Update on Approved TKIs Jorge Cortes, MD Chief, CML and AML Sections Department of Leukemia MD Anderson Cancer Center Houston, Texas

Results With Imatinib in Early CP CML – The IRIS Trial at 8-Years 304 (55%) patients on imatinib on study Projected results at 8 years: – CCyR 83% 82 (18%) lost CCyR, 15 (3%) progressed to AP/BP – Event-free survival 81% – Transformation-free survival 92% If MMR at 12 mo: 100% – Survival 85% (93% CML-related) Annual rate of transformation: 1.5%, 2.8%, 1.8%, 0.9%, 0.5%, 0%, 0%, & 0.4% Deininger M, et al. Blood 2009; 114(22): 1126.

Results of Studies With Standard-Dose Imatinib 12 Mo. Outcome IRISTOPSDASISIONENESTndCML IVSPIRIT No CCyR65** MMR39** Events3.32.5NR4.6NR Transformation NR TFS (at yrs)92 (8)95 (1.5)NR 87 (5)NR EFS (at yrs)81 (8)NR 92 (4) OS (at yrs)85 (8)99 (1.5)99 (1)97 (1.5)90 (5)NR Deininger et al; Blood 2009; 114: Abst# 1126; Cortes et al. JCO 2010; 28: ; Kantarjian et al. NEJM 2010; 362: ; Saglio et al. NEJM 2010; 362: ; Hehlmann et al. Blood 2009; 114: Abst# 339 ; Preudhomme et al. NEJM 2010; 363:

Survival in Early Chronic Phase CML Kantarjian et al. Blood 2012; 119:

IRIS 8-Year Update At least 37% Unacceptable Outcome Deininger M, et al. Blood. 2009;114(22):1126.

Symptom Burden in CML Patients on Imatinib Therapy Williams et al. Blood 2010; 116: abst #3838

Survival in Advanced Phase CML Kantarjian et al. Cancer 2011 (In press) Accelerated Phase Blast Phase

Improving Frontline Therapy in CML Standard-dose imatinib High-dose imatinib Imatinib-based combinations Second generation TKI ─ Dasatinib ─ Nilotinib ─ Bosutinib

Imatinib + IFN as Frontline Therapy for CML CML IV 1 – 1016 pts randomized to IM 400mg, IM 800mg or IM 400mg + IFNα (median dose 1.7 MU/d) – No improvement in response rate of 5-yr PFS with IFN SPIRIT 2 – 636 pts randomized to IM 400mg, IM 600mg, IM + ara-C, and IM 400mg + Peg-IFNα-2a – Higher rate of CCR, MMR and CMR at 24 mo – No difference in 4-yr EFS MDACC 3 – 91 pts randomized to IM 800mg ± Peg-IFN-2b – No difference in response, EFS, PFS 1 Hehlmann R, et al. JCO 2011 [Epub ahead of print] 2 Guilhot F, et al. NEJM 2010; 363: Cortes J, et al. Cancer. 2011; 117:

Comparison of Randomized Studies of Imatinib ± IFN CML-IVSPIRITMDACC Effect on CMRNoneImprovedNone Imatinib dose (mg) IFN-αRegularPEG 2aPEG 2b Start of IFNDay 1 6 mo Effect on EFSNone

TKI Frontline Therapy in CML CCyR AT Time Periods (ITT) IM400 IM800 NILOT DASAT 465 patients with CML frontline therapy − Imatinib 400 mg (n=71), imatinib 800 mg (n=201), nilotinib (n=100), and dasatinib (n=93) Alattar et al. ASH 2011; Abstract #745

TKI Frontline Therapy in CML Response AT Time Periods (ITT) CMRMMR IM400 IM800 NILOT DASAT Alattar et al. ASH 2011; Abstract #745

TKI Frontline Therapy in CML Long-Term Outcome By Response Time Event-Free Survival Transformation-Free Survival p<0.001 Alattar et al. ASH 2011; Abstract #745

Design of the ENESTnd Studies Patients with SoR/TF on imatinib 400 mg QD (including patients receiving dose escalation to imatinib 400 mg BID) on core study were allowed to enter the extension study receiving nilotinib 400 mg BID Patients with SoR/TF on nilotinib 300 mg BID on core study were allowed to enter the extension study receiving nilotinib 400 mg BID Imatinib 400 mg Nilotinib 300 mg BID RANDOMIZEDRANDOMIZED 800 mg N= centers 35 countries Nilotinib 400 mg BID CORE *Of 11 patients who discontinued nilotinib 400 mg BID due to TF in the core study, only 3 entered the extension study and received imatinib 400 mg BID. These patients are not summarized here. EXTENSION Nilotinib 400 mg BID Nilotinib 400 mg BID* Saglio et al. ASH 2011; Abstract #452; Hochhaus et al. ASH 2011; Abstract #114

Nilotinib vs Imatinib in Newly Diagnosed Chronic Phase CML 846 pts randomized to nilotinib 300 mg BID (n=282), nilotinib 400 mg BID (n=281), or imatinib 400 mg QD (n=283) Minimum follow-up 36 mo OutcomeNil 300Nil 400IM 400 % CCyR* % MMR** % BCR-ABL ≤0.0032%** % Transformation to AP/BP Saglio et al. ASH 2011; Abstract #452 * by 24 months, ** by 36 months

ENESTnd Extension Study for Subotpimal Response or Treatment Failure 54 pts changed to nilotinib 400 mg BID for suboptimal response or treatment failure to nilotinib 300 mg BID (n=19) or imatinib (n=35; 24 after dose escalation, 11 w/o dose escalation) Outcome From Nil 300 From Imatinib % No CCyR  CCyR 3358 % No MMR  MMR 3932 % 18 mo free from AP/BP9585 % 18 mo survival9487 Median months on Rx1816 % Discontinued therapy2637 Hochhaus et al. ASH 2011; Abstract #114

Dasatinib Versus Imatinib Study In Treatment- naïve CML (DASISION). Trial Design ● Primary endpoint: Confirmed CCyR by 12 months ● Secondary/other endpoints: Rates of CCyR and MMR; times to confirmed CCyR, CCyR and MMR; time in confirmed CCyR and CCyR; PFS; overall survival Follow-up 5 years Randomized* Imatinib 400 mg QD (n=260) Dasatinib 100 mg QD (n=259) N= centers 26 countries *Stratified by Hasford risk score Kantarjian et al. ASCO 2011; abstract #6510

Dasatinib vs Imatinib in Newly Diagnosed Chronic Phase CML 519 pts randomized to dasatinib 100 mg QD (n=259) or imatinib 400 mg QD (n=260) Median follow-up 28 mo OutcomeDas 100IM 400 % CCyR8682 % MMR6446 % BCR-ABL ≤0.0032%178 % discontinued therapy2325 % Transformation AP/BP Kantarjian et al. ASCO 2011; abstract #6510 * by 24 months

IM 800 IM 800 IM 800 Selective Dose Escalation and Early Switch for CML Therapy 210 pts: cohort 1 (n=105) IM 600  IM 800  Nil; cohort 2 (n=105) IM 600  Nil Median follow-up: cohort 1 = 33 mo, cohort 2 = 14 mo Still on Rx: Cohort 1 84% (55% IM, 29% Nil); cohort 2 89% (55% IM, 33% Nil) Yeung et al. ASH 2011; abstract #451 Cohort 2

TIDEL II: Molecular Response At 12 MonthsAt 24 Months Yeung et al. ASH 2011; abstract #

Percentage Transformed to AP/BP F/UImatinibNilotinibDasatinib ENESTnd 1 >24 mo (2.1) DASISION 2 >24 mo MDACC 3 >24 mo9 (1)20 TIDEL-II 4 23 mo2.4 Percentages shown in parenthesis are for nilotinib 400mg BID (ENESTnd) and imatinib 800mg (MDACC) 1. Hughes et al ASH 2010; Abstract #207; 2. Kantarjian et al, ASCO 2011; Abstract #6510; 3. Alattar et al. ASH 2011; Abstract #745; 4. Yeung et al. ASH 2011; Abstract #451 Rate of Transformation to AP/BP After Frontline Therapy

ENESTnd: Study Drug-Related Adverse Events and Grade 3/4 Myelosuppression Fluid retention Diarrhea Headache Muscle spasm Nausea Pruritus Rash Vomiting Anemia Neutropenia Thrombocytopenia Any grade Grade 3/ Rate difference (imatinib - nilotinib) with 95% CI Favors nilotinib (300 mg BID) Larson RA, et al. JCO 2011; 29: 421s [abstract 6511] Favors imatinib

Adverse Events by Therapy in CML-CP - DASISION Rate Difference (dasatinib-imatinib) with Exact 95% CI Favors dasatinib Favors imatinib Anemia Thrombocytopenia Neutropenia Rash Headache Fatigue Diarrhea Vomiting Nausea Myalgia Pleural effusion Superficial edema Fluid retention Any grade Grade 3/4 No. of patients DasatinibImatinib Shah et al. ASH 2010; abst #206

TKI Frontline Therapy in CML Treatment Discontinuation Percentage F/U (mo) IM400IM800NilotinibDasatinibBosutinib ENESTnd* ¥ > DASISION> BELA> MDACC> * Nilotinib 300mg BID shown ¥ Excludes patients who discontinued into extension study; rates are 38% imatinib and 29% nilotinib if all included Alattar et al. ASH 2011; Abstract #745; Saglio et al. ASH 2011; Abstract #452; Kantarjian et al. ASCO 2011; Abstract #6510; Cortes et al. ASH 2011; Abstract #455

Factors Influencing Early Discontinuation of 2 nd Generation TKI Adverse events Lack of efficacy Availability of alternative options Decrease tolerance to adverse events Unreasonable expectations regarding toxicity Suboptimal management of AEs Lack of familiarity

Take Home Message – CML 2012 ¼ Frontline therapy: new standard Imatinib is good 2 nd generation TKI (dasatinib, nilotinib, bosutinib?) probably better Earlier responses Possible improvement EFS, TFS Best drug vs best strategy? Sequential therapy? Adequate management is vital

Now in its third year the iCMLf has already achieved a great deal: Over 40 practicing hematologists (preceptors) have attended educational programs at internationally renowned CML centres of excellence Through the iCMLf Virtual Education Program the iCMLf has provided in excess of 5500 people access to up to date online CML education sessions from leading experts

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