On the use of lonafarnib in myelodysplastic syndrome and chronic myelomonocytic leukemia

Abstract

Lonafarnib is an orally bio-available farnesyltransferase inhibitor that prevents farnesylation of specific target proteins including Ras. In a multicenter study, 67 patients with advanced myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML) were treated with a continuous oral dose of 200-300 mg of lonafarnib and were evaluated for hematologic, pathologic and pharmacodynamic response. The median age of patients was 70 years (range 44-86). There were 32 patients with MDS (RAEB-20 and RAEB-t-12) and 35 with CMML. Overall 16 (24%) of the patients responded with two patients achieving a complete remission and one a partial response. Responses were seen in 6/32 and 10/35 patients with MDS and CMML, respectively. Of the 19 patients who were platelet transfusiondependent prior to treatment, 5 (26%) became transfusion-free for a median duration of 185 days. A decrease in the farnesylation of the HDJ-2 protein measured in patient-derived cells was observed in the majority of patients during treatment with lonafarnib, but no clear correlation between changes in farnesylation and clinical effect could be made. Gastrointestinal toxicity was significant with 19% of patients discontinuing therapy due to diarrhea, nausea and/or anorexia. Lonafarnib has demonstrable activity in patients with advanced MDS and CMML.

Clinical trial of a farnesyltransferase inhibitor in children with Hutchinson–Gilford progeria syndrome

“…This finding is commensurate with previous findings in cancer studies that also used HDJ-2 as a potential surrogate marker of farnesylation inhibition. Findings were similar for range of inhibition (12), variable longitudinal inhibition, and lack of clear association with clinical outcomes (21). Although HDJ-2 assessment confirms on-target biochemical activity of lonafarnib in a subset of patients, it does not provide a useful biomarker for predicting clinical benefit.…”

Oral prenylation inhibition with lonafarnib in chronic hepatitis D infection: a proof-of-concept randomised, double-blind, placebo-controlled phase 2A trial

“…Gastrointestinal side-effects (nausea, diarrhoea, abdominal bloating, and decreased appetite) were the most common, and are similar to studies evaluating lonafarnib for other disease states. 25–27 The exploration of antiemetics, antidiarrhoeal, and acid suppressive therapies might improve tolerability in future studies. The average weight loss of 4 kg in group 2 suggests that prolonged dosing could be challenging, especially in higher doses, and would warrant close monitoring.…”

Chronic Myelomonocytic Leukemia: a Genetic and Clinical Update

“…Median OS was statistically superior in the hydroxyurea arm (20 months versus 9 months). Several other trials evaluated agents such as low-dose cytarabine with or without the use of all-trans retinoic acid [57][58][59], topotecan [60,61], 9-nitro-campothecin (a novel topoisomerase inhibitor) [62], valproic acid (histone deacetylase inhibitor) [63], and lonafarnib (farnesyltransferase inhibitor) [64] in the treatment of CMML. Collectively, response rates in these trials were disappointing and treatment was associated with significant toxicities.…”