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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.
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.
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.
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.
- Jemal, A, Siegel, R, Ward, E (2007) Cancer statistics, 2007. CA Cancer J Clin 57: pp. 43-66 CrossRef
- Zinzani, PL (2005) Lymphoma: diagnosis, staging, natural history, and treatment strategies. Semin Oncol 32: pp. S4-10 CrossRef
- Zelenetz, AD, Advani, RH, Buadi, F (2006) Non-Hodgkin’s lymphoma: clinical practice guidelines in oncology. J Natl Compr Canc Netw 4: pp. 258-310
- International Agency for Research on Cancer. GLOBOCAN 2002 database: summary table by cancer [online]. Available from URL: http://www-dep.iarc.fr [Accessed 2007 Jul 3]
- Bayer Schering Pharma AG. Oral formulation of fludara approved in Japan [media release]. 2007 Jan 26
- Fludara® (fludarabine phosphate for injection and fludarabine phosphate tablets): product monograph. Toronto (ON): Bayer Inc., 2007 Mar 9
- Adkins, JC, Peters, DH, Markham, A (1997) Fludarabine: an update of its pharmacology and use in the treatment of haematological malignancies. Drugs 53: pp. 1005-37
- Plosker, GL, Figgitt, DP (2003) Oral fludarabine. Drugs 63: pp. 2317-23 CrossRef
- Fludara (fludarabine phosphate for injection): US summary of product characteristics. Richmond (CA): Berlex Laboratories, 2003
- Fludara (for injection or infusion): UK summary of product characteristics. Burgess Hill: Schering Health Care Limited, 2005 Dec 5
- Gaetano, N, Xiao, Y, Erba, E (2001) Synergism between fludarabine and rituximab revealed in a follicular lymphoma cell line resistant to the cytotoxic activity of either drug alone. Br J Haematol 114: pp. 800-9 CrossRef
- Nishioka, C, Ikezoe, T, Yang, J (2007) Fludarabine induces apoptosis of human T-cell leukemia virus type 1-infected T cells via inhibition of the nuclear factor-KB signal pathway. Leukemia 21: pp. 1044-9
- Gandhi, V, Plunkett, W (2002) Cellular and clinical pharmacology of fludarabine. Clin Pharmacokinet 41: pp. 93-103 CrossRef
- Lichtman, SM, Etcubanas, E, Budman, DR (2002) The pharmacokinetics and pharmacodynamics of fludarabine phosphate in patients with renal impairment: a prospective dose adjustment study. Cancer Invest 20: pp. 904-13 CrossRef
- Foran, JM, Oscier, D, Orchard, J (1999) Pharmacokinetic study of single doses of oral fludarabine phosphate in patients with “low-grade” non-Hodgkin’s lymphoma and B-cell chronic lymphocytic leukemia. J Clin Oncol 17: pp. 1574-9
- Oscier, D, Orchard, JA, Culligan, D (2001) The bioavailability of oral fludarabine phosphate is unaffected by food. Hematol J 2: pp. 316-21 CrossRef
- Klein, M, Ludwig, WD, Fülle, HH (1997) 2F-ara-A pharmacokinetics including systemic availability during treatment with fludarabine phosphate given either perorally as an immediate release tablet formulation or intravenously as a solution [abstract no 525]. Ontologie 20: pp. 137
- Fludara oral (film-coated tablets): UK summary of product characteristics. Burgess Hill: Schering Health Care Limited, 2006 Mar 28
- Hagenbeek, A, Eghbali, H, Monfardini, S (2006) Phase III intergroup study of fludarabine phosphate compared with cyclophosphamide, vincristine, and prednisone chemotherapy in newly diagnosed patients with stage III and IV low-grade malignant Non-Hodgkin’s lymphoma. J Clin Oncol 24: pp. 1590-6 CrossRef
- Klasa, RJ, Meyer, RM, Shustik, C (2002) Randomized phase III study of fludarabine phosphate versus cyclophosphamide, vincristine, and prednisone in patients with recurrent low-grade non-Hodgkin’s lymphoma previously treated with an alkylating agent or alkylator-containing regimen. J Clin Oncol 20: pp. 4649-54 CrossRef
- Foussard, C, Colombat, P, Maisonneuve, H (2005) Long-term follow-up of a randomized trial of fludarabine-mitoxantrone, compared with cyclophosphamide, doxorubicin, vindesine, prednisone (CHVP), as first-line treatment of elderly patients with advanced, low-grade non-Hodgkin’s lymphoma before the era of monoclonal antibodies. Ann Oncol 16: pp. 466-72 CrossRef
- Zinzani, PL, Magagnoli, M, Moretti, L (2000) Randomized trial of fludarabine versus fludarabine and idarubicin as frontline treatment in patients with indolent or mantle-cell lymphoma. J Clin Oncol 18: pp. 773-9
- Zinzani, PL, Pulsoni, A, Perrotti, A (2004) Fludarabine plus mitoxantrone with and without rituximab versus CHOP with and without rituximab as front-line treatment for patients with follicular lymphoma. J Clin Oncol 22: pp. 2654-61 CrossRef
- Forstpointner, R, Dreyling, M, Repp, R (2004) The addition of rituximab to a combination of fludarabine, cyclophosphamide, mitoxantrone (FCM) significantly increases the response rate and prolongs survival as compared with FCM alone in patients with relapsed and refractory follicular and mantle cell lymphomas: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood 104: pp. 3064-71 CrossRef
- Forstpointner, R, Unterhalt, M, Dreyling, M (2006) Maintenance therapy with rituximab leads to a significant prolongation of response duration after salvage therapy with a combination of rituximab, fludarabine, cyclophosphamide, and mitoxantrone (R-FCM) in patients with recurring and refractory follicular and mantle cell lymphomas: results of a prospective randomized study of the German Low Grade Lymphoma Study Group (GLSG). Blood 108: pp. 4003-8 CrossRef
- Tobinai, K, Watanabe, T, Ogura, M (2006) Phase II study of oral fludarabine phosphate in relapsed indolent B-Cell non-Hodgkin’s lymphoma. J Clin Oncol 24: pp. 174-80 CrossRef
- Cheson, BD, Horning, SJ, Coiffier, B (1999) Report of an international workshop to standardize response criteria for non-Hodgkin’s lymphomas. NCI Sponsored International Working Group. J Clin Oncol 17: pp. 1244-53
- Coiffier, B, Neidhardt-Bérard, EM, Tilly, H (1999) Fludarabine alone compared to CHVP plus interferon in elderly patients with follicular lymphoma and adverse prognostic parameters: a GELA study. Groupe d’Etudes des Lymphomes de l’Adulte. Ann Oncol 10: pp. 1191-7
- Tsimberidou, AM, McLaughlin, P, Younes, A (2002) Fludarabine, mitoxantrone, dexamethasone (FND) compared with an alternating triple therapy (ATT) regimen in patients with stage IV indolent lymphoma. Blood 100: pp. 4351-7 CrossRef
- Leblond, V, Lévy, V, Maloisel, F (2001) Multicenter, randomized comparative trial of fludarabine and the combination of cyclophosphamide-doxorubicin-prednisone in 92 patients with Waldenström macroglobulinemia in first relapse or with primary refractory disease. Blood 98: pp. 2640-4 CrossRef
- Tondini, C, Balzarotti, M, Rampinelli, I (2000) Fludarabine and cladribine in relapsed/refractory low-grade non-Hodgkin’s lymphoma: a phase II randomized study. Ann Oncol 11: pp. 231-3 CrossRef
- Flinn, IW, Byrd, JC, Morrison, C (2000) Fludarabine and cyclophosphamide with filgrastim support in patients with previously untreated indolent lymphoid malignancies. Blood 96: pp. 71-5
- Foran, JM, Rohatiner, AZS, Coiffier, B (1999) Multicenter phase II study of fludarabine phosphate for patients with newly diagnosed lymphoplasmacytoid lymphoma, Waldenström’s macroglobulinemia, and mantle-cell lymphoma. J Clin Oncol 17: pp. 546-53
- Santini, G, Chisesi, T, Nati, S (2004) Fludarabine, cyclophosphamide and mitoxantrone for untreated follicular lymphoma: a report from the non-Hodgkin’s lymphoma cooperative study group. Leuk Lymphoma 45: pp. 1141-7 CrossRef
- Velasquez, WS, Lew, D, Grogan, TM (2003) Combination of fludarabine and mitoxantrone in untreated stages III and IV low-grade lymphoma: S9501. J Clin Oncol 21: pp. 1996-2003 CrossRef
- Wilder, DD, Ogden, JL, Jain, VK (2002) Efficacy of fludarabine/mitoxantrone/dexamethasone alternating with CHOP in bulky follicular non-Hodgkin’s lymphoma. Clin Lymphoma 2: pp. 229-37 CrossRef
- Sacchi S, Pozzi S, Marcheselli R, et al. Rituximab in combination with fludarabine and cyclophosphamide in the treatment of patients with recurrent follicular lymphoma. Cancer Epub 2007 May 14
- Crawley, CR, Foran, JM, Gupta, RK (2000) A phase II study to evaluate the combination of fludarabine, mitoxantrone and dexamethasone (FMD) in patients with follicular lymphoma. Ann Oncol 11: pp. 861-5 CrossRef
- Ma, SY, Au, WY, Chim, CS (2004) Fludarabine, mitoxantrone and dexamethasone in the treatment of indolent B- and T-cell lymphoid malignancies in Chinese patients. Br J Haematol 124: pp. 754-61 CrossRef
- Tam, CS, Wolf, M, Prince, HM (2006) Fludarabine, cyclophosphamide, and rituximab for the treatment of patients with chronic lymphocytic leukemia or indolent non-Hodgkin lymphoma. Cancer 106: pp. 2412-20 CrossRef
- Tam, CS, Wolf, MM, Januszewicz, EH (2004) Fludarabine and cyclophosphamide using an attenuated dose schedule is a highly effective regimen for patients with indolent lymphoid malignancies. Cancer 100: pp. 2181-9 CrossRef
- Zinzani, PL, Bendandi, M, Magagnoli, M (1997) Results of a fludarabine induction and α-interferon maintenance protocol in pretreated patients with chronic lymphocytic leukemia and low-grade non-Hodgkin’s lymphoma. Eur J Haematol 59: pp. 82-8 CrossRef
- Genentech, Inc. Eastern Cooperative Oncology Group (ECOG) phase III trial of rituxan maintenance therapy in indolent non-Hodgkin’s lymphoma reaches pre-specified efficacy endpoint early [media release]. 2003 Nov 13
- Hochester HS, Weller RD, Gascoyne, T, et al. Cyclophosphamide and fludarabine (CF) in advanced indolent lymphoma: results from the ECOG/CALGB intergroup E1496 trial [abstract no. 8804]. J Clin Oncol 2007; 25 (18 Suppl. Pt 1)
- A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin’s lymphoma. Blood 89: pp. 3909-18
- Jost, LM, Kloke, O, Stahel, RA (2005) ESMO minimum clinical recommendations for diagnosis, treatment and follow-up of newly diagnosed large cell non-Hodgkin’s lymphoma. Ann Oncol 16: pp. i58-9 CrossRef
- Hiddeman, W, Dreyling, M, Stahel, RA (2005) Minimum clinical recommendations for diagnosis, treatment and follow-up of newly diagnosed follicular lymphoma. Ann Oncol 16: pp. 156-7 CrossRef
- Jost, LM, Stahel, RA (2005) ESMO minimum clinical recommendations for diagnosis, treatment and follow-up of relapsed large cell non-Hodgkin’s lymphoma. Ann Oncol 16: pp. 160-1
- Morgan, SJ, Seymour, JF, Grigg, A (2004) Predictive factors for successful stem cell mobilization in patients with indolent lymphoproliferative disorders previously treated with fludarabine [letter]. Leukemia 18: pp. 1034-8 CrossRef
- Zinzani, PL (2004) Clinical experience with fludarabine in indolent non-Hodgkin’s lymphoma. Hematol J 5: pp. S38-49 CrossRef
- Cvetković, RS, Perry, CM (2006) Rituximab: a review of its use in non-Hodgkin’s lymphoma and chronic lymphocytic leukaemia. Drugs 66: pp. 791-820 CrossRef
- Tam, CS, Seymour, JF, Prince, HM (2006) Treatment-related myelodysplasia following fludarabine combination chemotherapy. Haematologica 91: pp. 1546-50
- Tam, CS, Wolf, MM, Januszewicz, EH (2004) A new model for predicting infectious complications during fludarabine-based combination chemotherapy among patients with indolent lymphoid malignancies. Cancer 101: pp. 2042-9 CrossRef
- Agthoven, M, Kramer, MHH, Sonneveld, P (2005) Cost analysis of common treatment options for indolent follicular non-Hodgkin’s lymphoma. Haematologica 90: pp. 1422-32
- Herold, M, Hieke, K (2003) Costs of drug delivery for CHOP, COP/CVP, and fludarabine: an international assessment. Value Health 6: pp. 167-74 CrossRef
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