Phase I/II Study of Tipifarnib and Bortezomib in the Treatment of Poor Risk Adult Acute Myeloid Leukemia

Background. Outcome of elderly acute myeloid leukemia (AML) patients is dismal. Tipifarnib (Zarnestra, Z) and Bortezomib (Velcade, V) are new, targeted-treatments that might improve current results. In particular, Z is a farnesyltransferase inhibitor effective in AML, allowing complete remission (CR) rates ranging from 8 to 22%. Notably, the response rate appeared superior among patients with higher RASGRP1/APTX gene expression ratio. V is a proteasome inhibitor, possibly effective in AML as for phase I studies. Interestingly, Z and V appeared synergistic in AML cell lines.

Aim. We designed a phase I/II study aiming to assess the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of V in association with standard doses of Z and the efficacy and toxicity of the combination, in AML patients >18 years, unfit for conventional therapy, or >60 years, in relapse. Furthermore, we aimed to assess the correlation between RASGRP1/APTX ratio and treatment response.

Methods. V was administered as weekly infusion for three consecutive weeks (days 1, 8, 15), starting from 0.7 mg/m² and increasing by 0.3 mg/m² until the DLT was reached. Z was administered at the daily dose of 600 mg BID for 21 consecutive days. Response was assessed at the end of each cycle (28 days). Patients’ withdrawn was planned in case of progression or stable disease after six cycles. Real-time quantitative PCR (q-PCR) was used for RASGRP1/APTX genes evaluation.

Results. 45 patients were enrolled: 12 in the phase I and 33 in the phase II. 11/12 patients were evaluable in the phase I. Five patients received V at the dose of 0.7 mg/m² without reporting DLT. Conversely, DLT was reached at the dose of 1.0 mg/m² due to grade III SNC toxicity, recorded in 1/6 patients.

22/45 patients were evaluable for treatment response; transient reduction of peripheral blasts (> 50% to baseline) was observed in 20/22 cases. 2 patients achieved CR and 1 obtained a partial response (PR). 1 patient had a haematological improvement (HI), 12/22 had a stable disease (SD) and 5/22 showed progressive disease (PD). Interestingly, the 4 responders (CR+PR+HI) had a significant higher RASGRP1/APTX ratio respect to non responder (p=0.017).

Conclusion. We conclude that the MTD of V in association with Z is 1.0 mg/m². The association seemed to be safe, with response rate (18%) similar to what reported for Z alone. Finally, though in few cases, RASGPR1/APTX ratio was confirmed to be associated to treatment response.