Background: Tipifarnib (Zarnestra, Z) is a non-peptidomimetic farnesyltransferase inhibitor (FTI) with clinical activity in hematologic malignancies, including acute myeloid leukemia (AML), myelodysplastic syndrome (MDS) and chronic myeloid leukemia. Preclinical data suggest that tipifarnib may be synergistic with some chemotherapeutic agents.
Methods: We designed a phase I/II study in patients (pts) age 15–70 years, with previously untreated AML or high-risk MDS (blasts ≥ 10%), who received induction with idarubicin (Ida) 12 mg/m2/day on days 1–3, cytarabine (ara-C) 1.5 g/m2 IV over 24 hours daily on days 1–4 (days 1–3 only if age ≥ 60 years) and Z, with first cohort (n=6) receiving 200mg PO BID and all others 300 mg PO BID x 21 days every 28 days. Pts achieving a complete remission (CR) received consolidation (5 courses) with Ida 8 mg/m2/day on days 1–2, ara-C 0.75 g/m2/day on days 1–3, and Z 300 mg PO BID x 14 days every 4–6 weeks. Maintenance was with Z 300 mg PO BID x 21 days every 4–6 weeks for 6 months.
Results: We treated 95 pts, median age 50 yrs (range, 17–61 yrs), and all are evaluable for response with a median followup of 61 weeks (range, 35–138). Seventy pts (73%) responded: 61 (64%) achieved a CR and 9 (9%) a CRp. Median CR duration was 72 weeks, (range, 4–121) with median OS 70 weeks (range, 1–138). Response by cytogenetics was: 34/41 (83%) for diploid, 13/19 (69%) with −5/−7, 1/2 (50%) with t(8;21), and 21/32 (65%) with other abnormalities. Response by age was 31/43 (72%) for < 50 yrs, 12/18 (67%) for ≥ 50 yrs with diploid karyotype, and 18/34 (53%) for ≥ 50 yrs with abnormal karyotype. Response by FLT3 status was 12/16 (75%) for mutated, 51/66 (78%) for unmutated. Overall response rate (CR+CRp) in a similar historical population treated with the same chemotherapy regimen, idarubicin/cytarabine (IA), without Z was 72% (p=0.847), median CR duration 52 weeks (range, 2–319) (p=0.493), median OS 65 weeks (range, 3–322) (p=0.698). The most common grade ≥ 3 adverse events have included diarrhea (39%), hypokalemia (27%), rash (21%), and hepatic dysfunction (18%). Fifty-three (56%) pts have required treatment dose reductions during induction, 21 pts (40%) during consolidation, and 3 pts (18%) during maintenance.
Conclusion: We conclude that Z combined with IA induces a high rate of CR in high-risk MDS or AML, but the outcome may not be superior to what is obtained with IA alone.
Overexpression of X-linked Inhibitor of Apoptosis Protein (XIAP) is an Independent Unfavorable Prognostic Factor in Childhood de Novo Acute Myeloid Leukemia