Telomere Length Has Prognostic Impact in B-Cell Chronic Lymphocytic Leukemia (B-CLL).

Abstract

BACKGROUND. Germinal Center (GC) experience is a basic prognostic feature in B-CLL. Patients with VH-mutated GC-experienced CLL have a good prognosis while those with VH-unmutated GC-inexperienced CLL have a poor prognosis. In a recent study we demonstrated that telomere length (TL) of lymphoproliferative disorders strongly correlates with GC, pre-GC or post-GC origin (Ladetto M et al, Blood 2004). Aims of this study were to further define the relationship between TL and VH mutational status in B-CLL and correlate both these parameters with clinical outcome.PATIENTS AND METHODS. 109 B-CLL patients have been analyzed for telomere restriction fragments (TRF) length and are under evaluation for VH mutational status. All samples were taken at diagnosis or during the "watch and wait" phase. Male were 68, females 41. Median age was 62 years (range 34–87). Fifty-three patients were in stage A, 30 patients were in stage B and 16 were stage C according to Binet staging system. Our patient population has been monitored for a median time of 53 months (range 1–290). Sixty-three patients have been already treated for their disease while 46 have not required treatment, so far. TRF length was evaluated by Southern blot and VH mutational status by direct sequencing, as previously described (Ladetto M et al, Blood 2004). The standard cut-off of 2% deviation from any germ line VH sequence was employed to define VH mutational status. Survival analyses were performed using the Kaplan-Meier method.RESULTS. Overall, median TRF length was 5898bp (range 1737–14837bp). There was no correlation between TRF length and patient age, sex or stage. A cut-off of 4500bp discriminated two subgroups of patients characterized by different clinical outcome in terms of time to first treatment (TTFT) and time to disease progression (TTP) following first line treatment. Patients with TL < 4500bp had a median TTFT of 16 months and a median TTP of 14 months while patients with TL > 4500bp had a median TTFT of 36 months and a median TTP of 50 months (p<0.05 and p<0.005, respectively). VH sequencing is currently available in 72 patients. A comparison between TRF length (using the previously defined 4500bp cut-off) and VH mutational status showed the following: a) 100% concordance between VH-mutated status and TRF length >4500bp; b) 62% concordance between unmutated VH-status and TRF length <4500bp; c) the 10 discordant patients with VH-unmutated status and TRF >4500bp had a clinical outcome similar to that observed in patients with VH-mutated status (median TTFT: 22 months; median TTP:80 months).CONCLUSIONS Our data demonstrate that: 1) TL in B-CLL has a good correlation with VH mutational status; 2) TRF length has prognostic significance in B-CLL in terms of TTFT and TTP; 3) when discordance exists between these two parameters, the clinical behavior seems to be better predicted by TRF length compared to VH mutational status.