski G, et al. 2015; Etiology of ibrutinib therapy discontinuation and outcomes in patients with chronic lymphocytic leukemia. JAMA Oncol. 1:80–7. DOI: 10.1001/jamaoncol.2014.218. PMID: 26182309. PMCID: PMC4520535.

67. Woyach JA, Furman RR, Liu TM, et al. 2014; Resistance mechanisms for the Bruton's tyrosine kinase inhibitor ibrutinib. N Engl J Med. 370:2286–94. DOI: 10.1056/NEJMoa1400029. PMID: 24869598. PMCID: PMC4144824.

68. Hanada M, Delia D, Aiello A, Stadtmauer E, Reed JC. 1993; bcl-2 gene hypomethylation and high-level expression in B-cell chronic lymphocytic leukemia. Blood. 82:1820–8. DOI: 10.1182/blood.V82.6.1820.1820. PMID: 8104532.

69. Robertson LE, Plunkett W, McConnell K, Keating MJ, McDonnell TJ. 1996; Bcl-2 expression in chronic lymphocytic leukemia and its correlation with the induction of apoptosis and clinical outcome. Leukemia. 10:456–9.

70. Souers AJ, Leverson JD, Boghaert ER, et al. 2013; ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat Med. 19:202–8. DOI: 10.1038/nm.3048. PMID: 23291630.

71. Roberts AW, Davids MS, Pagel JM, et al. 2016; Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia. N Engl J Med. 374:311–22. DOI: 10.1056/NEJMoa1513257. PMID: 26639348. PMCID: PMC7107002.

72. Coutre S, Choi M, Furman RR, et al. 2018; Venetoclax for patients with chronic lymphocytic leukemia who progressed during or after idelalisib therapy. Blood. 131:1704–11. DOI: 10.1182/blood-2017-06-788133. PMID: 29305552. PMCID: PMC5922273.

73. Jones JA, Mato AR, Wierda WG, et al. 2018; Venetoclax for chronic lymphocytic leukaemia progressing after ibrutinib: an interim analysis of a multicentre, open-label, phase 2 trial. Lancet Oncol. 19:65–75. DOI: 10.1016/S1470-2045(17)30909-9.

74. Woyach JA, Ruppert AS, Heerema NA, et al. 2018; Ibrutinib regimens versus chemoimmunotherapy in older patients with untreated CLL. N Engl J Med. 379:2517–28. DOI: 10.1056/NEJMoa1812836. PMID: 30501481. PMCID: PMC6325637.

75. Shanafelt TD, Wang XV, Kay NE, et al. 2019; Ibrutinib-rituximab or chemoimmunotherapy for chronic lymphocytic leukemia. N Engl J Med. 381:432–43. DOI: 10.1056/NEJMoa1817073. PMID: 31365801. PMCID: PMC6908306.

76. Moreno C, Greil R, Demirkan F, et al. 2019; Ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab in first-line treatment of chronic lymphocytic leukaemia (iLLUMINATE): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 20:43–56. DOI: 10.1016/S1470-2045(18)30788-5. PMID: 30522969.

77. Fischer K, Al-Sawaf O, Bahlo J, et al. 2019; Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med. 380:2225–36. DOI: 10.1056/NEJMoa1815281. PMID: 31166681.

78. Seymour JF, Kipps TJ, Eichhorst B, et al. 2018; Venetoclax-rituximab in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 378:1107–20. DOI: 10.1056/NEJMoa1713976. PMID: 29562156.

79. Haferlach C, Dicker F, Weiss T, et al. 2010; Toward a comprehensive prognostic scoring system in chronic lymphocytic leukemia based on a combination of genetic parameters. Genes Chromosomes Cancer. 49:851–9. DOI: 10.1002/gcc.20794. PMID: 20552631.

80. Pflug N, Bahlo J, Shanafelt TD, et al. 2014; Development of a comprehensive prognostic index for patients with chronic lymphocytic leukemia. Blood. 124:49–62. DOI: 10.1182/blood-2014-02-556399. PMID: 24797299. PMCID: PMC4260976.

81. Malcikova J, Tausch E, Rossi D, et al. 2018; ERIC recommendations for TP53 mutation analysis in chronic lymphocytic leukemia-update on methodological approaches and results interpretation. Leukemia. 32:1070–80. DOI: 10.1038/s41375-017-0007-7. PMID: 29467486. PMCID: PMC5940638.

82. O'Brien S, Jones JA, Coutre SE, et al. 2016; Ibrutinib for patients with relapsed or refractory chronic lymphocytic leukaemia with 17p deletion (RESONATE-17): a phase 2, open-label, multicentre study. Lancet Oncol. 17:1409–18. DOI: 10.1016/S1470-2045(16)30212-1. PMID: 27637985.

83. Stilgenbauer S, Eichhorst B, Schetelig J, et al. 2016; Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion: a multicentre, open-label, phase 2 study. Lancet Oncol. 17:768–78. DOI: 10.1016/S1470-2045(16)30019-5. PMID: 27178240.

84. Stilgenbauer S, Eichhorst B, Schetelig J, et al. 2018; Venetoclax for patients with chronic lymphocytic leukemia with 17p deletion: results from the full population of a phase II pivotal trial. J Clin Oncol. 36:1973–80. DOI: 10.1200/JCO.2017.76.6840. PMID: 29715056.