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359 Excellent Outcomes at 3 Years with Nilotinib 800 Mg Daily In Early Chronic Phase, Ph+ Chronic Myeloid Leukemia (CML): Results of a Phase 2 GIMEMA CML WP Clinical TrialClinically Relevant Abstract

Program: Oral and Poster Abstracts
Type: Oral
Session: Chronic Myeloid Leukemia - Therapy: Optimizing Front-Line Therapy in CML
Monday, December 6, 2010: 11:30 AM
Valencia D (Orange County Convention Center)

Gianantonio Rosti, MD1, Fausto Castagnetti2*, Gabriele Gugliotta1*, Massimo Breccia3*, Luciano Levato4*, Adele Capucci5*, Mario Tiribelli6*, Alfonso Zaccaria7*, Monica Bocchia8*, Antonio Cuneo9*, Fabio Stagno10*, Giorgina Specchia11*, Ferdinando Porretto12*, Bruno Martino13*, Michele Cedrone14*, Tamara Intermesoli15*, Francesca Palandri16*, Marilina Amabile2*, Simona Soverini2*, Nicoletta Testoni2*, Giuliana Alimena17*, Fabrizio Pane18*, Giuseppe Saglio19, Giovanni Martinelli2 and Michele Baccarani2*

1Department of Hematology/Oncology , University of Bologna, Bologna, Italy
2Department of Hematology/Oncology "Serŕgnoli", University of Bologna, Bologna, Italy
3Chair of Hematology, Hematology, Roma, Italy
4Hematology Unit, AO Pugliese Ciaccio, Catanzaro, Italy
5Hematology Unit, Spedali Civili, Brescia, Italy
6Chair of Hematology, University of Udine, Udine, Italy
7Hematology Unit, Ospedale Santa Maria delle Croci, Ravenna, Italy
8Division of Hematology, University of Siena, Siena, Italy
9Department of Hematology, “Arcispedale Sant'Anna”, Ferrara, Italy
10Department of Hematology, University of Catania, Catania, Italy
11Department of Hematology, University of Bari, Bari, Italy
12Hematology and Bone Marrow Transplantation Unit, "La Maddalena" Hospital, Palermo, Italy
13Hematology Unit, Ospedale di Reggio Calabria, Reggio Calabria, Italy
14Hematology Unit, S.Giovanni Addolorata Hospital, Roma, Italy
15Hematology Unit, Ospedali Riuniti, Bergamo, Italy
16Department of Hematology and Oncologic Sciences, University of Bologna, Bologna, Italy
17Chair of Hematology, "La Sapienza" University, Roma, Italy
18CEINGE-Advanced Biotechnology, University of Naples, Napoli, Italy
19Department of Internal Medicine, Az. Ospedaliera San Luigi Gonzaga, University of Turin, Orbassano-Turin, Italy

Background: Nilotinib is a potent and selective inhibitor of BCR-ABL. In the phase 3 ENESTnd  trial, nilotinib demonstrated superior efficacy to imatinib with higher and faster molecular responses. With a median follow-up of 18.5 months (ASCO/EHA 2010), the rates of progression to accelerated or blast phase (AP/BC) were 0.7% and 0.4% with nilotinib 300 mg and 400 mg BID, respectively, and  significantly lower in comparison to imatinib (4.2% P = .006 and .003, respectively). Based on the results of the ENESTnd trial, nilotinib has been approved (FDA) for the frontline treatment of Ph+ CML. With imatinib 400 mg (IRIS trial), the rate of any event and the rate of progression to AP/BC were higher during the first 3 years on treatment (15.6% and 6.1%, respectively). Consequently, a confirmation of the durability of nilotinib responses at 3 years is extremely important. Aims: To evaluate responses (either cytogenetic and molecular) and to investigate outcomes of patients treated for 3-years with nilotinib 400 mg BID as frontline therapy.  Outcomes evaluated include Overall Survival (OS), Progression-Free Survival (PFS), Failure-Free Survival (FFS) and Event-Free Survival (EFS). Methods: A multicentre phase 2 trial (nilotinib 400 mg BID) was conducted by the GIMEMA CML Working Party (ClinicalTrials.gov.NCT00481052). The median follow-up  is currently 30 months (3 years by November 2010). Definitions: Major Molecular Response (MMR): BCR-ABL/ABL ratio < 0,1% IS; Complete Molecular Response (CMR): undetectable transcript levels and nested PCR negative; failures: no CHR at 3 months, no CgR at 6 months, no PCgR at 1 year, no CCgR at 18 months, loss CHR or CCgR, progression and death (according to the revised European LeukemiaNet recommendations); events: failures and treatment discontinuation for any reason. All the analysis has been made according to the intention-to-treat principle. Results: 73 patients have been enrolled; median age 51 years (range 18-83); 45% low, 41% intermediate and 14% high Sokal risk. The cumulative CCgR rate (primary endpoint) at 12 months was 100%. CCgR at each milestone:  78% at 3 months, 96% at 6, 12 and 18 months, 92% at 24 months. The cumulative rate of MMR was 96%, while the rates of MMR at 3, 6, 12, 18 and 24 months were 52%, 66%, 85%, 81% and 82%, respectively. The cumulative rate of CMR was 41%, while the rates of CMR at 12 and 24 months were 7% and 12%, respectively. None of the patients who achieved a MMR progressed to AP/BC. Only one patient progressed at 6 months to AP/BC: a 63 years old female with a high Sokal risk disease in CCgR at 3 months, who developed a T315I mutation. During the first 12 months, the mean daily dose was 600-800 mg, 400-599 mg, and less than 400 mg in 74%, 18% and 8% of patients, respectively. The nilotinib last daily dose was as follows: 800 mg in 48 (71%) patients, 400 mg in 19 (28%) patients and 200 mg in 1 (1%) patient. Adverse events (AEs) were mostly grade 1 or 2 and manageable with appropriate dose adaptations. Two patients (3%) showed a prolongation of the QTcF above 450 msec (none above 50 msec). Four events lead to permanent discontinuation of nilotinib: 3 patients discontinued after 9, 15 and 27 months on treatment for  recurrent episodes of amylase and/or lipase increase (no pancreatitis) and 1 patient after 25 months due to atrial fibrillation, unrelated to study drug. Three of them are currently on imatinib second-line and 1 on dasatinib third-line. Overall, 5 events have been recorded so far (1 progression to AB/BC and 4 permanent discontinuation of nilotinib due to AEs). At 30 months  the OS,  PFS and FFS are 99% and  the EFS is 92%. Conclusions: The rate of failures was very low during the first 3 years. Responses remain stable. The very high rates of responses achieved during the first 12 months on treatment are being translated into optimal outcome for most of the patients. Acknowledgements: European LeukemiaNet, COFIN, Bologna University, BolognAIL

Disclosures: Rosti: Novartis: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol Myers Squibb: Honoraria, Speakers Bureau; Roche: Speakers Bureau. Castagnetti: Novartis: Honoraria; Bristol Myers Squibb: Honoraria. Gugliotta: Novartis: Honoraria. Saglio: Bristol Myers Squibb: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau. Martinelli: Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; pfizer: Consultancy. Baccarani: Novartis: Consultancy, Research Funding, Speakers Bureau; Bristol Myers Squibb: Consultancy, Research Funding; Wyeth: Consultancy, Research Funding.

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