Treatment of Indolent CLL

It is not clear whether early therapy benefits patients with indolent CLL. This form of the disease includes patients with a median age of 64 yr displaying a survival greater than 10 yr. In indolent CLL, Chlorambucil (CB) given daily or intermittently, alone or combined with corticosteroids, is the most commonly used drug. It often provides a period of relief from any symptoms, even in advanced disease. However, there has been much uncertainty as to whether such chemotherapy should be started immediately or whether this therapy could be appropriately deferred until required for the relief of symptoms. Several randomized trials have been activated to address this question.

The French Cooperative Group in CLL performed two long-term trials (CLL-80 and CLL-85) in stage A patients addressing this question (9,10). In the CLL-80 trial (mean follow-up >11 yr), early therapy with CB using a daily continuous schedule (dCB), was compared with a watch and wait policy, whereas in the CLL-85 trial (mean follow-up > 6 yr) CB given in an intermittent schedule associated with prednisone (CBPr) was compared with a watching policy. The CLL-80 and -85 trials included, respectively, 609 and 926 previously untreated CLL stage A patients randomized according to a first intention to treat basis between no treatment (CLL-80, 308 patients; CLL-85, 466 patients) or dCB (CLL-80, 301 patients) or CBPr (CLL-85, 460 patients). Endpoints were overall survival, treatment response, and disease progression. No benefit for early treatment was observed in either trial: relative risk of death = 1.14; p = 0.23 [confidence interval (CI): 0.92-1.41] for CLL-80 and relative risk of death = 0.96; p = 0.74 (CI: 0.75-1.23) for CLL-85). In the CLL-80 and -85 trials, 76 and 70% of patients, respectively, responded to therapy.

Although a benefit of CB in slowing disease progression was observed, no effect on overall survival was found. In the abstention group from the CLL-80 trial, 49% of patients did not evolve and did not need any therapy after a follow-up of more than 11 yr. However, 31% of stage A patients died of causes related to disease, 43% progressed to stages B and C, and 53% required treatment during evolution. Similar results were observed for Rai stage 0 patients (27% of CLL-related deaths and 42% required subsequent treatment), which includes half as many patients as stage A (Table 2). When patients were segregated according to the French stages A' and A'', no demonstrable benefit could be observed for early treatment. Although some of these A' and A'' patients may have a different survival from each other there is no evidence that it is better to treat one group and not the other.

All together, these results indicate that neither of the two CB schedules prolonged survival in these patients. Since deferring therapy until it is required because of disease progression to stages B or C does not compromise survival, initial therapy could have been appropriately deferred for

Table 2

Long-Term Evolution of Rai and Binet Good-Prognosis Patients

Table 2

Long-Term Evolution of Rai and Binet Good-Prognosis Patients

% of patients

% of CLL-

% of patients

% of patients

Stage

% of patients

10-yr survival (%)

without evolution

related deaths

evolving to B or C

receiving treatment

0

31

59

57

27

32

43

A

65

51

47

31

41

53

this low-risk stage A group; this group constitutes almost two-thirds of patients with CLL and has a median age at diagnosis of 64 yr and an expected survival of more than 10 yr, which is close to the life expectancy of a normal population matched for sex and age (9,10). In addition, deferring therapy until disease progression demands it has been shown not to compromise survival (10).

The establishment of the International Workshop on CLL (IWCLL) allowed results to be shared. To answer the question further of whether early therapy with CB is better than deferring treatment for stage A CLL patients, a number of series were pooled (14): the 78 Medical Research Council (MRC)-CLLl trial (78 patients), the 84 MRC-CLL2 (239 patients) (11), the 76 Cancer and Leukemia Group B (CALGB) (45 patients) (12), the French Cooperative Trials 80 (609 patients) and 85 (926 patients) (9,10), and the Program for the Study and Treatment of Hematological Diseases (PETHEMA, 157 patients) (13). The additive results of treatment comparison for all deaths suggest that in terms of survival there is definately no evidence that treating patients immediately with standard CB treatments prolongs survival (10,14). Because more than 50% of these early-stage patients more than 50% may die of other causes, data for patients who died of something that was definitely not CLL were censored. Again, this analysis clearly showed that early treatment was unable to prolong survival in indolent CLL.

Although these results demonstrate that CB given in classical schedules fails to influence survival in indolent CLL, it has been proposed that high-dose continuous CB influences CLL survival. The International Society for Chemo- and Immunotherapy (IGCI) CLL-01 trial (15) compared the classical intermittent CB plus prednisone schedule with high-dose CB (15 mg fixed dose daily to either complete remission or toxicity or to a maximum of 6 mo). A significant difference in response, which was also translated into a survival difference in favor of high-dose CB, was observed, although these results need to be further confirmed.

These results also suggest that although the Rai and Binet staging systems have succeeded in identifying patients with a favorable prognosis (Rai stage 0 and Binet stage A), about 30% of these patients still die of causes related to CLL and about 50% of them require treatment during the course of disease (10). Thus, early identification of patients who will not evolve, i.e., a definition of smoldering CLL, is an important goal so we can therapeutic strategies better.

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Responses

  • tytti
    What is life expactancy patient with CLL with disonsed at 57?
    8 years ago

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