open access

Vol 13, No 1 (2022)
Review paper
Published online: 2022-05-20
Get Citation

IGHV mutational status and the choice of first-line therapy for patients with chronic lymphocytic leukaemia

Bartosz Puła1, Krzysztof Jamroziak2, Tomasz Wróbel3, Krzysztof Giannopoulos45, Iwona Hus1
DOI: 10.5603/HCP.2022.0003
·
Hematology in Clinical Practice 2022;13(1):7-14.
Affiliations
  1. Department of Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland, Indiry Gandhi 14, 02-776 Warszawa, Poland
  2. Department of Hematology, Transplantation and Internal Medicine, Medical University, Warsaw, Poland
  3. Department and Clinic of Hematology, Blood Neoplasms and Bone Marrow Transplantation, Wroclaw Medical University, Wroclaw, Poland, Wybrzeże Ludwika Pasteura 4, 52-007 Wroclaw, Poland
  4. Experimental Hematooncology Department, Medical University, Lublin, Poland; Department of Hematology, St. John's Cancer Center, Lublin, Poland;, Doktora Kazimierza Jaczewskiego 7, 20-090 Lublin, Poland
  5. Department of Hematology, St. John's Cancer Center, Lublin, Poland

open access

Vol 13, No 1 (2022)
REVIEW ARTICLES
Published online: 2022-05-20

Abstract

Chronic lymphocytic leukaemia (CLL) is an incurable lymphoid malignancy with a heterogeneous clinical course varying from relatively indolent cases characterized by long survival to more aggressive and treatment-resistant ones. Findings from randomized clinical trials and long-lasting retrospective observations have shown that somatic hypermutation (SHM) status of the immunoglobulin heavy chain variable gene (IGHV) comprising the B cell receptor (BCR) plays a significant prognostic and predictive role in patients with CLL. According to the current international and Polish guidelines, assessment of IGHV mutational status should be mandatory at first-line treatment initiation in addition to p53 pathway defects and comorbidities for therapy allocation. This review describes the rationale for IGHV mutational status assessment as well as discusses its prognostic role in patients with CLL in the first-line setting.

Abstract

Chronic lymphocytic leukaemia (CLL) is an incurable lymphoid malignancy with a heterogeneous clinical course varying from relatively indolent cases characterized by long survival to more aggressive and treatment-resistant ones. Findings from randomized clinical trials and long-lasting retrospective observations have shown that somatic hypermutation (SHM) status of the immunoglobulin heavy chain variable gene (IGHV) comprising the B cell receptor (BCR) plays a significant prognostic and predictive role in patients with CLL. According to the current international and Polish guidelines, assessment of IGHV mutational status should be mandatory at first-line treatment initiation in addition to p53 pathway defects and comorbidities for therapy allocation. This review describes the rationale for IGHV mutational status assessment as well as discusses its prognostic role in patients with CLL in the first-line setting.

Get Citation

Keywords

chronic lymphocytic leukaemia, ibrutinib, acalabrutinib, idelalisib, monoclonal antibodies, venetoclax, treatment, immunoglobulin heavy chain variable gene

About this article
Title

IGHV mutational status and the choice of first-line therapy for patients with chronic lymphocytic leukaemia

Journal

Hematology in Clinical Practice

Issue

Vol 13, No 1 (2022)

Article type

Review paper

Pages

7-14

Published online

2022-05-20

Page views

2018

Article views/downloads

322

DOI

10.5603/HCP.2022.0003

Bibliographic record

Hematology in Clinical Practice 2022;13(1):7-14.

Keywords

chronic lymphocytic leukaemia
ibrutinib
acalabrutinib
idelalisib
monoclonal antibodies
venetoclax
treatment
immunoglobulin heavy chain variable gene

Authors

Bartosz Puła
Krzysztof Jamroziak
Tomasz Wróbel
Krzysztof Giannopoulos
Iwona Hus

References (51)
  1. 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.
  2. Redaelli A, Laskin BL, Stephens JM, et al. The clinical and epidemiological burden of chronic lymphocytic leukaemia. Eur J Cancer Care (Engl). 2004; 13(3): 279–287.
  3. 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.
  4. Jamroziak K, Puła B, Walewski J. Current treatment of chronic lymphocytic leukemia. Curr Treat Options Oncol. 2017; 18(1): 5.
  5. Wierda WG, Kipps TJ, Mayer J, et al. Hx-CD20-406 Study Investigators. Ofatumumab as single-agent CD20 immunotherapy in fludarabine-refractory chronic lymphocytic leukemia. J Clin Oncol. 2010; 28(10): 1749–1755.
  6. Goede V, Fischer K, Busch R, et al. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med. 2014; 370(12): 1101–1110.
  7. 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. Blood. 2016; 127(2): 208–215.
  8. Hallek M, Fischer K, Fingerle-Rowson G, et al. International Group of Investigators, German Chronic Lymphocytic Leukaemia Study Group. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet. 2010; 376(9747): 1164–1174.
  9. Pula B, Iskierka-Jazdzewska E, Długosz-Danecka M, et al. Long-term efficacy of ibrutinib in relapsed or refractory chronic lymphocytic leukemia: results of the Polish Adult Leukemia Study Group Observational Study. Anticancer Res. 2020; 40(7): 4059–4066.
  10. 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(19): 2031–2042.
  11. Sharman JP, Coutre SE, Furman RR, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013; 369(1): 32–42.
  12. Kater AP, Seymour JF, Hillmen P, et al. Fixed duration of venetoclax-rituximab in relapsed/refractory chronic lymphocytic leukemia eradicates minimal residual disease and prolongs survival: post-treatment follow-up of the MURANO phase III study. J Clin Oncol. 2019; 37(4): 269–277.
  13. Fischer K, Al-Sawaf O, Bahlo J, et al. Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med. 2019; 380(23): 2225–2236.
  14. Wang L, Lawrence MS, Wan Y, et al. SF3B1 and other novel cancer genes in chronic lymphocytic leukemia. N Engl J Med. 2011; 365(26): 2497–2506.
  15. Quesada V, Conde L, Villamor N, et al. Exome sequencing identifies recurrent mutations of the splicing factor SF3B1 gene in chronic lymphocytic leukemia. Nat Genet. 2011; 44(1): 47–52.
  16. Puente XS, Pinyol M, Quesada V, et al. Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia. Nature. 2011; 475(7354): 101–105.
  17. Rossi D, Rasi S, Fabbri G, et al. Mutations of NOTCH1 are an independent predictor of survival in chronic lymphocytic leukemia. Blood. 2012; 119(2): 521–529.
  18. Balatti V, Bottoni A, Palamarchuk A, et al. NOTCH1 mutations in CLL associated with trisomy 12. Blood. 2012; 119(2): 329–331.
  19. Landau DA, Carter SL, Stojanov P, et al. Evolution and impact of subclonal mutations in chronic lymphocytic leukemia. Cell. 2013; 152(4): 714–726.
  20. Landau DA, Tausch E, Taylor-Weiner AN, et al. Mutations driving CLL and their evolution in progression and relapse. Nature. 2015; 526(7574): 525–530.
  21. Eichhorst B, Robak T, Montserrat E, et al. ESMO Guidelines Committee. Electronic address: clinicalguidelines@esmo.org. Chronic lymphocytic leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2021; 32(1): 23–33.
  22. 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.
  23. Hus I, Giannopoulos K, Jamroziak K, et al. Diagnostic and therapeutic recommendations of the Polish Society of Haematologists and Transfusiologists and Polish Adult Leukemia Group-CLL for chronic lymphocytic leukemia in 2021. Acta Haematol Pol. 2021; 52(5): 455–482.
  24. Ghia P, Stamatopoulos K, Belessi C, et al. European Research Initiative on CLL. ERIC recommendations on IGHV gene mutational status analysis in chronic lymphocytic leukemia. Leukemia. 2007; 21(1): 1–3.
  25. Lin KI, Tam CS, Keating MJ, et al. Relevance of the immunoglobulin VH somatic mutation status in patients with chronic lymphocytic leukemia treated with fludarabine, cyclophosphamide, and rituximab (FCR) or related chemoimmunotherapy regimens. Blood. 2009; 113(14): 3168–3171.
  26. Oscier DG, Gardiner AC, Mould SJ, et al. Multivariate analysis of prognostic factors in CLL: clinical stage, IGVH gene mutational status, and loss or mutation of the p53 gene are independent prognostic factors. Blood. 2002; 100(4): 1177–1184.
  27. Rosenquist R, Ghia P, Hadzidimitriou A, et al. Immunoglobulin gene sequence analysis in chronic lymphocytic leukemia: updated ERIC recommendations. Leukemia. 2017; 31(7): 1477–1481.
  28. 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. Blood. 2016; 127(3): 303–309.
  29. Tam CS, O'Brien S, Wierda W, et al. Long-term results of the fludarabine, cyclophosphamide, and rituximab regimen as initial therapy of chronic lymphocytic leukemia. Blood. 2008; 112(4): 975–980.
  30. Fink AM, Böttcher S, Ritgen M, et al. Prediction of poor outcome in CLL patients following first-line treatment with fludarabine, cyclophosphamide and rituximab. Leukemia. 2013; 27(9): 1949–1952.
  31. Stilgenbauer S, Bosch F, Ilhan O, et al. Lenalidomide maintenance after first-line therapy for high-risk chronic lymphocytic leukaemia (CLLM1): final results from a randomised, double-blind, phase 3 study. Lancet Haematol. 2017; 4(10): e475–e486.
  32. 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. Blood. 2015; 126(16): 1921–1924.
  33. Eichhorst B, Fink AM, Bahlo J, et al. international group of investigators, German CLL Study Group (GCLLSG). 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. 2016; 17(7): 928–942.
  34. Shanafelt TD, Wang XV, Hanson CA, et al. Ibrutinib-rituximab or chemoimmunotherapy for chronic lymphocytic leukemia. N Engl J Med. 2019; 381(5): 432–443.
  35. Woyach JA, Ruppert AS, Heerema NA, et al. Ibrutinib regimens versus chemoimmunotherapy in older patients with untreated CLL. N Engl J Med. 2018; 379(26): 2517–2528.
  36. Al-Sawaf O, Zhang C, Lu T, et al. Minimal residual disease dynamics after venetoclax-obinutuzumab treatment: extended off-treatment follow-up from the randomized CLL14 study. J Clin Oncol. 2021; 39(36): 4049–4060.
  37. 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(1): 43–56.
  38. 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.
  39. Sharman JP, Egyed M, Jurczak W, et al. Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzmab for treatment-naive chronic lymphocytic leukaemia (ELEVATE TN): a randomised, controlled, phase 3 trial. Lancet. 2020; 395(10232): 1278–1291.
  40. 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.
  41. Byrd JC, Furman RR, Coutre SE, et al. Three-year follow-up of treatment-naïve and previously treated patients with CLL and SLL receiving single-agent ibrutinib. Blood. 2015; 125(16): 2497–2506.
  42. Burger JA, Barr PM, Robak T, et al. Long-term efficacy and safety of first-line ibrutinib treatment for patients with CLL/SLL: 5 years of follow-up from the phase 3 RESONATE-2 study. Leukemia. 2020; 34(3): 787–798.
  43. 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(25): 2686–2694.
  44. Chai-Adisaksopha C, Brown JR. FCR achieves long-term durable remissions in patients with -mutated CLL. Blood. 2017; 130(21): 2278–2282.
  45. Thompson PA, Stingo F, Keating MJ, et al. Outcomes of patients with chronic lymphocytic leukemia treated with first-line idelalisib plus rituximab after cessation of treatment for toxicity. Cancer. 2016; 122(16): 2505–2511.
  46. Burger JA, Tedeschi A, Barr PM, et al. RESONATE-2 Investigators. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med. 2015; 373(25): 2425–2437.
  47. Ghia P, Dlugosz-Danecka M, Scarfò L, et al. Acalabrutinib: a highly selective, potent Bruton tyrosine kinase inhibitor for the treatment of chronic lymphocytic leukemia. Leuk Lymphoma. 2021; 62(5): 1066–1076.
  48. Lampson BL, Kasar SN, Matos TR, et al. Idelalisib given front-line for treatment of chronic lymphocytic leukemia causes frequent immune-mediated hepatotoxicity. Blood. 2016; 128(2): 195–203.
  49. Hus I, Puła B, Robak T. PI3K Inhibitors for the treatment of chronic lymphocytic leukemia: current status and future perspectives. Cancers (Basel). 2022; 14(6).
  50. Puła B, Jamroziak K. Rola wenetoklaksu w leczeniu chorych na przewlekłą białaczkę limfocytową. Hematologia. 2017; 8(1): 20–32.
  51. Robak T, Witkowska M, Smolewski P. The role of Bruton's kinase inhibitors in chronic lymphocytic leukemia: current status and future drections. Cancers (Basel). 2022; 14(3).

Regulations

Important: This website uses cookies. More >>

The cookies allow us to identify your computer and find out details about your last visit. They remembering whether you've visited the site before, so that you remain logged in - or to help us work out how many new website visitors we get each month. Most internet browsers accept cookies automatically, but you can change the settings of your browser to erase cookies or prevent automatic acceptance if you prefer.