Toward a comprehensive prognostic scoring system in chronic lymphocytic leukemia based on a combination of genetic parameters

Abstract

Chronic lymphocytic leukemia (CLL) is a heterogeneous disease with a variable clinical course. The aim of this study was to evaluate whether a combination of genetic parameters can improve prediction of outcome irrespective of clinical stage. The prognostic impact of chromosome banding analysis (CBA) in addition to FISH and IgVH mutation status was evaluated. In total, 482 patients were analyzed, but evaluation of prognostic factors was restricted to 399 untreated cases. The prognostic significance of age, white blood cell (WBC) count, IgVH status, and TP53 and ATM deletions was confirmed. In addition, a prognostic impact of translocations involving the IGH@ locus (t(IgH)) and of a complex aberrant karyotype was found. On the basis of these results, we propose a scoring system for overall survival (OS) based on: age >or=65 years, WBC >or=20 x 10(9)/l, unmutated IgVH status, TP53 deletion, t(IgH), and the number of chromosome aberrations observed with CBA. Three risk groups showed considerable differences in OS (94.5% vs. 64.3% vs. 41.1% surviving at 5 years, P < 0.0001). Time to treatment (TTT) can be predicted best by unmutated IgVH status, ATM deletion, t(IgH), and number of chromosome aberrations. Four distinct subgroups were separated with median TTT of 110.7 months, 39.8 months, 19.5 months, and 3.8 months, respectively (P < 0.0001). In conclusion, cytogenetic data from CBA add prognostic information. The proposed scoring systems for OS and TTT based on a combination of genetic markers improve the separation of prognostic subgroups in CLL already early in the course of the disease.

Proliferation centers in chronic lymphocytic leukemia: correlation with cytogenetic and clinicobiological features in consecutive patients analyzed on tissue microarrays

“…Three possible explanations may account for this observation: i) 14q32 translocation may appear more frequently at the tissue level than in the PB, as previously suggested for trisomy 12. 36 It is worth noting that cores for microarray construction were obtained from those areas with PC in the original lymph node section, and that PC may be viewed as a genetically unstable proliferation compartment releasing small lymphocytes in the accumulation compartment and in the PB 14 ; ii) 14q32 translocation may be associated with adenopathy and active disease requiring treatment, as suggested in two recent analyses 9,10 ; and iii) 14q32 translocation may represent in some of our cases a secondary anomaly acquired late during the course of the disease. Indeed, karyotype instability was detected in a fraction of CLL, [37][38][39] and 14q32/ IgH translocation may represent a late event in the progression of lymphoid neoplasias.…”

“…4,5 Evidence was also provided that 6q deletion may be found in a subset of SLL 6 and CLL with hyperleukocytosis and intermediate outcome 7,8 and that 14q32 translocations involving the immunoglobulin heavy (IgH) chain gene may be associated with unfavorable prognosis. 9,10 A characteristic histopathologic feature of SLL/CLL is represented by 'proliferation centers' (PCs), which consist of regularly distributed pale areas without a mantle with numerous prolymphocytes and paraimmunoblasts, resulting in a pseudofollicular pattern. 11 Unlike reactive germinal centers, the PCs are CD10-, Bcl6-, IRF4 þ and bcl2 þ , 12,13 and contain large Ki-67 þ cells, admixed to typical B-CLL cells.…”

Detection of Clonal Aberrations by Cytogenetic Analysis after Different Culture Methods and by FISH in 129 Patients with Chronic Lymphocytic Leukemia

“…This is of clinical relevance, because translocations may be associated with poor prognosis in patients with CLL [Mayr et al, 2006]. Furthermore, a complex aberrant karyotype had a negative prognostic impact on the overall survival and on the time to treatment, especially in early stage patients with CLL [Haferlach et al, 2010].…”

“…Recent studies [Put et al, 2009;Haferlach et al, 2010;Wülfing et al, 2013] and our results have shown that for the development of a comprehensive prognostic index in CLL patients CA data should now be included in all further studies until the absolute detection rate of clonal chromosome aberrations with newer techniques is identified and clinically interpreted.…”

Integrated CLL Scoring System, a New and Simple Index to Predict Time to Treatment and Overall Survival in Patients With Chronic Lymphocytic Leukemia

“…reviewed prognostic factors in CLL, discussed the usefulness of prognostic markers in clinical diagnosis and argued the need to identify a comprehensive "CLL prognostic index" [12]. In fact, during the last years several authors identified some clinical (age and size of the largest lymph node), hemato-chemical (white blood cell count, lymphocyte doubling time and LDH) and biological variables (17p deletion, U-IGHV, and somatic mutations of TP53, BIRC3, NOTCH1 and SF3B1 genes) to stratify patients' survival [13][14][15][16].…”