R115777 Has Significant Activity in CML and Myelofibrosis

HOUSTON—The farnesyl transferase inhibitor R115777 (tipifarnib, also known as Zarnestra) produced an overall response rate of 33% in patients with chronic myelogenous leukemia (CML) and decreased splenomegaly in most patients with myelofibrosis, but was not effective in multiple myeloma, reported Deborah Thomas, MD, at the 43rd Annual Meeting of the American Society of Hematology. Dr. Thomas is assistant professor in the Department of Leukemia at The University of Texas M. D. Anderson Cancer Center in Houston.

Dr. Thomas reported data on 36 patients treated with R115777. This included 21 patients with CML (10 in chronic phase, 5 in accelerated phase, 6 in blast phase), 10 patients with multiple myeloma, and 5 patients with myelofibrosis. All patients with accelerated or blast phase CML had previously received imatinib mesylate (Gleevec, also known as STI571), as had four of the patients with chronic phase CML.

For patients with CML, the median age was 54 years, the median time from diagnosis was 20 months, and the median number of prior therapies was 3 (range: 2 to 5). Three of 13 patients for whom ras mutation results are available had mutations of N-ras (n = 1) or K-ras (n = 2).

Patients received oral R115777, 600 mg bid for 28 days every 6 weeks. The doses were adjusted for myelosuppression and/or nonhematologic toxicity.

Response Data

Dr. Thomas said that six CML patients in chronic phase had a complete (n = 5) or partial (n = 1) hematologic response. Three of the patients with chronic phase CML achieved a minor cytogenetic response. One patient in accelerated phase (clonal evolution) had a complete hematologic response and minor cytogenetic response. None of the six patients in blast phase responded.

Eight patients with myelofibrosis were treated after a median time from diagnosis of 18 months (range: 11-32). They had received a median of 3 prior therapies (range: 1-5). Six of eight had a reduction in spleen size (more than 50% in two patients), from a median of 13 cm below costal margin to a median of 9 cm. One patient had hepatomegaly and had a modest reduction (15 to 12 cm). One patient was taken off study after 2 months because of skin toxicity, and one transformed to acute myelogenous leukemia 6 weeks after the start of therapy.

"The 10 heavily pretreated multiple myeloma patients exhibited no response," reported Dr. Thomas.

Ten of 21 patients with CML (48%) required dose reductions, mostly for hematologic toxicity. Hematologic toxicities included grade 3/4 thrombocytopenia (n = 10) or neutropenia (n = 7), which were more frequent in accelerated and blast phase CML.

Fatigue Most Common Toxicity

Nonhematologic grade 3/4 toxicities included skin rash (n = 4), liver toxicity (n = 2), peripheral neuropathy (n = 2), and fatigue (n = 1). Central nervous system toxicities included confusion in one-third of patients and tremor or peripheral neuropathy in one-third.

Dr. Thomas said that nearly half of the patients required dose reductions and that many required dose interruptions. Most patients received only one cycle of treatment. Most patients who discontinued treatment did so due to loss of response, but one patient dropped out because of intolerable fatigue. "The most common reported toxicity was fatigue—it was grade 3 in more than one-third of patients. One patient who was responding discontinued treatment due to fatigue," she said. "We need to look at alternative dosing schedules." In order to decrease toxicity, the starting dose has now been adjusted to 300 mg bid, given orally, for 21 days every 4 weeks.