A comparison of the efficacy and safety of oral and intravenous fludarabine in chronic lymphocytic leukemia in the LRF CLL4 trial.
BACKGROUND
An oral formulation of fludarabine was introduced for use in chronic lymphocytic leukemia in 2001 following studies demonstrating the bioequivalence of a 40 mg/m(2) oral dose with a 25 mg/m(2) intravenous dose. We assessed retrospectively the efficacy of these two routes of administration in the LRF CLL4 trial.


METHODS
A total of 777 patients were randomized from 1999-2004 to receive fludarabine, alone or with cyclophosphamide, or chlorambucil. In 2001, a protocol amendment allowed the oral formulation. There were 117 assessable patients who received fludarabine intravenously and 252 who received it orally. A total of 387 patients given chlorambucil acted as a control group.


RESULTS
Patients given oral fludarabine were less likely to receive the full dose (P = .0004) and experienced more, predominantly gastrointestinal, toxicity. Progression-free survival (PFS) and overall survival were not affected by the route of administration (PFS hazard ratio, 1.10; 95% confidence interval, 0.87-1.40), but the overall rate of response to treatment appeared to be lower with the oral formulation (P = .003). However, patients recruited since 2001 were older (P = .03) and were more likely to have TP53 deletion, and response rates after 2001 were also lower in the chlorambucil group. After excluding patients with TP53 deletion, no significant difference in outcome was attributable to the route of administration.


CONCLUSIONS
Although the LRF CLL4 data suggest no important difference in the effectiveness of oral compared with intravenous fludarabine, randomized trials are needed to reliably evaluate this comparison, particularly in combination with rituximab. Meanwhile, it is important to monitor compliance and gastrointestinal side effects with the oral route and to switch to intravenous therapy if a reduced dose is being received.
['Dearden|Claire E|CE|', 'Richards|Sue|S|', 'Else|Monica|M|', 'Catovsky|Daniel|D|', 'Hillmen|Peter|P|']
D061605:Administration, Intravenous D000284:Administration, Oral D000328:Adult D000368:Aged D000369:Aged, 80 and over D000970:Antineoplastic Agents D005260:Female D006801:Humans D015451:Leukemia, Lymphocytic, Chronic, B-Cell D008297:Male D008875:Middle Aged D012189:Retrospective Studies D016896:Treatment Outcome D014740:Vidarabine
oral intravenous fludarabine toxicity chronic lymphocyctic leukemia