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CC BY 4.0 · Glob Med Genet 2024; 11(01): 059-068
DOI: 10.1055/s-0044-1779668
Original Article

Association of Cytogenetics Aberrations and IGHV Mutations with Outcome in Chronic Lymphocytic Leukemia Patients in a Real-World Clinical Setting

Carolina Muñoz-Novas   *
1   Servicio de Hematología, Hospital Universitario Infanta Leonor, Madrid, Spain
,
Isabel González-Gascón-y-Marín   *
1   Servicio de Hematología, Hospital Universitario Infanta Leonor, Madrid, Spain
,
Iñigo Figueroa
2   Departamento de Medicina, Universidad Complutense, Madrid, Spain
,
Laura Sánchez-Paz
1   Servicio de Hematología, Hospital Universitario Infanta Leonor, Madrid, Spain
,
Claudia Pérez-Carretero
3   IBSAL, IBMCC, Centro de Investigación del Cáncer, Servicio de Hematología, Hospital Universitario de Salamanca, Universidad de Salamanca-CSIC, Salamanca, Spain
,
Miguel Quijada-Álamo
3   IBSAL, IBMCC, Centro de Investigación del Cáncer, Servicio de Hematología, Hospital Universitario de Salamanca, Universidad de Salamanca-CSIC, Salamanca, Spain
,
Ana-Eugenia Rodríguez-Vicente
3   IBSAL, IBMCC, Centro de Investigación del Cáncer, Servicio de Hematología, Hospital Universitario de Salamanca, Universidad de Salamanca-CSIC, Salamanca, Spain
,
María-Stefania Infante
1   Servicio de Hematología, Hospital Universitario Infanta Leonor, Madrid, Spain
,
María-Ángeles Foncillas
1   Servicio de Hematología, Hospital Universitario Infanta Leonor, Madrid, Spain
,
Elena Landete
1   Servicio de Hematología, Hospital Universitario Infanta Leonor, Madrid, Spain
,
Juan Churruca
1   Servicio de Hematología, Hospital Universitario Infanta Leonor, Madrid, Spain
,
Karen Marín
1   Servicio de Hematología, Hospital Universitario Infanta Leonor, Madrid, Spain
,
Victoria Ramos
1   Servicio de Hematología, Hospital Universitario Infanta Leonor, Madrid, Spain
,
Alejandro Sánchez Salto
1   Servicio de Hematología, Hospital Universitario Infanta Leonor, Madrid, Spain
,
José-Ángel Hernández-Rivas
1   Servicio de Hematología, Hospital Universitario Infanta Leonor, Madrid, Spain
2   Departamento de Medicina, Universidad Complutense, Madrid, Spain
› Author Affiliations Funding None.
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Abstract

Immunoglobulin heavy chain variable (IGHV) region mutations, TP53 mutation, fluorescence in situ hybridization (FISH), and cytogenetic analysis are the most important prognostic biomarkers used in chronic lymphocytic leukemia (CLL) patients in our daily practice. In real-life environment, there are scarce studies that analyze the correlation of these factors with outcome, mainly referred to time to first treatment (TTFT) and overall survival (OS). This study aimed to typify IGHV mutation status, family usage, FISH aberrations, and complex karyotype (CK) and to analyze the prognostic impact in TTFT and OS in retrospective study of 375 CLL patients from a Spanish cohort. We found unmutated CLL (U-CLL) was associated with more aggressive disease, shorter TTFT (48 vs. 133 months, p < 0.0001), and shorter OS (112 vs. 246 months, p < 0.0001) than the mutated CLL. IGHV3 was the most frequently used IGHV family (46%), followed by IGHV1 (30%) and IGHV4 (16%). IGHV5-51 and IGHV1-69 subfamilies were associated with poor prognosis, while IGHV4 and IGHV2 showed the best outcomes. The prevalence of CK was 15% and was significantly associated with U-CLL. In the multivariable analysis, IGHV2 gene usage and del13q were associated with longer TTFT, while VH1-02, +12, del11q, del17p, and U-CLL with shorter TTFT. Moreover, VH1-69 usage, del11q, del17p, and U-CLL were significantly associated with shorter OS. A comprehensive analysis of genetic prognostic factors provides a more precise information on the outcome of CLL patients. In addition to FISH cytogenetic aberrations, IGHV and TP53 mutations, IGHV gene families, and CK information could help clinicians in the decision-making process.

Keywords

chronic lymphocytic leukemia - IGHV mutation status - complex karyotype - overall survival - time to first treatment

Authors' Contribution

Writing original draft preparation, concept, and writing were done by C.M.-N. and I.G.-G.-y.-M.; review and editing by I.F., L.S.-P., C.P.-C., M.Q.-Á., A.-E.R.-V., M.-S.I., M.-A.F., E.L., J.C., K.M., V.R.-A., and J.-Á.H.- R. All authors have read and agreed to the published version of the manuscript.


* These authors contributed equally to this article.


Supplementary Material



Publication History

Article published online:
12 February 2024

© 2024. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)

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  • References

  • 1 Rozovski U, Hazan-Halevy I, Keating MJ, Estrov Z. Personalized medicine in CLL: current status and future perspectives. Cancer Lett 2014; 352 (01) 4-14
    CrossrefPubMedGoogle Scholar
  • 2 Parikh SA. Chronic lymphocytic leukemia treatment algorithm 2018. Blood Cancer J 2018; 8 (10) 93
    CrossrefPubMedGoogle Scholar
  • 3 Rai KR, Sawitsky A, Cronkite EP, Chanana AD, Levy RN, Pasternack BS. Clinical staging of chronic lymphocytic leukemia. Blood 1975; 46 (02) 219-234
    CrossrefPubMedGoogle Scholar
  • 4 Binet JL, Auquier A, Dighiero G. et al. A new prognostic classification of chronic lymphocytic leukemia derived from a multivariate survival analysis. Cancer 1981; 48 (01) 198-206
    CrossrefPubMedGoogle Scholar
  • 5 Baliakas P, Iskas M, Gardiner A. et al. Chromosomal translocations and karyotype complexity in chronic lymphocytic leukemia: a systematic reappraisal of classic cytogenetic data. Am J Hematol 2014; 89 (03) 249-255
    CrossrefPubMedGoogle Scholar
  • 6 Visentin A, Bonaldi L, Rigolin GM. et al. The combination of complex karyotype subtypes and IGHV mutational status identifies new prognostic and predictive groups in chronic lymphocytic leukaemia. Br J Cancer 2019; 121 (02) 150-156
    CrossrefPubMedGoogle Scholar
  • 7 Hamblin TJ, Davis Z, Gardiner A, Oscier DG, Stevenson FK. Unmutated Ig V(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood 1999; 94 (06) 1848-1854
    CrossrefPubMedGoogle Scholar
  • 8 Damle RN, Wasil T, Fais F. et al. Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia. Blood 1999; 94 (06) 1840-1847
    CrossrefPubMedGoogle Scholar
  • 9 Datta M, Jumaa H. Immunoglobulin gene sequence as an inherited and acquired risk factor for chronic lymphocytic leukemia. Cancers (Basel) 2022; 14 (13) 3045
    CrossrefPubMedGoogle Scholar
  • 10 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 (02) 208-215
    CrossrefPubMedGoogle Scholar
  • 11 Rotbain EC, Frederiksen H, Hjalgrim H. et al. IGHV mutational status and outcome for patients with chronic lymphocytic leukemia upon treatment: a Danish nationwide population-based study. Haematologica 2020; 105 (06) 1621-1629
    CrossrefPubMedGoogle Scholar
  • 12 International CLL-IPI working group. An international prognostic index for patients with chronic lymphocytic leukaemia (CLL-IPI): a meta-analysis of individual patient data. Lancet Oncol 2016; 17 (06) 779-790
    CrossrefPubMedGoogle Scholar
  • 13 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 (01) 23-33
    CrossrefPubMedGoogle Scholar
  • 14 NCCN Clinical Practice Guidelines in Oncology. (NCCN Guidelines ®). Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma [Internet]. 2023 [Accessed June 7, 2023]. Available at: https://www.nccn.org/professionals/physician_gls/pdf/cll.pdf
  • 15 Couillez G, Morel P, Clichet V. et al. Flow cytometry as a fast, cost-effective tool to assess IGHV mutational status in CLL. Blood Adv 2023; 7 (17) 4701-4704
    CrossrefPubMedGoogle Scholar
  • 16 González-Gascón Y Marín I, Hernández JA, Martín A. et al. Mutation status and immunoglobulin gene rearrangements in patients from northwest and central region of Spain with chronic lymphocytic leukemia. BioMed Res Int 2014; 2014: 257517
    CrossrefPubMedGoogle Scholar
  • 17 Marinelli M, Ilari C, Xia Y. et al. Immunoglobulin gene rearrangements in Chinese and Italian patients with chronic lymphocytic leukemia. Oncotarget 2016; 7 (15) 20520-20531
    CrossrefPubMedGoogle Scholar
  • 18 Chen L, Zhang Y, Zheng W. et al. Distinctive IgVH gene segments usage and mutation status in Chinese patients with chronic lymphocytic leukemia. Leuk Res 2008; 32 (10) 1491-1498
    CrossrefPubMedGoogle Scholar
  • 19 Ghia P, Stamatopoulos K, Belessi C. et al. Geographic patterns and pathogenetic implications of IGHV gene usage in chronic lymphocytic leukemia: the lesson of the IGHV3-21 gene. Blood 2005; 105 (04) 1678-1685
    CrossrefPubMedGoogle Scholar
  • 20 Bomben R, Dal Bo M, Capello D. et al. Comprehensive characterization of IGHV3-21-expressing B-cell chronic lymphocytic leukemia: an Italian multicenter study. Blood 2007; 109 (07) 2989-2998
    CrossrefPubMedGoogle Scholar
  • 21 Raponi S, Ilari C, Della Starza I. et al. Redefining the prognostic likelihood of chronic lymphocytic leukaemia patients with borderline percentage of immunoglobulin variable heavy chain region mutations. Br J Haematol 2020; 189 (05) 853-859
    CrossrefPubMedGoogle Scholar
  • 22 Harris NL, Jaffe ES, Diebold J. et al. World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues: report of the Clinical Advisory Committee meeting-Airlie House, Virginia, November 1997. J Clin Oncol 1999; 17 (12) 3835-3849
    CrossrefPubMedGoogle Scholar
  • 23 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
    CrossrefPubMedGoogle Scholar
  • 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 (01) 1-3
    CrossrefPubMedGoogle Scholar
  • 25 Kreinitz N, Polliack A, Tadmor T. Chronic lymphocytic leukemia is becoming more complex: how to define complex karyotype?. Leuk Lymphoma 2018; 59 (03) 521-522
    CrossrefPubMedGoogle Scholar
  • 26 Baliakas P, Jeromin S, Iskas M. et al; ERIC, the European Research Initiative on CLL. Cytogenetic complexity in chronic lymphocytic leukemia: definitions, associations, and clinical impact. Blood 2019; 133 (11) 1205-1216
    CrossrefPubMedGoogle Scholar
  • 27 Guo A, Lu P, Galanina N. et al. Heightened BTK-dependent cell proliferation in unmutated chronic lymphocytic leukemia confers increased sensitivity to ibrutinib. Oncotarget 2016; 7 (04) 4598-4610
    CrossrefPubMedGoogle Scholar
  • 28 Stamatopoulos B, Smith T, Crompot E. et al. The light chain IgLV3-21 defines a new poor prognostic subgroup in chronic lymphocytic leukemia: results of a multicenter study. Clin Cancer Res 2018; 24 (20) 5048-5057
    CrossrefPubMedGoogle Scholar
  • 29 Urbanova R, Humplikova L, Drimalova H. et al. Biological and clinical characteristics of patients with chronic lymphocytic leukemia with the IGHV3-21 and IGHV1-69; analysis of data from a single center. Neoplasma 2015; 62 (04) 618-626
    CrossrefPubMedGoogle Scholar
  • 30 Cahill N, Sutton LA, Jansson M. et al. IGHV3-21 gene frequency in a Swedish cohort of patients with newly diagnosed chronic lymphocytic leukemia. Clin Lymphoma Myeloma Leuk 2012; 12 (03) 201-206
    CrossrefPubMedGoogle Scholar
  • 31 Baliakas P, Agathangelidis A, Hadzidimitriou A. et al. Not all IGHV3-21 chronic lymphocytic leukemias are equal: prognostic considerations. Blood 2015; 125 (05) 856-859
    CrossrefPubMedGoogle Scholar
  • 32 Thorsélius M, Kröber A, Murray F. et al. Strikingly homologous immunoglobulin gene rearrangements and poor outcome in VH3-21-using chronic lymphocytic leukemia patients independent of geographic origin and mutational status. Blood 2006; 107 (07) 2889-2894
    CrossrefPubMedGoogle Scholar
  • 33 Kryachok I, Abramenko I, Bilous N, Chumak A, Martina Z, Filonenko I. IGHV gene rearrangements as outcome predictors for CLL patients: experience of Ukrainian group. Med Oncol 2012; 29 (02) 1093-1101
    CrossrefPubMedGoogle Scholar
  • 34 Potter KN, Orchard J, Critchley E, Mockridge CI, Jose A, Stevenson FK. Features of the overexpressed V1-69 genes in the unmutated subset of chronic lymphocytic leukemia are distinct from those in the healthy elderly repertoire. Blood 2003; 101 (08) 3082-3084
    CrossrefPubMedGoogle Scholar
  • 35 Panovska-Stavridis I, Ivanovski M, Siljanovski N, Cevreska L, Efremov DG. Chronic lymphocytic leukemia patients with a V1-69 gene rearrangement do not have inferior survival with respect to patients that express other unmutated V(H) genes. Leuk Res 2007; 31 (02) 245-248
    CrossrefPubMedGoogle Scholar
  • 36 Sutton LA, Kostareli E, Hadzidimitriou A. et al. Extensive intraclonal diversification in a subgroup of chronic lymphocytic leukemia patients with stereotyped IGHV4-34 receptors: implications for ongoing interactions with antigen. Blood 2009; 114 (20) 4460-4468
    CrossrefPubMedGoogle Scholar
  • 37 Stanganelli C, Torres DC, Ortega C. et al. Somatic hypermutation profiles in stereotyped IGHV4-34 receptors from South American chronic lymphocytic leukemia patients. Ann Hematol 2022; 101 (02) 341-348
    CrossrefPubMedGoogle Scholar
  • 38 Karan-Djurasevic T, Palibrk V, Kostic T. et al. Mutational status and gene repertoire of IGHV-IGHD-IGHJ rearrangements in Serbian patients with chronic lymphocytic leukemia. Clin Lymphoma Myeloma Leuk 2012; 12 (04) 252-260
    CrossrefPubMedGoogle Scholar
  • 39 Sandoval-Sus JD, Chavez JC, Dalia S. et al. Association between immunoglobulin heavy-chain variable region mutational status and isolated favorable baseline genomic aberrations in chronic lymphocytic leukemia. Leuk Lymphoma 2018; 59 (01) 59-68
    CrossrefPubMedGoogle Scholar
  • 40 Gladstone DE, Swinnen L, Kasamon Y. et al. Importance of immunoglobulin heavy chain variable region mutational status in del(13q) chronic lymphocytic leukemia. Leuk Lymphoma 2011; 52 (10) 1873-1881
    CrossrefPubMedGoogle Scholar
  • 41 Kharfan-Dabaja MA, Chavez JC, Khorfan KA, Pinilla-Ibarz J. Clinical and therapeutic implications of the mutational status of IgVH in patients with chronic lymphocytic leukemia. Cancer 2008; 113 (05) 897-906
    CrossrefPubMedGoogle Scholar
  • 42 Van Dyke DL, Werner L, Rassenti LZ. et al. The Dohner fluorescence in situ hybridization prognostic classification of chronic lymphocytic leukaemia (CLL): the CLL Research Consortium experience. Br J Haematol 2016; 173 (01) 105-113
    CrossrefPubMedGoogle Scholar
  • 43 Rigolin GM, Cavallari M, Quaglia FM. et al. In CLL, comorbidities and the complex karyotype are associated with an inferior outcome independently of CLL-IPI. Blood 2017; 129 (26) 3495-3498
    CrossrefPubMedGoogle Scholar
  • 44 Rigolin GM, del Giudice I, Formigaro L. et al. Chromosome aberrations detected by conventional karyotyping using novel mitogens in chronic lymphocytic leukemia: clinical and biologic correlations. Genes Chromosomes Cancer 2015; 54 (12) 818-826
    CrossrefPubMedGoogle Scholar
  • 45 Heerema NA, Muthusamy N, Zhao Q. et al. Prognostic significance of translocations in the presence of mutated IGHV and of cytogenetic complexity at diagnosis of chronic lymphocytic leukemia. Haematologica 2021; 106 (06) 1608-1615
    CrossrefPubMedGoogle Scholar
  • 46 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
    CrossrefPubMedGoogle Scholar
  • 47 Parikh SA, Strati P, Tsang M, West CP, Shanafelt TD. Should IGHV status and FISH testing be performed in all CLL patients at diagnosis? A systematic review and meta-analysis. Blood 2016; 127 (14) 1752-1760
    CrossrefPubMedGoogle Scholar
  • 48 Nabhan C, Raca G, Wang YL. Predicting prognosis in chronic lymphocytic leukemia in the contemporary era. JAMA Oncol 2015; 1 (07) 965-974
    CrossrefPubMedGoogle Scholar