Fludarabine phosphate: a synthetic purine antimetabolite with significant activity against lymphoid malignancies.

Abstract

Fludarabine phosphate is the 2-fluoro, 5'-monophosphate derivative of vidarabine (ara-A) with the advantages of resistance to deamination by adenosine deaminase (ADA) and improved solubility. The mechanism of cytotoxic action of the compound appears to involve metabolic conversion to the active triphosphate. Fludarabine phosphate has substantial activity against lymphoid malignancies, particularly chronic lymphocytic leukemia (CLL) and low-grade non-Hodgkin's lymphoma (NHL). Its single-agent activity in CLL appears at least comparable to those of other conventional combination regimens. Its activity in Hodgkin's disease, mycosis fungoides, and macroglobulinemia, although suggestive, needs to be further defined and clinical trials are warranted in hairy cell leukemia, prolymphocytic leukemia, and previously untreated myeloma. The compound does not appear active against most common solid tumors. Early clinical trials indicated significant myelosuppression and the potential for severe neurotoxicity. Toxicity on the currently used low-dose schedules includes transient and reversible myelosuppression, nausea and vomiting, diarrhea, somnolence/fatigue, and elevations of liver enzymes and/or serum creatinine. Possible pulmonary toxicity has been suggested in several patients. The currently used low-doses of fludarabine phosphate, even with repeated administration, are well tolerated and appear safe with a negligible risk for severe neurotoxicity. Based on its single-agent activity and tolerability, the Food and Drug Administration recently granted group C designation of the drug for the treatment of patients with refractory CLL outside the clinical trials setting. The use of fludarabine phosphate in combination regimens and its impact on the natural history of the lymphoid malignancies is yet to be determined. Fludarabine phosphate may well occupy a pivotal role in the management of CLL and low-grade NHL.

Skin cancer after nonmyeloablative hematopoietic cell transplantation

“…Fludarabine also inhibits DNA-polymerase, RNA-polymerase, DNA-ligase, DNA-primase and ribonucleotidereductase. 37,38 It is conceivable that the addition of fludarabine to a cyclophosphamide-containing regimen prevents repair of double-stranded breaks introduced by the alkylating agent. Fludarabine depletes CD3 þ , CD4 þ , and CD8 þ lymphocytes over a period of many months.…”

The prophylactic potential of fludarabine monophosphate in graft-versus-host disease after bone marrow transplantation in murine models

“…Indeed, in patients with lympho-proliferative disorders receiving fludarabine, both normal T and B cell levels have been shown to drop by 90% and 50%, respectively, even after a single cycle of therapy. 13,14,20 The drug's selective lympholytic activity holds promise for effective immunosuppression in some disorders, and may ultimately have an impact on the clinical approach to GVHD.…”

Fludarabine in combination with cyclophosphamide decreases incidence of GVHD and maintains effective graft-versus-leukemia effect after allogeneic stem cell transplantation in murine lymphocytic leukemia

“…The cytotoxic potential of fludarabine against T lymphocytes, coupled with its immunosuppressive qualities, has made it an attractive choice for both chemotherapy and immunomodulation, during allogeneic transplantation for leukemia. 11,12 Indeed, the use of fludarabine-containing regimens has altered the incidence, and the degree of graftversus-host disease (GVHD) in these patients and this regimen is used currently in a number of transplant centers. [8][9][10][11][12][13] Despite the impressive results in human hematopoietic stem cell transplantation, fludarabine has as yet not been adequately tested in animal models.…”

“…11,12 Indeed, the use of fludarabine-containing regimens has altered the incidence, and the degree of graftversus-host disease (GVHD) in these patients and this regimen is used currently in a number of transplant centers. [8][9][10][11][12][13] Despite the impressive results in human hematopoietic stem cell transplantation, fludarabine has as yet not been adequately tested in animal models. In this respect, there is some recent experimental evidence showing that it may be effective in transplantation across histocompatibility barriers in mice.…”