Clofarabine, a synthetic purine nucleoside, is an antimetabolite antineoplastic agent.1, 2, 4, 5, 6, 7
Clofarabine is used for the treatment of acute lymphocytic (lymphoblastic) leukemia (ALL) that is refractory to or has relapsed after at least 2 prior therapies in patients 1-21 years of age.1, 2, 3, 4, 5, 6, 7 Clofarabine is designated an orphan drug by the US Food and Drug Administration (FDA) for use in this condition.2, 3 Clofarabine became commercially available in the US under the principles and procedures of the accelerated review policy of the FDA, which allows approval based on analysis of surrogate markers of response rather than clinical end points.1, 2 The current indication for clofarabine is based on induction of complete responses; randomized studies showing increased survival or other clinical benefits have not been conducted to date.1
Efficacy of clofarabine has been evaluated in a single-arm study in 49 pediatric patients (median age: 12 years) with ALL that had relapsed or was refractory to 2 or more prior therapies.1, 3, 4, 5, 6, 7 Patients received IV clofarabine in a dosage of 52 mg/m2 daily for 5 days.1, 4, 8 Treatment cycles were repeated every 2-6 weeks based on response and tolerance.1, 4, 8 During the remission induction phase (maximum 2 cycles), no dose modification was allowed, while doses could be reduced or delayed during post-induction phase.1 Complete remission (defined as no evidence of circulating blast cells or extramedullary disease, M1 bone marrow [less than 5% blast cells], and recovery of peripheral blood counts [platelet counts exceeding 100,000/mm3 and absolute neutrophil counts exceeding 1000/mm3]) was achieved in 12.2%, complete remission in the absence of total platelet recovery (defined the same as complete response except for the presence of residual thrombocytopenia) was achieved in 8.2%, and partial response (defined as the complete disappearance of circulating blast cells, M2 bone marrow [more than 5 to less than 25% blast cells], and the appearance of normal progenitor cells or M1 bone marrow that did not qualify for complete remission or complete remission in the absence of total platelet recovery) was achieved in 10.2% of children.1, 6, 7 In those pediatric patients who achieved complete remission and did not undergo bone marrow transplantation following clofarabine therapy, the duration of remission ranged from 43 to 160 days.1
Clofarabine is administered by IV infusion over 2 hours.1
The patient's respiratory status and blood pressure should be monitored during infusion of clofarabine.1 Patients receiving drugs that affect blood pressure or cardiac function should be monitored especially closely.1 (See Systemic Inflammatory Response Syndrome/Capillary Leak Syndrome under Warnings/Precautions: Warnings, in Cautions.)
Commercially available clofarabine for IV infusion containing 1 mg of the drug per mL should be diluted prior to administration.1 The appropriate dose should be filtered through a sterile 0.2 µm filter and then further diluted with 5% dextrose injection or 0.9% sodium chloride injection.1 When diluted as directed, clofarabine solutions may be stored at room temperature and must be used within 24 hours of preparation.1
The manufacturer states that other drugs should not be infused through the same IV line.1 Parenteral clofarabine solutions should be inspected visually for particulate matter and discolorations prior to administration.1
Continuous administration of IV fluids throughout the 5 days of clofarabine administration is advised to reduce the effects of tumor lysis and other adverse effects.1 If tumor lysis is expected, allopurinol should be administered to prevent hyperuricemia.1 (See Tumor Lysis Syndrome under Warnings/Precautions: Warnings, in Cautions.)
Administration of corticosteroids (e.g., hydrocortisone 100 mg/m2 on days 1-3) may prevent signs and symptoms of cytokine release or capillary leak syndrome.1 (See Systemic Inflammatory Response Syndrome/Capillary Leak Syndrome under Warnings/Precautions: Warnings, in Cautions.)
The usual precautions for handling and preparing solutions of cytotoxic drugs should be observed when preparing or administering clofarabine.1
Dosage of clofarabine is based on the patient's body surface area and is calculated using the actual body weight and height of the patient before starting each cycle.1
For the treatment of acute lymphocytic leukemia (ALL) in patients 1-21 years of age, the recommended dosage of clofarabine is 52 mg/m2 administered by IV infusion over 2 hours daily for 5 consecutive days.1 The treatment cycle is repeated following recovery or return to baseline organ function, approximately every 2-6 weeks.1
If early manifestations of cytokine release or capillary leak syndrome occur, administration of clofarabine should be discontinued immediately and appropriate supportive measures initiated.1 Reinstitution of clofarabine therapy, generally at a lower dosage, may be considered once the patient is stable and organ function has returned to baseline levels.1, 8
If substantial increases in serum creatinine or bilirubin concentrations occur, clofarabine should be discontinued immediately.1 The drug may be reinstituted, possibly at a lower dosage, once the patient is stable and organ function has returned to baseline levels.1
If hypotension develops during administration of clofarabine, administration of the drug should be discontinued.1 Reinstitution of clofarabine therapy at a lower dosage may be considered if hypotension was transient and resolved without pharmacologic intervention.1
No special populations dosage recommendations at this time.1
The manufacturer states that there are no contraindications to use of clofarabine.1 However, clofarabine should be used with caution in patients with known hypersensitivity to the drug or any ingredient in the formulation.8
Clofarabine should be used under the supervision of a qualified clinician experienced in therapy with antineoplastic agents.1
Hematologic Effects and Infectious Complications
Bone marrow suppression (usually reversible and dose dependent) should be anticipated with use of the drug.1 Severe bone marrow suppression (neutropenia, anemia, thrombocytopenia) reported.1 Increased risk of developing infectious complications, including severe sepsis and opportunistic infections.1
May occur as the result of leukemia treatment.1 Patients should be monitored for signs and symptoms of tumor lysis syndrome.1 Use appropriate measures (e.g., hydration, allopurinol) to prevent hyperuricemia.1
Systemic Inflammatory Response Syndrome/Capillary Leak Syndrome
Capillary leak syndrome or systemic inflammatory response syndrome (i.e., signs and symptoms of cytokine release [tachypnea, tachycardia, hypotension, pulmonary edema]) has occurred in pediatric patients receiving clofarabine.1 Rapid onset of respiratory distress, hypotension, capillary leak (e.g., pleural and pericardial effusions), and multiorgan failure have been reported.1 Administration of corticosteroids may prevent signs and symptoms of cytokine release or capillary leak syndrome.1 Close monitoring for this syndrome and early intervention (discontinuance of clofarabine and supportive measures [use of corticosteroids, diuretics, and/or albumin]) is recommended; development of systemic inflammatory response syndrome or capillary leak syndrome may be fatal.1 Reinstitution of clofarabine (generally in a lower dosage) therapy may be considered once the patient is stable.1 (See Dosage and Administration: Dosage.)
Fetal/Neonatal Morbidity and Mortality
May cause fetal harm; teratogenicity demonstrated in animals.1 No adequate and well-controlled studies to date in humans.1 Pregnancy should be avoided during therapy.1 If used during pregnancy, apprise of potential fetal harm.1
Complete blood cell counts, including platelet count, should be performed at regular intervals in all patients receiving clofarabine; more frequent monitoring may be necessary in patients who develop cytopenias.1 Hepatic and renal function should be evaluated prior to initiating therapy and throughout the 5 days of clofarabine administration.1
Patients receiving drugs that affect blood pressure or cardiac function should be closely monitored while receiving clofarabine therapy.1
Category D.1 (See Users Guide.) (See Warnings: Fetal/Neonatal Morbidity and Mortality, in Cautions.)
Not known whether clofarabine or its metabolites are distributed into human milk.1 Because of the potential for serious adverse reactions to clofarabine in nursing infants, women should discontinue nursing while receiving clofarabine therapy.1
Safety and efficacy for treatment of relapsed or refractory acute lymphocytic leukemia (ALL) has been established in patients 1-21 years of age.1
Clofarabine has been evaluated in a limited number of children with refractory acute myeloid leukemia (AML)†.2, 4, 5, 6, 7
Safety and efficacy have not been established in adults.1 A dosage of 40 mg/m2 (given by IV infusion over 1-2 hours) daily for 5 days every 28 days was used in a phase 2 clinical study in adults with relapsed or refractory hematologic malignancies.1, 2, 6
Clofarabine has not been studied in patients with hepatic impairment.1 Use with great caution.1
In patients who experience substantial increases in bilirubin concentrations while receiving clofarabine therapy, the drug should be withheld until hepatic function returns to baseline values.1 Dosage adjustment may be considered.1
Clofarabine has not been studied in patients with renal impairment.1 Use with great caution.1
In patients who experience substantial increases in serum creatinine concentrations while receiving clofarabine therapy, the drug should be withheld until renal function returns to baseline values.1 Dosage adjustment may be considered.1
Most common adverse effects include nausea, vomiting, diarrhea, anemia, leukopenia, thrombocytopenia, neutropenia (including febrile neutropenia), and infections.1
Drug interaction studies have not been conducted to date.1
Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes
Interaction with drugs that induce or inhibit cytochrome P-450 (CYP) isoenzymes is not expected.1
Because clofarabine principally is excreted by the kidney, use of nephrotoxic drugs should be avoided throughout the 5 days of clofarabine administration.1
Because clofarabine can cause hepatotoxicity, concomitant use of clofarabine with hepatotoxic drugs should be avoided.1
Clofarabine, a purine nucleoside, differs from other purine nucleoside analogs (e.g., cladribine, fludarabine) by the presence of a halogen atom in both the purine ring (chlorine) and the ribose moiety (fluorine).1, 2, 5 Clofarabine is converted intracellularly to the active 5'-triphosphate metabolite.1, 5 Clofarabine triphosphate inhibits DNA synthesis, inhibits ribonucleoside reductase, and has direct effects on mitochondria; these effects lead to depletion of intracellular deoxynucleotide triphosphate pools, inhibition of the elongation of DNA strands during synthesis, and release of proapoptotic mitochondrial factors in both actively dividing and quiescent tumor cells.1, 2, 6
Data (using a 24-hour urine collection) from a pharmacokinetic study in pediatric patients indicate that 49-60% of a dose is excreted in urine unchanged.1 In vitro studies using isolated human hepatocytes indicate very limited (0.2%) metabolism of the drug;1 nonrenal routes of elimination have not been elucidated.1
Risk of dehydration secondary to vomiting and/or diarrhea.1 Importance of advising patients regarding appropriate measures (e.g., adequate fluid intake) to avoid dehydration.1
Patients should be advised to notify a clinician immediately if symptoms of hypotension (e.g., dizziness, lightheadedness, fainting spell) or decreased urine output occurs.1
Necessity of monitoring blood cell counts, renal function, and hepatic function.1
Necessity of advising women to use an effective method of contraception and to avoid breast-feeding while receiving clofarabine therapy.1 Importance of women informing a clinician immediately if they are or plan to become pregnant or plan to breast-feed.1 Advise pregnant women of risk to the fetus.1
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1
Importance of informing patients of other important precautionary information.1 (See Cautions.)
Additional Information
Overview® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
1. Genzyme Corporation. Clolar® (clofarabine) for intravenous infusion prescribing information. Cambridge, MA; 2005.
2. Anon. Clofarabine. Drugs R &D . 2004; 5:213-7.
3. Food and Drug Administration. Orphan designations pursuant to Section 526 of the Federal Food and Cosmetic Act as amended by the Orphan Drug Act (P.L. 97 414). Rockville, MD. From FDA website. Accessed 2005 Jan 25. [Web]
4. Jeha S, Razzouk B, Gaynon P et al. Phase II trials of clofarabine in pediatric acute leukemia. Presented at the American Society of Clinical Oncologists Annual Meeting 2005. From the ASCO website. Abstract No. 6588. Accessed 2005 Jun 21. [Web]
5. Jeha S, Gandhi V, Chan KW et al. Clofarabine, a novel nucleoside analog, is active in pediatric patients with advanced leukemia. Blood . 2004;103:784-9. [PubMed 14551141]
6. Faderl S, Gandhi V, Keating MJ et al. The role of clofarabine in hematologic and solid malignancies-development of a next-generation nucleoside analog. Cancer . 2005; 103:1985-95. [PubMed 15803490]
7. Jeha S, Razzouk BI, Rytting ME et al. Phase II trials of clofarabine in relapsed or refractory pediatric leukemia. Presented at the American Society of Hematology Annual Meeting 2004. From the ASH website. Abstract No. 684. Accessed 2005 Jun 30. [Web]
8. Genzyme Corporation, Cambridge, MA: personal communication.