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Selected Publications
Carson DA, Wasson DB, Esparza LM, et al. Oral antilymphocyte activity and induction of apoptosis by 2-chloro-2’-arabino-fluoro-2’-deoxyadenosine. Proc Natl Acad Sci U S A 1992;89:2970–4.
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Curran MP and Perry CM. Adis Drug Profile: Clofarabine. Clofarabine in Patients with Acute Lymphoblastic Leukemia. Pediatric Drugs 2005;7:259-264.
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Faderl S, Gandhi V, Keating MJ, Jeha S, Plunkett W, Kantarjian HM. The role of clofarabine in hematologic and solid malignancies—development of a next-generation nucleoside analog. Cancer 2005;103:1085–95.
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Faderl S, Gandhi V, Kantarjian HM, Plunkett W. New nucleoside analogs in clinical development. Cancer Chemother Biol Response Modif. 2002;20:37-58.
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Gandhi V, Kantarjian H, Faderl S, et al. Pharmacokinetics and pharmacodynamics of plasma clofarabine and cellular clofarabine triphosphate in patients with acute leukemias. Clin Cancer Res 2003;9:6335–42.
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Gaynon PS, Trigg ME, Heerema NA, et al. Children’s Cancer Group trials in childhood acute lymphoblastic leukemia; 1983-1995. Leukemia 2000;14:2223–33.
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Genini D, Adachi S, Chao Q, et al. Deoxyadenosine analogs induce programmed cell death in chronic lymphocytic leukemia cells by damaging the DNA and by directly affecting the mitochondria. Blood 2000;96:3537–43.
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Jeha S, Gandhi V, Chan K, et al. Clofarabine, a novel nucleoside analog, is active in pediatric patients with advanced leukemia. Blood 2004;103:784–9.
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Jeha S, Gaynon PS, Razzouk BI, et al. Phase II Study of Clofarabine in Pediatric Patients with Refractory or Relapsed Acute Lymphoblastic Leukemia. J Clin Oncol. 2006;24:1917-1923.
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Kantarjian H, Gandhi V, Kozuch P, et al. Phase I clinical and pharmacology study of clofarabine in patients with solid and hematologic cancers. J Clin Oncol 2003;21:1167–73.
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Lotfi K, Mansson E, Spasokoukotskaja T, et al. Biochemical pharmacology and resistance to 2-chloro-2'-arabino-fluoro-2'-deoxyadenosine, a novel analogue of cladribine in human leukemic cells. Clin Cancer Res 1999;5(9):2438-44.
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McDonald LR and McCarthy CH. Nursing Considerations for Clofarabine in the Treatment of Acute Lymphoblastic Leukemia in Children. Clin J Oncol Nurs 2006; 10:809-815
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McNeil DE, Cote TR, Clegg L, Mauer A. SEER update of incidence and trends in pediatric malignancies: acute lymphoblastic leukemia. Med Pediatr Oncol 2002;39:554–7.
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Montgomery JA, Shortnacy-Fowler AT, Clayton SD, Riordan JM, Secrist JA 3d. Synthesis and biologic activity of 2'-fluoro-2-halo derivatives of 9-ß-D-arabinofuranosyladenine. J Med Chem 1992; 35:397–401.
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Parker WB, Shaddix SC, Chang CH, et al. Effects of 2-chloro-9-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl) adenine on K562 cellular metabolism and the inhibition of human ribonucleotide reductase and DNA polymerases by its 5'-triphosphate. Cancer Res;1991;51:2386-94.
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Parker WB, Bapat AR, Shen JX, et al. Interaction of 2-halogenated dATP analogs (F, Cl, and Br) with human DNA polymerases, DNA primase, and ribonucleotide reductase. Mol Pharmacol 1988;34:485-91.
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Parker WB, Shaddix SC, Rose LM, et al. Comparison of the mechanism of cytotoxicity of 2-chloro-9-(2-deoxy-2-fluoro-ß-D-arabinofuranosyl) adenine, 2-chloro-9-(2-deoxy-2-fluoro-ß-D-ribofuranosyl) adenine, 2-chloro-9-(2-deoxy-2,2-difluoro-ß-D-ribofuranosyl) adenine in CEM cells. Mol Pharmacol. 1999;55:515-520.
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Smith MA, Gloeckler Ries LA, Gurney JG, Ross JA. Leukemia: SEER pediatric monograph. In: Ries LAG, Smith MA, Gurney JG, et al. (eds). Cancer incidence and survival among children and adolescents: United States SEER Program 1975-1995, National Cancer Institute, SEER Program. NIH Pub No. 99-4649. Bethesda, MD, 1999.
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Steinherz PG. Acute lymphoblastic leukemia of childhood. Hematol Oncol Clin North Am 1987;1:549-66.
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Weitman S, Ochoa S, Sullivan J, et al. Pediatric phase II cancer chemotherapy trials: a Pediatric Oncology Group study. J Pediatr Hematol Oncol 1997;19:187–91.
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Xie KC, Plunkett W. Deoxynucleotide pool depletion and sustained inhibition of ribonucleotide reductase and DNA synthesis after treatment of human lymphoblastoid cells with 2-chloro-9-(2-deoxy-2-fluoro-ß-D-arabinofuranosyl) adenine. Cancer Research 1996;56:3030–37.
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Indication
Clolar is indicated for the treatment of pediatric patients 1 to 21 years old with relapsed or refractory acute lymphoblastic leukemia after at least two prior regimens. This use is based on the induction of complete responses. Randomized trials demonstrating increased survival or other clinical benefit have not been conducted.
Important Safety Considerations
Clolar should be administered under the supervision of a qualified physician experienced in the use of antineoplastic therapy. Suppression of bone marrow function, which is usually reversible and dose dependent, should be anticipated and is likely to increase the risk of infection, including severe sepsis. Administration of Clolar results in a rapid reduction in peripheral leukemia cells. Patients should be evaluated and monitored for signs and symptoms of tumor lysis syndrome and cytokine release (e.g., tachypnea, tachycardia, hypotension, pulmonary edema) that could develop into systemic inflammatory response syndrome (SIRS)/capillary leak syndrome, and organ dysfunction. Clolar should be discontinued immediately in the event of clinically significant signs or symptoms of SIRS or capillary leak syndrome, either of which can be fatal, and use of steroids, diuretics, and albumin considered.
The most common adverse effects after Clolar treatment, regardless of causality, were gastrointestinal tract symptoms, including vomiting (grade 3: 8%; grade 4: 1%), nausea (grade 3: 15%; grade 4: 1%), and diarrhea (grade 3: 10%); hematologic effects, including anemia (grade 3: 70%; grade 4: 18%), leukopenia (grade 4: 99%), thrombocytopenia (grade 3: 36%; grade 4: 64%), neutropenia (grade 3: 3%; grade 4: 7%), and febrile neutropenia (grade 3: 53%; grade 4: 3%); and infection (grade 3: 56%; grade 4: 18%).
Hepato-biliary toxicities were frequently observed in pediatric patients during treatment with Clolar. The most frequently reported cardiac disorder was tachycardia (34%), which was, however, already present in 27.4% of patients at study entry. Left ventricular systolic dysfunction was also noted. Since Clolar is excreted primarily by the kidneys, drugs with known renal toxicity should be avoided during the 5 days of Clolar administration. In addition, since the liver is a known target organ for Clolar toxicity, concomitant use of medications known to induce hepatic toxicity should also be avoided.
Severe bone marrow suppression, including neutropenia, anemia, and thrombocytopenia, have been observed in patients treated with Clolar. Because of the pre-existing immunocompromised condition of these patients and prolonged neutropenia that can result from treatment with Clolar, patients are at increased risk for severe opportunistic infections.
Pericardial effusion was a frequent finding in these patients on post-treatment studies. Careful hematologic monitoring during therapy is important. Hepatic and renal function should be assessed prior to and during treatment with Clolar, as the liver is a target organ for Clolar toxicity and the kidneys are the predominant mode of Clolar excretion. Severe hepatotoxic events have been reported in an ongoing, phase 1/2 clinical trial investigating Clolar in combination with etoposide and cyclophosphamide in pediatric patients with relapsed or refractory acute leukemia. This study found that patients who had previously received a hematopoietic stem cell transplant may be at higher risk for hepatotoxicity.
Patients receiving Clolar may experience vomiting and diarrhea; they should therefore be advised regarding appropriate measures to avoid dehydration. Clolar may cause fetal harm when administered to a pregnant woman. Women of childbearing potential should be advised to avoid becoming pregnant and avoid breastfeeding while receiving treatment with Clolar.
For more information, please consult the Full Prescribing Information (PDF).
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| Contact Information |
| Genzyme Oncology |
| 500 Kendall Street |
| Cambridge, MA 02142 |
| 1-800-792-5652 |
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