Jak klinicky interpretovat výsledky TP53 analýz u chronické lymfocytární leukemie v kontextu dostupných terapeutických režimů

Czech version

Authors: B. Kunt Vonková ²; Š. Pavlová ^1,2; J. Malčíková ^1,2; K. Pál ²; Y. Brychtová ¹; A. Panovská ¹; Š. Pospíšilová ^1,2; M. Doubek ^1,2
Authors‘ workplace: Interní hematologická a onkologická klinika LF MU a FN Brno ¹; CEITEC – Středoevropský technologický institut, MU, Brno ²
Published in: Transfuze Hematol. dnes,29, 2023, No. 2, p. 117-123.
Category: Review/Educational Papers
doi: https://doi.org/10.48095/cctahd2023prolekare.cz11

Overview

TP53 gene mutations represent the most important adverse prognostic and predictive factor in patients with chronic lymphocytic leukaemia (CLL) and contribute to an overall worse disease course and risk of early relapse or resistance to chemoimmunotherapy. Results to date suggest that first-line chemoimmunotherapy (FCR) results in clonal selection of TP53 aberrant cells, which has an adverse effect on disease prognosis. Recent studies investigating the clonal evolution of TP53 mutations under BCR and Bcl-2 inhibitor therapy do not suggest a similar trend. Next-generation sequencing (NGS) methods are being increasingly used in the clinical diagnosis of TP53 aberrations, achieving sensitivity of allelic frequency detection below 10% compared to standard Sanger sequencing. In recent years, the focus of CLL research has been on TP53 gene mutations with allelic frequencies below 10% and their clinical significance. In the following review article, we summarize the results published so far on the clonal evolution of TP53 gene mutations under different therapeutic regimens, especially with respect to mutations with an allelic frequency < 10% and their clinical interpretation.

Keywords:

chronic lymphocytic leukemia – TP53 mutations – clonal evolution – FCR – BRC and Bcl-2 inhibitors

Sources

1. Pospíšilová Š, Jarošová M, Doubek M. Chronická lymfocytární leukemie – současné využití moderních prognostických a prediktivních faktorů v diagnostice. Transfuze Hematol Dnes. 2019; (1): 66–71.

2. Campo E, Cymbalista F, Ghia P, et al. TP53 aberrations in chronic lymphocytic leukemia: an overview of the clinical implications of improved diagnostics. Haematologica. 2018; 103 (12): 1956–1968. doi: 10.3324/haematol. 2018.187583

3. Malcikova J, Smardova J, Rocnova L, et al. Monoallelic and biallelic inactivation of TP53 gene in chronic lymphocytic leukemia: selection, impact on survival, and response to DNA damage. Blood. 2009; 114 (26): 5307–5314. doi: 10.1182/blood-2009-07-234708

4. 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

5. Eichhorst B, Robak T, Montserrat E, et al. Chronic lymphocytic leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2021; 32 (1): 23–33. doi: 10.1016/j.annonc.2020.09.019

6. Malcikova J, Tausch E, Rossi D, et al. ERIC recommendations for TP53 mutation analysis in chronic lymphocytic leukemia – update on methodological approaches and results interpretation. Leukemia. 2018; 32 (5): 1070–1080. doi: 10.1038/s41375-017-0007-7

7. Hallek M, Cheson BD, Catovsky D, et al. iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL. Blood. 2018; 131 (25): 2745–2760. doi: 10.1182/blood-2017-09-806398

8. Smolej L, Špaček M, Pospíšilová Š, et al. Doporučení pro diagnostiku a léčbu chronické lymfocytární leukemie (CLL) 2021. Transfuze Hematol Dnes. 2021; 27 (1): 91–106. doi: 10. 48095/cctahd202191

9. 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 (10): 1409–1418. doi: 10.1016/S1470-2045 (16) 30212-1

10. Brown JR, Byrd JC, Coutre SE, et al. Idelalisib, an inhibitor of phosphatidylinositol 3-kinase p110d, for relapsed/refractory chronic lymphocytic leukemia. Blood. 2014; 123 (22): 3390–3397. doi: 10.1182/blood-2013-11-535047

11. Roberts AW, Davids MS, Pagel JM, et al. Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia. N Engl J Med. 2016; 374 (4): 311–322. doi: 10.1056/NEJMoa1513 257

12. Malcikova J, Pavlova S, Kunt Vonkova B, et al. Low-burden TP53 mutations in CLL: clinical impact and clonal evolution within the context of different treatment options. Blood. 2021; 138 (25): 2670–2685. doi: 10.1182/ blood.2020009530

13. Woyach JA, Ruppert AS, Heerema NA, et al. Long-term results of alliance A041202 show continued advantage of ibrutinib-based regimens compared with bendamustine plus rituximab (BR) chemoimmunotherapy. Blood. 2021; 138 (Suppl 1): 639–639. doi: 10.1182/ blood-2021-153146

14. Sharman JP, Egyed M, Jurczak W, et al. Efficacy and safety in a 4-year follow-up of the ELEVATE-TN study comparing acalabrutinib with or without obinutuzumab versus obinutuzumab plus chlorambucil in treatment-naïve chronic lymphocytic leukemia. Leukemia. 2022; 36 (4): 1171–1175. doi: 10.1038/s41375-021-01485-x

15. Al-Sawaf O, Zhang C, Tandon M, et al. Venetoclax plus obinutuzumab versus chlorambucil plus obinutuzumab for previously untreat- ed chronic lymphocytic leukaemia (CLL14): follow-up results from a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2020; 21 (9): 1188–1200. doi: 10.10 16/S1470-2045 (20) 30443-5

16. Gonzalez D, Martinez P, Wade R, et al. Mutational status of the TP53 gene as a predictor of response and survival in patients with chronic lymphocytic leukemia: results from the LRF CLL4 trial. J Clin Oncol. 2011; 29 (16): 2223–2229. doi: 10.1200/JCO.2010.32.0838

17. Stilgenbauer S, Schnaiter A, Paschka P, et al. Gene mutations and treatment outcome in chronic lymphocytic leukemia: results from the CLL8 trial. Blood. 2014; 123 (21): 3247–3254. doi: 10.1182/blood-2014-01-546150

18. Rossi D, Khiabanian H, Ciardullo C, et al. Clinical impact of small TP53 mutated subclones in chronic lymphocytic leukemia. Blood. 2013; 122 (21): 116–116. doi: 10.1182/blood.V122.21.116.116

19. Nadeu F, Delgado J, Royo C, et al. Clinical impact of clonal and subclonal TP53, SF3B1, BIRC3, NOTCH1, and ATM mutations in chronic lymphocytic leukemia. Blood. 2016; 127 (17): 2122–2130. doi: 10.1182/blood-2015-07-659144

20. Brieghel C, Kinalis S, Yde CW, et al. Deep targeted sequencing of TP53 in chronic lymphocytic leukemia: clinical impact at diagnosis and at time of treatment. Haematologica. 2019; 104 (4): 789–796. doi: 10.3324/haematol.2018.195818

21. Bomben R, Rossi FM, Vit F, et al. TP53 mutations with low variant allele frequency predict short survival in chronic lymphocytic leukemia. Clin Cancer Res. 2021; 27 (20): 5566–5575. doi: 10.1158/1078-0432.CCR-21-0701

22. Blakemore SJ, Clifford R, Parker H, et al. Clinical significance of TP53, BIRC3, ATM and MAPK-ERK genes in chronic lymphocytic leukaemia: data from the randomised UK LRF CLL4 trial. Leukemia. 2020; 34 (7): 1760–1774. doi: 10.1038/s41375-020-0723-2

23. Cherng HJ, Khwaja R, Kanagal‐Shamanna R, et al. TP53 ‐altered chronic lymphocytic leukemia treated with firstline Bruton’s tyrosine kinase inhibitor‐based therapy: A retrospective analysis. Am J Hematol. 2022; 97 (8): 1005–1012. doi: 10.1002/ajh.26595

24. Bomben R, Rossi FM, D’Agaro T, et al. Clinical impact of clonal and subclonal TP53 mutations and deletions in chronic lymphocytic leukemia: an Italian multicenter experience. Blood. 2019; 134 (Suppl 1): 480–480. doi: 10.1182/blood- 2019-124647

25. Landau DA, Carter SL, Stojanov P, et al. Evolution and impact of subclonal mutations in chronic lymphocytic leukemia. Cell. 2013; 152 (4): 714–726. doi: 10.1016/j.cell.2013.01.019

26. Malcikova J, Stano-Kozubik K, Tichy B, et al. Detailed analysis of therapy-driven clonal evolution of TP53 mutations in chronic lymphocytic leukemia. Leukemia. 2015; 29 (4): 877–885. doi: 10.1038/leu.2014.297

27. Gángó A, Alpár D, Galik B, et al. Dissection of subclonal evolution by temporal mutation profiling in chronic lymphocytic leukemia patients treated with ibrutinib. Int J Cancer. 2020; 146 (1): 85–93. doi: 10.1002/ijc.32502

28. Cafforio L, Raponi S, Cappelli LV, et al. Treatment with ibrutinib does not induce a TP53 clonal evolution in chronic lymphocytic leukemia. Haematologica. 2021; 107 (1): 334–337. doi: 10.3324/haematol.2020.263715

Labels

Haematology Internal medicine Clinical oncology

Molecular pathophysiology of ribosomopathies – disorders of ribosome dysfunction

Treatment of patients with Hodgkin lymphoma after disease relapse or progression – chemosensitivity, transplantation and targeted therapy

The changes in the diagnostics and treatment of hepatic veno-occlusive disease in children

rFVIIIFc in treatment of haemophilia A from perspective of real clinical practice in three centers for treatment of haemophilia in the Czech Republic

Blocking of antigen caused by anti-K antibody

Standardization of PET/CT in patients with multiple myeloma – Joint recommendation of The Czech Myeloma Group and The Czech Society of Nuclear Medicine

Vzácné choroby provázené hypergamaglobulinémií a zánětlivými projevy aneb „diagnostikovat jednotku, o níž nevíme, že existuje, asi není možné…“

Cena České hematologické společnosti za nejlepší původní vědeckou práci a monografii v oboru hematologie v roce 2022

Prof. Milan Bláha – 85. narozeniny

Article was published in

Transfusion and Haematology Today

2023 Issue 2