Abstract
We examined the significance of IgM peaks in chronic lymphocytic leukemia (CLL), including its association with newly reported MYD88, BIRC3, NOTCH1 and SF3B1 mutations. A total of 27, 25, 41 and 57 patients with monoclonal IgM or IgG peaks (IgM and IgG groups), hypogammaglobulinemia (Hypo-γ group) and normal immunoglobulin serum levels (normal-γ group) were, respectively, included. IgM peaks were mainly associated with Binet stage C and the del(17p). Biased usage of IGHV3-48 was shared by both IgM and IgG groups. IGHV3-74 and IGHV4-39 gene rearrangements were specific for IgM and IgG peaks, respectively. SF3B1, NOTCH1, MYD88 and BIRC3 mutation frequencies were 12%, 4%, 2% and 2%, respectively, being over-represented in IgM, IgG and Hypo-γ groups for SF3B1, and being equal between normal-γ and IgM groups for MYD88. Overall, 76%, 87%, 49% and 42% of cases from IgM, IgG, Hypo-γ and normal-γ groups had at least one intermediate or poor prognosis genetic marker, respectively. By multivariate analysis, IgM peaks were associated with shorter treatment-free survival independently from any other univariate poor prognosis biological parameters, including IgG peaks, Hypo-γ, IGHV status, SF3B1 mutations, cytogenetics and lymphocytosis. Therefore, as with IgG peaks, IgM peaks aggravated the natural course of CLL, with increased accumulation of adverse genetic events.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Butler T, Gribben JG . Biologic and clinical significance of molecular profiling in Chronic Lymphocytic Leukemia. Blood Rev 2010; 24: 135–141.
Rosenquist R, Cortese D, Bhoi S, Mansouri L, Gunnarsson R . Prognostic markers and their clinical applicability in chronic lymphocytic leukemia: where do we stand? Leuk Lymphoma 2013; 54: 2351–2364.
Van Bockstaele F, Verhasselt B, Philippé J . Prognostic markers in chronic lymphocytic leukemia: a comprehensive review. Blood Rev 2009; 23: 25–47.
Fabbri G, Rasi S, Rossi D, Trifonov V, Khiabanian H, Ma J et al. Analysis of the chronic lymphocytic leukemia coding genome: role of NOTCH1 mutational activation. J Exp Med 2011; 208: 1389–1401.
Rossi D, Bruscaggin A, Spina V, Rasi S, Khiabanian H, Messina M et al. Mutations of the SF3B1 splicing factor in chronic lymphocytic leukemia: association with progression and fludarabine-refractoriness. Blood 2011; 118: 6904–6908.
Rossi D, Fangazio M, Rasi S, Vaisitti T, Monti S, Cresta S et al. Disruption of BIRC3 associates with fludarabine chemorefractoriness in TP53 wild-type chronic lymphocytic leukemia. Blood 2012; 119: 2854–2862.
Rossi D, Rasi S, Spina V, Bruscaggin A, Monti S, Ciardullo C et al. Integrated mutational and cytogenetic analysis identifies new prognostic subgroups in chronic lymphocytic leukemia. Blood 2013; 121: 1403–1412.
Jeromin S, Weissmann S, Haferlach C, Dicker F, Bayer K, Grossmann V et al. SF3B1 mutations correlated to cytogenetics and mutations in NOTCH1, FBXW7, MYD88, XPO1 and TP53 in 1160 untreated CLL patients. Leukemia 2013; 28: 108–117.
Landau DA, Carter SL, Stojanov P, McKenna A, Stevenson K, Lawrence MS et al. Evolution and impact of subclonal mutations in chronic lymphocytic leukemia. Cell 2013; 152: 714–726.
Treon SP . XIII. Waldenström’s macroglobulinaemia: an indolent B-cell lymphoma with distinct molecular and clinical features. Hematol Oncol 2013; 31 (Suppl 1): 76–80.
Wang H, Chen Y, Li F, Delasalle K, Wang J, Alexanian R et al. Temporal and geographic variations of Waldenstrom macroglobulinemia incidence: a large population-based study. Cancer 2012; 118: 3793–3800.
Treon SP, Hunter ZR . A new era for Waldenstrom macroglobulinemia: MYD88 L265P. Blood 2013; 121: 4434–4436.
Gachard N, Parrens M, Soubeyran I, Petit B, Marfak A, Rizzo D et al. IGHV gene features and MYD88 L265P mutation separate the three marginal zone lymphoma entities and Waldenström macroglobulinemia/lymphoplasmacytic lymphomas. Leukemia 2013; 27: 183–189.
Pangalis GA, Kyrtsonis M-C, Kontopidou FN, Siakantaris MP, Dimopoulou MN, Vassilakopoulos TP et al. Differential diagnosis of Waldenstrom’s macroglobulinemia and other B-cell disorders. Clin Lymphoma 2005; 5: 235–240.
McMaster ML, Landgren O . Prevalence, clinical aspects, and natural history of IgM MGUS. Cytometry B Clin Cytom 2010; 78 (Suppl 1): S91–S97.
Kyle RA, Therneau TM, Rajkumar SV, Remstein ED, Offord JR, Larson DR et al. Long-term follow-up of IgM monoclonal gammopathy of undetermined significance. Blood 2003; 102: 3759–3764.
Chng WJ, Schop RF, Price-Troska T, Ghobrial I, Kay N, Jelinek DF et al. Gene-expression profiling of Waldenstrom macroglobulinemia reveals a phenotype more similar to chronic lymphocytic leukemia than multiple myeloma. Blood 2006; 108: 2755–2763.
Gutiérrez NC, Ocio EM, de Las Rivas J, Maiso P, Delgado M, Fermiñán E et al. Gene expression profiling of B lymphocytes and plasma cells from Waldenström’s macroglobulinemia: comparison with expression patterns of the same cell counterparts from chronic lymphocytic leukemia, multiple myeloma and normal individuals. Leukemia 2007; 21: 541–549.
Vardi A, Agathangelidis A, Sutton L-A, Chatzouli M, Scarfò L, Mansouri L et al. IgG-Switched CLL has a distinct immunogenetic signature from the common MD Variant: ontogenetic implications. Clin Cancer Res Off J Am Assoc Cancer Res 2014; 20: 323–330.
Xu W, Wang Y-H, Fan L, Fang C, Zhu D-X, Wang D-M et al. Prognostic significance of serum immunoglobulin paraprotein in patients with chronic lymphocytic leukemia. Leuk Res 2011; 35: 1060–1065.
Oscier DG, Stevens J, Hamblin TJ, Pickering RM, Lambert R, Fitchett M . Correlation of chromosome abnormalities with laboratory features and clinical course in B-cell chronic lymphocytic leukaemia. Br J Haematol 1990; 76: 352–358.
Van Dongen JJM, Langerak AW, Brüggemann M, Evans PAS, Hummel M, Lavender FL et al. Design and standardization of PCR primers and protocols for detection of clonal immunoglobulin and T-cell receptor gene recombinations in suspect lymphoproliferations: report of the BIOMED-2 Concerted Action BMH4-CT98-3936. Leukemia 2003; 17: 2257–2317.
Lossos IS, Alizadeh AA, Eisen MB, Chan WC, Brown PO, Botstein D et al. Ongoing immunoglobulin somatic mutation in germinal center B cell-like but not in activated B cell-like diffuse large cell lymphomas. Proc Natl Acad Sci USA 2000; 97: 10209–10213.
Döhner H, Stilgenbauer S, Benner A, Leupolt E, Kröber A, Bullinger L et al. Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med 2000; 343: 1910–1916.
Bastard C, Raux G, Fruchart C, Parmentier F, Vaur D, Penther D et al. Comparison of a quantitative PCR method with FISH for the assessment of the four aneuploidies commonly evaluated in CLL patients. Leukemia 2007; 21: 1460–1463.
Rizzo D, Lotay A, Gachard N, Marfak I, Faucher J-L, Trimoreau F et al. Very low levels of surface CD45 reflect CLL cell fragility, are inversely correlated with trisomy 12 and are associated with increased treatment-free survival. Am J Hematol 2013; 88: 747–753.
Dighiero G, Travade P, Chevret S, Fenaux P, Chastang C, Binet JL . B-cell chronic lymphocytic leukemia: present status and future directions. French Cooperative Group on CLL. Blood 1991; 78: 1901–1914.
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: 1848–1854.
Damle RN, Wasil T, Fais F, Ghiotto F, Valetto A, Allen SL et al. Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia. Blood 1999; 94: 1840–1847.
Gachard N, Salviat A, Boutet C, Arnoulet C, Durrieu F, Lenormand B et al. Multicenter study of ZAP-70 expression in patients with B-cell chronic lymphocytic leukemia using an optimized flow cytometry method. Haematologica 2008; 93: 215–223.
Victor Hoffbrand A, Hamblin TJ . Is « leukemia » an appropriate label for all patients who meet the diagnostic criteria of chronic lymphocytic leukemia? Leuk Res 2007; 31: 273–275.
Del Giudice I, Mauro FR, De Propris MS, Santangelo S, Marinelli M, Peragine N et al. White blood cell count at diagnosis and immunoglobulin variable region gene mutations are independent predictors of treatment-free survival in young patients with stage A chronic lymphocytic leukemia. Haematologica 2011; 96: 626–630.
Agathangelidis A, Darzentas N, Hadzidimitriou A, Brochet X, Murray F, Yan X-J et al. Stereotyped B-cell receptors in one-third of chronic lymphocytic leukemia: a molecular classification with implications for targeted therapies. Blood 2012; 119: 4467–4475.
Strefford JC, Sutton L-A, Baliakas P, Agathangelidis A, Malčíková J, Plevova K et al. Distinct patterns of novel gene mutations in poor-prognostic stereotyped subsets of chronic lymphocytic leukemia: the case of SF3B1 and subset #2. Leukemia 2013; 27: 2196–2199.
Lin P, Hao S, Handy BC, Bueso-Ramos CE, Medeiros LJ . Lymphoid neoplasms associated with IgM paraprotein: a study of 382 patients. Am J Clin Pathol 2005; 123: 200–205.
Xu L, Hunter ZR, Yang G, Zhou Y, Cao Y, Liu X et al. MYD88 L265P in Waldenström macroglobulinemia, immunoglobulin M monoclonal gammopathy, and other B-cell lymphoproliferative disorders using conventional and quantitative allele-specific polymerase chain reaction. Blood 2013; 121: 2051–2058.
Jiménez C, Sebastián E, Chillón MC, Giraldo P, Mariano Hernández J, Escalante F et al. MYD88 L265P is a marker highly characteristic of, but not restricted to, Waldenström’s macroglobulinemia. Leukemia 2013; 27: 1722–1728.
Pratt G, Harding S, Holder R, Fegan C, Pepper C, Oscier D et al. Abnormal serum free light chain ratios are associated with poor survival and may reflect biological subgroups in patients with chronic lymphocytic leukaemia. Br J Haematol 2009; 144: 217–222.
Hojjat-Farsangi M, Jeddi-Tehrani M, Razavi SM, Sharifian RA, Mellstedt H, Shokri F et al. Immunoglobulin heavy chain variable region gene usage and mutational status of the leukemic B cells in Iranian patients with chronic lymphocytic leukemia. Cancer Sci 2009; 100: 2346–2353.
Rossi D, Cerri M, Capello D, Deambrogi C, Rossi FM, Zucchetto A et al. Biological and clinical risk factors of chronic lymphocytic leukaemia transformation to Richter syndrome. Br J Haematol 2008; 142: 202–215.
Rossi D, Spina V, Bomben R, Rasi S, Dal-Bo M, Bruscaggin A et al. Association between molecular lesions and specific B-cell receptor subsets in chronic lymphocytic leukemia. Blood 2013; 121: 4902–4905.
Zibellini S, Capello D, Forconi F, Marcatili P, Rossi D, Rattotti S et al. Stereotyped patterns of B-cell receptor in splenic marginal zone lymphoma. Haematologica 2010; 95: 1792–1796.
Warsame AA, Aasheim H-C, Nustad K, Trøen G, Tierens A, Wang V et al. Splenic marginal zone lymphoma with VH1-02 gene rearrangement expresses poly- and self-reactive antibodies with similar reactivity. Blood 2011; 118: 3331–3339.
Bikos V, Darzentas N, Hadzidimitriou A, Davis Z, Hockley S, Traverse-Glehen A et al. Over 30% of patients with splenic marginal zone lymphoma express the same immunoglobulin heavy variable gene: ontogenetic implications. Leukemia 2012; 26: 1638–1646.
Cortese D, Sutton L-A, Cahill N, Smedby KE, Geisler C, Gunnarsson R et al. On the way towards a « CLL prognostic index »: focus on TP53, BIRC3, SF3B1, NOTCH1 and MYD88 in a population-based cohort. Leukemia 2013; 28: 710–713.
Puente XS, Pinyol M, Quesada V, Conde L, Ordóñez GR, Villamor N et al. Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia. Nature 2011; 475: 101–105.
Di Ianni M, Baldoni S, Rosati E, Ciurnelli R, Cavalli L, Martelli MF et al. A new genetic lesion in B-CLL: a NOTCH1 PEST domain mutation. Br J Haematol 2009; 146: 689–691.
Sportoletti P, Baldoni S, Cavalli L, Del Papa B, Bonifacio E, Ciurnelli R et al. NOTCH1 PEST domain mutation is an adverse prognostic factor in B-CLL. Br J Haematol 2010; 151: 404–406.
Wang L, Lawrence MS, Wan Y, Stojanov P, Sougnez C, Stevenson K et al. SF3B1 and other novel cancer genes in chronic lymphocytic leukemia. N Engl J Med 2011; 365: 2497–2506.
Villamor N, Conde L, Martínez-Trillos A, Cazorla M, Navarro A, Beà S et al. NOTCH1 mutations identify a genetic subgroup of chronic lymphocytic leukemia patients with high risk of transformation and poor outcome. Leukemia 2013; 27: 1100–1106.
Balatti V, Bottoni A, Palamarchuk A, Alder H, Rassenti LZ, Kipps TJ et al. NOTCH1 mutations in CLL associated with trisomy 12. Blood 2012; 119: 329–331.
Maurer MJ, Cerhan JR, Katzmann JA, Link BK, Allmer C, Zent CS et al. Monoclonal and polyclonal serum free light chains and clinical outcome in chronic lymphocytic leukemia. Blood 2011; 118: 2821–2826.
Hamblin TJ, Oscier DG, Stevens JR, Smith JL . Long survival in B-CLL correlates with surface IgM kappa phenotype. Br J Haematol 1987; 66: 21–26.
Yin CC, Lin P, Carney DA, Handy BC, Rassidakis GZ, Admirand JH et al. Chronic lymphocytic leukemia/small lymphocytic lymphoma associated with IgM paraprotein. Am J Clin Pathol 2005; 123: 594–602.
Shvidel L, Tadmor T, Braester A, Bairey O, Rahimi-Levene N, Herishanu Y et al. Serum immunoglobulin levels at diagnosis have no prognostic significance in stage A chronic lymphocytic leukemia: a study of 1113 cases from the Israeli CLL Study Group. Eur J Haematol 2014; 93: 29–33.
Rozman C, Montserrat E, Viñolas N . Serum immunoglobulins in B-chronic lymphocytic leukemia. Natural history and prognostic significance. Cancer 1988; 61: 279–283.
Letestu R, Lévy V, Eclache V, Baran-Marszak F, Vaur D, Naguib D et al. Prognosis of Binet stage A chronic lymphocytic leukemia patients: the strength of routine parameters. Blood 2010; 116: 4588–4590.
Codony C, Crespo M, Abrisqueta P, Montserrat E, Bosch F . Gene expression profiling in chronic lymphocytic leukaemia. Best Pract Res Clin Haematol 2009; 22: 211–222.
Ramsay AD, Rodriguez-Justo M . Chronic lymphocytic leukaemia—the role of the microenvironment pathogenesis and therapy. Br J Haematol 2013; 162: 15–24.
Acknowledgements
We thank Dr Jeanne Cook-Moreau for careful scientific rereading of the manuscript and English editing. We thank Pr Annick Rousseau for biostatistical analysis of the manuscript. We thank the French tumor bank of University Campus Hospital of Limoges and Angers for providing biological material. We thank Mrs Emilie Villeger (Laboratoire d’Hématologie, CHU Dupuytren, Limoges, France) for excellent technical help. We thank Comités Limousin de la Ligue contre le Cancer and Comité d’Orientation de la Recherche sur le Cancer en Limousin for their financial support.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Additional information
Supplementary Information accompanies this paper on the Leukemia website
Supplementary information
Rights and permissions
About this article
Cite this article
Rizzo, D., Chauzeix, J., Trimoreau, F. et al. IgM peak independently predicts treatment-free survival in chronic lymphocytic leukemia and correlates with accumulation of adverse oncogenetic events. Leukemia 29, 337–345 (2015). https://doi.org/10.1038/leu.2014.198
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/leu.2014.198
This article is cited by
-
Loss of AID exacerbates the malignant progression of CLL
Leukemia (2022)