, Volume 67, Issue 11, pp 1633-1657
Date: 14 Sep 2012

Fludarabine

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Summary

Abstract

Fludarabine (Fludara®), a purine nucleoside analogue, has been extensively evaluated in the treatment of a number of lymphoproliferative malignancies, including various types of non-Hodgkin’s lymphoma. Clinical studies have shown that fludarabine (alone, and particularly as a component of combination therapy) can result in high overall and complete response in adults with various types of non-Hodgkin’s lymphoma, including follicular lymphoma. As mono- or combination therapy, intravenous fludarabine is as effective as several other standard treatment regimens in treatment-naive patients and is also effective in patients with recurrent or refractory disease. The efficacy of fludarabine therapy is improved with the use of rituximab, as part of the initial therapeutic regimen or as maintenance therapy, and deserves consideration. The once-daily oral formulation was effective in the treatment of patients with relapsed indolent B-cell non-Hodgkin’s lymphoma; however, further studies are required to confirm its role and establish its efficacy relative to that of standard treatment in this patient population. Fludarabine has generally acceptable tolerability; however, it is associated with haematological adverse events, including myelosuppression. Fludarabine, therefore, provides a highly effective first- or second-line option in the treatment of non-Hodgkin’s lymphoma.

Pharmacological Properties

Fludarabine is a purine (adenine) nucleoside analogue that is converted first to 9-β-D-arabino-furanosyl-2-fluoradenine (F-ara-A) and then into the active metabolite F-ara-A triphosphate (F-ara-ATP), which interrupts DNA and RNA synthesis. Fludarabine also induces cell death through apoptosis.

The cytotoxic effects of fludarabine are time- and concentration-dependent. Fludarabine potentiates the activity of antitumour agents, such as cisplatin, cytarabine, mitoxantrone and gallium nitrate, and has a synergistic effect with rituximab and complement on cell lysis. Fludarabine is active against certain murine tumour models and reduces lymphocyte proliferation.

The conversion of fludarabine into F-ara-A occurs within 5 minutes of intravenous administration. F-ara-A has linear pharmacokinetics and exhibits a biphasic or triphasic decline in plasma concentration. After multiple doses of fludarabine, F-ara-A shows moderate or no accumulation in the plasma. The elimination half-life is ≈20 hours. In adults, 19–29% of F-ara-A is bound to plasma protein and elimination occurs mainly in the urine.

Oral fludarabine also has a linear, dose-dependent pharmacokinetic profile. After oral administration, the time to maximum plasma concentration is ≈1 hour. The bioavailability of oral fludarabine is 50–65% and is unaffected by food. The elimination half-life of orally administered fludarabine is similar to that of intravenously administered fludarabine.

Therapeutic Efficacy

Fludarabine, as mono- or combination therapy, has shown efficacy in the first- and second-line treatment of non-Hodgkin’s lymphoma in phase II and III trials. As intravenous monotherapy in patients with various types of non-Hodgkin’s lymphoma, first-line fludarabine was at least as effective as cyclophosphamide, vincristine and prednisone (CVP) based on progression rate in the largest trial. As second-line therapy, fludarabine monotherapy was more effective than CVP based on the 2-year progression-free survival rate. First- or second-line fludarabine monotherapy was also as effective as CVP therapy based on other endpoints, such as survival and overall response rates, and was more effective than CVP therapy based on complete response rates.

First-line treatment with fludarabine plus mitoxantrone was more effective than cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) in patients with follicular lymphoma and more effective than a CHOP-like regimen of cyclophosphamide, doxorubicin, vindesine and prednisone (CHVP) in patients with indolent non-Hodgkin’s lymphoma, based on the primary endpoint measures of overall response after six cycles of treatment and complete response. Although first-line treatment with fludarabine was as effective as combination therapy with fludarabine plus idarubicin with regard to the complete response rate, combination therapy was more effective than monotherapy with regard to relapse-free and progression-free survival at 36 months, and was as effective as monotherapy with regard to the overall response rate.

The efficacy of intravenous fludarabine is improved by the addition of rituximab immunotherapy in conjunction with chemotherapy and/or as subsequent maintenance therapy. In patients with follicular lymphoma, the response to first-line treatment with fludarabine plus mitoxantrone was maintained or increased with subsequent rituximab therapy. Likewise, the efficacy of fludarabine, cyclophosphamide and mitoxantrone given in conjunction with rituximab was improved in previously treated patients with follicular or mantle cell lymphoma; the benefits of initial treatment were maintained and a longer response duration was seen with subsequent rituximab therapy than with no further treatment.

Oral fludarabine monotherapy has shown efficacy in the second-line treatment of patients with B-cell non-Hodgkin’s lymphoma, with almost two-thirds of patients showing an overall response and one-third of patients showing a complete response to oral fludarabine treatment.

Tolerability

In general, intravenous fludarabine monotherapy showed tolerability similar to that of CHOP-like regimens (CVP and CHVP) in previously treated and untreated adults with various types of non-Hodgkin’s lymphoma. Intravenous fludarabine as a component of combination therapy generally had a better non-haematological adverse-event profile than the CHOP and CVP regimens, and a similar haematological adverse event profile to the CHVP regimen, in previously untreated patients. The most common adverse events with intravenous fludarabine, as mono- or combination-therapy, and oral fludarabine monotherapy include myelosuppression, nausea, vomiting, diarrhoea, fever and infection. Fludarabine may also be associated with suppression of bone marrow function, autoimmune haemolytic anaemia and severe neurological effects. In phase III trials, markedly higher rates of haematological adverse events were observed in treatment-naive and previously treated patients receiving intravenous fludarabine monotherapy than in those receiving CVP treatment, and significantly more previously treated patients with low-grade non-Hodgkin’s lymphoma receiving intravenous fludarabine monotherapy than those receiving CVP experienced lower leucocyte counts (WHO grade 3 or 4). However, in the same trials, significantly fewer fludarabine than CVP recipients presented with neurotoxicity and fewer fludarabine plus mitoxantrone than CHVP recipients experienced alopecia. In two phase III trials, discontinuation of treatment because of adverse events and death was observed in more fludarabine than CVP or CHVP recipients. A total of 17 possible treatment-related deaths were reported in three phase III trials of fludarabine mono- or combination therapy.