This protocol has been superseded as it is not considered best practice for this patient population as superior combination regimens are available.
Catovsky et al (2007)r report on a multicentre study of 777 previously untreated patients with CLL who were randomised to receive either chlorambucil (n=387), fludarabine (n=194) or fludarabine and cyclophosphamide (n=196). Overall survival was the primary endpoint and response rate, progression-free survival, toxic effects and quality of life were the secondary endpoints.
The CLL Trialists' Collaborative Group (1999)r reported a meta-analysis of 10 trials, involving >2000 patients with CLL, comparing combination therapy with chlorambucil (with or without prednisolone).
There are several different published treatment schedules for chlorambucil in CLL with no clear advantage for any single schedule. The chlorambucil schedule used here is widely used internationally and is the schedule used in the UK CLL4 clinical trial.
Efficacy
Catovsky et al (2007)r found that overall survival was the not statistically different between the three arms of the study. However, both complete (CRR) and overall response rates (ORR) were better in the fludarabine and cyclophosphamide arm than in the fludarabine arm, which in turn was better than the chlorambucil arm. These results are summarised in the table below.
Regimen |
CRR(%) |
ORR(%) |
Fludarabine/Cyclophosphamide |
38 |
94 |
Fludarabine |
15 (p<0.0001) |
80 (p<0.0001) |
Chlorambucil |
7 (p<0.006) |
72 (p<0.04) |
Overall survival and progression free survival data:r
© Lancet 2007
The CLL Trialists' Collaborative Group (1999)r meta-analysis of over 2000 patients showed an identical 5 year survival of 48% in both groups. Six of the 10 studies included an anthracycline and a subgroup analysis of these trials showed no survival advantage compared with chlorambucil.r
Fludarabine has been show to have a higher ORR, CR rate and duration of response than chlorambucil or anthracycline containing combination chemotherapy. There was no statistically significant difference in the survival for patients receiving fludarabine although the crossover nature of some of these studies and the high response rate to second line treatment may have influenced these results.
More recent studies comparing fludarabine and cyclophosphamide with fludarabine have shown a prolonged progression free survival for patients receiving the combination therapy.r
© Journal of Clinical Oncology 2014
Toxicity
Toxic effects by treatment:r
Patients spent more time in hospital and had more neutropenia with fludarabine and cyclophosphamide or fludarabine than with chlorambucil.
© Lancet 2007