Staging and Prognostic Factors in CLL

Chronic lymphocytic leukemia (CLL) is a disease with a variable natural history. Until recently, patients with CLL have been staged utilizing either the Rai or Binet system (Tables 1 and 2).^1,2 Both of these discriminate CLL by the sites of disease and degree of cytopenias induced due to replacement of the bone marrow by leukemia cells.

Thus far, no study has shown a survival advantage with early treatment in patients with CLL and a subset of CLL patients will never require therapy. This has led to research efforts in CLL that have identified several specific biologic or clinical prognostic factors that predict time to progression and overall survival. With these recent advances in the understanding of the molecular biology of CLL, some prognostic factors such as bone marrow infiltration pattern, which requires an invasive procedure at diagnosis, have not maintained their usefulness in predicting disease progression.

These newer prognostic markers are summarized below. It should be emphasized, however, that the presence of one or more adverse biologic features still does not alter the initial approach to how a patient with CLL is managed. Specifically, we utilize observation until symptoms develop that are referable to the disease.

Lymphocyte Doubling Time (LDT)

LDT is defined as the period in months in which the lymphocytes double in number as compared to the amount found at diagnosis. An LDT of ≤12 months not only portends a rapid disease progression but also a worse overall survival regardless of the stage of the disease.³ LDT is therefore an easy and reliable method that can be used to predict progression and outcome of CLL. Our approach is to follow patients every 3 months during the first year, and if little change in clinical or laboratory parameters occurs, we extend this period to every 6 months in the absence of new complaints.

Thymidine Kinase Activity (TKA)

Thymidine kinase is an enzyme involved in the salvage pathway of DNA synthesis and correlates with proliferative activity. An elevated TKA has been observed to be predictive of early progression in a subgroup of untreated patients with smoldering CLL.⁴

Beta-₂-Microglobulin (β₂M)

β₂M is an extracellular protein component of the HLA Class I complex. β₂M has been shown to have significant prognostic relevance in lymphoma and multiple myeloma, and correlates with disease burden in CLL. Elevated β₂M is an independent predictor of shortened progression free survival (PFS) for both untreated and previously treated patients.^5-7 Elevated β₂M has also been observed in patients with high tumor burden and extensive bone marrow infiltration. In addition to disease progression, both β₂M^8-10 and TKA¹¹ have been associated with short duration of remission and inferior survival following treatment.

Soluble CD23 (sCD23)

sCD23 is a protein derived from the B-cell membrane CD23 antigen and is selectively elevated in the serum of CLL patients. Elevation of sCD23 levels above the median value predicts a significantly shorter time to disease progression and overall survival.¹²

CD38 Expression

Studies have shown that expression of CD38 on CLL cells is an independent prognostic marker in CLL. High CD38 expression (>30%) is associated with both a shorter time from diagnosis to treatment and inferior survival.^13-16

Chromosomal Abnormalities

Because of the low in vitro mitotic activity of CLL cells, the use of conventional metaphase cytogenetics to identify chromosomal abnormalities in CLL is limited. Therefore, we currently utilize interphase cytogenetics of known abnormalities by fluorescence in situ hybridization (FISH) to accurately distinguish the various genetic subtypes of CLL.

Abnormalities noted in descending frequency of occurrence include:

• Trisomy 12
• Deletions at 13q14
• Structural aberrations of 14q32
• Deletions of 11q, 17p, and 6q¹⁷

The interphase cytogenetics by FISH can accurately detect chromosomal abnormalities in more than 80% of all cases. Dohner and colleagues²¹ and others have shown that most of these abnormalities can be used to predict not only the median time to first treatment but also median survival, as shown in Table 3.

Metaphase karyotyping when done under appropriate conditions by an experienced CLL cytogeneticist can generate useful karyotypes in approximately 50% of patients. Complex karyotype (three or more abnormalities) occurs in approximately 15% of patients and predicts for rapid disease progression, Richter’s transformation, and inferior survival.^18-20

Immunoglobulin Variable Heavy Chain (IgV_H) Mutational Status

Examination of IgV_H genes in CLL cells suggests that there may be two subsets of CLL:

1. CLL whose cell of origin has the mutated IgVH. Approximately 60% of CLL patients have cells with mutated IgV_H genes. These cells are less than 98% identical to germline, naïve B-cells.
2. CLL whose cell of origin has the un-mutated IgV_H. These cells have a 98% or greater sequence identity with germline, naïve B-cells.

The prognostic significance of the IgV_H gene mutation is substantial, with all studies uniformly noting an inferior survival and high likelihood of requiring early treatment in patients with the un-mutated IgV_H gene as shown in Table 3.^21-28 The mutational status of the IgV_H gene can now be easily determined with the help of a commercially available assay available from Genzyme Genetics (www.genzymegenetics.com).

How Do We Use Staging and Biomarkers to Determine the Prognosis of CLL in 2007?

The rapid advances in CLL research over the last two decades have significantly improved our understanding of the biology of CLL. It has also resulted in the discovery of many new and clinically relevant biomarkers, some of whom have now been validated in prospective studies, and are extremely useful for predicting disease progression and overall survival. However, no study to date has demonstrated that early treatment will benefit the patient in terms of overall survival, even in the higher risk groups with a relatively short time to disease progression.

Therefore, at the present time, the use of staging and predictive biomarkers should be used only to provide patients with information relative to the expected course of their disease. At our own center, we typically obtain clinical staging information, β₂M, CD38 expression, interphase and metaphase cytogenetics, and immunoglobulin gene mutational analysis. ZAP70 analysis at this time yields conflicting results from different reputable laboratories and therefore should not be used for counseling patients.

Outside of a Clinical Trial, These Results Should Never Be Used to Initiate Therapy in Patients with Asymptomatic Disease and No Indication for Treatment.

We recommend having a detailed discussion with the patient prior to performing these predictive tests and educating them about the role of these tests in the management of their disease. Patients should also be given the option of not performing these tests, which may lead to significant anxiety and a request for early treatment in the event that a high-risk feature is identified.

*Nodal Areas counted as one each of the following: axillary, cervical, inguinal lymph nodes, whether unilateral or bilateral, spleen and liver

Adapted from ^21,28,29

References

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