High-Risk Myelodysplastic Syndrome (MDS): First Results of International Phase 2 Study with Oral Farnesyltransferase Inhibitor R115777 (ZARNESTRA^TM).

R115777 is an oral selective inhibitor of farnesyltransferase which disrupts critical signaling pathways resulting in antiangiogenic, antiproliferative and apoptotic effects. Single-agent activity of R115777 in patients (pt) with MDS, with manageable toxicity, was previously reported in single-institution studies. The current multicenter study assesses the response rate (IWG-criteria) and survival of R115777 in pt with high-risk MDS, defined by FAB classification as RAEBt and RAEB or CMML with ≥10% bone marrow (BM) blasts. Starting dose of R115777 was 300 mg bid for the first 21 days of every 28-day cycle. Eighty-two pt were enrolled (median age 67 yrs; range 39–86) with RAEBt (n=23), RAEB (n=40) and CMML (n=19). Thirty-six pt (44%) had IPSS score high, 32 (39%) int-2 and 14 (17%) int-1. Fifty-two pt were therapy-naïve, while 30 (37%) had received prior therapy for MDS. Pt were treated for a median of 3 cycles (range: 6 to 553+ days), with 78% relative dose intensity. Pt discontinued treatment primarily for progressive disease (n=37) or for adverse event (n=20), with 6 pt still on therapy. Responses were seen in 28 pt (33%; 6 CR, 2 CR with incomplete platelet recovery, 2 PR, 18 hematological improvement-HI), both in therapy-naïve and pre-treated pt. Responses were durable, with median duration of 14+ months (mo) for CR-PR (11+ to 20+ mo) and 6.7 mo for HI (3–15 mo). In 68 pt with at least 1 on-study BM assessment, BM response (either normalization or ≥50% decrease in BM blast count) was observed in 35 pt (51%). Median time to leukemic transformation (mTTL) was 14.1 mo, median time to leukemia or death (mTTLorD) was 6.4 mo and median overall survival (mOS) was 11.9 mo. Results (in mo) by risk-group are tabulated.

Myelosuppression was the most common side effect, with 24% grade (G) 3–4 neutro-penia and 37% G3–4 thrombocytopenia. Non-hematological toxicity was mostly G1–2, rarely G3–4. Most frequently reported were nausea (35%; 4% G3), fatigue (35%; 2% G3), diarrhea (34%; 1% G3), fever (23%, 10% G3), dyspnea (20%; 2% G3–4), purpura (20%; 4% G3) and rash (19%; 2% G3). Conclusion: In a large cohort of pt with high-risk MDS as defined by FAB and IPSS, clinical activity with durable responses and limited toxicity is confirmed for R115777. Further study is warranted.