Document Detail


Farnesyl transferase inhibitor (lonafarnib) in patients with myelodysplastic syndrome or secondary acute myeloid leukaemia: a phase II study.
MedLine Citation:
PMID:  18641985     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Although an activating mutation of Ras is commonly observed in myelodysplastic syndrome (MDS), the role of Ras in the natural history of MDS remains largely unknown. We prospectively studied efficiency and tolerance of lonafarnib, a compound able to inhibit Ras signalling pathway through an inhibition of farnesyl transferase, in patients with MDS or secondary acute myeloid leukaemia (sAML). Lonafarnib was administered orally at a dose of 200 mg twice daily for three courses of 4 weeks (separated by 1 to 4 weeks without treatment). Sixteen patients were included: FAB/RAEB (n = 10), RAEB-T (n = 2), sAML (n = 2) and chronic myelomonocytic leukaemia (CMML; n = 2); WHO/RAEB-1 (n = 4), RAEB-2 (n = 5), AML (n = 5), CMML (n = 2). Median age was 70 (53-77) years. The karyotype was complex or intermediate in 11 patients, and the International Prognostic Scoring Systems (IPSS) risk groups were low in two patients, INT-1 in one patient, INT-2 in four patients and high in six patients (unknown or not applicable in three patients). Among the 14 patients tested, five had Ras mutations in codons 12, 13 or 61 of N-Ras, K-Ras or H-Ras. One patient was excluded of the analysis for protocol violation, and 15 patients were assessable for tolerance. Gastrointestinal toxicities (diarrhoea, nausea and anorexia) and myelosuppression were the major side effects. Other toxicities included infections, fatigue, increase of liver enzymes, arrhythmia and skin rash. One patient died of infection, and the treatment was stopped in one other who developed atrial fibrillation. Doses were reduced in all but one patient treated with more than one course of farnesyl transferase inhibitor. Responses were assessable in 12 patients. A partial response in one sAML patient and a very transient decrease of blast cell count with normalisation of karyotype in one MDS patient were observed. No relation between improvement of marrow parameters and detected Ras mutations was observed. Lonafarnib alone, administered following our schedule, has shown limited activity in patients with MDS or secondary AML. Gastrointestinal and haematological toxicities appear the limiting toxicity in this population of patients.
Authors:
Christophe Ravoet; Philippe Mineur; Valérie Robin; Louisette Debusscher; André Bosly; Marc André; Hakim El Housni; Anne Soree; Dominique Bron; Philippe Martiat
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Publication Detail:
Type:  Clinical Trial, Phase II; Journal Article     Date:  2008-07-19
Journal Detail:
Title:  Annals of hematology     Volume:  87     ISSN:  1432-0584     ISO Abbreviation:  Ann. Hematol.     Publication Date:  2008 Nov 
Date Detail:
Created Date:  2008-09-29     Completed Date:  2008-11-12     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9107334     Medline TA:  Ann Hematol     Country:  Germany    
Other Details:
Languages:  eng     Pagination:  881-5     Citation Subset:  IM    
Affiliation:
Jules Bordet Institute, Rue Héger-Bordet, 1, 1000 Brussels, Belgium. christophe.ravoet@bordet.be
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MeSH Terms
Descriptor/Qualifier:
Aged
Farnesyltranstransferase / antagonists & inhibitors*
Female
Gastrointestinal Diseases / chemically induced
Genes, ras / genetics
Humans
Leukemia, Myeloid, Acute / drug therapy*
Male
Middle Aged
Myelodysplastic Syndromes / drug therapy*
Piperidines / adverse effects*
Pyridines / adverse effects*
Chemical
Reg. No./Substance:
0/Piperidines; 0/Pyridines; 193275-84-2/lonafarnib; EC 2.5.1.29/Farnesyltranstransferase

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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