Fluorescence in situ Hybridization Detection of Cytogenetic Abnormalities in B-cell Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Routine cytogenetic analysis of B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma (B-CLL/SLL) frequently fails to identify an abnormal clone due to the low rate of spontaneous mitoses and poor response to mitogen stimulation. Recent studies utilizing interphase fluorescence in situ hybridization (FISH) suggest that prognostically significant chromosomal abnormalities occur more frequently in B-CLL/SLL than has been previously recognized. The purpose of this study was to compare the chromosomal abnormalities detected by karyotyping and FISH in cases of B-CLL/SLL, and to correlate these with clinical features and survival. Seventy-two cases were studied for chromosome 3, 12 or 18 aneuploidy, and for rearrangements involving 11q13, 11q23, 13q14, 14q32 and 17p13. The median age of the patients was 54 years (range, 30-87 years). Clinical staging of B-CLL patients showed that 70% of the patients were Rai stage 0, 1, or 2, and 30% stage 3 or 4. Karyotyping identified chromosomal abnormalities in 31% of the cases, whereas FISH studies were abnormal in 72% of cases including 64% of the cases with normal karyotypes. The most common abnormalities were deletion 13q14 (46%), trisomy 12 (21%), and 14q32 rearrangements (21%). At diagnosis, patients with trisomy 12 were more likely to have a high LDH (P = 0.04), but no other significant differences in the clinical or laboratory features, Rai stage, or survival were found among patients with normal cytogenetics vs. those with chromosomal abnormalities. Univariate analysis showed that B-symptoms (P = 0.044), anemia (P = 0.0006), absolute lymphocytosis > or = 30,000/mm3 (P = 0.029), and Rai stage 3 or 4 (P = 0.0038) at initial presentation were associated with an increased risk of death, but only Rai stage 3 or 4 (P = 0.0038) was significant in multivariate analysis. Interphase FISH studies improve the cytogenetic diagnosis when performed in conjunction with karyotyping in B-CLL/SLL, but the prognostic relevance of various abnormalities could not be confirmed in this study.

[1]  E. Jaffe.  Pathology and Genetics: Tumours of Haematopoietic and Lymphoid Tissues , 2003 .

[2]  J. O'fallon,et al.  Chromosome anomalies detected by interphase fluorescence in situ hybridization: correlation with significant biological features of B‐cell chronic lymphocytic leukaemia , 2003, British journal of haematology.

[3]  M. Angelopoulou,et al.  B‐chronic lymphocytic leukemia: practical aspects , 2002, Hematological oncology.

[4]  D. Oscier,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. , 2002, Blood.

[5]  P. Vyas,et al.  Pathology and genetics: Tumours of haematopoietic and lymphoid tissues , 2001 .

[6]  A Benner,et al.  Genomic aberrations and survival in chronic lymphocytic leukemia. , 2000, The New England journal of medicine.

[7]  C. Kittas,et al.  B-chronic lymphocytic leukemia, small lymphocytic lymphoma, and lymphoplasmacytic lymphoma, including Waldenström's macroglobulinemia: a clinical, morphologic, and biologic spectrum of similar disorders. , 1999, Seminars in hematology.

[8]  A. Pagliuca.  Strongyloides hyperinfection in adult T‐cell leukaemia/lymphoma , 1999, British journal of haematology.

[9]  L. Kanz,et al.  Multimodality treatment including early high-dose chemotherapy with peripheral blood stem cell transplantation in limited-disease small cell lung cancer. , 1998, Seminars in oncology.

[10]  M. Dyer,et al.  p53 abnormalities in CLL are associated with excess of prolymphocytes and poor prognosis , 1997, British journal of haematology.

[11]  J. Whittaker,et al.  Deletions at 11q identify a subset of patients with typical CLL who show consistent disease progression and reduced survival , 1997, Leukemia.

[12]  R. Mesa,et al.  Clinical correlations of immunophenotypic variations and the presence of trisomy 12 in B-cell chronic lymphocytic leukemia. , 1997, Cancer genetics and cytogenetics.

[13]  Robert Vlietinck,et al.  Further characterization of morphologically defined typical and atypical CLL: a clinical, immunophenotypic, cytogenetic and prognostic study on 390 cases , 1997, British journal of haematology.

[14]  H. Döhner,et al.  Cytogenetic and molecular cytogenetic analysis of B cell chronic lymphocytic leukemia: specific chromosome aberrations identify prognostic subgroups of patients and point to loci of candidate genes. , 1997, Leukemia.

[15]  L. Peterson,et al.  Karyotype correlates with peripheral blood morphology and immunophenotype in chronic lymphocytic leukemia. , 1996, American journal of clinical pathology.

[16]  C. Mecucci,et al.  Cytogenetic analysis of B cell chronic lymphoid leukemias classified according to morphologic and immunophenotypic (FAB) criteria. , 1995, Leukemia.

[17]  C. Fegan,et al.  Karyotypic evolution in CLL: identification of a new sub-group of patients with deletions of 11q and advanced or progressive disease. , 1995, Leukemia.

[18]  A Benner,et al.  p53 gene deletion predicts for poor survival and non-response to therapy with purine analogs in chronic B-cell leukemias. , 1995, Blood.

[19]  H. Dohy,et al.  Japanese B cell chronic lymphocytic leukaemia: a cytogenetic and molecular biological study , 1993, British journal of haematology.

[20]  S. Knuutila,et al.  Prognostic subgroups in B-cell chronic lymphocytic leukemia defined by specific chromosomal abnormalities. , 1990, The New England journal of medicine.

[21]  G. Gahrton,et al.  Chromosome aberrations in B-cell chronic lymphocytic leukemia. Pathogenetic and clinical implications. , 1990, Cancer genetics and cytogenetics.

[22]  D. Catovsky,et al.  Prognostic significance of chromosome abnormalities in chronic lymphocytic leukaemia , 1984, British journal of haematology.

[23]  Mark J. Thomas,et al.  A new prognostic classification of chronic lymphocytic leukemia derived from a multivariate survival analysis , 1981, Cancer.

[24]  N. Mantel.  Evaluation of survival data and two new rank order statistics arising in its consideration. , 1966, Cancer chemotherapy reports.

[25]  E. Kaplan,et al.  Nonparametric Estimation from Incomplete Observations , 1958 .

[26]  M. Negrini,et al.  Late appearance of the 11q22.3-23.1 deletion involving the ATM locus in B-cell chronic lymphocytic leukemia and related disorders. Clinico-biological significance. , 2002, Haematologica.

[27]  C. Croce,et al.  ATM mutations in B-cell chronic lymphocytic leukemia. , 1999, Cancer research.

[28]  Peter Lichter,et al.  Chromosome aberrations in B-cell chronic lymphocytic leukemia: reassessment based on molecular cytogenetic analysis , 1999, Journal of Molecular Medicine.

[29]  B. Cheson,et al.  Chronic lymphocytic leukemia: staging and prognostic factors. , 1998, Seminars in oncology.

[30]  P. Nowell,et al.  Cytogenetic Findings and Survival in B-cell Chronic Lymphocytic Leukemia. Second IWCCLL Compilation of Data on 662 Patients. , 1991, Leukemia & lymphoma.

[31]  D C Case,et al.  Clinical staging of chronic lymphocytic leukemia. , 1977, The Journal of the Maine Medical Association.

[32]  D.,et al.  Regression Models and Life-Tables , 2022 .