Medical Pharmacology Chapter 33-34:  Anticancer Drugs

• Antimetabolites

  • Purine Analogues:

    • Clofarabine (Clolar)

      • Clofarabine (Clolar)

         

        • Overview:

          • Clofarabine is classified as a second-generation purine nucleoside analog which must be activated by sequential phosphorylation steps intracellularly.⁹ 

            • The cytotoxic active form, the triphosphate metabolite, is an enzyme inhibitor of both DNA polymerase and ribonucleotide reductase.

              • A consequence of inhibition of these enzymes is both DNA repair dysfunction and inhibition of DNA and RNA synthesis .

            • Clofarabine also is disruptive to mitochondrial function in membrane integrity.

              • This effect results in release of pre-apoptotic factors leading to programmed cell death.

                • Pre-apoptotic factors include both cytochrome C and apoptotic-inducing molecules.⁹

          • Clofarabine (Clolar) may be used for treating children who suffer from relapsed or refractory acute lymphoblastic leukemia (ALL), after the use of at least two previous treatment protocols.^1,8 

            • In such circumstances clofarabine administration results in complete remission in about 25% of this subgroup of patients.¹ 

              • In addition clofarabine exibits anti-cancer activity in pediatric and adult acute myelogenous leukemia (AML) and in myelodysplasia.

          • New Agents in Relapsed Acute Lymphoblastic Leukemia (ALL)¹⁰

            Attribution: Sen S New Agents in Relapsed All HOPE Series II-Mumbai July 2016 "New Agents-Clofarabine & Nelarabine in ALL." https://www.youtube.com/watch?v=z3sscSFEfME HOPE Meetings Youtube Channel https://www.youtube.com/channel/UCI3Orh6bGioos1KJIs3l-JQ

             

  • 2017 FDA Approvals for Hematologic Malignancies¹¹

    "2017 a banner year for FDA approvals in hematologic malignancies. In this graphic, purple=4 new drug approvals for AML; red=5 new drugs for ALL/NHL; orange=supplemental approvals for new indications" https://twitter.com/FDAOncology/status/945290604132610048

    • Clofarabine administration results in increasing intracellular cytosine arabinoside, thus enhancing ara-C cytotoxicity.¹ 

      • Both uptake and metabolic activation of clofarabine in tumor cells proceed along the same course as cladribine and other purine nucleosides.

        • In the activated triphosphate form, clofarabine triphosphate exhibits a relatively long intracellular t_1/2 (halftime) of about one day.

    • Following incorporation into DNA, clofarabine triphosphate results in DNA synthesis termination and activation of apoptosis (programmed cell death).¹ 

      • Clofarabine is also inhibitor of RNR (ribonucleotide reductase).¹

    • Mechanism of Action:

      • Clofarabine (2-chloro-2'-arabinosyladenenine) incorporates a 2-chloro substituent of cladribine which confers glycosylase resistance.¹ 

        • Also incorporated is a 2'-fluoro-arabinosyl substitution which both improves drug uptake and phosphorylation (thus enhancing activation by deoxycytidine kinase) as well as enhancing drug stability.¹ 

      • Clofarabine is, following cell uptake, converted to the 5'-triphosphate metabolite by means of a process comparable to that seen with cladribine and fludarabine activation.⁸ 

        • However, clofarabine appears to be a better substrate compared to fludarabine or cladribine for deoxycytidine kinase.⁸  

          • The activated triphosphate form inhibits both DNA synthesis and repair.

          • Following DNA incorporation:

            • Clofarabine nucleotide inhibits ribonucleotide reductase (RNR),

            • Inhibits DNA polymerases and

            • Depletes intracellular deoxynucleotides.

          • Elongation of DNA strands is also inhibited.

        • Binding to the active site of RNR both decreases dATP levels while promoting clofarabine triphosphate incorporation into DNA.

        • Clofarabine administration promotes apoptosis by causing mitochondrial damage.⁸ 

         

    • Absorption, Distribution, Biotransformation, Excretion

      • In children, clofarabine is administered by IV infusion (2-hour infusion per day for 5 days).¹

      • The principal elimination half-time (t_1/2) is about 6.5 hours.¹ 

      • About 50% of the administered dose is excreted in the urine unchanged.¹² 

        • In patients with renal dysfunction as evidenced by decreased creatinine clearance, dosage adjustment is appropriate.¹

      • The volume of distribution is about 170 L/m².

      • In pediatric patients (ranging from 2-19 years of age) exhibiting relapsed or refractory ALL (acute lymphoblastic leukemia) or AML (acute myelogenous leukemia) receiving a dosage of 52 mg/m² exhibit a clearance of about 30 L/h/m².¹²

    • Clinical Use:⁸

      • Clofarabine is used in the treatment of pediatric patients exhibiting refractory acute lymphoblastic leukemia (ALL) or relapsed ALL following at least two previous treatment approaches.

        • This agent also increases intracellular levels of cytosine arabinoside with resultant potentiation of ara-C toxicity.

         

    • Adverse Effects/Toxicities:

      • The major toxicity associated with clofarabine administration is myelosuppression which increases the likelihood of infectionous complications.

        • Up to 25% of patients may exhibit a reversible hepatic transaminase enzyme increase.

        • A number of other side effects have been identified including:

          • Nausea

          • Fatigue

          • Edema and plantar Palmer dysesthesia.

        • A small number of patients exhibit capillary leak syndrome.

          • This syndrome presents as hypotension with:

            • Increased heart rate (tachypnea)

            • Fever and

            • Pulmonary edema (x-ray).

          • Drug discontinuation is appropriate when patients present with capillary leak syndrome.

        • Electrolyte abnormalities including hypophosphotemia and hypokalemia may also be noted during treatment.

        • Acute renal injury has been documented in about 30 cases involving refractory/relapse AML being treated using clofarabine.