Abstract 1805: Improving on Imatinib for targeted therapy of chronic myeloid leukemia: First line treatment with Nilotinib 800 mg daily results in unprecedentedly high rate of rapid, “deep” and stable molecular responses - Results of a phase 2 trial of the GIMEMA CML working party
Authors: Martinelli Giovanni , Poerio Angela , Soverini Simona , Saglio Giuseppe , Pane Fabrizio , Castagnetti Fausto , Capucci Adele , Tiribelli Mario , Stagno Fabio , Palandri Francesca , Gugliotta Gabriele , Zaccaria Alfonso , Intermesoli Tamara , Martino Bruno , Biasco Guido , Bocchia Monica , Cedrone Michele , Testoni Nicoletta , Amabile Marilina , Iacobucci Ilaria , Breccia Massimo , Alimena Giuliana , Levato Luciano , Baccarani Michele , Rosti Gianantonio 
Published: February 2011

Abstract
Imatinib (IM) 400 mg daily is the standard treatment for chronic myeloid leukemia (CML) in early chronic phase (ECP). Nilotinib is a second generation TKI born to be more potent and selective than IM. To investigate the molecular therapeutic efficacy of nilotinib 400 mg BID in previously untreated, ECP, Philadelphia-positive CML patients, the Italian GIMEMA CML Working Party is conducting an multicenter phase II study (ClinicalTrials.gov NCT00481052). The primary endpoint is the CCgR rate at 1 year. The kinetic of molecular response is being studied by Q-PCR at baseline and after 1, 2, 3, 6, 9, 12, 18 and 24 months from treatment start.
Seventy-three patients have been enrolled by eighteen GIMEMA centers between June, 2007 and February, 2008. The median age was 51 years (range 18-83), 45% low, 41% intermediate and 14% high Sokal risk. Median follow-up is currently 572 days (range 433-727 days). The CCgR rate at 1 year was 96% (71/73 patients; one patient progressed at 6 months to lymphoid blast crisis because of a T315I mutation and one patient permanently discontinued nilotinib at 9 months, while in major molecular response [MMR], because of grade 4 lipase elevation). A MMR, defined as a BCR-ABL: ABL ratio &lt;0.1% according to the International Scale, was already achieved in 2 patients after only 1 month of nilotinib treatment; this proportion rapidly increased to 21% at 2 months, 52% at 3 months, 66% at 6 months 73% at 9 months and 85% at 12 months (Table 1). By comparison, the MMR rate reported in the IRIS study for patients receiving first-line IM was 53% at 12 months and reached 80% only at 4 years. The median BCR-ABL transcripts level at 1, 2, 3, 6, 9 and 12 months was 4.704, 0.456, 0.063, 0.018, 0.018 and 0.006, respectively. A complete molecular response (CMR; defined as a BCR-ABL: ABL ratio &lt;0.001%IS and a negative nested PCR) was already achieved in 7 patients at 12 months. The log-reduction in BCR-ABL/ABL level at 3 months was predictive of the probability of MMR at 12 months: a reduction of less than half-log, between half- and 1-log, and more than 1-log corresponded to a probability to obtain a MMR at 12 months of 42%, 62% and 95%, respectively. The molecular results achieved in our study strongly support the notion that in ECP CML patients molecular responses to nilotinib are substantially faster and “deeper” than those to IM. More rapid reduction of residual disease might help to reduce failures and to improve the late outcome of therapy.
Supported by AIRC, BolognAIL, European LeukemiaNet, COFIN, Fondazione Del Monte di Bologna e Ravenna.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1805.