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N.A. Heerema et al.
treatment, 13 deaths occurred. The overall survival esti- mates are 91% (95% CI: 79%-96%) at 1 year, 84% (95% CI: 70%-92%) at 3 years, and 77% (95% CI 61%-87%) at 5 years after starting CLL treatment. In these treated patients, Rai stage 3-4 and del(17p) were associated with shorter survival in univariable analyses with a hazard ratio of 5.36 (95% CI: 1.62-17.76), and 6.88 (95% CI: 2.20- 21.50), respectively.
Table 5 shows correlations of interphase FISH abnor- malities with both the presence of a translocation and with karyotype complexity. Del(11q), del(17p), three copies of MYC, and three copies of BCL6 were all highly associated both with the presence of a translocation and with karyotypic complexity. An opposite trend was seen for cases with del(13q); del(13q) was more frequent both in cases without a translocation and in non-complex cases. Trisomy 12 was frequent in complex cases, but was not associated with the presence of a translocation. Deletion of 6q was not associated with either karyotypic complex- ity or the presence of a translocation. Deletion of 13q as the sole FISH-identified abnormality, typically indicative of a good prognosis, occurred in 119 cases. Twelve of these cases had a translocation, and three had a complex karyotype. In addition, ten cases with a translocation had no abnormalities detected by FISH, emphasizing the need for metaphase cytogenetics.
Discussion
Previous studies have found a significant impact of translocations on the outcome of patients with CLL.5,9,17-19 We show that when detected within 1 year of diagnosis, the presence of a translocation in cases with mutated IGHV appears to negate the positive impact of mutated IGHV. However, in cases of unmutated IGHV, the pres- ence of a translocation did not appear to influence progno- sis. In this study, patients with mutated IGHV who did not have a translocation had a significantly longer TFT than those with mutated IGHV and a translocation or those with unmutated IGHV regardless of the presence of a translocation (Figure 1).
Figure 1. Time to first treatment of patients with chronic lymphocytic leukemia. Data are plotted for patients according to whether they had mutated or unmutated IGHV and whether they did or did not have a translocation.
Baliakas et al.9 found that translocations were strongly associated with CD38+ expression, karyotypic complexity, abnormal 17p and abnormal 11q. However, the presence of a translocation did not influence TFT, although those cases with an unbalanced translocation and those with a complex karyotype had a significantly shorter TFT. Translocations were also associated with complexity, del(17p), and del(11q) in our series. However, when con- sidering their impact on outcome, those cases with a mutated IGHV and a translocation had a poor TFT com- pared with cases with mutated IGHV and no transloca- tion. Rigolin et al.19 showed that unbalanced translocations were associated with shorter TFT and overall survival. In our studies, both balanced and unbalanced translocations were considered together and overall had an impact on TFT.
These results add to the factors that may influence the outcome of CLL patients with mutated IGHV. IGHV- mutated patients with high expression of CD49d and those with high expression of CXCR4 have an inferior outcome compared to patients with low expression of these variables.30-32 As neither CD49d nor CXCR4 was evaluated in our patients, we are unable to compare their effects with those of the presence of a translocation. Whether these factors influence chromosome instability, a possible factor in generation of a translocation, was not investigated.
Complex karyotypes have also been associated with an adverse prognosis in CLL.4-16,19 While some studies15,16 found that the association of karyotypic complexity was more significant when complexity was defined as ≥5 aber- rations than when defined as ≥3 aberrations, we found that complexity defined as ≥3 abnormalities was as signif- icant as complexity defined as ≥5 abnormalities. Although karyotypic complexity detected within 1 year of diagnosis of CLL remained significant in a multivariable analysis, the hazard ratio for the presence of a translocation in patients with mutated IGHV was much higher than that for karyotypic complexity (HR for complexity=1.78, HR for presence of a translocation=3.53). Among patients with a translocation, karyotypic complexity added prog- nostic information.
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