It is thought that soluble factors such as cytokines, stromal

cells, T cells and nurse like cells Aloe-emodin

are involved in maintaining the CLL cell,s viability within the

bone marrow or lymph node and allowing development of drug

resistance.6 Disruption of this microenvironment and removal of these

protective stimuli may lead to CLL cell death. We will discuss

treatments targeting these pathobiological processes in more detail

below. Diagnosis and Staging CLL is a heterogenous disease with a

wide variability in disease presentation and course. While some

patients with CLL will never require therapeutic intervention, many

others require multiple lines of chemotherapy and often die from the

disease.
Current guidelines outline diagnosis and staging of CLL

based on the characteristic immunophenotype of CD19 and CD5

positivity present on.5 ???09/L peripheral blood B lymphocytes.2 The

iwCLL guidelines recommend disease assessment using Rai or Binet

Staging systems to guide treatment initiation as these provide a

reliable prediction of a patient,s prognosis based solely on physical

examination and blood counts.7,8 Prognosis A variety of prognostic

biomarkers have been studied in CLL.9 Analysis of somatic mutations

of the immunoglobulin heavy chain variable region is used to stratify

CLL patients into two distinct biological and prognostic groups on

the basis of whether the IGHV genes are hypermutated or

unmutated.10,11 As this is a difficult and expensive test to perform

routinely in clinical laboratories, surrogate markers such as zeta

associated protein 70 and CD38 expression have been evaluated.
12

15 The use of a combination of both CD38 expression and ZAP70 can

classify CLL patients in to 2 risk groups with a double negative

result equating to an excellent prognosis and double positive a poor

prognosis.16 Cytogenetic abnormalities are detected in approximately

80% of CLL patients using interphase fluorescence in situ

hybridisation.17 Dohner et al investigated 325 mainly untreated CLL

patients and identified five prognostic categories. Of these,

patients with 17p deletions and 11q deletions had the worst outcome.

The median treatment free interval for these groups was 9 and 13

months, respectively. More recently, it has been shown that the

addition of rituximab to standard chemotherapy may overcome the

adverse prognostic significance of 11q deletions but not of

del17p.
18,19 Mono or bi allelic mutations of TP53 without del17p

also confer a poor prognosis and chemotherapy refractoriness.

Del17p/TP53 abnormalities occur in about 8% of patients at diagnosis

and 25% of fludarabine refractory cases.20,21 It is therefore

recommended to test for deletions and/or mutations of TP53 before

each course of treatment. Response Prediction Using Whole Genome

Approaches As outlined in more detail below, treatment of patients

with CLL has evolved in recent years and many patients are exposed to

potentially more toxic agents like purine analogues or alemtuzumab.

Besides, modern chemo immunotherapy is significantly more expensive

than single agent chlorambucil.