Survival And Prognostic Factors

A 5-yr relative survival rate of 78.8% (observed expected survival compared withy the same age control population) was recorded by the Surveillance, Epidemiology, and End Results (SEER)

Fig. 1. CLL cases recorded during the 1984-1994 period and proportion of younger and older patients observed per year. Black bars, 55 yr old or younger; open bars, 55 yr or older; solid black line, no. of patients.
Fig. 2. Gender and age distribution of CLL cases recorded during the 1984-1994 period. Black bars, women; open bars, men; solid black line, no. of patients.

program registry for CLL patients younger than 65 yr during the 1989-1985 time period (20). In our series, the overall median survival probability for patients 55 yr or younger was 10 yr, in line with the range of median survival values for young patients included in other series (3-6,8,9). Paradoxically, young age did not represent a survival advantage, since both younger and older patients showed a similar survival probability. The 10-yr survival probability for young and old CLL patients was significantly lower compared with the expected survival probability for the age-and sex-matched Italian population: 55 yr or younger, controls 96.2% vs CLL 45.3%; older than 55 yr, controls 81.7% vs CLL 54.8%. When the relative survival rates were calculated, younger patients showed a lower relative survival rate than older patients (47% vs 67%). In addition to the greater impact of the disease on survival in the younger than in the older age group, deaths from causes directly related to CLL progression were significantly greater in the younger age group (9). These findings indicate that a diagnosis of CLL implies a more adverse effect on survival in younger than in older people.

Several authors have analyzed whether well-documented prognostic factors have the same impact on survival of younger patients. In our series, stage, peripheral blood lymphocytes, marrow histology, LDT, and clinical signs of AD, as observed in older patients, correlated significantly with survival. However, in multivariate analysis, parameters indicative of early disease progression (LDT and AD) represented the only independent factors capable of significantly predicting survival for young CLL patients (9) (Fig. 3). Forty percent of young patients with an extremely good prognostic likelihood could be identified within stage A: 94% of them were projected long-term survivors at 12 yr from diagnosis without treatment (9) (Fig. 4).

The different outcome of CLL patients has recently been better defined by the exciting identification of biological features, such as the presence of certain cytogenetic abnormalities and the mutational pattern of the IgVH genes (21-23), which have had a high predictive value for disease progression and survival. The different patterns of genomic aberrations, i.e., 17p deletion, 11q deletion, 12q trisomy, and 13q deletion as a single aberration, are observed in approx 80% of cases using molecular genetic techniques (21). The pattern of cytogenetic aberrations appears to be related to clinical features at CLL presentation, to the time of disease progression, and to survival probability. Preliminary results of a new prospective study performed by the German CLL Study Group in stage A patients revealed the presence of genomic aberrations with unfavorable prognostic value in approx 15% of patients (13). Two different CLL variants have been identified according to the mutational status of the IgV genes. The pregerminal variant originates from naive B-lymphocytes, shows no IgV gene mutation, and is characterized by a poor prognosis. The postgerminal variant originates from memory B-lymphocytes, shows IgV gene somatic hypermutations and is characterized by a better outcome (22-25). Cytogenetic aberrations with unfavorable prognostic effects, such as 17p and 11q deletion, as well as a CD38 expression level greater than 30%, have been found in CLL cases characterized by nonmutated IgV genes (23-25).

In a series of CLL patients with long-lasting stable disease without treatment for 10-23 yr observed at our institution, we documented a number of features that appear to correlate with indolent disease: an immunophenotypic profile of classic CLL, a mutated IgV gene status, the absence of p53 aberrations, a very low incidence of poor-prognosis cytogenetic abnormalities, a lack of CD38 expression, and a normal CD4/CD8 T-cell subset distribution (ms. in preparation).

To our knowledge, no study has yet specifically focused on the distribution and prognostic significance of such biological markers within the younger age group of CLL patients. Ideally, an integrated clinical-biological prognostic assessment at CLL presentation should be offered to

Fig. 3. Survival of young CLL patients according to lymphocyte doubling time (LDT) or presence of active disease (AD).

months

Fig. 4. Projected survival probability of young stage A CLL patients according to disease status.

months

Fig. 4. Projected survival probability of young stage A CLL patients according to disease status.

all patients, particularly to the younger ones, since it may prove of primary relevance in predicting a stable or a progressive outcome and may thus be important to plan the most adequate therapeutic management, particularly for stage A patients.

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