クロファラビン
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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/07/12 00:43:58」(JST)
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Clofarabine
|
| Systematic (IUPAC) name |
|
5-(6-amino-2-chloro-purin-9-yl) -4-fluoro-2- (hydroxymethyl)oxolan-3-ol
|
| Clinical data |
| Trade names |
Clolar, Evoltra |
| AHFS/Drugs.com |
monograph |
| MedlinePlus |
a607012 |
| Legal status |
|
Routes of
administration |
Intravenous |
| Identifiers |
| CAS Registry Number |
123318-82-1 Y |
| ATC code |
L01BB06 |
| PubChem |
CID: 119182 |
| IUPHAR/BPS |
6802 |
| DrugBank |
DB00631 Y |
| ChemSpider |
106472 Y |
| UNII |
762RDY0Y2H Y |
| KEGG |
D03546 Y |
| ChEBI |
CHEBI:681569 Y |
| ChEMBL |
CHEMBL1750 Y |
| Chemical data |
| Formula |
C10H11ClFN5O3 |
| Molecular mass |
303.677 g/mol |
SMILES
-
Clc1nc(c2ncn(c2n1)[C@@H]3O[C@@H]([C@@H](O)[C@@H]3F)CO)N
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InChI
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InChI=1S/C10H11ClFN5O3/c11-10-15-7(13)5-8(16-10)17(2-14-5)9-4(12)6(19)3(1-18)20-9/h2-4,6,9,18-19H,1H2,(H2,13,15,16)/t3-,4+,6-,9-/m1/s1 Y
-
Key:WDDPHFBMKLOVOX-AYQXTPAHSA-N Y
|
| Y (what is this?) (verify) |
Clofarabine is a purine nucleoside antimetabolite marketed in the US and Canada as Clolar. In Europe and Australia/New Zealand the product is marketed under the name Evoltra. It is FDA-approved for treating relapsed or refractory acute lymphoblastic leukaemia (ALL) in children after at least two other types of treatment have failed. It is not known if it extends life expectancy. Some investigations of effectiveness in cases of acute myeloid leukaemia (AML) and juvenile myelomonocytic leukaemia (JMML) have been carried out. Ongoing trials are assessing its efficacy, if any, for managing other cancers.
Contents
- 1 Side effects
- 2 Contraindications
- 3 Drug interactions
- 4 Delivery
- 5 Results of clinical trials
- 6 Approval
- 7 External links
Side effects
- 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 enough red blood cells, white blood cells, and platelets. Serious side effects that can happen because of bone marrow suppression include severe infection (sepsis), bleeding, and anemia.
- Effects on pregnancy and breastfeeding. Girls and women should not become pregnant or breastfeed during treatment which may harm the baby.
- Dehydration and low blood pressure. Clofarabine can cause vomiting and diarrhea which may lead to low body fluid (dehydration). Signs and symptoms of dehydration include dizziness, lightheadedness, fainting spells, or decreased urination.
- Other side effects. The most common side effects are stomach problems (including vomiting, diarrhea, and nausea), 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 cause tachycardia and can affect the liver and kidneys.
Contraindications
- pregnancy or planned pregnancy
- breast-feeding
- liver problems
- kidney problems
Drug interactions
- nephrotoxic drugs
- hepatotoxic drugs
Delivery
- By intravenous infusion.
- Dosage is a 2 hour infusion (52 mg/m²) every day for five days. The cycle is repeated every 2 to 6 weeks.
- Regular blood tests to monitor his or her blood cells, kidney function, and liver function.
Results of clinical trials
Efficacy and safety were demonstrated in a single multi-center trial that enrolled 40 patients aged 2-19. The patients were suffering with relapsed or refractory acute lymphoblastic leukaemia (ALL) (An additional nine patients suffering with acute myelogenous leukaemia (AML) had similar pharmacokinetics but are not included in the figure below.) Most patients had received two to four prior regimens and 15/49 (31%) had undergone at least one transplant. The median age was 12 years. Clofarabine was given at a dose of 52 mg/m2, intravenously, over two hours daily x 5 repeated every two to six weeks following recovery or return to baseline organ function. The study endpoints were the rate of complete response (CR) and the rate of complete response without platelet recovery (CRp). The former was defined as no evidence of circulating blasts or extramedullary disease, an M1 bone marrow, and recovery of peripheral platelet and absolute neutrophil counts; the latter was defined as meeting all criteria for CR except for platelet count recovery. Response rates were determined by an independent response review panel (IRRP).
Six patients (12%) achieved a CR and four patients (8%) achieved a CRp, while five patients (10%) achieved a PR. Of the 15 responding patients, six had post-clofarabine bone marrow transplantation. Hence, response durations could not be determined. In the patients who were not transplanted, the response durations for CR were 43, 50, 82, 93+, and 160+ days; for CRp the response duration was 32 days.
The principal clofarabine toxicities were nausea, vomiting, hematologic toxicity, febrile neutropenia, hepatobiliary toxicity, infections and renal toxicity. Clofarabine can produce systemic inflammatory response syndrome/capillary leak syndrome (SIRS), manifested by the rapid development of tachypnea, tachycardia, hypotension, shock, and multi-organ failure. Cardiac toxicity was characterized as left ventricular systolic dysfunction; tachycardia may also occur.
Approval
Clolar was Food and Drug Administration (FDA) approved 28 December 2004. (Under accelerated approval regulations requiring further clinical studies.)
External links
- Clofarabine information on Cancerbackup.
- FDA usage leaflet.
- Clolar.com homepage.
- FDA approval notice.
UpToDate Contents
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English Journal
- Update on biology and treatment of T-cell acute lymphoblastic leukaemia.
- Patrick K1, Vora A.
- Current opinion in pediatrics.Curr Opin Pediatr.2015 Feb;27(1):44-9. doi: 10.1097/MOP.0000000000000171.
- PURPOSE OF REVIEW: In this article, new insights into the clinical and biological features of paediatric T-lineage acute lymphoblastic leukaemia (ALL) and their impact on treatment outcome have been described.RECENT FINDINGS: T-lineage ALL has considerable phenotypic and biological heterogeneity. Co
- PMID 25502893
- Phase I/II Study of Clofarabine, Etoposide, and Mitoxantrone in Patients With Refractory or Relapsed Acute Leukemia.
- Abbi KK1, Rybka W2, Ehmann WC2, Claxton DF3.
- Clinical lymphoma, myeloma & leukemia.Clin Lymphoma Myeloma Leuk.2015 Jan;15(1):41-6. doi: 10.1016/j.clml.2014.06.005. Epub 2014 Jun 11.
- BACKGROUND: Clofarabine, a second-generation nucleoside analogue, was studied in combination with etoposide and mitoxantrone in acute leukemia.PATIENTS AND METHODS: In the phase I portion of this study clofarabine was given 20 or 25 mg/m(2) daily for 5 days (Days 2-6) with etoposide 100 mg/m(2) fro
- PMID 25085441
- G-CSF priming, clofarabine, and high dose cytarabine (GCLAC) for upfront treatment of acute myeloid leukemia, advanced myelodysplastic syndrome or advanced myeloproliferative neoplasm.
- Becker PS1, Medeiros BC, Stein AS, Othus M, Appelbaum FR, Forman SJ, Scott BL, Hendrie PC, Gardner KM, Pagel JM, Walter RB, Parks C, Wood BL, Abkowitz JL, Estey EH.
- American journal of hematology.Am J Hematol.2014 Dec 24. doi: 10.1002/ajh.23927. [Epub ahead of print]
- Prior study of the combination of clofarabine and high dose cytarabine with granulocyte colony-stimulating factor (G-CSF) priming (GCLAC) in relapsed or refractory acute myeloid leukemia resulted in a 46% rate of complete remission despite unfavorable risk cytogenetics. A multivariate analysis demon
- PMID 25545153
Japanese Journal
- 再発・難治小児急性リンパ性白血病に対するクロファラビン併用化学療法
- 再発・難治性急性リンパ性白血病に対するクロファラビンの有効性と安全性 (特集 急性リンパ性白血病をめぐる最近の進歩)
- ALLに対するクロファラビン (特集 急性リンパ性白血病(ALL))
Related Links
- クロファラビン[Clofarabine] (Clolar[クロラール]、Clofarex[クロファレックス]) 原文 2006/10/5掲載 2012/07/16更新 このページは、クロファラビンの簡単な説明と、本治療薬の用法、研究結果および現在進行中の臨床試験に関する情報 ...
- 海外販売名：Clolar／一般名：clofarabine／治験成分記号：- 対象疾患： 小児急性リンパ性白血病 国内における開発状況： 検討当時の状況：国内治験前 治験開始の検討要請中（2007/4/26現在） 治験準備中(2007/6/18現在) ...
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