OVERVIEW

Introduction

Fludarabine is a purine analogue and antineoplastic agent used in the therapy of chronic lymphocytic leukemia (CLL) and in immunosuppressive regimens in preparation of hematopoietic cell transplantation (HCT). Fludarabine is associated with a low rate of transient serum enzyme elevations during therapy and has only rarely been implicated in cases of clinically apparent acute liver injury with jaundice. Fludarabine has potent immunosuppressive activity and has been associated with many cases of reactivation of hepatitis B.

Background

Fludarabine (floo dar' a been) phosphate is a purine analogue that is used commonly in the treatment of chronic lymphocyte leukemia. Fludarabine phosphate is a fluorinated derivative of the antiviral agent adenine arabinoside monophosphate (2-fluoro-ara-AMP). Fludarabine is converted intracellularly to the active triphosphate, which competes with adenine triphosphate for use by DNA polymerase leading to inhibition of DNA synthesis. Fludarabine was found to have activity against several forms of leukemia and lymphoma and was approved for use as an antineoplastic agent in the United States in 1991. Current indications are therapy of chronic lymphocyte leukemia. Fludarabine is also used off-label for hairy cell leukemia, mycosis fungoides, and both Hodgkin and non-Hodgkin lymphomas as well as in immunosuppressive regimens for nonmyeloablative hematopoietic cell transplantation (HCT). Fludarabine is available as a powder or solution for injection generically and under the trade name Fludara. Oral formulations are also available as tablets of 10 mg generically and under the trade name Oforta. The typical adult dose for CLL is 25 mg/m2 intravenously or 40 mg/m2 orally each day for 5 days; each 5 day course given is every 28 days. The dose regimen for nonmyeloablative HCT is typically 30 mg/m2 intravenously for 3 days in the week before transplant, usually in combination with total body irradiation or other alkylating agents. Common side effects include bone marrow suppression, leucopenia, infections, fever, nausea, vomiting, anorexia, diarrhea, headache, fatigue and skin rash.

Hepatotoxicity

In clinical trials, serum enzymes elevations occurred in only a small proportion of patients treated with fludarabine for leukemia. The role of fludarabine as opposed to other antineoplastics used in antileukemic regimens was not always clear from these studies. Cases of clinically apparent liver injury due to fludarabine have been reported to occur, but few details were available and most patients were receiving other cancer chemotherapeutic agents.

Fludarabine is immunosuppressive and decreases total white blood cell counts and specifically lymphocyte counts and CD8 T cells. As a consequence, fludarabine therapy has been linked to cases of reactivation of chronic hepatitis B, including instances of reverse seroconversion marked by development of HBsAg and active disease in a patient who had resolved hepatitis B before chemotherapy, as shown by presence of anti-HBc without HBsAg. Reactivation typically occurs after 3 to 6 courses of anticancer mediations and most commonly 2 to 4 months after completing chemotherapy. The frequency and severity of reactivation after fludarabine therapy has led to recommendations that patients be screened for HBsAg and anti-HBc before treatment, and give prophylaxis with antiviral therapy using an oral nucleoside with potent activity against HBV, such as lamivudine, tenofovir or entecavir. If prophylaxis is not used, careful monitoring and early institution of antiviral therapy is warranted. Fludarabine has also been associated with development of opportunistic infections including herpes virus and adenovirus infection of the liver.

Likelihood score: E* (Unproven but suspected cause of clinically apparent liver injury).

Mechanism of Injury

Hepatotoxicity from fludarabine is likely due to direct toxicity. Reactivation of hepatitis B is likely due to the immunosuppressive activity of fludarabine. The specific role of fludarabine in situations in which patients also receive corticosteroids, rituximab or HCT cannot always be determined.

Outcome and Management

The severity of the liver injury linked to fludarabine therapy is generally self-limited and mild, and resolves with stopping therapy. Reactivation of hepatitis B, in contrast, can be severe and lead to acute liver failure and death.

Drug Class: Antineoplastic Agents, Antimetabolites

Other Drugs in the Subclass, Purine Analogues: Azathioprine, Cladribine, Clofarabine, Mercaptopurine, Nelarabine, Pentostatin, Thioguanine

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Fludarabine (Injectable) – Generic, Fludara®

Fludarabine (Oral) – Generic, Oforta®

DRUG CLASS

Antineoplastic Agents

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULA AND STRUCTURE

ANNOTATED BIBLIOGRAPHY

References updated: 01 February 2018

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