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Previous Volume 343:1910-1916 December 28, 2000 Number 26 Next

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ABSTRACT

Background Fluorescence in situ hybridization has improved the detection of genomic aberrations in chronic lymphocytic leukemia. We used this method to identify chromosomal abnormalities in patients with chronic lymphocytic leukemia and assessed their prognostic implications.

Methods Mononuclear cells from the blood of 325 patients with chronic lymphocytic leukemia were analyzed by fluorescence in situ hybridization for deletions in chromosome bands 6q21, 11q22–23, 13q14, and 17p13; trisomy of bands 3q26, 8q24, and 12q13; and translocations involving band 14q32. Molecular cytogenetic data were correlated with clinical findings.

Results Chromosomal aberrations were detected in 268 of 325 cases (82 percent). The most frequent changes were a deletion in 13q (55 percent), a deletion in 11q (18 percent), trisomy of 12q (16 percent), a deletion in 17p (7 percent), and a deletion in 6q (6 percent). Five categories were defined with a statistical model: 17p deletion, 11q deletion, 12q trisomy, normal karyotype, and 13q deletion as the sole abnormality; the median survival times for patients in these groups were 32, 79, 114, 111, and 133 months, respectively. Patients in the 17p- and 11q-deletion groups had more advanced disease than those in the other three groups. Patients with 17p deletions had the shortest median treatment-free interval (9 months), and those with 13q deletions had the longest (92 months). In multivariate analysis, the presence or absence of a 17p deletion, the presence or absence of an 11q deletion, age, Binet stage, the serum lactate dehydrogenase level, and the white-cell count gave significant prognostic information.

Conclusions Genomic aberrations in chronic lymphocytic leukemia are important independent predictors of disease progression and survival. These findings have implications for the design of risk-adapted treatment strategies.

Source Information

From the Department of Internal Medicine III University of Ulm, Ulm (H.D., S.S., E.L., A.K., L.B., K.D., M.B.); and the Deutsches Krebsforschungszentrum, Heidelberg (A.B., P.L.) — both in Germany.

Address reprint requests to Dr. Hartmut Döhner at the Department of Internal Medicine III, University of Ulm, Robert-Koch-Str. 8, 89081 Ulm, Germany, or at hartmut.doehner{at}medizin.uni-ulm.de.

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• Marasca, R., Maffei, R., Morselli, M., Zucchini, P., Castelli, I., Martinelli, S., Fontana, M., Ravanetti, S., Curotti, M., Leonardi, G., Cagossi, K., Partesotti, G., Torelli, G. (2005). Immunoglobulin Mutational Status Detected through Single-Round Amplification of Partial VH Region Represents a Good Prognostic Marker for Clinical Outcome in Chronic Lymphocytic Leukemia. J. Mol. Diagn. 7: 566-574 [Abstract] [Full Text]  
• Caballero, D., Garcia-Marco, J. A., Martino, R., Mateos, V., Ribera, J. M., Sarra, J., Leon, A., Sanz, G., de la Serna, J., Cabrera, R., Gonzalez, M., Sierra, J., San Miguel, J. (2005). Allogeneic Transplant with Reduced Intensity Conditioning Regimens may Overcome the Poor Prognosis of B-Cell Chronic Lymphocytic Leukemia with Unmutated Immunoglobulin Variable Heavy-Chain Gene and Chromosomal Abnormalities (11q- and 17p-). Clin. Cancer Res. 11: 7757-7763 [Abstract] [Full Text]  
• Calin, G. A., Ferracin, M., Cimmino, A., Di Leva, G., Shimizu, M., Wojcik, S. E., Iorio, M. V., Visone, R., Sever, N. I., Fabbri, M., Iuliano, R., Palumbo, T., Pichiorri, F., Roldo, C., Garzon, R., Sevignani, C., Rassenti, L., Alder, H., Volinia, S., Liu, C.-g., Kipps, T. J., Negrini, M., Croce, C. M. (2005). A MicroRNA Signature Associated with Prognosis and Progression in Chronic Lymphocytic Leukemia. NEJM 353: 1793-1801 [Abstract] [Full Text]  
• Oppezzo, P., Vasconcelos, Y., Settegrana, C., Jeannel, D., Vuillier, F., Legarff-Tavernier, M., Kimura, E. Y., Bechet, S., Dumas, G., Brissard, M., Merle-Beral, H., Yamamoto, M., Dighiero, G., Davi, F., for the French Cooperative Group on CLL, (2005). The LPL/ADAM29 expression ratio is a novel prognosis indicator in chronic lymphocytic leukemia. Blood 106: 650-657 [Abstract] [Full Text]  
• Sorror, M. L., Maris, M. B., Sandmaier, B. M., Storer, B. E., Stuart, M. J., Hegenbart, U., Agura, E., Chauncey, T. R., Leis, J., Pulsipher, M., McSweeney, P., Radich, J. P., Bredeson, C., Bruno, B., Langston, A., Loken, M. R., Al-Ali, H., Blume, K. G., Storb, R., Maloney, D. G. (2005). Hematopoietic Cell Transplantation After Nonmyeloablative Conditioning for Advanced Chronic Lymphocytic Leukemia. JCO 23: 3819-3829 [Abstract] [Full Text]  
• Kienle, D. L., Korz, C., Hosch, B., Benner, A., Mertens, D., Habermann, A., Krober, A., Jager, U., Lichter, P., Dohner, H., Stilgenbauer, S. (2005). Evidence for Distinct Pathomechanisms in Genetic Subgroups of Chronic Lymphocytic Leukemia Revealed by Quantitative Expression Analysis of Cell Cycle, Activation, and Apoptosis-Associated Genes. JCO 23: 3780-3792 [Abstract] [Full Text]  
• Rubio-Moscardo, F., Climent, J., Siebert, R., Piris, M. A., Martin-Subero, J. I., Nielander, I., Garcia-Conde, J., Dyer, M. J. S., Terol, M. J., Pinkel, D., Martinez-Climent, J. A. (2005). Mantle-cell lymphoma genotypes identified with CGH to BAC microarrays define a leukemic subgroup of disease and predict patient outcome. Blood 105: 4445-4454 [Abstract] [Full Text]  
• Calin, G. A., Trapasso, F., Shimizu, M., Dumitru, C. D., Yendamuri, S., Godwin, A. K., Ferracin, M., Bernardi, G., Chatterjee, D., Baldassarre, G., Rattan, S., Alder, H., Mabuchi, H., Shiraishi, T., Hansen, L. L., Overgaard, J., Herlea, V., Mauro, F. R., Dighiero, G., Movsas, B., Rassenti, L., Kipps, T., Baffa, R., Fusco, A., Mori, M., Russo, G., Liu, C.-G., Neuberg, D., Bullrich, F., Negrini, M., Croce, C. M. (2005). Familial Cancer Associated with a Polymorphism in ARLTS1. NEJM 352: 1667-1676 [Abstract] [Full Text]  
• Jahrsdorfer, B., Wooldridge, J. E., Blackwell, S. E., Taylor, C. M., Griffith, T. S., Link, B. K., Weiner, G. J. (2005). Immunostimulatory oligodeoxynucleotides induce apoptosis of B cell chronic lymphocytic leukemia cells. J. Leukoc. Biol. 77: 378-387 [Abstract] [Full Text]  
• Shanafelt, T. D., Lee, Y. K., Bone, N. D., Strege, A. K., Narayanan, V. L., Sausville, E. A., Geyer, S. M., Kaufmann, S. H., Kay, N. E. (2005). Adaphostin-induced apoptosis in CLL B cells is associated with induction of oxidative stress and exhibits synergy with fludarabine. Blood 105: 2099-2106 [Abstract] [Full Text]  
• Chiorazzi, N., Rai, K. R., Ferrarini, M. (2005). Chronic Lymphocytic Leukemia. NEJM 352: 804-815 [Full Text]  
• Nuckel, H., Rebmann, V., Durig, J., Duhrsen, U., Grosse-Wilde, H. (2005). HLA-G expression is associated with an unfavorable outcome and immunodeficiency in chronic lymphocytic leukemia. Blood 105: 1694-1698 [Abstract] [Full Text]  
• Dighiero, G. (2005). CLL Biology and Prognosis. ASH Education Book 2005: 278-284 [Abstract] [Full Text]  
• Gribben, J. G. (2005). Salvage Therapy for CLL and the Role of Stem Cell Transplantation. ASH Education Book 2005: 292-298 [Abstract] [Full Text]  
• Pettitt, A. R., Carter, A., Lin, K., Sherrington, P. D., Atherton, M., Pearson, K., Douglas, A., Burford, A., Brito-Babapulle, V., Matutes, E., Catovsky, D. (2004). Associations between Chromosomal Aberrations and Functional Impairment of the P53 Pathway in Chronic Lymphocytic Leukaemia.. ASH ANNUAL MEETING ABSTRACTS 104: 953-953 [Abstract]  
• Rodriguez, A., Martinez, N., Camacho, F. I., Ruiz-Ballesteros, E., Algara, P., Garcia, J.-F., Menarguez, J., Alvaro, T., Fresno, M. F., Solano, F., Mollejo, M., Martin, C., Piris, M. A. (2004). Variability in the Degree of Expression of Phosphorylated I{kappa}B{alpha} in Chronic Lymphocytic Leukemia Cases With Nodal Involvement. Clin. Cancer Res. 10: 6796-6806 [Abstract] [Full Text]  
• Ritgen, M., Stilgenbauer, S., von Neuhoff, N., Humpe, A., Bruggemann, M., Pott, C., Raff, T., Krober, A., Bunjes, D., Schlenk, R., Schmitz, N., Dohner, H., Kneba, M., Dreger, P. (2004). Graft-versus-leukemia activity may overcome therapeutic resistance of chronic lymphocytic leukemia with unmutated immunoglobulin variable heavy-chain gene status: implications of minimal residual disease measurement with quantitative PCR. Blood 104: 2600-2602 [Abstract] [Full Text]  
• Haslinger, C., Schweifer, N., Stilgenbauer, S., Dohner, H., Lichter, P., Kraut, N., Stratowa, C., Abseher, R. (2004). Microarray Gene Expression Profiling of B-Cell Chronic Lymphocytic Leukemia Subgroups Defined by Genomic Aberrations and VH Mutation Status. JCO 22: 3937-3949 [Abstract] [Full Text]  
• Montserrat, E. (2004). Assessing prognosis in patients with chronic lymphocytic leukemia a quarter of a century after Rai and Binet staging systems. Ann Oncol 15: 1450-1451 [Full Text]  
• Goldin, L. R., Pfeiffer, R. M., Li, X., Hemminki, K. (2004). Familial risk of lymphoproliferative tumors in families of patients with chronic lymphocytic leukemia: results from the Swedish Family-Cancer Database. Blood 104: 1850-1854 [Abstract] [Full Text]  
• Rosenwald, A., Chuang, E. Y., Davis, R. E., Wiestner, A., Alizadeh, A. A., Arthur, D. C., Mitchell, J. B., Marti, G. E., Fowler, D. H., Wilson, W. H., Staudt, L. M. (2004). Fludarabine treatment of patients with chronic lymphocytic leukemia induces a p53-dependent gene expression response. Blood 104: 1428-1434 [Abstract] [Full Text]  
• Calin, G. A., Liu, C.-G., Sevignani, C., Ferracin, M., Felli, N., Dumitru, C. D., Shimizu, M., Cimmino, A., Zupo, S., Dono, M., Dell'Aquila, M. L., Alder, H., Rassenti, L., Kipps, T. J., Bullrich, F., Negrini, M., Croce, C. M. (2004). MicroRNA profiling reveals distinct signatures in B cell chronic lymphocytic leukemias. Proc. Natl. Acad. Sci. USA 101: 11755-11760 [Abstract] [Full Text]  
• Kohlhammer, H., Schwaenen, C., Wessendorf, S., Holzmann, K., Kestler, H. A., Kienle, D., Barth, T. F. E., Moller, P., Ott, G., Kalla, J., Radlwimmer, B., Pscherer, A., Stilgenbauer, S., Dohner, H., Lichter, P., Bentz, M. (2004). Genomic DNA-chip hybridization in t(11;14)-positive mantle cell lymphomas shows a high frequency of aberrations and allows a refined characterization of consensus regions. Blood 104: 795-801 [Abstract] [Full Text]  
• Rassidakis, G. Z., Lai, R., Herling, M., Cromwell, C., Schmitt-Graeff, A., Medeiros, L. J. (2004). Retinoblastoma Protein Is Frequently Absent or Phosphorylated in Anaplastic Large-Cell Lymphoma. Am. J. Pathol. 164: 2259-2267 [Abstract] [Full Text]  
• Lozanski, G., Heerema, N. A., Flinn, I. W., Smith, L., Harbison, J., Webb, J., Moran, M., Lucas, M., Lin, T., Hackbarth, M. L., Proffitt, J. H., Lucas, D., Grever, M. R., Byrd, J. C. (2004). Alemtuzumab is an effective therapy for chronic lymphocytic leukemia with p53 mutations and deletions. Blood 103: 3278-3281 [Abstract] [Full Text]  
• Rush, L. J., Raval, A., Funchain, P., Johnson, A. J., Smith, L., Lucas, D. M., Bembea, M., Liu, T.-H., Heerema, N. A., Rassenti, L., Liyanarachchi, S., Davuluri, R., Byrd, J. C., Plass, C. (2004). Epigenetic Profiling in Chronic Lymphocytic Leukemia Reveals Novel Methylation Targets. Cancer Res. 64: 2424-2433 [Abstract] [Full Text]  
• Dreger, P., Stilgenbauer, S., Benner, A., Ritgen, M., Krober, A., Kneba, M., Schmitz, N., Dohner, H. (2004). The prognostic impact of autologous stem cell transplantation in patients with chronic lymphocytic leukemia: a risk-matched analysis based on the VH gene mutational status. Blood 103: 2850-2858 [Abstract] [Full Text]  
• Shanafelt, T. D., Geyer, S. M., Kay, N. E. (2004). Prognosis at diagnosis: integrating molecular biologic insights into clinical practice for patients with CLL. Blood 103: 1202-1210 [Abstract] [Full Text]  
• Schwaenen, C., Nessling, M., Wessendorf, S., Salvi, T., Wrobel, G., Radlwimmer, B., Kestler, H. A., Haslinger, C., Stilgenbauer, S., Dohner, H., Bentz, M., Lichter, P. (2004). Automated array-based genomic profiling in chronic lymphocytic leukemia: Development of a clinical tool and discovery of recurrent genomic alterations. Proc. Natl. Acad. Sci. USA 101: 1039-1044 [Abstract] [Full Text]  
• Byrd, J. C., Stilgenbauer, S., Flinn, I. W. (2004). Chronic Lymphocytic Leukemia. ASH Education Book 2004: 163-183 [Abstract] [Full Text]  
• Vasconcelos, Y., Davi, F., Levy, V., Oppezzo, P., Magnac, C., Michel, A., Yamamoto, M., Pritsch, O., Merle-Beral, H., Maloum, K., Ajchenbaum-Cymbalista, F., Dighiero, G. (2003). Binet's Staging System and VH Genes Are Independent but Complementary Prognostic Indicators in Chronic Lymphocytic Leukemia. JCO 21: 3928-3932 [Abstract] [Full Text]  
• Albesiano, E., Messmer, B. T., Damle, R. N., Allen, S. L., Rai, K. R., Chiorazzi, N. (2003). Activation-induced cytidine deaminase in chronic lymphocytic leukemia B cells: expression as multiple forms in a dynamic, variably sized fraction of the clone. Blood 102: 3333-3339 [Abstract] [Full Text]  
• Kienle, D., Krober, A., Katzenberger, T., Ott, G., Leupolt, E., Barth, T. F. E., Moller, P., Benner, A., Habermann, A., Muller-Hermelink, H. K., Bentz, M., Lichter, P., Dohner, H., Stilgenbauer, S. (2003). VH mutation status and VDJ rearrangement structure in mantle cell lymphoma: correlation with genomic aberrations, clinical characteristics, and outcome. Blood 102: 3003-3009 [Abstract] [Full Text]