Second Generation Purine Nucleoside Analog

Clolar is a hybrid of fludarabine and cladribine -- synthesized as a rational extension of these analog experiences¹. Purine nucleoside analogs such as cladribine and fludarabine are among the most widely used agents in leukemias. However, they are not generally used as single agents, and are used at dose levels associated with neurotoxicities^2,3. An addition to the purine nucleoside analog family (see figure), Clolar has shown favorable activity as a single agent in pediatric relapsed and refractory ALL^2,3.

In vitro studies suggest Clolar retains the 2-halogenated adenine of both fludarabine and cladribine, which makes it resistant to deamination, and also incorporates fluorine to make the glycosidic bond resistant to phosphorolysis, which limits the release of halogenated adenine^4,5.

References

1. 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.
2. 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.
3. 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(10):1085–95.
4. Montgomery JA, Shortnacy-Fowler AT, Clayton SD, Riordan JM, Secrist JA 3d.Synthesis and biologic activity of 2'-fluoro-2-halo derivatives of 9-beta-D-arabinofuranosyladenine. J Med Chem 1992; 35(2):397–401.
5. Xie C, 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.

---

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.

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).