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By G. Rosti M. Baccarani G. Saglio G. Martinelli F. Pane G. Alimena G. Specchia M. Cavo S. Soverini C. Venturi G. Binotto E. Trabacchi M. Cedrone M. Salvucci F. Cavazzini M. Tiribelli M. Bocchia G. Rossi E. Usala L. Levato E. Abruzzese A.M. Carella A. Gozzini L. Luciano C. Fava B. Martino F. Stagno M. Breccia F. Castagnetti G. Gugliotta


Nilotinib (NIL) is approved for the first-line treatment of CML based\ud on the results of the ENESTnd study that demonstrated a higher efficacy\ud compared to imatinib (IM). However, there are concerns on the vascular\ud toxicity of NIL, disclosed by an increased rate of cardiovascular adverse\ud events (CVAEs) with respect to imatinib. For this reason, we investigated\ud the CVAEs in 2 studies of the GIMEMA CML WP that included NIL as\ud first-line treatment of CML: the GIMEMA CML 0307 trial (73 pts; NIL\ud 400 mg BID), and the GIMEMA CML 0408 trial (123 pts; 3-months alternating\ud regime of NIL 400 mg BID and IM 400 mg QD). The median\ud age at CML diagnosis of all 196 pts was 55 (18-84) years; 59 (30%) pts\ud were ≥65 years; 52% were males; cardiovascular risk factors (CVRF: hypertension,\ud dyslipidemia, diabetes, BMI ≥30, and prior ischemic disease)\ud were present in 74 (38%) pts (median 1, range 1-4). There were no significant\ud differences between the pts characteristics in the 2 studies. The\ud median f-up was 61 months. Nineteen CVAEs occurred in 17 (8.6%) pts:\ud 7 acute myocardial infarctions (MI); 5 PAODs; 2 carotid stenosis, 2 aortic\ud atherosclerosis, 1 stroke, 1 unstable angina, and 1 stable angina (1 patient\ud had 1 PAOD, 1 stroke, and 1 MI). In pts with CVAEs, the median age at\ud CML diagnosis was 67 (43-84 years), and the median interval from CML\ud diagnosis to CVAE was 38(1-76) months. Out of the 17 pts with CVAEs 53% were males; 70% were ≥65 years at CML diagnosis; 76% had at\ud least 1 CVRF, and 65% were treated with NIL alone. All pts but one\ud (who died at 90 years for congestive heart failure post MI) are alive.\ud Treatment of CVAEs included coronary angioplasty in 5 pts, lower limb\ud amputation in 2 pts, and peripheral vascular surgery in 2 pts; all other\ud pts received medical treatment; 12/17 pts permanently discontinued\ud NIL. In univariate analysis, the occurrence of CVAEs was associated with\ud age≥65 years (12/59[20%] vs 5/137[3.6%]; p=0.0004), the presence of at\ud least one CVRF (13/74[18%] vs 4/122[3.3%]; p=0.001), and the\ud monotherapy with NIL (11/73[15%] vs 6/123[4.8%]; p=0.018). CVAEs\ud occurred at a significant rate in pts treated with NIL-based regimes, and\ud in particularly in pts ≥65 years and/or with CVRF. Noteworthy, the alternating\ud schedule of NIL and IM resulted in a lower incidence of CVAEs\ud compared to NIL monotherapy. Thus, considering the morbidity associated\ud to CVAEs, the risk/benefit ratio of NIL monotherapy should be\ud carefully evaluated in selected groups of patients

Year: 2015
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