Efficacy of the farnesyl transferase inhibitor R115777 in chronic myeloid leukemia and other hematologic malignancies

Abstract

We investigated the clinical activity of the farnesyl transferase inhibitor R115777 in 22 patients with chronic myelogenous leukemia (CML) in chronic, accelerated, or blastic phase and in 8 patients with myelofibrosis (MF) and 10 patients with multiple myeloma (MM). R115777 was administered at 600 mg orally twice daily for 4 weeks every 6 weeks. Seven patients with CML (6 in chronic phase, 1 in advanced phase) achieved complete or partial hematologic response. Four of them had a minor cytogenetic response. Responses were transient, with a median duration of 9 weeks (range, 3-23 weeks).Two patients discontinued therapy because of toxicity while in complete hematologic response. Two MF patients had a significant decrease in splenomegaly, one had normalization of white blood cell count and differential, and one became transfusion independent. One patient with MM had a reduction in monoclonal protein of 34%. Adverse events included nausea in 22 patients (55%; all grade 2 or lower) and fatigue in 19 (48%; grade 3 or higher in 1). Other grade 3 or 4 toxicities included skin rash (4 patients, 10%), peripheral neuropathy (2 patients, 5%), and liver toxicity (2 patients, 5%). Patients who responded to therapy had significantly higher plasma vascular endothelial growth factor (VEGF) concentrations prior to treatment than nonresponders. Plasma concentrations decreased significantly during therapy among responders. R115777 showed clinical activity in patients with CML and MF. The effect on VEGF needs to be further investigated to determine whether this might be a possible mechanism of action

Modern management of myelofibrosis

“…In a trial including eight patients, this drug provided 25% favourable responses in anaemia and splenomegaly, with the responses being significantly associated with higher VEGF plasma levels at the start of treatment (Cortes et al, 2003b). In other study of 13 patients, an effect on the splenomegaly was seen, but not in the anaemia (Mesa et al, 2003b).…”

A multicenter phase 2 study of the farnesyltransferase inhibitor tipifarnib in intermediate- to high-risk myelodysplastic syndrome

“…25 Significant biologic activity with single-agent tipifarnib was reported in multiple myeloma, with 64% disease stabilization in heavily pretreated patients, 26 in myelofibrosis with myeloid metaplasia, 27 with 61% symptomatic decrease in organomegaly, and in myeloproliferative disorders 28 with 65% biologic responses. In chronic myeloid leukemia (CML), tipifarnib has single-agent activity 29 as well as activity in combination with imatinib in patients with CML refractory to imatinib. 30,31 In the current study, tipifarnib 300 mg orally twice a day for the first 21 days of each 28-day cycle appears to be an active oral outpatient therapy that results in durable responses and HI with transfusion independence.…”

Hyperleukocytosis complicating lonafarnib treatment in patients with chronic myelomonocytic leukemia

“…6 No similar cases have been reported to date in preliminary testing of tipifarnib in patients with either myelodysplastic or myeloproliferative syndromes, raising consideration that pharmacologic features unique to lonafarnib may be responsible for this potential biologic effect. 7 Nonetheless, in selected cell line models, suppression of Ras signaling or the farnesylated Rho-B proteins promotes heterotypic adhesion through activation of beta-1 and/or beta-2 integrin binding avidity or increased sensitivity to the inhibitory effects of TGFb, suggesting that promotion of heterotypic adhesion may arise as a class effect of Ras protein signal inhibition. 8 Although cure rates in childhood acute lymphoblastic leukaemia (ALL) have improved with a current long-term event-free 5-year survival of 80%, the role of molecular aberrations on the prognosis of leukaemia remains to be understood.…”