Ten-Year Follow-up of Patients with Chronic Myeloid Leukemia Treated with Nilotinib in First-Line: Final Results of the Gimema CML 0307 Trial
Authors: Gugliotta Gabriele , Castagnetti Fausto , Breccia Massimo , Levato Luciano , Intermesoli Tamara , D'adda Mariella , Salvucci Marzia , Stagno Fabio , Rege Cambrin Giovanna , Tiribelli Mario , Martino Bruno , Bocchia Monica , Trabacchi Elena , Cavazzini Francesco , Porretto Ferdinando , Sorà Federica , Caocci Giovanni , Albano Francesco , Martinelli Giovanni , Soverini Simona , Foà Robin , Pane Fabrizio , Cavo Michele , Saglio Giuseppe , Baccarani Michele , Rosti Gianantonio 
Published: November 2019

BACKGROUND: In chronic phase (CP) chronic myeloid leukemia (CML) nilotinib (NIL) showed better efficacy compared to imatinib. The higher rates of deep molecular response with NIL may translate into more patients (pts) eligible for treatment discontinuation. On the other hand, cardiovascular toxicity may limit NIL use in selected groups of pts (e.g. elderly pts). Long follow-up is required for a proper evaluation of the benefit-risk ratio between efficacy (including treatment-free remission [TFR] rates) and toxicity. However, only few data are currently available on the very long-term outcome of NIL treated pts.
AIM: To describe the very-long term outcome of patients treated with nilotinib first-line.
METHODS: The GIMEMA CML WP initiated in 2007 a phase II study (NCT 00481052) with NIL first-line (400 mg BID). Seventy-three adult (≥18 years old) pts with newly diagnosed, CP-CML were enrolled at 18 GIMEMA Centers in Italy. Median age was 51 (18-83) years. ELTS risk score was low in 64.4% of pts, intermediate in 30.1% of pts, and high in 5.5% of pts. Early and mid-term results have been previously published. Here, we report the very long-term outcome of this study, focusing on survival measures, TFR rates and adverse events. The updated, final results (with 10-year follow-up) of the trial will be available for presentation at the meeting.
RESULTS: After a median follow-up of 92 months, 70 (95.9%) pts are alive and progression-free. Three pts (4.1%) died (progression to blast phase, n=1; CML-unrelated death, n=2). Failures according to ELN 2013 recommendation occurred in 5 (6.8%) pts (progression to BP, n=1; BCR-ABL transcript level > 1% at 12 months, n=2; confirmed loss of major molecular response, n=2). At last contact, 45 (61.6%) pts were still on NIL (dose ≥ 600 mg/day in 29 pts; 400 or 450 mg/day in 12 pts; ≤ 300 mg in 4 pts). Reasons for permanent NIL discontinuation in the remaining 28 (38.4%) pts were: adverse events (n=17, 23.3%; two of these pts maintained a deep molecular response without treatment - TFR); successful TFR attempts (n=9, 12.3%); failures (n=2 pts, 2.7%). The median age at CML diagnosis of pts obtaining the TFR was 47 (21-70) years. Fifteen athero-thrombotic events (ATEs) occurred in 13 (17.8%) pts (peripheral arterial occlusive disease, n=5; acute myocardial infarction, n=5; others ATEs, n=5), after a total NIL exposure of 478 years (3.1 events/100 pt-years). The median age at CML diagnosis of these pts was 66 (43 - 83) years; 8/13 (61.5%) pts had at least a baseline cardiovascular risk factor (hypertension, diabetes, hypercholesterolemia, or BMI ≥ 30).
SUMMARY: These data highlight the efficacy of first-line NIL in the long-term, with excellent overall survival. TFR was obtained in 15% of pts, and particularly in younger ones. Some safety concerns remain, with ATEs occurring in 17.8% of pts (mainly in elderly ones), although none of these events was fatal.

Disclosures
Gugliotta: Incyte: Honoraria; Pfizer: Honoraria; Novartis: Honoraria. Castagnetti:Incyte: Honoraria; Pfizer: Honoraria; Bristol Myers Squiib: Consultancy, Honoraria; Novartis: Honoraria. Breccia:Novartis: Honoraria; Incyte: Honoraria; BMS: Honoraria; Pfizer: Honoraria; Celgene: Honoraria. Levato:BMS: Honoraria; Incyte: Honoraria; Pfizer: Honoraria; Novartis: Honoraria. Stagno:Pfizer: Honoraria; Novartis: Honoraria; BMS: Honoraria; Incyte: Honoraria. Tiribelli:Incyte: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees. Bocchia:Incyte: Honoraria; BMS: Honoraria; Novartis: Honoraria. Cavazzini:Novartis: Honoraria; Incyte: Honoraria; Pfize: Honoraria. Caocci:Novartis: Honoraria; Celgene: Honoraria. Albano:Incyte: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Martinelli:Ariad: Consultancy, Other: trial grant; Amgen: Consultancy, Other: trial grant; Novartis: Consultancy, Other: trial grant; Pfizer: Consultancy, Other: trial grant; Janssen: Consultancy, Other: trial grant; Abbvie: Consultancy, Honoraria, Other: trial grant; Incyte: Consultancy, Other: trial grant; Daiichi Sankyo: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Other: trial grant; Roche: Consultancy, Other: trial grant. Soverini:Incyte: Consultancy. Foà:Abbvie: Consultancy, Speakers Bureau; Celltrion: Membership on an entity's Board of Directors or advisory committees; Amgen Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Shire: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Consultancy, 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, Speakers Bureau; Amgen Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Pane:GSK: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: research founding; BMS: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Cavo:amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations, Speakers Bureau; janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations, Speakers Bureau; bms: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; novartis: Honoraria; takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Saglio:Celgene: Consultancy; BMS: Consultancy; Novartis: Consultancy; Ariad: Consultancy; Incyte: Consultancy; Pfizer: Consultancy; Jansen: Consultancy. Baccarani:Novartis: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Takeda: Consultancy. Rosti:BMS: Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.