Tipifarnib (Zarnestra, R115777) as Maintenance Therapy for Adults in Complete Remission (CR) Following Induction and Consolidation Therapies for Poor-Risk Acute Myelogenous Leukemia (AML): A Phase II Trial.

Disease-free survival (DFS) is short in patients ≥ age 60 or with secondary AML, adverse cytogenetics, or leukostasis at presentation. In such patients, median CR duration is ≤ 8 mos and only 20% achieve 1 yr DFS. Historically, maintenance therapy with low doses of cytotoxic chemotherapy has not prolonged DFS. We tested the hypothesis that Tipifarnib (T) might be active as maintenance therapy for adults with poor-risk AML in first CR after induction and consolidation therapies. Oral T 400 mg bid for 2/3 wks was begun median 2.4 mos (range 1.0–4.1) after start of final consolidation cycle and given for up to 48 wks (16 cycles) to 36 adults with median age 63 (range 27–82), secondary AML 31%, adverse cytogenetics 47%, leukostasis 17%, ≥ 2 risk factors 40%. T was well-tolerated, with only 4 of 36 unable to complete 2 cycles because of constitutional symptoms (1 rash, 3 non-compliant). To date, 256 cycles have been administered (median 8 per pt, range 1–16), with hospitalization required during only 4 (1.5%) cycles (infection 3, bowel obstruction 1). Dose reductions for myelosuppression (400 mg bid to 300 mg bid) occurred in 17/32 (53%) by cycle 3, and 2 (6%) needed platelet transfusions. A total of 9 patients completed all planned 16 cycles of T with a median CR duration of 24 mos (range 15–36+). Five of the 9 remain in continuous CR (CCR) 19+-36+ mos, median 26+), compared with 4 who relapsed after CR of 15–24 mos (median 22). There are 8 additional pts in CCR and still receiving T (2–12 cycles) with CCR 4+-12+ mos. A total of 15 patients progressed while on T at median 6.5 mos CR (range 3.5–12). Median CR duration for all patients is 10+ mos (range 3.5–36+), with 88% ≥ 6 mos and 48% ≥ 12 mos. In 13 “comparable” poor-risk pts (age ≥ 60 46%, secondary AML 25%, adverse cytogenetics 46%, leukostasis 23%) who were eligible for but declined T, 4 are in unmaintained CCR at 14+-25+ mos, 9 have relapsed at median 7.5 mos (5–13 mos). Treatment with T did not have a negative impact on reinduction chemotherapy at relapse, as 6 of 9 patients achieved second CR. Administration of T in CR after induction and consolidation therapy has low toxicity and is associated with prolonged DFS in some adults with poor-risk AML. Phase 3 studies are warranted in this patient population.