Pattern of Chromosomal Aberrations and IgVH Mutation Status in Patients with Monoclonal B-Cell Lymphocytosis (MBL)

Abstract

The separation between chronic lymphocytic leukemia (CLL) and monoclonal B-cell lymphocytosis (MBL) with CLL-phenotype by the presence of more than 5,000/μl lymphocytes in peripheral blood has been debated due to the rather continuous spectrum of clinical and biological features of both entities. Furthermore, this separation is influenced by non-malignant cells since it is based on the total lymphocyte count and not only on the count of cells with CLL-phenotype. To broaden the insights into the genetic background of MBL at the boarder to CLL we analyzed 188 cases with less than 5,000/μl CLL-phenotype cells for chromosomal aberrations by fluorescence in situ hybridization (FISH) using a standard panel of probes as well as for their IgVH mutation status. In addition, in 116 of these cases conventional chromosome analysis has been performed. Patient characteristic were (median/range): age, 66.0/27.5–86.6 years; WBC count, 10,600/1,700–22,660/μl; cells with CLL-phenotype 26/4-94% and 3,081/264–4,998/μl, respectively. The proportion of aberrant/analyzed cases for the respective chromosome aberrations as determined by FISH were: 11q-, 10/182 (5.5%); +12, 39/183 (21.3%); 6q-, 2/182 (1.1%); 13q-, 88/185 (47.6%); 17p-, 3/183 (1.6%); and t(11;14), 8/183 (4.4%). In 57/185 (30.8%) cases no aberration was found by FISH. A comparison to a previous series of 518 CLL cases revealed similar frequencies for +12, 6q-, and t(11;14) but higher frequencies in CLL for 11q-, 5.5 vs. 13.1%, p=0.004; 13q-, 47.6 vs. 57.8%, p=0.020; and 17p-, 1.6 vs. 8.1%, p=0.001. Within the present series, a relation between the respective chromosome aberration and the count of cells with CLL-phenotype was found for 6q- vs. no 6q-, 1,214 vs. 2,910/μl, p=0.079; 13q- vs. no 13q-, 3,285 vs. 2,486/μl, p<0.001; t(11;14) vs. no t(11;14), 2,025 vs. 2,920/μl, p=0.087 but not for 11q-, +12, and 17p- aberrations. IgVH mutation status has been analyzed in 172 cases and was found unmutated (IgVHunmut) in 44 (25.6%) und mutated (IgVHmut) in 111 (64.5%). No clonal IgVH rearrangement was detectable in 17 (9.9%). A relation to the count of cells with CLL-phenotype was found: IgVHmut vs. IgVHunmut, 3,071 vs. 2,629/μl, p=0.052. Conventional chromosome analysis has been performed in addition in 116 of these cases resulting in 111 (95.7%) evaluable cases. In general, results obtained by FISH were confirmed: 11q-, n=3 (1.8%); +12, n=21 (21.3%); 6q- 1 (0.9%); 13q-, n=39 (35.1%), and t(11;14), n=5 (4.5%). Additional aberrations were found and included other trisomies (n=13), other balanced translocations/inversions (n=13), 14q- (n=8), loss of sex chromosome (n=3), t(14;18) (n=1), and 2q- (n=1). Thus, a total of 39 chromosome aberrations have been found in 111 cases as assessed by conventional chromosome analysis which could not be detected by FISH using a standard panel of probes. In 30 cases (27%) a normal karyotype was found. These data indicate that the genetic background of MBL is highly related to the one of classical CLL as defined today although 11q-, 13q- and 17p- occur more frequently in CLL. Chromosome aberrations are present in clearly more than half of the cases and an unmutated IgVH status can be detected in a quarter of cases. Similar to CLL, conventional chromosome analysis reveals a substantial number of aberrations not detectable by FISH using a standard panel of probes. It is suggested to further analyze the genetic spectrum of MBL and early CLL cases and its clinical impact and to challenge based on these data the rather arbitrarily defined cut-off values like 5,000/μl lymphocytes.