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IGHV gene mutational status and LPL/ADAM29 gene expression as clinical outcome predictors in CLL patients in remission following treatment with oral fludarabine plus cyclophosphamide

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Abstract

Several prognostic factors can predict the rapid progression in chronic lymphocytic leukaemia (CLL), including IGHV mutational status, cytogenetic abnormalities and, more recently, LPL/ADAM29 expression. In contrast, few studies have been devoted to the influence of these factors on clinical outcome in responding patients after therapy. We here propose to analyse the impact of IGHV gene status, LPL and ADAM29 gene expression on disease-free survival (DFS) and overall survival (OS) in 41 stage B or C CLL patients in remission after oral fludarabine plus cyclophosphamide. The median follow-up was of 64 (16–74) months. Sequencing of IGHV showed mutated (M) VH genes in 16 of 41 cases and unmutated (UM) in 25 cases. Analysis of LPL and ADAM29 expression in 35 of 41 cases showed overexpression of ADAM29 in 17 cases (14 M and three UM) and LPL in 18 cases (all UM). Patients expressing UM IGHV and LPL had shorter DFS and OS when compared to patients expressing M IGHV and/or ADAM29. Furthermore, blood minimal residual disease (MRD) evaluation using four-colour flow cytometry was performed in 33 out the 41 patients. We showed that patients who achieved phenotypic remission displayed longer DFS than those with MRD+. Our results support the use of LPL and ADAM29 gene expression associated to IGHV mutational status for predicting the clinical outcome of patients treated by oral fludarabine + cyclophosphamide and could be considered for treatment strategies.

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References

  1. Binet JL, Auquier A, Dighiero G, Chastang C, Piguet H, Goasguen J, Vaugier G, Potron G, Colona P, Oberling F, Thomas M, Tchernia G, Jacquillat C, Boivin P, Lesty C, Duault MT, Monconduit M, Belabbes S, Gremy F (1981) A new prognostic classification of chronic lymphocytic leukemia derived from a multivariate survival analysis. Cancer 48:198–206. doi:10.1002/1097-0142(19810701)48:1<198::AID-CNCR2820480131>3.0.CO;2-V

    Article  CAS  PubMed  Google Scholar 

  2. Byrd JC, Gribben JG, Peterson BL, Grever MR, Lozanski G, Lucas DM, Lampson B, Larson RA, Caligiuri MA, Heerema NA (2006) Select high-risk genetic features predict earlier progression following chemoimmunotherapy with fludarabine and rituximab in chronic lymphocytic leukemia: justification for risk-adapted therapy. J Clin Oncol 24:437–443. doi:10.1200/JCO.2005.03.1021

    Article  CAS  PubMed  Google Scholar 

  3. Cazin B, Divine M, Lepretre S, Travade P, Tournilhac O, Delmer A, Jaubert J, Feugier P, Dreyfus B, Mahe B, Grosbois B, Maloisel F, Eghbali H, Dumontet C, Benichou J, Guibon O, Leleu X, Leporrier M, Maloum K (2008) High efficacy with five days schedule of oral fludarabine phosphate and cyclophosphamide in patients with previously untreated chronic lymphocytic leukaemia. Br J Haematol 143:54–59. doi:10.1111/j.1365-2141.2008.07309.x

    Article  CAS  PubMed  Google Scholar 

  4. Cheson BD, Bennett JM, Grever M, Kay N, Keating MJ, O'Brien S, Rai KR (1996) National Cancer Institute-Sponsored Working Group guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis and treatment. Blood 87:4990–4997

    CAS  PubMed  Google Scholar 

  5. Crespo M, Bosch F, Villamor N, Bellosillo B, Colomer D, Rozman M, Marce S, Lopez-Guillermo A, Campo E, Montserrat E (2003) ZAP-70 expression as a surrogate for immunoglobulin-variable-region mutations in chronic lymphocytic leukemia. N Engl J Med 348:1764–1775. doi:10.1056/NEJMoa023143

    Article  CAS  PubMed  Google Scholar 

  6. Damle RN, Wasil T, Fais F, Ghiotto F, Valetto A, Allen SL, Buchbinder A, Budman D, Dittmar K, Kolitz J, Lichtman SM, Schulman P, Vinciguerra VP, Rai KR, Ferrarini M, Chiorazzi N (1999) Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia. Blood 94:1840–1847

    CAS  PubMed  Google Scholar 

  7. Dighiero G, Travade P, Chevret S, Fenaux P, Chastang C, Binet JL (1991) B-cell chronic lymphocytic leukemia: present status and future directions. French Cooperative Group on CLL. Blood 78:1901–1914

    CAS  PubMed  Google Scholar 

  8. Dohner H, Stilgenbauer S, Benner A, Leupolt E, Krober A, Bullinger L, Dohner K, Bentz M, Lichter P (2000) Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med 343:1910–1916. doi:10.1056/NEJM200012283432602

    Article  CAS  PubMed  Google Scholar 

  9. Grever MR, Lucas DM, Dewald GW, Neuberg DS, Reed JC, Kitada S, Flinn IW, Tallman MS, Appelbaum FR, Larson RA, Paietta E, Jelinek DF, Gribben JG, Byrd JC (2007) Comprehensive assessment of genetic and molecular features predicting outcome in patients with chronic lymphocytic leukemia: results from the US Intergroup Phase III Trial E2997. J Clin Oncol 25:799–804. doi:10.1200/JCO.2006.08.3089

    Article  CAS  PubMed  Google Scholar 

  10. Hallek M, Langenmayer I, Nerl C, Knauf W, Dietzfelbinger H, Adorf D, Ostwald M, Busch R, Kuhn-Hallek I, Thiel E, Emmerich B (1999) Elevated serum thymidine kinase levels identify a subgroup at high risk of disease progression in early, nonsmoldering chronic lymphocytic leukemia. Blood 93:1732–1737

    CAS  PubMed  Google Scholar 

  11. Hamblin TJ, Davis Z, Gardiner A, Oscier DG, Stevenson FK (1999) Unmutated Ig V(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood 94:1848–1854

    CAS  PubMed  Google Scholar 

  12. Heintel D, Kienle D, Shehata M, Krober A, Kroemer E, Schwarzinger I, Mitteregger D, Le T, Gleiss A, Mannhalter C, Chott A, Schwarzmeier J, Fonatsch C, Gaiger A, Dohner H, Stilgenbauer S, Jager U (2005) High expression of lipoprotein lipase in poor risk B-cell chronic lymphocytic leukemia. Leukemia 19:1216–1223. doi:10.1038/sj.leu.2403748

    Article  CAS  PubMed  Google Scholar 

  13. Keating MJ, O'Brien S, Robertson L, Huh Y, Kantarjian H, Plunkett W (1993) Chronic lymphocytic leukemia—correlation of response and survival. Leuk Lymphoma 11(Suppl 2):167–175. doi:10.3109/10428199309064278

    Article  PubMed  Google Scholar 

  14. Laurenti L, Tarnani M, De Padua L, Efremov DG, Zini G, Garzia M, Piccirillo N, Chiusolo P, Sora F, Innocenti I, Sica S, Leone G (2008) Oral fludarabine and cyclophosphamide as front-line chemotherapy in patients with chronic lymphocytic leukemia. The impact of biological parameters in the response duration. Ann Hematol 87:891–898

    Article  CAS  PubMed  Google Scholar 

  15. Maloum K, Charlotte F, Divine M, Cazin B, Lesty C, Merle-Beral H (2006) A comparison of the sensitivity of flow cytometry and bone marrow biopsy in the detection of minimal residual disease in chronic lymphocytic leukemia. Haematologica 91:860–861

    PubMed  Google Scholar 

  16. Maloum K, Davi F, Merle-Beral H, Pritsch O, Magnac C, Vuillier F, Dighiero G, Troussard X, Mauro FF, Benichou J (2000) Expression of unmutated VH genes is a detrimental prognostic factor in chronic lymphocytic leukemia. Blood 96:377–379

    CAS  PubMed  Google Scholar 

  17. Maloum K, Sutton L, Baudet S, Laurent C, Bonnemye P, Magnac C, Merle-Beral H (2002) Novel flow-cytometric analysis based on BCD5+ subpopulations for the evaluation of minimal residual disease in chronic lymphocytic leukaemia. Br J Haematol 119:970–975. doi:10.1046/j.1365-2141.2002.03956.x

    Article  PubMed  Google Scholar 

  18. Moreton P, Kennedy B, Lucas G, Leach M, Rassam SM, Haynes A, Tighe J, Oscier D, Fegan C, Rawstron A, Hillmen P (2005) Eradication of minimal residual disease in B-cell chronic lymphocytic leukemia after alemtuzumab therapy is associated with prolonged survival. J Clin Oncol 23:2971–2979. doi:10.1200/JCO.2005.04.021

    Article  CAS  PubMed  Google Scholar 

  19. Nikitin EA, Malakho SG, Biderman BV, Baranova AV, Lorie YY, Shevelev AY, Peklo MM, Vlasik TN, Moskalev EA, Zingerman BV, Vorob'ev IA, Poltaraus AB, Sudarikov AB, Vorobjev AI (2007) Expression level of lipoprotein lipase and dystrophin genes predict survival in B-cell chronic lymphocytic leukemia. Leuk Lymphoma 48:912–922. doi:10.1080/10428190701245112

    Article  CAS  PubMed  Google Scholar 

  20. Nuckel H, Huttmann A, Klein-Hitpass L, Schroers R, Fuhrer A, Sellmann L, Duhrsen U, Durig J (2006) Lipoprotein lipase expression is a novel prognostic factor in B-cell chronic lymphocytic leukemia. Leuk Lymphoma 47:1053–1061. doi:10.1080/10428190500464161

    Article  PubMed  CAS  Google Scholar 

  21. Oppezzo P, Vasconcelos Y, Settegrana C, Jeannel D, Vuillier F, Legarff-Tavernier M, Kimura EY, Bechet S, Dumas G, Brissard M, Merle-Beral H, Yamamoto M, Dighiero G, Davi F (2005) The LPL/ADAM29 expression ratio is a novel prognosis indicator in chronic lymphocytic leukemia. Blood 106:650–657. doi:10.1182/blood-2004-08-3344

    Article  CAS  PubMed  Google Scholar 

  22. Oscier DG, Gardiner AC, Mould SJ, Glide S, Davis ZA, Ibbotson RE, Corcoran MM, Chapman RM, Thomas PW, Copplestone JA, Orchard JA, Hamblin TJ (2002) 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 100:1177–1184

    CAS  PubMed  Google Scholar 

  23. Pritsch O, Troussard X, Magnac C, Mauro FR, Davi F, Payelle-Brogard B, Dumas G, Pulik M, Clerget F, Mandelli F, Chiorazzi N, Schroeder HW Jr, Leporrier M, Dighiero G (1999) VH gene usage by family members affected with chronic lymphocytic leukaemia. Br J Haematol 107:616–624. doi:10.1046/j.1365-2141.1999.01757.x

    Article  CAS  PubMed  Google Scholar 

  24. Rai KR, Sawitsky A, Cronkite EP, Chanana AD, Levy RN, Pasternack BS (1975) Clinical staging of chronic lymphocytic leukemia. Blood 46:219–234

    CAS  PubMed  Google Scholar 

  25. Rawstron AC, Kennedy B, Evans PA, Davies FE, Richards SJ, Haynes AP, Russell NH, Hale G, Morgan GJ, Jack AS, Hillmen P (2001) Quantitation of minimal disease levels in chronic lymphocytic leukemia using a sensitive flow cytometric assay improves the prediction of outcome and can be used to optimize therapy. Blood 98:29–35. doi:10.1182/blood.V98.1.29

    Article  CAS  PubMed  Google Scholar 

  26. Sarfati M, Chevret S, Chastang C, Biron G, Stryckmans P, Delespesse G, Binet JL, Merle-Beral H, Bron D (1996) Prognostic importance of serum soluble CD23 level in chronic lymphocytic leukemia. Blood 88:4259–4264

    CAS  PubMed  Google Scholar 

  27. van't Veer MB, Brooijmans AM, Langerak AW, Verhaaf B, Goudswaard CS, Graveland WJ, van Lom K, Valk PJ (2006) The predictive value of lipoprotein lipase for survival in chronic lymphocytic leukemia. Haematologica 91:56–63

    PubMed  Google Scholar 

  28. Van Bockstaele F, Pede V, Janssens A, Callewaert F, Offner F, Verhasselt B, Philippe J (2007) Lipoprotein lipase mRNA expression in whole blood is a prognostic marker in B cell chronic lymphocytic leukemia. Clin Chem 53:204–212. doi:10.1373/clinchem.2006.076331

    Article  PubMed  CAS  Google Scholar 

  29. Weiss MA, Glenn M, Maslak P, Rahman Z, Noy A, Zelenetz A, Scheinberg DA, Golde DW (2000) Consolidation therapy with high-dose cyclophosphamide improves the quality of response in patients with chronic lymphocytic leukemia treated with fludarabine as induction therapy. Leukemia 14:1577–1582. doi:10.1038/sj.leu.2401892

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Service d’Hématologie Biologique, CHU Pitié-Salpêtrière, Paris, France

    Karim Maloum, Catherine Settegrana, Elise Chapiro, Florence Nguyen-Khac, Claude Lesty, Frederic Davi & Hélène Merle-Béral

  2. Service des maladies du sang, CHRU de Lille Hôpital Huriez, Lille, France

    Bruno Cazin

  3. CLCC H. Becquerel, Rouen, France

    Stéphane Leprêtre

  4. Service d’Hématologie Clinique, Hôpital de Reims, Reims, France

    Alain Delmer

  5. Service d’Hématologie Clinique, Hôpital Clémenceau, Caen, France

    Michel Leporrier

  6. Service d’Hématologie Clinique, CHU La Milétrie, Poitiers, France

    Brigitte Dreyfus

  7. Service d’Hématologie Clinique, Hôtel-Dieu, CHU de Clermont Ferrand, France

    Olivier Tournilhac

  8. Service Hématologie Clinique, CHU Hôtel Dieu, Nantes, France

    Beatrice Mahe

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  1. Karim Maloum
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Correspondence to Karim Maloum.

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Maloum, K., Settegrana, C., Chapiro, E. et al. IGHV gene mutational status and LPL/ADAM29 gene expression as clinical outcome predictors in CLL patients in remission following treatment with oral fludarabine plus cyclophosphamide. Ann Hematol 88, 1215–1221 (2009). https://doi.org/10.1007/s00277-009-0742-6

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  • DOI: https://doi.org/10.1007/s00277-009-0742-6

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