Pilot study of lonafarnib, a farnesyl transferase inhibitor, in patients with chronic myeloid leukemia in the chronic or accelerated phase that is resistant or refractory to imatinib therapy

Abstract

BACKGROUNDLonafarnib (SCH66336) is a nonpeptidomimetic farnesyl transferase inhibitor that has demonstrated significant preclinical activity against chronic myelogenous leukemia (CML) cells and in CML animal models.METHODSIn the current study, the efficacy of lonafarnib was investigated in patients with CML in the chronic or accelerated phase that was resistant or intolerant to imatinib. Thirteen patients with CML in the chronic (n = 6 patients) or accelerated (n = 7 patients) phase were treated with lonafarnib at a dose of 200 mg orally twice daily. Ten patients had failed therapy with imatinib and 3 patients were intolerant to imatinib. The median age of the patients was 62 years (range, 38–80 yrs) and the median time from the diagnosis of CML to therapy with lonafarnib was 5 years (range, 0.3–13 yrs). In addition to imatinib mesylate, all patients had received prior therapy with interferon‐α and seven patients had received other treatments. The median duration of therapy with lonafarnib was 8 weeks (range, 2–41 wks).RESULTSTwo patients responded. One patient in the accelerated phase of CML returned to the chronic phase, a response that lasted for 3 months. Another patient with chronic phase disease had lowering of the leukocyte count without the need for hydroxyurea and normalization of the differential count that lasted for 5 months. The most common adverse event was diarrhea, which was noted in 11 patients (84%) (Grade ≥ 3 in 4 patients; 31%; toxicity was graded according to the National Cancer Institute Common Toxicity Criteria [version 2.0]). Therapy was discontinued in one patient because of diarrhea not responding to dose adjustments.CONCLUSIONSSingle‐agent lonafarnib appears to have clinical activity in a small proportion of patients with CML refractory to imatinib. Cancer 2006. © 2005 American Cancer Society.

Important Therapeutic Targets in Chronic Myelogenous Leukemia

“…Lonafarnib, another farnesyl transferase inhibitor, showed efficacy in CML (93). Two responses were noted among 13 patients with CML in chronic or accelerated phase resistant to imatinib treated with lonafarnib (93).…”

Novel Agents in CML Therapy: Tyrosine Kinase Inhibitors and Beyond

“…70 However, the results of a pilot study investigating lonafarnib in patients with imatinib-resistant CML have been discouraging with only 2 of 13 patients achieving a clinical response. 71 A recent report showed that lonafarnib is able to sensitize primitive, quiescent Bcr-Abl-positive progenitors to imatinib. 72 Recently, the FTI BMS-214662 was reported to enhance the cytotoxic effect of imatinib or dasatinib in primary CD34 + CML cells and significantly reduce the numbers of undivided primitive quiescent CML stem cells, either alone or in combination with imatinib or dasatinib.…”

Experimental non-ATP-competitive therapies for chronic myelogenous leukemia

“…69 Ftase inhibitors (FTIs) inhibit farnesylation of a variety of proteins including RAS. 70 Although FTIs have shown only modest activity in CML as single agents, 71 the combination of imatinib with either tipifarnib 72 or lonafarnib 73 demonstrated significant clinical activity in phase I studies in imatinib-resistant CP CML, including in T315I-carrying patients. 72 A combination study of dasatinib and the FTI BMS214662, with 68-fold higher killing potency against quiescent (IC 50 0.7 mM) than proliferating (IC 50 47.5 mM) K562 cells, 74 is underway.…”