title: Farnesyl transferase inhibitor (lonafarnib) in patients with myelodysplastic syndrome or secondary acute myeloid leukaemia: a phase II study.
abstract: 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.affiliation: Jules Bordet Institute, Rue Héger-Bordet, 1, 1000 Brussels, Belgium. christophe.ravoet@bordet.be
authors.forename: Christophe
authors.initials: C
authors.lastname: Ravoet
authors.forename: Philippe
authors.initials: P
authors.lastname: Mineur
authors.forename: Valérie
authors.initials: V
authors.lastname: Robin
authors.forename: Louisette
authors.initials: L
authors.lastname: Debusscher
authors.forename: André
authors.initials: A
authors.lastname: Bosly
authors.forename: Marc
authors.initials: M
authors.lastname: André
authors.forename: Hakim
authors.initials: H
authors.lastname: El Housni
authors.forename: Anne
authors.initials: A
authors.lastname: Soree
authors.forename: Dominique
authors.initials: D
authors.lastname: Bron
authors.forename: Philippe
authors.initials: P
authors.lastname: Martiat
mesh_terms: D000368:Aged; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors*; D005260:Female; D005767:Gastrointestinal Diseases / Q000139:chemically induced; D011905:Genes, ras / Q000235:genetics; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000188:drug therapy*; D010880:Piperidines / Q000009:adverse effects*; D011725:Pyridines / Q000009:adverse effects*; D003986:Dibenzocycloheptenes
chemical_list: D051231:Farnesyltranstransferase; D010880:Piperidines; D011725:Pyridines; C115354:lonafarnib; D003986:Dibenzocycloheptenes