Distribution of Genetic and Molecular Prognostic Markers in Young Patients with Chronic Lymphocytic Leukemia (CLL) in Different Phases of the Disease.

Abstract 4373

In chronic lymphocytic leukemia (CLL), the distribution and prognostic impact of genetic and molecular markers have been mostly investigated in retrospective studies including patients in different phases of the disease. From November 2002 to May 2009, we prospectively assessed the clinical and biologic features of 219 young CLL patients ('65 years), distributed in three different cohorts: 124 cases at diagnosis, of which 99 in Binet stage A (group 1), 68 at first progression (group 2), 27 at progression after one or more therapies (group 3). Median age was 52 years for group 1, 57 years for group 2 and 61 years for group 3. Advanced disease defined as Rai stage III/IV was present in 6%, 19% and 48% patients and as Binet stages B/C in 19%, 68% and 78% patients in the 3 cohorts, respectively. The proportion of unmutated IgVH cases progressively and significantly increased, being 36% in group 1, 48.5% in group 2 and 75% in group 3 (p 0.001). The same trend was found for CD38 (p 0.01). The incidence of ZAP-70 expression and p53 mutations showed a trend towards a progressive increase among the three groups (41%, 55% and 56.5% for ZAP-70 and 4%, 7% and 12.5% for p53 mutations), without however reaching significance. The incidence of del(17p) ≥20% raised progressively from group 1, to groups 2 and 3 (2%, 4.5% and 18.5%, respectively; p 0.001). The incidence of del(11q) increased from group 1 to 2 (10% and 16%; p 0.18), though it was not higher in group 3 (7.5%). Focusing the comparison to groups 1 and 2 only, i.e. patients with CLL at diagnosis in all stages and patients at first progression of the disease requiring therapy, the distribution of prognostic markers did not differ significantly, except for a lower proportion of cases expressing CD38, although the proportion of del(17p) >20% and >10% and of +12 doubled. When the analysis was restricted to stage A CLL at diagnosis, there was a highly significant difference in the lower proportion of unmutated IgVH (0.003), CD38 expression (p 0.009), ZAP-70 expression (p 0.004), del(17p) (p 0.034) and in the higher proportion of del(13q) (p 0.028) in comparison with CLL at first progression. No patient with stage A CLL at diagnosis showed del(17p) ≥20%, whilst 2% showed del(17p) >10% and 3% harbored p53 mutations. Of the 40 patients evaluated by FISH at multiple time points, 35% showed clonal evolution. Only previous treatment was significantly associated with the development of clonal evolution, whilst no correlation with the IgVH mutational status, ZAP-70 or CD38 expression was found. Patients of group 1 required treatment after a median time of 49.6 months from diagnosis. Treatment-free interval (TFI) was significantly shorter in cases with IgVH unmutated vs. mutated (at 48 months, 16.5% and 68.3%, respectively p<0.0001), CD38 pos vs. neg (at 48 months 12.5% vs. 61.3%, p<0.0001) and ZAP-70 pos vs neg (39.1% vs. 58.9%, p=0.0049). Cases with del(17p) or del(11q) had a TFI at 48 months of 0% versus 25% for cases with +12 and 61.7% for cases with del(13q) or no abnormalities (p<0.0001). IgVH status and white blood cell count were the only independent predictors of TFI in multivariate analysis (p=0.0005 and p=0.012, respectively). The same prognostic impact was shown in the stage A subgroup. The variable incidence of the biologic factors with prognostic impact has to be considered when patients in different phases of the disease are investigated, both in terms of the timing of the assessment and of the design of clinical trials. Reassessment of genetic abnormalities during the course of CLL is warranted, especially after treatment.