Telomere length identifies two different prognostic subgroups among VH-unmutated B-cell chronic lymphocytic leukemia patients

Abstract

Some evidences suggest that telomere restriction fragment length (TRF-L) is an effective indicator of histopathogenesis in B-cell tumors. As histopathogenesis is relevant for B-cell chronic lymphocytic leukemia (B-CLL) prognosis, TRF-L was assessed by Southern blot in 201 patients and compared to variable immunoglobulin heave chain gene mutational status (VH-MS) and to other known prognostic features. Overall survival (OS), time to first treatment (TTFT) and progressionfree survival (PFS) were evaluated. Our results indicate the following: (1) TRF-L is heterogeneous among B-CLL patients (median 6014 bp, range 1465-16 762); (2) TRF-L correlates to VH-MS (r 2 ¼ 0.1994, Po0.0001) with VH-mutated patients showing long and VH-unmutated short telomeres; however, 41% of VH-unmutated and 5% of VH-mutated patients did not show this correlation and were thus defined as 'discordant'; (3) TRF-L effectively predicts outcome in terms of TTFT, PFS and OS; (4) VH-unmutated discordant patients have a better clinical outcome than VH-unmutated concordant patients (OS Po0.01, PFS Po0.05) and similar to that of VH-mutated patients (OS, PFS P ¼ NS). Compared to VH-unmutated concordant patients, VHunmutated discordant patients showed no peculiarity in their immunoglobulin rearrangement nor in their flow cytometry or fluorescence in situ hybridization profile. In conclusion, TRF-L can be helpful to refine prognostication of B-CLL patients, particularly those with a VH-unmutated immunoglobulin sequence.

Telomere length is an independent predictor of survival, treatment requirement and Richter's syndrome transformation in chronic lymphocytic leukemia

“…22 On the basis of these premises, it is not surprising that TL bears independent prognostic value in CLL. 28,29 Previous studies have shown that TL associates with IGHV homology, high-risk cytogenetics and poor TFS. 25,26 Subsequent reports outlined the existence of patients in which discordance exists between TL and IGHV-MS and suggested a superior predictive value of TL.…”

“…25,26 Subsequent reports outlined the existence of patients in which discordance exists between TL and IGHV-MS and suggested a superior predictive value of TL. 28,29 Finally, Roos et al 47 were able to link TL with poor cytogenetics in a series of 152 patients, including samples collected both at diagnosis and after treatment. Notably, the independent effect of TL on OS was not demonstrated in any of the previously published reports.…”

“…29,35 Peak TL was preferred to Table 1 Biological and clinical characteristics of the learning CLL series from the UT (n ¼ 191) and the validation CLL series from the AAUEP (n ¼ 210) 35 Briefly, 2 mg of genomic DNA was digested by mixing HinfI and RsaI (Roche Diagnostics, Mannheim, Germany). Telomere restriction fragments were separated by 0.8% agarose gel electrophoresis.…”

“…29 IGHV sequences were aligned to ImMunoGeneTics directories (www.imgt. cines.fr), and considered mutated if homology to the corresponding germ-line gene was o98%.…”

“…[24][25][26][27] Although early studies postulated that telomere length (TL) was mostly acting as a surrogate marker for IGHV-MS, a number of subsequent reports indicated that in discordant cases TL performed better than IGHV-MS, suggesting that TL deserved further consideration as a prognostic biomarker in CLL. 28,29 Despite these encouraging results, additional experience needs to be accumulated on TL as a prognostic marker in CLL. First, a larger patient sample is required to establish the prognostic role of TL fully, define the optimal cutoff value and confirm results in a blinded validation series.…”