Medical Pharmacology Chapter 33-34:  Anticancer Drugs

• Antimetabolites

  • Purine Analogues:  6-Thiopurines:

    • Fludarabine (Fludara)

      • Fludarabine (Fludara)

        • Overview:

          • Fludarabine (9-β-d-arabinosyl-2-fluoroadenine monophosphate, F-ara AMP, Fludara) is an antineoplastic drug used for treating CLL (chronic lymphocytic leukemia).⁶ 

            • "New CLL Treatments, the Standard of Care and the Importance of Clonal Evolution."¹⁰

              Attribution: Hallek M New CLL treatments, the standard of care and the importance of clonal evolution https://www.youtube.com/watch?v=44JRoGr7G9E (11/2016) VJ VJHemonc-Video Journal of Hematological Oncology Youtube Channel: https://www.youtube.com/channel/UCsQXL4_zTA-FoG9RA1tEGiw Abbreviations: CLL:  Chronic Lymphocytic Leukemia FCR:  (Fludarabine, Cyclophosphamide, Rituximab)

            • Fludarabine is a monophosphate adenosine analog with the monophosphate form responsible for the aqueous solubility that allows IV administration.⁹ 

              • Fludarabine monophosphate is hydrolyzed to fludarabine in the bloodstream.

                • Fludarabine monophosphate exhibits both adenosine deaminase resistance and ready incorporation into DNA, resulting in chain termination.⁹

            • "Overcoming the Shortfalls of Ibrutinib with Fludarabine in CLL Patients"⁸

              Attribution: Ahn I Overcoming the Shortfalls of Ibrutinib with Fludarabine in CLL Patients https://www.youtube.com/watch?v=m-NhJZIqy1I (7/2017) VJHemOnc-Video Jounal of Hematogical Oncology Youtube Channel:  https://www.youtube.com/channel/UCsQXL4_zTA-FoG9RA1tEGiw

            • This agent exhibits anticancer activity also in the setting of: ⁶

              • Indolent non-Hodgkin's lymphoma,

              • Prolymphocytic leukemia,

              • Cutaneous T-cell lymphoma and

              • Waldenstrom macroglobulinemia.

            • Fludarabine administration may be also associated with significant immunosuppression.¹

          • Fludarabine is not effective for treating solid tumors.⁶

          • Fludarabine is related to the antiviral drug vidarabine (9-β-d-arabinofuranosyl-adenenine).¹ 

            • Fludarabine phosphate differs from vidarabine in that it is fluorinated, phosphorylated, and deamination-resistant.¹

      • Mechanism of Fludarabine Action: 

        • Following IV infusion, fludarabine phosphate is rapidly dephosphorylated (in plasma) to the nucleoside, 9-β-d-arabinosyl-2-fluoroadenine (F-ara-A).⁹ 

          • F-ara-A by means of the equilibrative carrier ENT1 (a.k.a. hENT1) and then phosphorylated to F-ara-ATP, the active form.

          • Cytotoxicity requires fludarabine triphosphate (F-ara-ATP). F-ara-ATP is an inhibitor of several important enzymes central to DNA replication.

            • These enzymes include:

              • DNA polymerase

              • DNA primase, and

              • DNA ligase I.^9,6 

          • Following fludarabine incorporation into DNA, F-ara AMP causes DNA chain termination (3' end of DNA).

            • The loss of "clonogenicity" is linearly associated with the extent of fludarabine incorporation into DNA.

          • The 3'-terminal F-ara AMP, following incorporation, is not readily subject to excision repair and, as a result, initiates "programmed cell death" or apoptosis.⁹ 

        • F-ara ADP is an inhibitor of ribonucleotide reductase.

          • This effect decreases dATP levels and enhances incorporation of the inhibitor instead of normally occurring dAMP into DNA.⁹

        • In distinction from other antineoplastic antimetabolite agents, fludarabine is also active against nondividing cells.

          • Fludarabine's primary anticancer effects may be due to initiation of programmed cell death (apoptosis).

          • Activity against nondividing cells may provide a basis for understanding fludarabine activity in indolent lymphoproliferative disease exhibiting "low growth fractions".

        • Fudarabine incorporation into RNA results in inhibition of RNA function, processing and mRNA translation.¹

      • Absorption, Disposition, Biotransformation, Excretion ^1,9

        • Fludarabine phosphate may be administered orally and by the IV route of administration.

          • The monophosphate form is converted to fludarabine in the plasma.^1,9  

            • The dephosphorylating reaction (2-F-ara-A AMP to F-ara-A) is catalyzed by erythrocyte and endothelial cell 5' nucleotidase.^1,9

        • Following oral administration maximal drug fludarabine in plasma is reached in about 1.5 hours.¹ 

          • The oral bioavailability is about 50%-60% with the t_1/2 plasma elimination is approximately 10 hours.¹ 

            • Drug clearance appears stable with repeated doses in individuals.⁹ 

              • In circulating leukemic cells, peak F-ara ATP occurs in about four hours after IV fludarabine administration.⁹ 

                • F-ara ATP exibits an intracellular half-life of about 15 hours, long enough to explain effectiveness of a daily administration protocol.

          • Plasma concentrations of F-ara-A (9-beta-D-arabinofuranosyl-2-fluoroadenine) are reflected directly in intracellular F-ara ATP leukemic cells.⁹ 

        • Excretion of F-ara-A is mainly renal (urine) with about a 55% recovery.

          • No metabolites are detectable. Individuals with renal impairment when compared to patients with normal renal function exhibit decreasing clearance of 2-F-ara-A.

          • Dosage reduction in patients with impaired renal function have been recommended depending on, in part, the extent of renal dysfunction.⁹

      • Toxicity:⁹   (primary reference for this section:  Hande KR Chabner BA Purine Analogs Chapter 10 in:  Cancer Chemotherapy, Immunotherapy and Biotherapy Principles and Practice Chabner BA Longo DL, eds 6e Wolters Kluwer 2019.)

        • The major dose-limiting fludarabine toxicities include myelosuppression and complications, typically infectious, due to immunosuppression.⁹ 

          • Both oral and intravenous administration of fludarabine are comparable in their toxicity profiles.

        • Fludarabine administration may induce a reversible leukopenia and thrombocytopenia at various levels of severity.

          • Myelosuppression is more likely to occur in those cases in which fludarabine is combined with other anticancer drugs, including rituximab.

        • As many as 25% of patients receiving fludarabine may present with fever often not associated with infection although perhaps one-third of patients presenting with fever will have a documented infectious cause.

        • Immunosupressive activity of fludarabine is substantial as it inhibits signal transduction central to lymphocyte activation.⁹ 

          • Accordingly, fludarabine treatment may render a patient susceptible to opportunistic infection in accord with reduced T-lymphocyte subpopulations CD4 and CD8.

            • Immunosuppression-related lymphopenia may last more than one year.

        • Respiratory infectious complications are the most likely and the specific infections include: ⁹

          • Cryptococcus

          • Listeria monocytogenes

          • Pneumocystis jiroveci (previously knows as Pneumocystis carinii)

          • Cytomegalovirus

          • Herpes Smplex Virus

          • Varicella-zoster and

          • Mycobacterial infections.

        • Autoimmune hemolytic anemia may be observed following fludarabine due to suppression of T-reg lymphocytes.⁹ 

        • Hemolysis may also occur during treatment cycles, most likely during cycles 1 through 3.

        • A fatal complication in patients with CLL and indolent lymphoma treated with fludarabine is acute tumor lysis.

        • Numerous other toxicities have been reported such as mild nausea and vomiting, peripheral sensorimotor neuropathy, hepatocellular toxicity and rash.

        • Neurotoxicity may occur in about 16% of patients receiving fludarabine at higher doses,

          • This form presents as in irreversible neurotoxicity syndrome described as including cortical blindness, encepalopathy, optic neuritis, generalized seizures and coma.⁹ 

            • Lower doses of fludarabine, in terms of neurotoxicity, is more likely to cause a mild in reversible form.

        • In about 5%-10% of patients interstitial pneumonitis may occur and pulmonary toxicity more generally is associated with fever, cough, and hypoxia.

        • Late adverse effects of fludarabine therapy may include myelodysplasia and acute myelogenous leukemia (AML).⁹