Clofarabine is apurinenucleosideantimetabolite marketed in the United States and Canada asClolar. In Europe and Australia/New Zealand the product is marketed under the nameEvoltra. It is FDA-approved for treating relapsed or refractoryacute lymphoblastic leukaemia (ALL) in children after at least two other types of treatment have failed. Some investigations of effectiveness in cases ofacute myeloid leukaemia (AML) and juvenile myelomonocytic leukaemia (JMML) have been carried out. Ongoing trials are assessing its efficacy for managing other cancers.
Tumor lysis syndrome (TLS). Clofarabine quickly kills leukaemia cells in the blood. The body may react to this. Signs include hyperkalemia, hyperuricemia, and hyperphosphatemia. TLS is very serious and can lead to death if it is not treated right away.
Systemic inflammatory response syndrome (SIRS): symptoms include fast breathing, fast heartbeat, low blood pressure, and fluid in the lungs.
Bone marrow problems (suppression). Clofarabine can stop the bone marrow from making enoughred blood cells,white blood cells, andplatelets. Serious side effects that can happen because of bone marrow suppression include severe infection (sepsis), bleeding, andanemia.
Effects onpregnancy andbreastfeeding. Girls and women should not become pregnant or breastfeed during treatment which may harm the baby.
Dehydration andlow blood pressure. Clofarabine can causevomiting anddiarrhea which may lead to low body fluid (dehydration). Signs and symptoms of dehydration include dizziness, lightheadedness, fainting spells, or decreasedurination.
Other side effects. The most common side effects are stomach problems (including vomiting, diarrhea, andnausea), and effects on blood cells (including low red blood cells count, low white blood cell count, low platelet count,fever, and infection). Clofarabine can also causetachycardia and can affect theliver andkidneys.
Clofarabine is a second-generation purine nucleoside analog designed to overcome biological limitations observed with ara-A and fludarabine. A 2´(S)-fluorine in clofarabine significantly increased the stability of the glycosidic bond in acidic solution and toward phosphorolytic cleavage as compared to fludarabine.[3] A chlorine substitution at the 2-position of the adenine base avoids production of a 2-fluoroadenine analog, a precursor to the toxic 2-fluoro-adenosine-5´-triphosphate and prevents deamination of the base as compared to ara-A.[4]
Clofarabine can be administered intravenously or given orally. Clofarabine enters cells via hENT1, hENT2, and hCNT2, where upon it is phosphorylated by deoxycytidine kinase to generate clofarabine-5´-monophosphate. The rate-limiting step in clofarabine metabolism is clofarabine-5´-diphosphosphate. Clofarabine-5´-triphosphate is the active-metabolite, and it inhibitsribonucleotide reductase, resulting in a decrease cellular dNTP concentrations, which promotes greater incorporation of clofarabine-5´-triphosphate during DNA synthesis. Embedded clofarabine-5´-monophosphate in the DNA promotes polymerase arrest at the replication fork, triggering DNA repair mechanisms that without repair lead to DNA strand breaks in vitro and cytochrome c-mediated apoptosis in vitro. Studies using cell lines have shown that clofarabine-5´-triphosphate can also be incorporated into RNA.[5]
Mechanisms of resistance and turnover have been reported. Clofarabine-resistance arises from decreased deoxycytidine kinase activity in vitro.[6] ABC transporter ABCG2 promotes export of clofarabine-5´-monophosphate and thus limits the cytotoxic effects of this analog in vivo.[7] Biochemically, clofarabine-5’-triphosphate was shown to be substrate for SAMHD1, thus potentially limiting the amount of active compound in cells.[8]
^Bonate PL, Arthaud L, Cantrell WR Jr, Stephenson K, Secrist JA 3rd, Weitman S (Feb 2014). "Discovery and development of clofarabine: a nucleoside analogue for treating cancer".Nat Rev Drug Discov.5 (10):855–63.doi:10.1038/nrd2055.PMID17016426.S2CID21361350.
^Lotfi K, Månsson E, Spasokoukotskaja T, Pettersson B, Liliemark J, Peterson C, Eriksson S, Albertioni F (1999). "Biochemical pharmacology and resistance to 2-chloro-2'-arabino-fluoro-2'deoxyadenosine, a novel analogue of cladribine in human leukemic cells".Clin Cancer Res.5 (9):2438–44.PMID10499616.
