Prognostic Factors

The Role of Classical Predictive Factors in Deciding When to Treat

We will speak a great deal about the newly developing thinking utilizing “predictive factors.” However, doctors consulted in the writing of this website were unanimous in stating that, although they are aware of the new molecular prognostic factors, their decision to treat is still based on the clinical manifestations of the Rai Staging System, a classification developed decades ago.

Rai Staging System

Stage Low Risk Lymphocytosis in blood and marrow only
Stage 1,2 Intermediate Risk Lymphadenopahty (swollen nodes or spleen/liver)
Stage 3,4 High Risk Anemia (low red counts), thrombocytopenia (low platelets)

Other classification methods take into account whether there is lymphadenopathy above and below the diaphragm, and which body organs may be involved. To arrive at proper staging, the doctor should consider blood results, biopsies, and body scans.

An important method of analysis, flow cytometry, is the measurement of so-called “clusters of differentiation,” antigens/proteins, called CDs. Cells carry these markers on their outer surface, and the type and strength of expression of these markers help doctors determine whether the disease is CLL/SLL. The markers classically characteristic of CLL/SLL are CD5, CD20, and CD23.

The Role of Novel/Molecular Diagnostics in Prognosis

Patients with CLL/SLL can have very different experiences before and after diagnosis. Some people may live for a long time without ever requiring therapy, while others may experience a rapid progression of their disease. The healthcare and research communities do not completely understand all the genetic changes present in cancerous cells. However, researchers have been able to identify and link the presence or absence of certain mutations (changes) to how the disease will behave. Techniques have been developed to examine the genes of cells and their possible mutational status.

In the last decade, impressive progress has been made in understanding the genetics of CLL/SLL through the development of new diagnostic tests for CLL/SLL. Investigators have identified mutations or measurable factors in the bloodstream thought to be of value in predicting how the disease will behave. Having found the same abnormalities in many CLL/SLL patients, and observing the course of their disease, scientists establish "prognostic factors." The ultimate value of new prognostic tests for determining treatment is not yet clear. Future and ongoing clinical trials are being conducted to determine whether patients at high risk for disease progression actually benefit from early treatment intervention. A person, for example, with early stage CLL/SLL that is demonstrating several unfavorable risk factors may wish to participate in clinical trials designed to measure the benefit of early treatment with chemotherapy in combination with immunotherapy.

FISH (fluorescent in-situ hybridization) is a new and useful technique for looking at chromosomal abnormalities, which reflect gene abnormalities. Chromosomes 11, 12, 13 and 17 are of particular interest. Of importance is the presence of the p53 gene, which has an effect on regulating cell death (apoptosis). Hematologists pay particular attention to aberrations (variations from the norm) in the 17th chromosome where the p53 gene is located, since the normal function of p53 is important for the response to chemotherapy.

IgVH
The mutational status of a gene known as IgVH helps predict how quickly a person with CLL/SLL might progress. Every B-cell rearranges its genes to make specific antibodies to a particular target (antigen) which, for instance, may be on a bacteria. When CLL/SLL is derived from cells that undergo the change to make antibodies (mutated genes), an individual will have a more indolent (slow-growing) course of disease. A person with un-mutated (unchanged) IgVH will likely have a more progressive and/or aggressive disease than those with the mutated gene.

ZAP-70
ZAP-70 is a substance involved with cell activation. Researchers have found that the leukemic cells that have ZAP-70 seem to progress faster than those leukemic cells that do not have ZAP-70.

CD-38
CD-38 is a protein antigen attached on the outside of leukemia cells. The presence of CD-38 suggests a faster progression, but scientists still do not completely understand why CD-38 plays a role in CLL/SLL.

Summary

As scientists continue to research how CLL/SLL occurs and progresses, they will continue to develop a better understanding of these factors. Many patients get very anxious about their “progression status” and worry about what this will mean and how long it will be before they need treatment. It is important to remember that at this time most hematologists/oncologists decide when to start treatment for CLL/SLL patients based on the clinical (classical) Rai staging, not novel/molecular prognostic factors. Treatment initiation is thus never based on these markers/factors, although they may impact how patients are ultimately treated.