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The Hematology Journal : the Official... 2004Intravenous fludarabine is a well-established therapy for the first-line treatment of chronic lymphocytic leukemia and the standard of care for second-line treatment.... (Review)
Review
Intravenous fludarabine is a well-established therapy for the first-line treatment of chronic lymphocytic leukemia and the standard of care for second-line treatment. More recently, an oral formulation of fludarabine has been developed, with equivalent efficacy and tolerability to the intravenous formulation, but with improved convenience of administration and potentially greater cost effectiveness. In previously treated patients receiving oral fludarabine monotherapy, overall response rates of 46-51% were achieved, depending on the response criteria used. Oral fludarabine is also an effective first-line treatment, both as monotherapy (overall response 72-80%) and in combination with cyclophosphamide (overall response 80%). Infusion-related adverse effects are eliminated with oral administration. Importantly, WHO performance status is maintained or improved in more than 50% of patients. As oral fludarabine can be taken at home, administration costs are greatly reduced due to fewer physician and nursing interventions and less time spent in hospital. Oral fludarabine was approved first in the UK as second-line therapy for chronic lymphocytic leukemia and, based on its ease of administration and potentially greater cost effectiveness, is recommended in preference to the intravenous formulation by the UK National Institute for Clinical Excellence. The oral formulation is also now available in the majority of European countries. Therefore, with equivalent efficacy and tolerability to the intravenous preparation, oral fludarabine gives the hematologist an important new option in the management of chronic lymphocytic leukemia.
Topics: Administration, Oral; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Treatment Outcome; Vidarabine
PubMed: 15079151
DOI: 10.1038/sj.thj.6200389 -
Onkologie Apr 2008
Topics: Administration, Oral; Antineoplastic Agents; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Tumor Lysis Syndrome; Vidarabine
PubMed: 18418014
DOI: 10.1159/000120154 -
Cancer Metastasis Reviews 1987This article summarizes recent studies characterizing nucleoside transport in mammalian cells and discusses evidence for a role of membrane transport in the... (Review)
Review
This article summarizes recent studies characterizing nucleoside transport in mammalian cells and discusses evidence for a role of membrane transport in the pharmacologic action of nucleoside analogues. Some of these studies have also addressed the controversy concerning the multiplicity in transport routes. It seems clear that erythrocytes and, perhaps, some other mammalian cells possess a single, broadly specific system for transporting nucleosides. However, substantial evidence from valid studies discriminating between transport and intracellular metabolism suggests that at least some mammalian cells, including some tumor cells, possess more than a single system. Evidence now exists for a determining role of membrane transport of nucleoside analogues in their cytotoxicity and, in the case of one pyrimidine nucleoside (AraC), in therapeutic responsiveness in leukemic patients. There are also numerous examples of transport-related resistance to nucleoside analogues. Included in this article are the results of studies from the authors' laboratory pertaining to the therapeutic activity of the purine nucleoside, FAraA, in murine tumor models. These studies provide evidence for a determining role of both membrane transport and intracellular phosphorylation in the selective antitumor action of this agent against murine leukemia. Substantially increased transport inward of FAraA occurs at pharmacologically achievable concentrations of this agent in tumor cells as compared to drug-limiting, normal proliferative epithelium of the small intestine. The basis for this differential appears to be the kinetic duality of FAraA and adenosine transport inward found in tumor cells, but not in proliferative intestinal epithelial cells. Tumor cells have highly saturable (low influx Km) and poorly saturable (high influx Km) systems for adenosine transport, both of which are shared by FAraA. In contrast, proliferative epithelial cells have only a poorly saturable system for these substrates. If a similar kinetic duality of nucleoside transport is found in other tumor cells certain implications arise concerning the significance of the duality to neoplastic transformation.
Topics: Animals; Antineoplastic Agents; Biological Transport; Cell Membrane; Humans; Nucleosides; Vidarabine
PubMed: 3327628
DOI: 10.1007/BF00047462 -
Leukemia & Lymphoma Feb 2001The purine nucleoside analogs fludarabine and 2-chloro-2'-deoxyadenosine display substantial activity in the treatment of various chronic lymphoproliferative disorders.... (Review)
Review
The purine nucleoside analogs fludarabine and 2-chloro-2'-deoxyadenosine display substantial activity in the treatment of various chronic lymphoproliferative disorders. Their major toxicities are primarily immunosuppression and myelosuppression. The profound influence of these drugs on the immune system has raised questions as to the emergence of secondary neoplasms or auto-immune disorders after their use. Based on a literature review and on personal observations, this article reviews the potential clinical importance of these concerns.
Topics: Antineoplastic Agents; Autoimmunity; Cladribine; Humans; Immunosuppressive Agents; Neoplasms; Neoplasms, Second Primary; Vidarabine
PubMed: 11426527
DOI: 10.3109/10428190109097653 -
Cancer Dec 1993There are three new purine analogs, fludarabine, 2'-deoxycoformycin, and 2-chlorodeoxyadenosine, all of which have major activity in the treatment of indolent lymphoid... (Review)
Review
There are three new purine analogs, fludarabine, 2'-deoxycoformycin, and 2-chlorodeoxyadenosine, all of which have major activity in the treatment of indolent lymphoid malignancies. These three agents, with cytotoxicity against dividing and resting lymphocytes, have revolutionized the treatment of these diseases and, accordingly, represent a significant therapeutic advance. The development of these drugs emanated from an enhanced understanding of purine metabolism in lymphocytes and the mechanism of lymphocytotoxicity in severe combined immunodeficiency disease. Preclinical studies and phase I clinical trials are reviewed, as are phase II studies of these three purine analogs in chronic lymphocytic leukemia, hairy cell leukemia, non-Hodgkin lymphoma, cutaneous T-cell lymphoma, and the myeloid leukemias. Potential future strategies exploring possible synergy between these purine analogs and the concurrent administration of both alkylators and biologic response modifiers are explored. The development of the purine analogs and their appropriate clinical applications exemplifies the model for rational drug design and development.
Topics: Antineoplastic Agents; Cladribine; Humans; Leukemia; Lymphoma; Pentostatin; Vidarabine
PubMed: 7902205
DOI: 10.1002/1097-0142(19931201)72:11+<3470::aid-cncr2820721614>3.0.co;2-0 -
Seminars in Oncology Dec 1992Several new antimetabolites have been evaluated in clinical trials in recent years. Those with the most promising activity include the structurally related purine... (Review)
Review
Several new antimetabolites have been evaluated in clinical trials in recent years. Those with the most promising activity include the structurally related purine analogs fludarabine, 2-chlorodeoxyadenosine, and 2'-deoxycoformycin. These compounds have shown impressive activity against a broad spectrum of indolent lymphoproliferative disorders, including hairy-cell leukemia, chronic lymphocytic leukemia, and low-grade non-Hodgkin's lymphomas. They may also be useful in the treatment of acute leukemias. In contrast, they lack activity against common solid tumors. They have been generally well tolerated in large clinical trials; however, each of them is myelosuppressive and immunosuppressive. It is unlikely that any one of these drugs, when used as a single agent, will provide optimal therapy for any disease other than, possibly, hairy-cell leukemia. Combinations with other cytotoxic agents and biologics are in development, and perhaps they will lead to more effective regimens in the future.
Topics: Animals; Antimetabolites, Antineoplastic; Cladribine; Clinical Trials as Topic; Drugs, Investigational; Forecasting; Humans; Immunosuppression Therapy; Leukemia; Lymphoma; Pentostatin; Purines; Vidarabine
PubMed: 1361080
DOI: No ID Found -
The Hematology Journal : the Official... 2004Fludarabine is a synthetic adenine nucleoside analog that is indicated for first- and second-line treatment of chronic lymphocytic leukemia (CLL). The recommended... (Comparative Study)
Comparative Study Review
Fludarabine is a synthetic adenine nucleoside analog that is indicated for first- and second-line treatment of chronic lymphocytic leukemia (CLL). The recommended intravenous (i.v.) dosage regimen is 25 mg/m2 daily for 5 consecutive days, with treatment cycles repeated every 28 days. In treatment-naïve patients with Binet stage B and C CLL, i.v. fludarabine produces superior responses to established first-line chemotherapies. Fludarabine produces a higher overall remission rate (60-70%) and longer progression-free survival (median approximately 20-30 months) than standard therapy with chlorambucil+/-prednisone and CAP (cyclophosphamide/doxorubicin/prednisone), and a comparable overall remission rate to CHOP (cyclophosphamide/vincristine/prednisone/doxorubicin). Fludarabine demonstrates high efficacy in both intermediate-risk (Rai stage I or II) and high-risk (Rai stage III or IV) patients. Furthermore, fludarabine is equally effective in younger (< or =65 years) and older (>65 years) patients. Fludarabine has significant activity as monotherapy in previously treated CLL, producing objective response rates of up to 94% in typically small-scale, noncomparative studies, with the majority of studies yielding rates of 30-60%. In a phase III multicenter study, the overall remission rate was significantly higher with fludarabine than with CAP (48 versus 27%) among the subset of treatment-refractory patients (n=96). For those patients who are refractory to or have relapsed following conventional chemotherapy (chlorambucil, CAP and CHOP), fludarabine can be considered the treatment of choice for second-line therapy. Moreover, patients with relapsed CLL may benefit from retreatment with fludarabine if they have previously demonstrated sensitivity to the drug. Standard-dose i.v. fludarabine has an established safety profile and comparable tolerability to anthracycline-based regimens (CAP and CHOP) in terms of its myelosuppressive and immunosuppressive effects, and offers the advantage of a markedly lower incidence of gastrointestinal effects (nausea/vomiting) and alopecia.
Topics: Antineoplastic Combined Chemotherapy Protocols; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Treatment Outcome; Vidarabine
PubMed: 15079149
DOI: 10.1038/sj.thj.6200387 -
The Oncologist 2000Allogeneic stem cell transplantation is used to treat a variety of malignant and nonmalignant hematologic diseases. Conventionally, high-dose chemoradiotherapy-based... (Review)
Review
Allogeneic stem cell transplantation is used to treat a variety of malignant and nonmalignant hematologic diseases. Conventionally, high-dose chemoradiotherapy-based preparative regimens were considered essential both for tumor eradication and facilitation of donor stem cell engraftment. It is now apparent that an immune-mediated graft-versus-tumor effect has a pivotal role in the curative potential of allogeneic stem cell transplantation. This has prompted the development of less toxic, nonmyeloablative but profoundly immunosuppressive preparative regimens, often fludarabine- or radiation-based. Full donor engraftment can be achieved; however, a significant number of patients achieve a mixed chimeric state. Mixed hematopoietic chimerism provides a platform for the use of adoptive immunotherapy using donor lymphocyte infusions to maximize the immune-mediated antitumor effect, but the optimal usage has yet to be determined. Immediate procedure-related mortality with nonmyeloablative regimens has been low, but graft-versus-host disease remains a major clinical concern and treatment challenge. Major tumor responses have been seen in many hematologic malignancies primarily including patients with highly chemorefractory disease. Follow-up data have been short and additional time is needed to determine the efficacy and toxicities of this immunotherapy. This approach has potential for widespread clinical application including HLA mismatched and matched unrelated donor transplantation, exploration of a graft-versus-solid tumor effect, and correction of phenotypic expression in nonmalignant disorders.
Topics: Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Histocompatibility Testing; Humans; Leukemia; Transplantation, Homologous; Vidarabine; Whole-Body Irradiation
PubMed: 11110600
DOI: 10.1634/theoncologist.5-6-487 -
[Rinsho Ketsueki] the Japanese Journal... Jun 2015A 67-year-old woman was diagnosed with chronic lymphocytic leukemia (CLL) in October 2001. In August 2004, she received chemotherapy consisting of fludarabine and... (Review)
Review
A 67-year-old woman was diagnosed with chronic lymphocytic leukemia (CLL) in October 2001. In August 2004, she received chemotherapy consisting of fludarabine and cyclophosphamide (FC therapy). After three cycles of FC therapy, the number of tumor cells was markedly decreased. However, anemia progressed. She was diagnosed with pure red cell aplasia (PRCA) by bone marrow examination and was successfully treated with cyclosporin A (CsA). In October 2008, anemia progressed with the exacerbation of CLL and she received three cycles of fludarabine therapy. Although the number of tumor cells diminished, the anemia did not improve. She was diagnosed with PRCA recurrence and was again successfully treated with CsA. PRCA is a rare complication in patients with CLL and has been attributed to T cell-mediated mechanisms. Six cases with PRCA that developed after fludarabine therapy for CLL have already been reported. Fludarabine therapy may be toxic to Treg, resulting in the loss of self-tolerance. It is important to consider the possibility of PRCA in patients with progressive anemia after fludarabine therapy for CLL.
Topics: Aged; Antineoplastic Agents; Cyclosporine; Female; Humans; Immunosuppressive Agents; Leukemia, Lymphocytic, Chronic, B-Cell; Red-Cell Aplasia, Pure; Treatment Outcome; Vidarabine
PubMed: 26256883
DOI: 10.11406/rinketsu.56.705 -
Zhongguo Shi Yan Xue Ye Xue Za Zhi Jun 2010Fludarabine (Flu), a purine nucleoside analogue, is the firstline drug for patients with chronic lymphocytic leukemia (CLL), and can induce apoptosis of malignant cells... (Review)
Review
Fludarabine (Flu), a purine nucleoside analogue, is the firstline drug for patients with chronic lymphocytic leukemia (CLL), and can induce apoptosis of malignant cells in CLL patients. However, CLL remains an incurable disease. Fludarabine-resistance is one of the predominant reasons for treatment failure. In this paper, the metabolism, action and drug-resistance mechanisms of Fludarabine in CLL as well as possible reversible strategies are reviewed, with particular emphasis on recent advances in the characterization of nucleoside transporters and p53-mediated apoptosis and on the potential role of activating or inactivating enzymes in the induction of clinical resistance to Flu.
Topics: Drug Resistance, Neoplasm; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Vidarabine
PubMed: 20561458
DOI: No ID Found