A Reappraisal of the Biological and Clinical Implications of Chromosomal Translocations in Chronic Lymphocytic Leukemia

Abstract 3915

Although chromosomal translocations (CTRAs) are detected relatively frequently, CLL is conspicuous for the paucity of recurrent CTRAs. The biological and clinical significance of CTRAs in CLL remains uncertain, likely reflecting the underlying genetic heterogeneity. Here we reappraise CTRAs in CLL in a cohort of 893 patients with reliable classic cytogenetic data, selected with an intentional bias towards cases carrying CTRAs. The study group included 568 males and 325 females with a median age of 65.4 years; information about Binet stages at diagnosis was available for 761 cases: A, 650/B, 76/C, 35; 419/646 (64.8%) cases with available data carried mutated IGHV genes (M-IGHV). The median time from diagnosis to classic cytogenetic analysis was 2.3 months; FISH data was available for 556/893 cases. Overall, 311 cases were found to carry ≥1 CTRAs; 193/311 (62%) cases carried balanced CTRAs whereas the remaining 118 cases (38%) carried ≥1 unbalanced CTRAs. The most frequent chromosome breakpoints were 13q (14% of all translocation partners, TPs), followed by 14q (6%), 18q (5%), 17q (3.5%) and 17p (3.5%); notably, CTRAs involving chromosome 13q showed a wide spectrum of TPs. When compared to CTRA- cases (n=582), CTRA+ cases exhibited a significantly higher prevalence of complex karyotype (three or more structural and/or numerical aberrations; 112/311 CTRA+ cases vs. 46/582 CTRA- cases, p<0.001). Karyotype complexity was significantly associated with U-IGHV status (p=0.003) and aberrations of chromosome 17 (p<8b0.001). Interestingly, the spectrum of chromosome breakpoints and concurrent cytogenetic aberrations in CTRA+ CLL was different depending on the status of chromosome 17p. Indeed, CTRA+ cases with involvement of chromosome 17p as a TP or co-existing with chromosome 17p aberrations on either karyotype or FISH exhibited: (i) significantly (p<8b0.05) more frequent involvement of chromosomes 2p and 14q as TPs; (ii) significantly (p<8b0.05) lower frequency of chromosome 13q deletion and, especially, marked under-representation (p<8b0.001) of trisomy 12. Further evidence for distinct cytogenetic profiles was also obtained for subgroups defined on the basis of the status of chromosome 11q. In particular, CTRA+ cases with 11q involvement exhibited significantly lower frequency as TPs of chromosomes 1p (p=0.01) and 18q (p=0.005) and, in contrast, higher frequency of chromosome 6q (p=0.02). Regarding prognostic implications, to avoid confounding effects of different treatments, the analysis was limited to time-to-first-treatment (TTFT). On univariate analysis, and in contrast to a previous study, the presence of CTRAs did not influence TTFT. Significant (p<8b0.05) factors for shorter TTFT were advanced clinical stage, U-IGHV status, aberrations of chromosome 17p and complex karyotype. Notably, complex karyotype was associated with shorter TTFT (p=0.006) even among M-IGHV cases and also impacted adversely on TTFT (p=0.002) among CTRA+ cases. On multivariate analysis, advanced clinical stage, U-IGHV status, aberrations of chromosome 17p and karyotype complexity retained independent prognostic significance (p<8b0.05). In conclusion, we document that all CTRAs in CLL are not equivalent, rather they can be assigned to two broad categories: (i) CTRAs in a context of complex karyotype, often with involvement of chromosome 17p aberrations, mostly albeit not exclusively in U-CLL: in such cases, karyotype complexity rather than the presence of CTRAs per se negatively impacts on survival; and, (ii) CTRAs in cases not carrying a complex karyotype, with limited if any impact on survival. The distinct cytogenetic profiles of CTRA+ cases with or without aberrations of chromosomes 17p and 11q indicate different pathways of genomic evolution in CLL.