During the study period, the Cancer Registry registered 388 new cases of CLL, which is equivalent to an age-adjusted incidence of 3.8/100 000/year. This corresponds well with a recent American study, where an age-adjusted incidence of 3.83/100 000/year is reported, with a clear male dominance (15), but is somewhat lower than previously published Nordic studies which could indicate an incidence of 4/100 000/year (16, 17).
The primary aim of the study was to survey the involvement of biological markers with prognostic significance in an unselected material, and doctors were urged to carry out the tests in question on all recently diagnosed patients. This was done, if not fully, for those who were included. They were substantially younger than those who were not included (median 65 years, versus 73 years). The tests in question are quite resource- and cost-intensive. It therefore seems likely that the doctors did not conduct these tests on the oldest patients because the result would not have consequences for the choice of treatment.
The failure to include mainly elderly patents has little impact on our calculations of the relative distribution of prognostic factors in the patient population because these factors do not show a different distribution in different age groups. There is a clear gender difference, however – high risk factors are seen more frequently in men than in women (4) – (6). Our project can nonetheless claim to be population-based and representative, but it is not unselected. The selection appears very largely to have been made by the doctors, because some geographical areas are not represented in the study, as in a previous study (1). Calculations of incidence and gender distribution were based on mandatory notifications to the Cancer Registry and were therefore carried out on an unselected material.
In the first studies that described the preferred VH gene’s mutational status in CLL there were almost equal numbers of patients with mutated and with unmutated VH genes (4, 5). However, we found that 69 % of the patients had a mutated VH gene and 31 % an unmutated gene. This is consistent with recently published, population-based studies from Europe and the USA (18, 19), which should indicate that our study is representative. The first reports came from specialised hospital departments, whereas our study and the more recent international studies are population-based and therefore cover a patient population that to a greater extent includes those with indolent disease, where we would expect CLL with a mutated VH gene to predominate.
As early as in 1988, Kipps et al. described CLL cells as using a limited repertoire of VH genes (20). These observations are confirmed in several studies, and a meta-analysis shows that the preferred VH gene families associated with CLL differ from the repertoire of normal B-lymphocytes (21, 22). Our study is one more in the series.
CLL where both IgH genes are rearranged and expressed is well known. This is called biallelic CLL, as opposed to biclonal CLL, where two different CLL clones occur side by side (23, 24). The incidence of biallelic CLL has not been described previously. In our material, 9 % of the patients had biallelic CLL, and one or both of the preferred VH genes were unmutated in the majority (61 %).
Like other investigators, we found that the CLL cells of just over a quarter of the patients expressed CD38 at the cell surface (19). CD38-positive CLL usually used an unmutated VH gene (58 %), but CD38 expression cannot be used as a surrogate marker for the VH gene’s mutational status (7).
Hospitals report that about 80 % of patients have genetic aberrations in the CLL cells when they are tested for del(13q14), del(11q22), del(17p13) or trisomy 12 using FISH analysis, while about 20 % do not have cytogenetic aberrations (6). In our material, the percentage without cytogenetic aberrations is somewhat higher (33 %), but the distribution of the various cytogenetic aberrations is the same as that reported by others (Table 2). We found more than one cytogenetic aberration in 12 % of the patients. Others have pointed out that the prognosis of these patients is determined by the aberration associated with the poorest prognosis (6).
There may be a number of explanations for the somewhat higher proportion without cytogenetic aberrations in our material. Methodological factors that resulted in aberrations not being detected is one possibility, but if this were the explanation, we would also have expected differences in the distribution of cytogenetic aberrations in relation to other materials. The cytogenetic aberrations in question are not regarded as primary pathogenetic events associated with chronic lymphocytic leukaemia; they come about along the way. One might therefore expect a higher proportion of patients without cytogenetic aberrations in a population-based material than in materials from specialist departments. One limitation of our material is that cytogenetic testing was conducted on a relatively low percentage of the patients (48 %).
The biological markers have strong prognostic significance, and may be of great assistance in providing prognostic information to the individual patient. This is particularly important because the bulk of the patients are diagnosed in an asymptomatic phase of the disease when treatment is not indicated. At present, treatment based on biological markers is not an option – with one exception: In the case of chronic lymphocytic leukaemia characterised by del(17p13) there is consensus that patients should receive treatment that is independent of the p53 signal path (the TP53 gene lies in chromosome band 17p13) in order to be effective (25). Immunochemotherapy (rituximab, fludarabine and cyclophosphamide) are considered today to be the optimal first-line treatment for CLL for those who tolerate aggressive therapy (age 70 or younger and no comorbidity). Immunochemotherapy is particularly effective with an unmutated VH gene, del(13q14) and/or del(11q23) (26).