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• W2045153119 abstract "Novel biological markers have been proposed to stratify newly diagnosed patients with early stage chronic lymphocytic leukaemia (CLL) in subsets carrying a different risk of progression (reviewed in Van Bockstaele et al, 2009). When evaluated singly, ZAP70 overexpression, CD38 overexpression and unmutated IGHV status have been consistently associated with a worse outcome. These prognostic factors are often concordant in individual cases, but a discordant pattern can be detected in up to 30% of patients. As to the hierarchy of these markers in predicting the tendency for progression, results from different studies are not univocal, due to differences in patient population, timing of the test, statistical methodology and laboratory methods. Prognostic scores have been proposed, based on combinations of these new parameters. Such scores might be helpful in clinical practice, to plan patient monitoring and predict the time to therapeutic need. A recent report (Morabito et al, 2009) proposed a prognostic scoring system capable of stratifying 262 stage A patients into three distinct groups based on the combination of three biological parameters that are supposed to remain stable over time: ZAP70 expression, CD38 expression (cut-off level ≥ 30%) and IGHV mutational status. In this retrospective series, at a median follow-up of 3 years (range 1–15 years), 19·5% of patients received treatment. Patients without any unfavourable marker (low-risk group, 56%) experienced a very long treatment-free interval (TFI), with an expected rate of 80% at 12 years. In contrast, the median TFI was about 4 years for patients carrying two or three markers (high-risk group, 21%) and it was about 10 years for patients with one marker (intermediate-risk group, 23%). In order to validate the prognostic information on TFI as a measure of progression risk, we applied the same score to 329 consecutive stage A patients (median age: 59 years, range: 34–81 years) followed at our Institution. In 70% of cases, marker assessment was performed on samples collected at diagnosis, while in the remaining 30% analysis was carried out after a median interval of 38 months from diagnosis (1–10 years) before any treatment. Informed consent for routine diagnostic and follow-up procedures was achieved according to institutional procedures. For CD38 expression (anti-CD38-PE; Becton Dickinson Lab, San Jose, CA, USA), we evaluated two different cut-off values: 124 patients (38%) were considered positive with a 7% cut-off, while 42 patients (13%) were positive with a 30% cut-off. ZAP70 expression (Alexa Fluor 488; Caltag Lab, Burlingame, CA, USA; cut-off point ≥ 20%) was observed in 68 patients (21%). IGHV genes were unmutated in 115 cases (35%) (2% mutation threshold, analysis according to ImMunoGeneTics). Less than 10% of cases carried unfavourable cytogenetic abnormalities (del11q or del17p) at fluorescence in situ hybridization analysis. Our patient cohort was comparable to that reported by Morabito et al (2009) regarding mutational status and ZAP70 expression, while the percentage of CD38 positive cases was lower. During follow-up (median 4 years, range 1–19 years from diagnosis), 124 patients (37%) required treatment. Most patients started treatment according to National Cancer Institute Working Group Guidelines (Cheson et al, 1996), while, in the 1990′s, some patients were treated at clinical progression according to attending physician decision. Among the evaluated biomarkers, mutational status was the only independent predictor of TFI in multivariate analysis (Cox multivariate regression model: Hazard Ratio 2·6, P < 0·00001, 95% confidence interval 1·7–3·8) at both CD38 cut-off levels. In our experience, the scoring system designed by Morabito et al (2009) could not be fully validated. In agreement with their results, the absence of unfavourable markers was actually predictive of the best outcome, while concordance for unfavourable parameters was associated with the shortest TFI. As to the discordant pattern, however, our results were different in that we detected a relative overlap of the TFI curves for patients carrying one or two unfavourable markers (Table I). By combining these patients, we identified an intermediate-risk group (discordant group) with a TFI significantly different from both concordant favourable and concordant unfavourable subsets. Comparable results were achieved regardless of the cut-off point chosen for CD38 expression (≥30% or ≥7%), but the lower cut-off level allowed a more stringent selection of low-risk patients (Fig 1). Kaplan–Meier estimates of TFI according to the combination of the three prognostic factors: concordant favourable, discordant, and concordant unfavourable (cut-off level for CD expression: ≥7%); P-values from the Gehan-Wilcoxon test. Our results in a cohort of patients with early stage disease seem to validate the prognostic score described by Morilla et al (2008), who simultaneously analysed all three variables in a series of 142 patients with different characteristics (all Binet stages, treatment rate 93% with 98 patients enrolled into a treatment trial). Morilla et al (2008) stratified their patients into three groups with a significantly different relative risk of progression applying the same grouping system we identified: concordant favourable, concordant unfavourable and discordant cases. As expected, median TFI was shorter in the English study (62 months, 27 months, and 11 months, for the three subsets, respectively) (Morilla et al, 2008) than in our series, probably due to the difference in patient population. The comparison of prognostic scores from different studies remains difficult. Standardisation of laboratory methods and clear-cut threshold values are firstly required and the validity issue should be a warning against a systematic application of those scoring systems in clinical practice. We agree that the simultaneous analysis of all three biological variables provides a more discriminatory prediction of TFI. A complete prognostic assessment proves helpful in differentiating early stage CLL patients with concordant favourable markers and a long TFI from patients with concordant adverse prognostic markers who carry the highest risk of early progression and require strict clinical monitoring. To this aim, the choice of 7% cut-off point for CD38 expression allows a more stringent selection and the evaluation of the mutational status of IGHV genes is essential, although laborious and time-consuming. However, as to the large proportion of patients with discordant factors (44·5% in our experience), reliable prognostic information is still lacking. We need to know more on disease biology and collect data from prospective and methodologically comparable studies. EMO designed the study, collected and analysed clinical data and drafted the article. SZ performed IGHV analysis. CP performed statistical analysis. LV performed immunophenotyping. PL collected and analysed clinical data. All authors revised the manuscript critically and gave final approval of the version to be submitted. No conflicts of interest and financial support." @default.
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• W2045153119 title "Biological markers and prognostic scoring systems in chronic lymphocytic leukaemia" @default.
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