Treatment of Chronic Lymphocytic Leukemia with TP53 Aberrations

Česká verzia

Authors: D. Lysák ¹; J. Schwarz ²
Authors place of work: Hematologicko‑onkologické oddělení, FN Plzeň ¹; Ústav hematologie a krevní transfuze, Praha ²
Published in the journal: Klin Onkol 2015; 28(Supplementum 3): 39-44
doi: https://doi.org/10.14735/amko20153S39

Summary

Patients with chronic lymphocytic leukemia with deletion of the short arm of chromosome 17 (17p‑ ) or mutation of the TP53 gene have significantly worse prognosis with a higher risk of progression to symptomatic disease, worse and shorter responses to chemo‑ immunotherapy, and more frequent occurrence of Richter‘s syndrome. TP53 deletion/ mutation is currently the only genetic abnormality that independently predicts response to treatment and also affects the choice of therapeutic approach in chronic lymphocytic leukemia. This work summarizes treatment options available for this poor prognosis variant of chronic lymphocytic leukemia. Traditional chemo‑ immunotherapy (e. g. FCR) does not offer long‑term disease control, and patients with TP53 deletion/ mutation were usually considered to undergo allogeneic bone marrow transplantation. New molecules from the group of BCR inhibitors or BCL2 antagonists achieve excellent efficacy in chronic lymphocytic leukemia with del17p even in relapsed/ refractory (R/ R) cases, with a higher percentage of responses and prolonged survival without progression. Clinical trials are ongoing to determine optimal therapeutic approach and to induce long‑term remission of the disease. The new molecules change algorithms for treatment of patients with TP53 aberration, including indication for allogeneic transplantation. Especially younger patients should be consulted in centers of intensive hematological care to consider their inclusion into clinical trials testing new molecules or to indicate allogeneic transplantation at the optimal time.

Key words:
chronic lymphocytic leukemia – risk factors – deletion 17p – TP53 – transplantation

This study was supported by the Charles University Research Fund (project number P36) and by the project of Ministry of Health, Czech Republic –conceptual development of research organization (Faculty Hospital in Pilsen – FNPl, 00669806).

The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study.

The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.

Submitted:
4. 8. 2015

Accepted:
5. 8. 2015

Zdroje

1. Döhner H, Fischer K, Bentz M et al. p53 gene deletion predicts for poor survival and non‑response to therapy with purine analogs in chronic B‑ cell leukemias. Blood 1995; 85(6): 1580– 1589.

2. Best G, Thompson P, Tam CS. Diagnostic techniques and therapeutic challenges in patients with TP53 dysfunctional chronic lymphocytic leukemia. Leuk Lymphoma 2012; 53(11): 2105– 2115. doi: 10.3109/ 10428194.2012.692088.

3. Stilgenbauer S, Zenz T. Understanding and managing ultra high‑risk chronic lymphocytic leukemia. Hematology. Am Soc Hematol Educ Program 2010; 2010: 481– 488. doi: 10.1182/ asheducation‑ 2010.1.481.

4. Zenz T, Gribben JG, Hallek M et al. Risk categories and refractory CLL in the era of chemoimmunotherapy. Blood 2012; 119(18): 4101– 4107. doi: 10.1182/ blood‑ 2011‑ 11‑ 312421.

5. Shindiapina P, Brown JR, Danilov AV. A new hope: novel therapeutic approaches to treatment of chronic lymphocytic leukaemia with defects in TP53. Br J Haematol 2014; 167(2): 149– 161. doi: 10.1111/ bjh.13042.

6. Hallek M, Fischer K, Fingerle‑ Rowson G et al. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomized, open‑ label, phase 3 trial. Lancet 2010; 376(9747): 1164– 1174. doi: 10.1016/ S0140‑ 6736(10)61381‑ 5.

7. Zent CS, Kay NE. Management of patients with chronic lymphocytic leukemia with a high risk of adverse outcome: the mayo clinic approach. Leuk Lymphoma 2011; 52(8): 1425– 1434. doi: 10.3109/ 10428194.2011.568654.

8. Zenz T, Eichhorst B, Busch R et al. TP53 mutation and survival in chronic lymphocytic leukemia. J Clin Oncol 2010; 28(29): 4473– 4479. doi: 10.1200/ JCO.2009.27.8762.

9. Zenz T, Mertens D, Kuppers R et al. From pathogenesis to treatment of chronic lymphocytic leukaemia. Nat Rev Cancer 2010; 10(1): 37– 50. doi: 10.1038/ nrc2764.

10. Zenz T, Häbe S, Denzel T et al. Detailed analysis of p53 pathway defects in fludarabine‑ refractory chronic lymphocytic leukemia (CLL): dissecting the contribution of 17p deletion, TP53 mutation, p53– p21 dysfunction, and miR34a in a prospective clinical trial. Blood 2009; 114(13): 2589– 2597. doi: 10.1182/ blood‑ 2009‑ 05‑ 224071.

11. Rossi D, Cerri M, Deambrogi C et al. The prognostic value of TP53 mutations in chronic lymphocytic leukemia is independent of Del17p13: implications for overall survival and chemorefractoriness. Clin Cancer Res 2009; 15(3): 995– 1004. doi: 10.1158/ 1078‑ 0432.CCR‑ 08‑ 1630.

12. Badoux XC, Keating MJ, Wierda WG. What is the best frontline therapy for patients with CLL and 17p deletion? Curr Hematol Malig Rep 2011; 6(1): 36– 46. doi: 10.1007/ s11899‑ 010‑ 0069‑ 3.

13. Malcikova J, Stalika E, Davis Z et al. The frequency of TP53 gene defects differs between chronic lymphocytic leukaemia subgroups harbouring distinct antigen receptors. Br J Haematol 2014; 166(4): 621– 625. doi: 10.1111/ bjh.12893.

14. Hallek M, Cheson BD, Catovsky D et al. International workshop on chronic lymphocytic leukemia. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International workshop on chronic lymphocytic leukemia updating the National Cancer Institute‑ Working Group 1996 guidelines. Blood 2008; 111(12): 5446– 5456. doi: 10.1182/ blood‑ 2007‑ 06‑ 093906.

15. Pospisilova S, Gonzalez D, Malcikova J et al. ERIC recommendations on TP53 mutation analysis in chronic lymphocytic leukemia. Leukemia 2012; 26(7): 1458– 1461. doi: 10.1038/ leu.2012.25.

16. Strati P, Keating MJ, O‘Brien SM et al. Outcomes of first‑line treatment for chronic lymphocytic leukemia with 17p deletion. Haematologica 2014; 99(8): 1350– 1355. doi: 10.3324/ haematol.2014.104661.

17. Best OG, Gardiner AC, Davis ZA et al. A subset of Binet stage A CLL patients with TP53 abnormalities and mutated IGHV genes have stable disease. Leukemia 2009; 23(1): 212– 214. doi: 10.1038/ leu.2008.260.

18. Tam CS, Shanafelt TD, Wierda WG et al. De novo deletion 17p13.1 chronic lymphocytic leukemia shows significant clinical heterogeneity: the M. D. Anderson and Mayo Clinic experience. Blood 2009; 114(5): 957– 964. doi: 10.1182/ blood‑ 2009‑ 03‑ 210591.

19. Schuh A, Becq J, Humphray S et al. Monitoring chronic lymphocytic leukemia progression by whole genome sequencing reveals heterogeneous clonal evolution patterns. Blood 2012; 120(20): 4191– 4196. doi: 10.1182/ blood‑ 2012‑ 05‑ 433540.

20. Bosch F, Abrisqueta P, Villamor N et al. Rituximab, fludarabine, cyclophosphamide, and mitoxantrone: a new, highly active chemoimmunotherapy regimen for chronic lymphocytic leukemia. J Clin Oncol 2009; 27(27): 4578– 4584. doi: 10.1200/ JCO.2009.22.0442.

21. Eichhorst B, Fink A, Busch R et al. Frontline chemoimmunotherapy with fludarabine (F), cyclophosphamide (C),and rituximab (R) (FCR) shows superior efficacy in comparison to bendamustine (B) and rituximab (BR) in previously untreated and physically fit patients (pts) with advanced chronic lymphocytic leukemia (CLL): final analysis of an international, randomized study of German CLL Study Group (GCLLSG) (CLL10 Study). Blood 2014; 124: abstr. 19.

22. Badoux XC, Keating MJ, Wang X et al. Fludarabine, cyclophosphamide, and rituximab chemoimmunotherapy is highly effective treatment for relapsed patients with CLL. Blood 2011; 117(11): 3016– 3024. doi: 10.1182/ blood‑ 2010‑ 08‑ 304683.

23. Smolej L, Prochazka V, Spacek M et al. Guidelines for alemtuzumab treatment in chronic lymphocytic leukaemia (CLL). Vnitr Lek 2012; 58(3): 232– 236.

24. Doubek M, Jungova A, Brejcha M et al. Alemtuzumab in chronic lymphocytic leukemia treatment: retrospective analysis of outcome according to cytogenetics. Vnitr Lek 2009; 55(6): 549– 554.

25. Stilgenbauer S, Zenz T, Winkler D et al. Subcutaneous alemtuzumab in fludarabine‑ refractory chronic lymphocytic leukemia: Clinical results and prognostic marker analyses from the CLL2H study of the german chronic lymphocytic leukemia study group. J Clin Oncol 2009; 27(24): 3994– 4001. doi: 10.1200/ JCO.2008.21.1128.

26. Lozanski G, Heerema NA, Flinn IW et al. Alemtuzumab is an effective therapy for chronic lymphocytic leukemia with p53 mutations and deletions. Blood 2004; 103(9): 3278– 3281.

27. Fiegl M, Erdel M, Tinhofer I et al. Clinical outcome of pretreated B‑ cell chronic lymphocytic leukemia following alemtuzumab therapy: a retrospective study on various cytogenetic risk categories. Ann Oncol 2010; 21(12): 2410– 2419. doi: 10.1093/ annonc/ mdq236.

28. Hillmen P, Skotnicki AB, Robak T et al. Alemtuzumab compared with chlorambucil as first‑line therapy for chronic lymphocytic leukemia. J Clin Oncol 2007; 25(35): 5616– 5623.

29. Pettitt AR, Jackson R, Carruthers S et al. Alemtuzumab in combination with methylprednisolone is a highly effective induction regimen for patients with chronic lymphocytic leukemia and deletion of TP53: final results of the national cancer research institute CLL206 trial. J Clin Oncol 2012; 30(14): 1647– 1655. doi: 10.1200/ JCO.2011.35.9695.

30. Keating MJ, Flinn I, Jain V et al. Therapeutic role of alemtuzumab (CAMPATH‑ 1H) in patients who have failed fludarabine: results of a large international study. Blood 2002; 99(10): 3554– 3561.

31. Bowen DA, Call TG, Jenkins GD et al. Methylprednisolone‑ rituximab is an effective salvage therapy for patients with relapsed chronic lymphocytic leukemia including those with unfavorable cytogenetic features. Leuk Lymphoma 2007; 48(12): 2412– 2417.

32. Pileckyte R, Jurgutis M, Valceckiene V et al. Dose‑dense high‑dose methylprednisolone and rituximab in the treatment of relapsed or refractory high‑risk chronic lymphocytic leukemia. Leuk Lymphoma 2011; 52(6): 1055– 1065. doi: 10.3109/ 10428194.2011.562572.

33. Wierda WG, Kipps TJ, Mayer J et al. Ofatumumab as single‑agent CD20 immunotherapy in fludarabine‑ refractory chronic lymphocytic leukemia. J Clin Oncol 2010; 28(10): 1749– 1755. doi: 10.1200/ JCO.2009.25.3187.

34. Wierda WG, Kipps TJ, Dürig J et al. Chemoimmunotherapy with O‑ FC in previously untreated patients with chronic lymphocytic leukemia. Blood 2011; 117(24): 6450– 6458. doi: 10.1182/ blood‑ 2010‑ 12‑ 323980.

35. Byrd JC, Brown JR, O‘Brien S et al. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med 2014; 371(3): 213– 223. doi: 10.1056/ NEJMoa1400376.

36. Doubek M, Brychtova Y, Panovska A et al. Ofatumumab added to dexamethasone in patients with relapsed or refractory chronic lymphocytic leukemia: results from a phase II study. Am J Hematol 2015; 90(5): 417– 421. doi: 10.1002/ ajh.23964.

37. Badoux XC, Keating MJ, Wen S et al. Phase II study of lenalidomide and rituximab as salvage therapy for patients with relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol 2013; 31(5): 584– 591. doi: 10.1200/ JCO.2012.42.8623.

38. Burger JA, Keating MJ, Wierda WG et al. Safety and activity of ibrutinib plus rituximab for patients with high‑risk chronic lymphocytic leukaemia: a single‑arm, phase 2 study. Lancet Oncol 2014; 15(10): 1090– 1099. doi: 10.1016/ S1470‑ 2045(14)70335‑ 3.

39. Byrd JC, Furman RR, Coutre SE et al. Three‑year follow‑up of treatment‑ naive and previously treated patients with CLL and SLL receiving single‑agent ibrutinib. Blood 2015; 125(16): 2497– 2506. doi: 10.1182/ blood‑ 2014‑ 10‑ 606038.

40. Furman RR, Sharman JP, Coutre SE et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med 2014; 370(11): 997– 1007. doi: 10.1056/ NEJMoa1315226.

41. O’Brien S, Lamanna N, Kipps TJ et al. Update on a phase 2 study of idelalisib in combination with rituximab in treatment‑ naive patients ≥ 65 years with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Blood 2014; 124: abstr. 1994.

42. Byrd JC, Furman RR, Coutre SE et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med 2013; 369(1): 32– 42. doi: 10.1056/ NEJMoa1215637.

43. Thompson PA, O’Brien SM, Wierda WG et al. Complex karyotype is a stronger predictor than del(17p) for an inferior outcome in relapsed or refractory chronic lymphocytic leukemia patients treated with ibrutinib‑based regimens. Cancer 2015. In press. doi: 10.1002/ cncr.29566.

44. 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(2): 169– 176. doi: 10.1016/ S1470‑ 2045(14)71182‑ 9.

45. Roberts AW, Ma S, Brander DM et al. Determination of recommended phase 2 dose of ABT‑ 199 (GDC‑ 199) combined with rituximab (R) in patients with relapsed/ refractory (R/ R) chronic lymphocytic leukemia (CLL). Blood 2014; 124(21): abstr. 325.

46. Woyach JA, Ruppert A, Lozanski G et al. Association of disease progression on ibrutinib therapy with the acquisition of resistance mutations: a single‑center experience of 267 patients. Clin Oncol 2014; 32: abstr. 7010.

47. 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. Blood 2010; 116(14): 2438– 2447. doi: 10.1182/ blood‑ 2010‑ 03‑ 275420.

48. 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. Blood 2013; 121(16): 3284– 3288. doi: 10.1182/ blood‑ 2012‑ 11‑ 469627.

49. Schetelig J, van Biezen A, Brand R et al. Allogeneic hematopoietic stem‑ cell transplantation for chronic lymphocytic leukemia with 17p deletion: A retrospective european group for blood and marrow transplantation analysis. J Clin Oncol 2008; 26(31): 5094– 5100. doi: 10.1200/ JCO.2008.16.2982.

50. Khouri IF, Bassett R, Poindexter N et al. Nonmyeloablative allogeneic stem cell transplantation in relapsed/ refractory chronic lymphocytic leukemia: long‑term follow‑up, prognostic factors, and effect of human leukocyte histocompatibility antigen subtype on outcome. Cancer 2011; 117(20): 4679– 4688. doi: 10.1002/ cncr.26091.

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 Clin Oncol 2008; 26(30): 4912– 4920. doi: 10.1200/ JCO.2007.15.4757.

52. Poon ML, Fox PS, Samuels BI et al. Allogeneic stem cell transplant in patients with chronic lymphocytic leukemia with 17p deletion: consult‑ transplant versus consult‑ no‑ transplant analysis. Leuk Lymphoma 2015; 56(3): 711– 715. doi: 10.3109/ 10428194.2014.930848.

53. Ritgen M, Stilgenbauer S, von Neuhoff N et al. Graft‑ versus‑ leukemia activity may overcome therapeutic resistance of chronic lymphocytic leukemia with unmutated immunoglobulin variable heavy‑chain gene status: implications of minimal residual disease measurement with quantitative PCR. Blood 2004; 104(8): 2600– 2602.

54. Richardson SE, Khan I, Rawstron A et al. Risk‑stratified adoptive cellular therapy following allogeneic hematopoietic stem cell transplantation for advanced chronic lymphocytic leukemia. Br J Hematol 2013; 160(5): 640– 648. doi: 10.1111/ bjh.12197.

55. Dreger P, Corradini P, Kimby E et al. Indications for allogeneic stem cell transplantation in chronic lymphocytic leukemia: the EBMT transplant consensus. Leukemia 2007; 21(1): 12– 17.

56. Michallet M, Sobh M, Milligan D et al. The impact of HLA matching on long‑term transplant outcome after allogeneic hematopoietic stem cell transplantation for CLL: a retrospective study from the EBMT registry. Leukemia 2010; 24(10): 1725– 1731. doi: 10.1038/leu.2010.165.