Impact of cytogenetic and molecular prognostic markers on the clinical management of chronic lymphocytic leukemia

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Haematologica, Vol 93, Issue 1, 14-19 doi: 10.3324/haematol.12319

Impact of cytogenetic and molecular prognostic markers on the clinical

management of chronic lymphocytic leukemia

W. Hauswirth, Ulrich Jäger

Division of Hematology and Hemostaseology, Department of Medicine I, Medical

University of Vienna, Austria, E-mail: ulrich.jaeger@...

The prognosis of patients with B-cell chronic lymphocytic leukemia (B-CLL) has

long been determined by the clinical staging systems of Binet and Rai.1-4

Unfortunately, these systems fail to identify patients in early stages whose

disease will rapidly progress. Neither can this approach clearly predict the

response of individual patients to specific therapies. In recent years, numerous

genetic approaches have provided new markers for prognosis and response

prediction.5 The predictive potential of genetic factors associated with CLL

outcome is determined by (i) its accessibility for routine use; (ii) its

stability throughout the course of disease; and (iii) its sensitivity and

specificity. Prognostic factors are largely dependent on the conventional

therapeutic regimens used (i.e. chemotherapy) as well as on the availability of

specific targeting drugs. There is increasing evidence that the behavior of the

leukemia is not only dependent on genetic factors within the CLL clone, but also

on the genetic background of the host in general (susceptibility) and in

particular of the microenvironment.

We will discuss advances in the genetics of CLL with a special focus on

molecular markers. We will first focus on well-established prognostic markers

and then review the current status of molecular predictive markers and their

potential influence on treatment decisions.

Prognostic markers

Conventional cytogenetics

Karyotypes from CLL cells collected from peripheral blood or bone marrow are

difficult to assess. However, stimulation by CD40L or CpG oligonucleotides has,

in most cases, yielded positive results.6 One of the most important findings was

that the number of chromosomal translocations has largely been underestimated.

Patients with translocations have a poor prognosis with short treatment free and

overall survival times.6 Recent advances were also made in identifying

chromosomal regions predisposing for familial CLL. Regions on chromosomes 13q as

well as 1, 3, 6, 12, and 17 have been linked to pathogenesis of inherited

disease.7-9 However, while relatives of CLL patients have increased numbers of

circulating CD19+/CD5+ B-cells (a phenomenon called B-cell monoclonal

lymphocytosis), the risk factors leading to the final development of overt CLL

are still unclear.10 Furthermore, familial CLL does not seem to be associated

with a shorter survival in affected individuals.11 Micro RNAs (MiRs) are also

connected to familial disease12 although their impact is not yet clear.

Fluorescence in situ hybridization

The prognostic value of aberrations has long been established following the

hierarchical model described by Döhner et al.13,14 Half of the B-CLL cases have

a del 13q, indicating good prognosis. By contrast, 11q deletions are associated

with bulky disease, and are associated with short survival times. This is even

more pronounced for 17p deletions which predict for very poor outcome.15,16

Interphase cytogenetics have been extended to a molecular level by microarray

analysis in several studies.17-19 Therefore, a number of genes over- or

under-expressed in association with chromosomal aberrations have been

identified. Some of these are directly related to the location on deleted or

duplicated chromosomes (gene dosage effect). However, a number of genes from

unaffected chromosomes change their expression, suggesting trans-acting effects.

These genes have only partially been evaluated.20

Molecular prognostic markers

Molecular markers can be classified according to their presence on the DNA level

(mutations, polymorphisms) or on the RNA level (gene expression) (Table 1). Most

markers are predictive at diagnosis, but dynamic markers predicting response to

therapy, such as minimal residual disease, are also available.

Full article with tables is available at

http://www.haematologica.org:80/cgi/content/full/93/1/14?ct=ct