ReviewPrognostic markers in chronic lymphocytic leukemia: A comprehensive review
Introduction
Chronic lymphocytic leukemia (CLL) is a chronic lymphoproliferative malignancy characterized by progressive lymphocytosis caused by the clonal accumulation of CD5 + CD19 + B cells in peripheral blood, bone marrow and lymphoid organs. It is the most common leukemia in adults in the Western world, occurring predominantly in elderly people. Although CLL is generally considered an indolent disease, about half of the patients will progress more rapidly than initially anticipated and although ‘watchful waiting’ is the standard of care for patients with early stage CLL, these patients might benefit from treatment before progression occurs. Therefore, it is necessary to identify reliable prognostic markers, especially in early stage CLL. Moreover, accurate prognostication of patients is also needed to evaluate the usefulness of new treatment options like antibody-chemotherapy or autologous and allogeneic stem cell transplantation.
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Classical staging systems and prognostic parameters
Classification of CLL patients into different prognostic subgroups based on clinical observations and standard laboratory tests was introduced over thirty years ago by Rai et al.1, 2 and Binet et al.3, 4 Both systems reflect the overall tumor burden in the patient and allow assessing prognosis at the time of diagnosis (see Table 1). Because of their simplicity and reproducibility, these staging systems have been widely adopted, and their prognostic value has been validated in many studies.
Serum markers
A number of serum markers may reflect disease burden and cellular activity, such as lactate dehydrogenase (LDH), β2-microglobulin (β2-M), soluble CD23, CD27, and CD44 (sCD23, sCD27, sCD44), circulating CD20 (cCD20), certain interleukins and thrombopoietin (TPO).
The serum LDH level is considered a marker of cell turnover and is commonly elevated in patients with hematopoietic malignancies or other neoplastic disorders. In CLL patients, increased LDH levels are associated with a shorter survival
Proliferation markers
Although CLL is generally considered a disease of accumulation rather than proliferation, a recent study based on the oral administration of heavy water (2H2O) to CLL patients demonstrated that CLL cells have an in vivo birth rate of 0.1% to >1% of the total leukemic clone per day.45 Since the dynamic behavior of the CLL clone can be indicative for possible disease progression, markers reflecting the proliferative capacity of the leukemic cells can provide additional prognostic information to
Markers of angiogenesis
Not only solid tumors depend on angiogenesis or neovascularization for their growth and metastasis, the pathogenesis of hematopoietic malignancies is also related to angiogenesis. Early studies in CLL described abnormal microvessel density in the bone marrow and lymph nodes, linked to clinical stage and disease progression.61, 62, 63
Further evidence for the importance of angiogenesis in CLL came from the observation that CLL cells expressed and released considerable amounts of pro-angiogenic
Cytogenetic markers
The first reports describing chromosomal aberrations in CLL cells date from the late 1970s.84, 85 The use of B cell mitogens allowed detection of specific chromosomal abnormalities by conventional chromosome banding analysis (CBA) in 40–50% of CLL cases.86, 87, 88 CBA of metaphases has recently improved thanks to the application of CD40L stimulation89, 90 or the use of immunostimulatory oligonucleotides in combination with IL-2 during culture.91, 92 A genome-wide screening for chromosome
Mutation status and IgVH gene usage
In normal B cell development, B cells that are stimulated by antigen enter lymphoid follicles in the secondary lymphoid organs. A germinal centre (GC) is formed, and under the influence of T cells and in the presence of antigen presented by follicular dendritic cells, affinity maturation takes place.137, 138 This process is based on the generation of random somatic mutations in the variable region of the immunoglobulin gene, resulting in random changes of the antibody’s affinity for the
Potential surrogate markers for the mutation status
The determination of the IgVH mutation status is laborious, expensive and time-consuming. Moreover, specialized equipment is needed, rendering this method difficult to implement in the routine hematological laboratory. Therefore many efforts have been made to identify possible surrogate markers with the same prognostic value as the mutation status. CD38 expression was the first marker that was found to correlate with mutation status.148 Based on genome-wide gene expression studies,170, 171, 172
AID
Activation-induced cytidine deaminase (AID) is essential for somatic hypermutation and class switch recombination in B cells. Since the lack of somatic hypermutations is one of the most important adverse prognostic factors in CLL, several groups investigated AID expression in mutated and unmutated CLL cases. High AID mRNA expression was associated with unmutated IgVH genes, while mutated cases were generally AID negative.238, 239, 240, 241 AID positive patients were more likely to have
Minimal residual disease (MRD)
MRD detection in CLL gained interest during the last decade, since new treatment options like hematopoietic stem cell transplantation and immunotherapy allow to attain MRD eradication,269, 270, 271, 272, 273, 274 in contrast to conventional chemotherapeutic agents. Assessment of MRD status can be performed by PCR-based techniques,269, 270, 272, 274, 275, 276 or by flow cytometric analyses270, 271, 273, 275, 276, 277 which have been largely standardized and are reviewed in [278] and [279]. As in
Conclusion
The need for accurate prognostic markers has since long been recognized by clinicians and researchers in the field of CLL. Major breakthroughs were achieved by the identification of specific cytogenetic aberrations associated with clinical outcome, and by the observation that the IgVH mutation status allowed to distinguish between two different prognostic subgroups. The difficulty in performing this mutation analysis sparked numerous studies on possible surrogate markers and alternative markers
Conflict of interest statement
The authors declare no conflict of interest.
Acknowledgements
This work was supported by Grant No G.0026.06 from the Research Foundation – Flanders (FWO-Vlaanderen), Grant No. 01J02006 from the Bijzonder Onderzoeksfonds from Ghent University and Grant 2007 from Centrum voor Gezwelziekten, Ghent University Hospital. B.V. is a Senior Clinical Investigator and F.V.B. is a Research Assistant of the Research Foundation – Flanders (FWO-Vlaanderen).
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