1. SPIRIT3 support includes Biobanking: broadly as for SPIRIT2, but plus genomic DNA (mouth wash via kit) Correlative Science: Biomarkers LSC biology NGS: mutation analysis : hypothesis generation

2. Example: Imatinib Metabolism NQO1 &2 TXN CYP3A4/5 St John’s Wort carbamazepine phenytoin ketoconazole erythromycin grapefruit juice minor metabolites CYPs: 1A1, 1B1, 1A2, 2D6, 2C9, 2C19 imatinib (t ½ = 18hrs) CGP-74588 (t ½ = 40hrs) EXCRETION ROS GSTs NATs, UGTs DNA damage cell damage

3. T1 v M1 v T1+M1 v none Time to CCR0.255 Overall Survival0.273 Treatment Failure0.041 Treatment Failure and Intolerance< 0.000 Progression Free Survival (PFS)0.029 Event Free Survival (EFS)0.047 Mantel-Cox Log Rank Test (p values) p < 0.000 n = 11 n = 17 n = 88 n = 77 GSTT1{del} and GSTM1{del} Results Davies et al 2012, EHA Amsterdam (abstract)

4. Imatinib 400 mg QD (n = 283) Nilotinib 300 mg BID (n = 282) RANDOMISED*RANDOMISED* Nilotinib 400 mg BID (n = 281) N = 846 217 centres 35 countries * Stratification by Sokal risk score. 10 years of follow-up are planned Primary endpoint = MMR at 12 months. This is superior in nilotinib recipients (either dose) compared with imatinib (P <.0001; Saglio et al NEJM 2010 ). ENESTnd: Study Design Kantarjian HM, et al. Blood. 2012;120(21):[abstract 1676].

5. Arterial Events by 3 Years (All Grades) Patients, n (%) Nilotinib 300 mg BID n = 279 Nilotinib 400 mg BID n = 277 Imatinib 400 mg QD n = 280 IHD9 (3.2)11 (4.0)3 (1.1) PAOD4 (1.4)3 (1.1)0 11/23 IHD events occurred between years 2 and 3 (4 on nilotinib 300 mg BID, 5 on nilotinib 400 mg BID, 2 on imatinib) 3 patients on nilotinib 400 mg BID discontinued study drug due to IHD 2/7 PAOD events occurred between years 2 and 3; both occurred on nilotinib 400 mg BID 6/7 patients (85%) with PAOD had pre-existing risk factors at baseline No patient discontinued because of PAOD No patient at any time on study in either nilotinib arm had a QTcF > 500 ms or LVEF < 45% IHD, ischaemic heart disease; PAOD, peripheral arterial occlusive disease. 5 LVEF, left ventricular ejection fraction. Data cutoff: 27Jul2011.

6. ENESTnd: arterial Events by 4 Years Patients, n (%) Nilotinib 300 mg BID n = 279 Nilotinib 400 mg BID n = 277 Imatinib 400 mg QD n = 280 IHD (3 yrs in brackets)11 (9)14 (11)3 (3) PAOD (3 yrs in brackets)4 (4)5 (3)0  Between years 3 and 4, five new patients had an IHD event (2 in the nilotinib 300 mg BID arm and 3 in the nilotinib 400 mg BID arm), and 2 new patients had a PAOD event (both in the nilotinib 400 mg BID arm)  1 patient in the nilotinib 400 mg BID arm with previously reported PAOD had a newly reported drug-related SAE (arterial stenosis limb) leading to treatment discontinuation Including cerebrovascular events:18 24 4 6 Data cutoff: 27Jul 2012.