Fludarabine

Fludarabine monophosphate (2-fluoro-ara-AMP) is the purine analog with the most clinical activity in CLL. Fludarabine is water-soluble and is relatively resistant to adenosine deaminase; it is rapidly dephosphorylated to F-ara-A after intravenous administration, enters the cells by a carrier-mediated transport system, and undergoes intracellular rephosphorylation to its active metabolite, 2-fluoro-arabinofuranosyl-adenosine-triphosphate (F-ara-ATP), by the rate-limiting enzyme deoxycytidine kinase (39). F-ara-ATP inhibits DNA and RNA synthesis and affects DNA repair, but the exact mechanism of cytotoxicity in quiescent cells, such as malignant lymphocytes, is not known. The activity of F-ara-ATP in CLL could be mediated by the induction of apoptosis (28,40).

Fludarabine was introduced into clinical trials in the early 1980s; the first results using this agent to treat CLL were published in 1988 by Grever et al. (41). In this study, 32 patients with advanced stage CLL were treated at a dose of 20 mg/m2 daily for five consecutive days; the complete remission rate was 3%, with an overall response rate of 12% (41). Keating et al. (42) treated 68 patients with relapsed or refractory CLL with fludarabine 25-30 mg/m2 daily for 5 d. The complete remission rate was 15%, and the overall response rate was 44%.

Since the first positive reports, fludarabine has been used extensively in the management of patients with relapsed or refractory CLL. At the University of Texas M.D. Anderson Cancer Center, a series of studies was conducted with fludarabine: a 5-d schedule at a dose of 30 mg/m2, a 3-d schedule at a dose of 30 mg/m2, a combination of fludarabine (30 mg/m2 for 5 d) and prednisone, and fludarabine given once a week at a dose of 30 mg/m2. The response rate with the

3-d schedule of fludarabine was slightly less than that observed with the 5-d regimen (overall response rate 46% vs 59%); the 3-d schedule produced less immunosuppression (43). O'Brien et al. (44) reported the results in 169 patients treated with fludarabine and prednisone: the overall response rate was 52%, and the median duration of response was 22 mo. These results were similar to those obtained with the 5-d schedule of single-agent fludarabine, but the incidence of opportunistic infections was increased with the combination of fludarabine and prednisone (44). The once-a-week schedule had a lower overall response rate (24%) in 46 previously treated patients compared with the 5- and 3-d schedules (45). Survival correlated with response to treatment in the above studies. The most durable responses were observed in patients who obtained a complete response and in patients with less prior treatment.

A retrospective analysis of previously treated patients who received single-agent fludarabine as salvage therapy showed that response rates were higher in patients with early-stage disease, minimal prior therapy, age less than 70 yr and normal serum albumin levels (44,46).

Table 3

Large Randomized Studies of Fludarabine in Previously Untreated CLL

Table 3

Large Randomized Studies of Fludarabine in Previously Untreated CLL

Regimen

Entry period

No. of patients

CR (%)

PR (%)

Survival (mo)

F vs IChOP vs CAP (50)

1990-1998

938

40/15/30

31/43/42

69/70/67

F vs CAP (48)

1990-1992

100

23/17

48/43

NA

F vs Chl (3)

1990-1994

509

20/4

43/33

66/56

F, fludarabine; ChOP, Binet modified CHOP (doxorubicin 25 mg/m ); CAP, cyclophosphamide, doxorubicine, and prednisone; CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisone; Chl, chlorambucil; CR, complete remission; PR, partial remission; NA, not available.

F, fludarabine; ChOP, Binet modified CHOP (doxorubicin 25 mg/m ); CAP, cyclophosphamide, doxorubicine, and prednisone; CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisone; Chl, chlorambucil; CR, complete remission; PR, partial remission; NA, not available.

Sorensen et al. (47) reported the outcome of 724 patients with relapsed or alkylating agent-refractory CLL treated with fludarabine. The overall response rate was 32%, the median duration of response was 13.1 mo, and the overall survival was 12.6 mo.

The French Cooperative Group conducted a randomised trial of fludarabine vs cyclophosphamide, doxorubicin, and prednisone (CAP) in 96 previously treated patients. Patients treated with fludarabine had a higher overall response rate and higher complete response rate than patients treated with CAP (48% and 13% vs 27% and 6%, respectively). There were no differences between the two treatment groups in median response duration and median survival (48).

Fludarabine has also been evaluated as front-line therapy for CLL. Keating et al. (49) observed an overall response rate of 80% and a complete remission rate of 37% in 35 patients; the median response duration was 33 mo. The addition of prednisone to fludarabine did not improve the response rate in previously untreated patients (44).

Front-line treatment with fludarabine has been compared with alkylating agent-based therapy in randomized clinical trials (Table 3). The French Cooperative Group assigned 100 patients with advanced CLL to receive treatment with fludarabine or the anthracycline-containing alkylating agent-based regimen CAP. The overall response rates and complete response rates were 71 and 23%, respectively, among the 52 patients who received fludarabine and 60 and 17%, among the 48 patients treated with CAP. Treatment with fludarabine induced significantly longer remissions than CAP, and this translated into a trend toward overall longer survival (48).

The French Cooperative Group compared fludarabine and two anthracycline-containing alkylating agent-based regimens: CAP and modified CHOP for initial treatment of CLL. In all, 938 patients were entered on the study, and 924 were evaluable for response. Among the 336 patients treated with fludarabine, the overall response rate was 71%, and the complete response rate was 40%. Among the 237 patients treated with CAP, the overall response rate was 58%, and the complete response rate was 15%. The modified CHOP regimen produced an overall response rate of 71% and a complete response rate of 30% in 351 patients. Fludarabine treatment produced a higher rate of complete remission and was better tolerated than the modified CHOP; both fludarabine and ChOP produced higher overall response rates than CAP. The median survival was similar in the three arms (69, 67, and 70 mo for fludarabine, modified CHOP, and CAP, respectively) (50).

A large Intergroup trial compared fludarabine with chlorambucil or a combination of the two agents as front-line treatment for CLL. Over 500 patients were treated among the three arms. Fludarabine produced an overall response rate of 63% and a complete response rate of 20%

compared with an overall response rate of 37% and a complete response rate of only 4% with chlorambucil. Fludarabine plus chlorambucil resulted in an overall response rate of 61%; this arm of the study was terminated early because of excessive toxicity. Fludarabine was superior to chlorambucil in terms of median duration of remission and median progression-free survival, but overall survival was not significantly different between the two treatment arms (66 vs 56 mo). Crossover was allowed for lack of response or early relapse: 79 patients received fludarabine after failing chlorambucil, and 46% of them had a complete or partial remission; only 7% of the 29 patients who received chlorambucil after failing fludarabine responded (3). A higher rate of serious infections was observed in the combination arm. There was a trend toward a higher rate of bacterial infections with fludarabine compared with chlorambucil, although the incidence of such infections was low in both arms. Fludarabine was associated with an increased incidence of viral reactivation (51).

The most common toxicities with fludarabine treatment are immunosuppression, myelo-suppression, and resultant infection (52,53). The immunosuppression may be prolonged, but infections are uncommon in patients in remission (54). Tumor lysis syndrome is a rare complication of fludarabine treatment, as well as of alkylating agents and fludarabine-based combinations (55). The association of fludarabine treatment and the development of hemolytic anemia has been reported, but a causal relationship has not been proved (56).

An oral formulation of fludarabine has been developed with a bioavailability of 55%; pharmacokinetic studies have demonstrated that a once-daily dose oral of 40 mg/m2is equivalent to the standard intravenous dose of 25 mg/m2 (57). A multicenter trial using oral fludarabine in patients who had received prior chlorambucil was conducted in Europe. Among 78 evaluable patients, the overall response rate was 51%, and complete remissions were obtained in 18% (58). The optimal treatment duration was six cycles; as seen with the intravenous formulation, responses rates with oral fludarabine were higher in patients with early-stage disease. The oral formulation had a toxicity profile similar to that of the parental formulation, with a mild increase in gastrointestinal adverse events.

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