The discovery of novel biological risk factors in chronic lymphocytic leukemia (CLL) has improved prognostic accuracy, provided new insights into the pathophysiology of the disease, and led to risk-stratified management. However, because a large number of potentially useful prognostic factors have been described in a relatively short period of time, there are limited data on how to effectively apply these biomarkers in clinical research and practice. The current challenge is to translate this new knowledge into better care for patients with CLL.
Interphase fluorescence in situ hybridization (FISH) is an accurate and sensitive method of detecting known genetic defects in CLL cells [Citation1]. FISH analysis in patients with CLL is very useful for the detection of deletions of TP53 at 17p13 and ATM at 11q22, which are critical for the normal function of the p53 pathway. Although both of these deletions are usually monoallelic in CLL, loss of one allele can be a surrogate marker for complete loss of gene function. Over 80% of patients with 17p13− have a dysfunctional mutation in the remaining TP53 allele, and these patients have poor responses to standard chemoimmunotherapy with short survival [Citation2]. About 30% of patients with 11q22− have a dysfunctional mutation in the remaining ATM allele, which is associated with poorer prognosis compared to those patients with 11q22− and residual ATM function [Citation3]. Identification of 11q22− in patients with progressive CLL is clinically important because these patients have better responses when treated with chemoimmunotherapy regimens containing cyclophosphamide [Citation4]. Thus, while FISH analysis is a useful surrogate assay for defective p53 pathway defects in CLL, optimal management of these patients will require the development of functional assays of p53 pathway integrity.
The clinical significance of the other genetic defects routinely detected by FISH in patients with CLL is less well defined. Trisomy 12 is associated with an intermediate risk of disease progression. Deletion of 13q14 is the most common abnormality detected by FISH in CLL, and usually results in loss of the coding regions for miR15 and miR16 [Citation5]. 13q14− detected as the sole abnormality by FISH in patients with CLL is associated with a low risk of progression of CLL [Citation1]. Although the hierarchical prognostic stratification of FISH considers only the highest-risk defect [Citation1], there is now evidence that 13q14− could attenuate the poor prognosis associated with 17p13− [Citation5]. The size and position of 13q14− in patients with CLL could have prognostic implications [Citation6], but there is no significant difference in prognosis between patients with homozygous versus heterozygous 13q14− [Citation5]. Ongoing research will increase our understanding of the biological and prognostic consequences of detection of 13q14−, and is likely to improve the prognostic value of this biomarker.
The extent of somatic hypermutation in the variable region of the immunoglobulin heavy chain variable region gene (IGHV) provides important prognostic information in patients with CLL. Patients with unmutated IGHV (<2% variance from germline sequence) have a significantly poorer prognosis compared to those with somatic hypermutation (≥2%) [Citation7,8]. However, use of the VH3-21 gene segment is associated with more aggressive disease irrespective of mutation status [Citation9]. IGHV mutation analysis can be used together with other biological factors to improve prognostic accuracy. The combination of IGHV mutation analysis and CD38 expression is useful for improving risk stratification [Citation10], and patients with CLL with defective TP53 function have a poorer prognosis if they have unmutated IGHV [Citation11]. These findings suggest that multi-parameter prognostication could be useful in the management of CLL.
The clinical utility of biological prognostic factors in patients with CLL could be optimized by using algorithms based on multiple validated prognostic parameters. In this issue of Leukemia and Lymphoma, Gladstone et al. report a study that examined the influence of IGHV mutation status on the prognostic value of detection of 13q14− in patients with CLL [Citation12]. In a retrospective analysis of 79 patients with CLL with 13q14− who had IGHV mutation analysis, they identified the 47 patients with 13q14− as the sole abnormality by FISH. The 13 patients with unmutated IGHV and 13q14− had a significantly higher risk of disease progression and need for treatment compared with the 34 patients with a mutated IGHV, but there was no significant difference in overall survival. These results should be considered preliminary because of the constraints of the study size and design, but do suggest that larger prospective studies could be very useful in developing algorithms using FISH, IGHV analysis, and other prognostic factors to improve the accuracy of prognostication in CLL.
There have been impressive advances in developing biomarkers predicting time to initial treatment, time to subsequent treatment, and survival in patients with CLL. The current challenge is to develop multi-parameter algorithms for accurate and cost-efficient prognostic evaluation. Application of these methods to clinical trials and routine practice could result in major improvements in care for patients with CLL.
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