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

Mutations of the IGH variable region in patients with chronic lymphocytic leukemia are associated with a favorable prognosis, whereas 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 1 year of diagnosis of chronic lymphocytic leukemia and correlated these features with outcome and other clinical features including IGHV mutational status. Of 329 untreated patients, 53 (16.1%) had a complex karyotype, and 85 (25.8%) had a translocation. The 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, 2-microglobulin >3.5 mg/L, log-transformed white blood cell count, unmutated IGHV, a complex karyotype, a translocation, and trisomy 8, del(11q) or del(17p) detected by fluorescence in situ hybridization. In multivariable analysis, there was a 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 an over 3.5 times higher risk of starting treatment than those without a translocation (P<0.001); however, among IGHV-unmutated patients, a translocation did not significantly increase the risk of starting treatment (hazard ratio 1.00, P=0.99). The effect of Rai stage 3-4, log-transformed white blood cell count and complex karyotype remained statistically significant, whereas that of 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.