Prognostic significance of translocations in the presence of mutated IGHV and of cytogenetic complexity at diagnosis of chronic lymphocytic leukemia.

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Mutations of the IGH variable region in patients with chronic lymphocytic leukemia (CLL) are associated with a favorable prognosis. Cytogenetic complexity (>3 unrelated aberrations) and translocations have been associated with an unfavorable prognosis. While mutational status of IGHV is stable, cytogenetic aberrations frequently evolve. However, the relationships of these features as prognosticators at diagnosis are unknown. We examined the CpG-stimulated metaphase cytogenetic features detected within one year of diagnosis of CLL and correlated these features with outcome and other clinical features including IGHV. Of 329 untreated patients, 53 (16.1%) had a complex karyotype (16.1%), and 85 (25.8%) had a translocation. Median time to first treatment (TFT) was 47 months. In univariable analyses, significant risk factors for shorter TFT (p<0.05) were Rai stage 3-4, beta2-microglobulin >3.5, log-transformed WBC, unmutated IGHV, complex karyotype, translocation, and FISH for trisomy 8, del(11q) and del(17p). In multivariable analysis, there was significant effect modification of IGHV status on the relationship between translocation and TFT (p=0.002). In IGHV mutated patients, those with a translocation had over 3.5 times higher risk of starting treatment than those without a translocation (p<0.001); however, in IGHV unmutated patients, a translocation did not significantly increase the risk of starting treatment (HR 1.00, p=0.99). Rai Stage 3-4, log-transformed WBC and complex karyotype remained statistically significant; however, del(17p) did not (p=0.51). In summary, the presence of a translocation in IGHV mutated patients appeared to negate the improved prognosis of mutated IGHV, but the presence of a translocation did not have an effect on TFT in high-risk IGHV unmutated patients.

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