RASGRP1/APTX Ratio Is a Strong Biomarker of Clinical Response and Survival In AML Patients Treated with Tipifarnib: A Phase I-II Preliminary Results

Abstract 4359

We conducted a phase I-II study aiming to assess efficacy and toxicity of tipifarnib-bortezomib treatment in elderly AML patients. RASGRP1/APTX genetic ratio, which is associated with treatment response in patients treated with tipifarnib alone, was tested.

Eighty patients were enrolled with secondary-AML: 14 had high risk cytogenetics; 42 were previously untreated. Seventy-five patients were treated.

Nine patients achieved complete remission (CR), 1 patient obtained a partial response (PR) and in 2 cases an hematological improvement (HI) was documented for an overall response rate (ORR) of 19%. Median time to response was 112 days, corresponding to 4 cycles (range 2–14). Marrow response (CR+PR) was significantly associated with overall survival (OS) (p<0.0001). RASGRP1/APTX was evaluated before treatment initiation on bone marrow (BM), peripheral blood (PB) or both. The median RASGRP/APTX value on BM was 15.3 (15-19.8) in responder patients and 2.2 (0.5-25.9) in non responders, respectively (p=0.00006). Its median value on PB was 31.6 (19.3-35.5) in responders and 6.4 (0.5-27.1) in non responders, respectively (p=0.00001). Interestingly, no marrow responses were recorded in patients with marrow RASGRP1/APTX ratio <8, while the response rate was 43% [how many were CR?] in patients with RASGRP1/APTX >8 (p<0.0001). Finally, RASGRP1/APTX levels significantly correlated with OS (p=0.001) with a median OS of 490 days and 162 days in patients with RASGRP1/APTX >8 and <8 respectively.

We conclude that the clinical efficacy of the combination of tipifarnib and bortezomib was evident. We confirmed that the RASGPR1/APTX BM or PB level is an effective predictor of response and survival and our now studying the response of such patients to tipifarnib, alone.

Supported by: European LeukemiaNet, AIL, AIRC, Fondazione Del Monte di Bologna e Ravenna, FIRB 2006, PRIN 2008, Ateneo RFO grants, Project of integrated program (PIO), Programma di Ricerca Regione – Università 2007 – 2009.