Molecular genetic aberrations in Richter transformation of chronic lymphocytic leukaemia

Czech version

Authors: A. Petráčková ¹; T. Papajík ²; E. Kriegová ¹
Authors‘ workplace: Ústav imunologie, Lékařská fakulta, Univerzita Palackého a Fakultní nemocnice Olomouc ¹; Hemato-onkologická klinika, Lékařská fakulta, Univerzita Palackého a Fakultní nemocnice Olomouc ²
Published in: Transfuze Hematol. dnes,26, 2020, No. 1, p. 36-54.
Category: Review/Educational Papers

Overview

Richter transformation (Richter syndrome – RT) is defined as the transformation of chronic lymphocytic leukaemia (CLL) into high-grade lymphoma. Development of diffuse large B-cell lymphoma (DLBCL) clonally related to CLL is most common, less frequent is transformation to Hodgkin´s lymphoma. RT occurs in approximately 2–10% of CLL patients during the disease course. It develops in patients treated with immunochemotherapy as well as in those treated with novel agents (ibrutinib, idelalisib, venetoclax). In this review, we discuss recent discoveries in the understanding of molecular genetic changes associated with RT. The most common molecular events in RT are concurrent disruptions of TP53 and CDKN2A genes that occur in approximately one half of RT patients. The occurrence of TP53 and CDKN2A aberrations is often associated with aberrant activation of the MYC gene, which is usually caused by structural changes (gain 8q, t(8; 14)) or indirectly by mutations in the MGA gene. In 30% RT patients, activating NOTCH1 mutations are detected, which are often present already prior to transformation. Approximately 20% RT patients carry heterogeneous molecular genetic aberrations. RT in ibrutinib-treated patients is also associated with TP53 and CDKN2A disruptions, activation of MYC as well as NOTCH1 mutations. Additionally, in 40% patients who develop RT on ibrutinib, mutations in BTK and PLCG2 genes were identified, known to be associated with treatment resistance. To date, the genetic landscape associated with RT on idelalisib and venetoclax was not studied. Despite improved understanding of molecular genetic changes linked to RT, genetic aberrations driving RT development have not been reported as yet. Further studies on large patient cohorts together with the development of more sensitive molecular technologies may help elucidate the underlying genetic risk factors in these difficult-to-treat patients.

Keywords:

mutations – chronic lymphocytic leukaemia – signalling pathway inhibitors – Richter syndrome – molecular genetic aberrations

Sources

1. Bockorny B, Codreanu I, Dasanu CA. Hodgkin lymphoma as Richter transformation in chronic lymphocytic leukaemia: a retrospective analysis of world literature. Br J Haematol. 2012;156:50–66.

2. Ding W. Richter transformation in the era of novel agents. Hematology Am Soc Hematol Educ Program. 2018;2018(1):256–263.

3. Doubek M, Špaček M, Pospíšilová Š, et al. Doporučení pro diagnostiku a léčbu chronické lymfocytární leukemie (CLL) – 2018. Transfuze Hematol. Dnes. 2018;24:203–216.

4. Rossi D, Spina V, Deambrogi C, et al. The genetics of Richter syndrome reveals disease heterogeneity and predicts survival after transformation. Blood. 2011;117:3391–3401.

5. Rossi D, Gaidano G. Richter syndrome: pathogenesis and management. Semin Oncol. 2016;43:311–319.

6. Chigrinova E, Rinaldi A, Kwee I, et al. Two main genetic pathways lead to the transformation of chronic lymphocytic leukemia to Richter syndrome. Blood. 2013;122:2673–2682.

7. Eyre TA, Schuh A. An update for Richter syndrome - new directions and developments. Br J Haematol. 2017;178:508–520.

8. Rossi D, Spina V, Gaidano G. Biology and treatment of Richter syndrome. Blood. 2018;131:2761–2772.

9. Fabbri G, Khiabanian H, Holmes AB, et al. Genetic lesions associated with chronic lymphocytic leukemia transformation to Richter syndrome. J Exp Med. 2013;210:2273–2288.

10. Parikh SA, Shanafelt TD. Risk factors for Richter syndrome in chronic lymphocytic leukemia. Curr Hematol Malig Rep. 2014;9:294–299.

11. Allan JN, Furman RR. Current trends in the management of Richter‘s syndrome. Int J Hematol Oncol. 2019;7(4). DOI 10.2217/ijh-2018-0010. Elektronicky publikováno 8. ledna 2019.

12. Khan M, Siddiqi R, Thompson PA. Approach to Richter transformation of chronic lymphocytic leukemia in the era of novel therapies. Ann Hematol. 2018;97:1–15.

13. Ahn IE, Underbayev C, Albitar A, et al. Clonal evolution leading to ibrutinib resistance in chronic lymphocytic leukemia. Blood. 2017;129:1469–1479.

14. Balatti V, Tomasello L, Rassenti LZ, et al. MiR-125a and MiR-34a expression predicts Richter syndrome in chronic lymphocytic leukemia patients. Blood. 2018;132:2179–2182.

15. Van Roosbroeck K, Bayraktar R, Calin S, et al. The involvement of microRNA in the pathogenesis of Richter syndrome. Haematologica. 2019;104:1004–1015.

16. Rossi D, Lobetti Bodoni C, Genuardi E, et al. Telomere length is an independent predictor of survival, treatment requirement and Richter’s syndrome transformation in chronic lymphocytic leukemia. Leukemia. 2009;23:1062–1072.

17. Wang Y, Tschautscher MA, Rabe KG, et al. Clinical characteristics and outcomes of Richter transformation: Experience of 204 patients from a single center. Haematologica; publikováno elektronicky 13. června 2019. DOI 10.3324/haematol.2019.224121.

18. Strati P, Abruzzo LV, Wierda WG, et al. Second cancers and Richter transformation are the leading causes of death in patients with trisomy 12 chronic lymphocytic leukemia. Clin Lymphoma Myeloma Leuk. 2015;15:420–427.

19. Rossi D, Spina V, Cerri M, et al. Stereotyped B-cell receptor is an independent risk factor of chronic lymphocytic leukemia transformation to Richter syndrome. Clin Cancer Res. 2009;15:4415–4422.

20. Rasi S, Spina V, Bruscaggin A, et al. Avariant of the LRP4 gene affects the risk of chronic lymphocytic leukaemia transformation to Richter syndrome. Br J Haematol. 2011;152:284–294.

21. Catherwood MA, Gonzalez D, Donaldson D, et al. Relevance of TP53 for CLL diagnostics. J Clin Pathol. 2019;72:343–346.

22. Serrano M, Hannon GJ, Beach D. A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4. Nature. 1993;366:704–707.

23. Pomerantz J, Schreiber-Agus N, Liegeois NJ, et al. The Ink4a tumor suppressor gene product, p19Arf, interacts with MDM2 and neutralizes MDM2‘s inhibition of p53. Cell. 1998;92:713–723.

24. Knoepfler PS. Myc goes global: New tricks for an old oncogene. Cancer Res. 2007;67:5061–5063.

25. Dang CV, O’Donnell KA, Zeller KI, et al. The c-Myc target gene network. Semin Cancer Biol. 2006;16:253–264.

26. Edelmann J, Holzmann K, Miller F, et al. High-resolution genomic profiling of chronic lymphocytic leukemia reveals new recurrent genomic alterations. Blood. 2012;120:4783–4794.

27. De Paoli L, Cerri M, Monti S, et al. MGA, a suppressor of MYC, is recurrently inactivated in high risk chronic lymphocytic leukemia. Leuk Lymphoma. 2013;54:1987–1990.

28. Balatti V, Bottoni A, Palamarchuk A, et al. NOTCH1 mutations in CLL associated with trisomy 12. Blood. 2012;119:329–331.

29. Del Giudice I, Rossi D, Chiaretti S, et al. NOTCH1 mutations in +12 chronic lymphocytic leukemia (CLL) confer an unfavorable prognosis, induce a distinctive transcriptional profiling and refine the intermediate prognosis of +12 CLL. Haematologica. 2012;97:437–441.

30. Rossi D, Rasi S, Spina V, et al. Different impact of NOTCH1 and SF3B1 mutations on the risk of chronic lymphocytic leukemia transformation to Richter syndrome. Br J Haematol. 2012;158:426–429.

31. Kopan R, Ilagan MX. The canonical Notch signaling pathway: unfolding the activation mechanism. Cell. 2009;137:216–233.

32. Guruharsha KG, Kankel MW, Artavanis-Tsakonas S. The Notch signalling system: recent insights into the complexity of a conserved pathway. Nat Rev Genet. 2012;13:654–666.

33. Fabbri G, Holmes AB, Viganotti M, et al. Common nonmutational NOTCH1 activation in chronic lymphocytic leukemia. Proc Natl Acad Sci USA. 2017;114(14):E2911–E2919.

34. Rosati E, Baldoni S, De Falco F, et al. NOTCH1 Aberrations in chronic lymphocytic leukemia. Front Oncol. 2018;8:229.

35. Di Ianni M, Baldoni S, Rosati E, et al. A new genetic lesion in B-CLL: a NOTCH1 PEST domain mutation. Br J Haematol. 2009;146:689–691.; Woyach JA, Ruppert AS, Guinn D, et al. BTK(C481S)-mediated resistance to ibrutinib in chronic lymphocytic leukemia. J Clin Oncol. 2017;35:1437–1443.

36. Maddocks KJ, Ruppert AS, Lozanski G, et al. Etiology of ibrutinib therapy discontinuation and outcomes in patients with chronic lymphocytic leukemia. JAMA Oncol. 2015;1(1):80–87.

37. 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. Blood. 2018;131:2357–2366.

38. Jain P, Keating M, Wierda W, et al. Outcomes of patients with chronic lymphocytic leukemia after discontinuing ibrutinib. Blood. 2015;125:2062–2067.

39. Jain P, Thompson PA, Keating M, et al. Long-term outcomes for patients with chronic lymphocytic leukemia who discontinue ibrutinib. Cancer. 2017;123:2268–2273.

40. Kadri S, Lee J, Fitzpatrick C, et al. Clonal evolution underlying leukemia progression and Richter transformation in patients with ibrutinib-relapsed CLL. Blood Adv. 2017;1:715–727.

41. Ding W, LaPlant BR, Call TG, et al. Pembrolizumab in patients with CLL and Richter transformation or with relapsed CLL. Blood. 2017;129:3419–3427.

42. Miller CR, Ruppert AS, Heerema NA, et al. Near-tetraploidy is associated with Richter transformation in chronic lymphocytic leukemia patients receiving ibrutinib. Blood Adv. 2017;1:1584–1588.

43. Davids MS, Roberts AW, Seymour JF, et al. Phase I first-in-human study of venetoklax in patients with relapsed or refractory non-Hodgkin lymphoma. J Clin Oncol 2017;35:826–833.

44. Burger JA, Landau DA, Taylor-Weiner A, et al. Clonal evolution in patients with chronic lymphocytic leukaemia developing resistance to BTK inhibition. Nat Commun. 2016;7:11589.

45. Lampson BL, Brown JR. Are BTK and PLCG2 mutations necessary and sufficient for ibrutinib resistance in chronic lymphocytic leukemia? Expert Rev Hematol. 2018;11:185–194.

46. Rossi D, Rasi S, Fabbri G, et al. Mutations of NOTCH1 are an independent predictor of survival in chronic lymphocytic leukemia. Blood. 2012;119:521–529.

47. Analysis of the chronic lymphocytic leukemia coding genome: role of NOTCH1 mutational activation. J Exp Med. 2011;208:1389–1401.

48. Fabbri G, Dalla-Favera R. The molecular pathogenesis of chronic lymphocytic leukaemia. Nat Rev Cancer. 2016;16:145–162.

49. Gaidano G, Foà R, Dalla-Favera R. Molecular pathogenesis of chronic lymphocytic leukemia. J Clin Invest. 2012;122:3432–3438.

50. O‘Brien S, Furman RR, Coutre SE, et al. Ibrutinib as initial therapy for elderly patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma: an open-label, multicentre, phase 1b/2 trial. Lancet Oncol. 2014;15:48–58.

51. Farooqui MZ, Valdez J, Martyr S, et al. Ibrutinib for previously untreated and relapsed or refractory chronic lymphocytic leukaemia with TP53 aberrations: a phase 2, single-arm trial. Lancet Oncol. 2015;16:169–176.

52. Woyach JA, Ruppert AS, Heerema NA, et al. Ibrutinib regimens versus chemoimmunotherapy in older patients with untreated CLL. N Engl J Med. 2018;379:2517–2528.

53. Mato AR, Nabhan C, Thompson MC, et al. Toxicities and outcomes of 616 ibrutinib-treated patients in the United States: a real-world analysis. Haematologica. 2018;103:874–879.

54. O‘Brien SM, Byrd JC, Hillmen P, et al. Outcomes with ibrutinib by line of therapy and post-ibrutinib discontinuation in patients with chronic lymphocytic leukemia: Phase 3 analysis. Am J Hematol. 2019;94:554–562.

55. Dimou M, Iliakis T, Pardalis V, et al. Safety and efficacy analysis of long-term follow up real-world data with ibrutinib monotherapy in 58 patients with CLL treated in a single-center in Greece. Leuk Lymphoma. 2019;60:2939–2945.

56. Moreno C, Greil R, Demirkan F, et al. 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. 2019;20:43–56.

57. Burger JA, Sivina M, Jain N, et al. Randomized trial of ibrutinib vs ibrutinib plus rituximab in patients with chronic lymphocytic leukemia. Blood. 2019;133:1011–1019.

58. Burger JA, Tedeschi A, Barr PM, et al. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med. 2015;373:2425–2437.

59. Byrd JC, Furman RR, Coutre SE, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013;369:32–42.

60. UK CLL Forum. Ibrutinib for relapsed/refractory chronic lymphocytic leukemia: a UK and Ireland analysis of outcomes in 315 patients. Haematologica. 2016;101:1563–1572.

61. O‘Brien S, Jones JA, Coutre SE, et al. Ibrutinib for patients with relapsed or refractory chronic lymphocytic leukaemia with 17p deletion (RESONATE-17): a phase 2, open-label, multicentre study. Lancet Oncol. 2016;17:1409–1418.

62. Byrd JC, Wierda WG, Schuh A, et al. Acalabrutinib monotherapy in patients with relapsed/refractory chronic lymphocytic leukemia: updated results from the phase 1/2 ACE-CL-001 Study. Blood. 2017;130:498.

63. Huang X, Qiu L, Jin J, et al. Ibrutinib versus rituximab in relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma: a randomized, open-label phase 3 study. Cancer Med. 2018;7:1043–1055.

64. Nuttall E, Tung J, Trounce E, et al. Real-world experience of ibrutinib therapy in relapsed chronic lymphocytic leukemia: results of a single-center retrospective analysis. J Blood Med. 2019;10:199–208.

65. Byrd JC, Hillmen P, O‘Brien S, et al. Long-term follow-up of the RESONATE phase 3 trial of ibrutinib vs ofatumumab. Blood. 2019;133:2031–2042.

66. Winqvist M, Andersson PO, Asklid A, et al. Long-term real-world results of ibrutinib therapy in patients with relapsed or refractory chronic lymphocytic leukemia: 30-month follow up of the Swedish compassionate use cohort. Haematologica. 2019;104:e208–e210.

67. Awan FT, Schuh A, Brown JR, et al. Acalabrutinib monotherapy in patients with chronic lymphocytic leukemia who are intolerant to ibrutinib. Blood Adv. 2019;3:1553–1562.

68. 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. Leukemia. 2019;33:969–980.

69. O‘Brien SM, Lamanna N, Kipps TJ, et al. A phase 2 study of idelalisib plus rituximab in treatment-naïve older patients with chronic lymphocytic leukemia. Blood. 2015;126:2686–2694.

70. Furman RR, Sharman JP, Coutre SE, et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med. 2014;370:997–1007.

71. 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. Lancet Oncol. 2017;18:297–311.

72. Flinn IW, Hillmen P, Montillo M, et al. The phase 3 DUO trial: duvelisib vs ofatumumab in relapsed and refractory CLL/SLL. Blood. 2018;132:2446–2455.

73. Cramer P, von Tresckow J, Bahlo J, et al. Bendamustine followed by obinutuzumab and venetoclax in chronic lymphocytic leukaemia (CLL2-BAG): primary endpoint analysis of a multicentre, open-label, phase 2 trial. Lancet Oncol. 2018;19:1215–1228.

74. Flinn IW, Gribben JG, Dyer MJS, et al. Phase 1b study of venetoclax-obinutuzumab in previously untreated and relapsed/refractory chronic lymphocytic leukemia. Blood. 2019;133:2765–2775.

75. Stilgenbauer S, Eichhorst B, Schetelig J, et al. Venetoclax for patients with chronic lymphocytic leukemia with 17p deletion: results from the full population of a phase II pivotal trial. J Clin Oncol. 2018;36:1973–1980.

76. Roberts AW, Davids MS, Pagel JM, et al. Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia. N Engl J Med. 2016;374:311–322.

77. Seymour JF, Ma S, Brander DM, et al. Venetoclax plus rituximab in relapsed or refractory chronic lymphocytic leukaemia: a phase 1b study. Lancet Oncol. 2017;18:230–240.

78. Seymour JF, Kipps TJ, Eichhorst B, et al. Venetoclax-rituximab in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2018;378:1107–1120.

79. 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. Lancet Oncol. 2018;19:65–75.

80. Coutre S, Choi M, Furman RR, et al. Venetoclax for patients with chronic lymphocytic leukemia who progressed during or after idelalisib therapy. Blood. 2018;131:1704–1711.

81. Rogers KA, Huang Y, Ruppert AS, et al. Phase 1b study of obinutuzumab, ibrutinib, and venetoclax in relapsed and refractory chronic lymphocytic leukemia. Blood. 2018;132:1568–1572.

82. Eyre TA, Kirkwood AA, Gohill S, et al. Efficacy of venetoclax monotherapy in patients with relapsed chronic lymphocytic leukaemia in the post-BCR inhibitor setting: a UK wide analysis. Br J Haematol. 2019;185:656–669.