Copyright © 2011 Research To Practice. All rights reserved. Interest in Topics Related to the Treatment of Patients with CML (Percent Responding 9 or 10) 36% 38% 39% 42% 32%34%36%38%40%42%44% Resistance mutations in BCR-ABL Monitoring patients during therapy New agents/regimens Sequencing of TKIs TKI-refractory CML Efficacy and tolerability of TKIs* *Tyrosine kinase inhibitors: Imatinib, dasatinib, nilotinib

Chronic Myeloid Leukemia (CML) Susan M O’Brien, MD

IRIS 8-Year Update: Outcome After Imatinib 37% Deininger M et al; Blood 2009;114(22):462.

Nilotinib vs Imatinib in Newly Dx CML (ENESTnd) Primary endpoint: MMR at 12 months Key secondary endpoint: Durable MMR at 24 months Other endpoints: CCyR by 12 months, time to MMR and CCyR, EFS, PFS, time to AP/BC on study treatment, OS including follow-up *Stratification by Sokal risk score Imatinib 400 mg QD (n = 283) Nilotinib 300 mg BID (n = 282) RANDOMIZED*RANDOMIZED* Nilotinib 400 mg BID (n = 281) N = centers 35 countries Follow-up 5 years Hughes et al. ASH 2010; abst #207

Nilotinib vs Imatinib in Newly Dx CML-CP (ENESTnd). Primary Endpoint - MMR Rate at 12 Months (ITT Population) P <.0001 Patients with MMR (%) Larson RA et al. J Clin Oncol 2010;28; Abstract Saglio G et al. N Engl J Med 2010;362; Abstract 2251.

IRIS 8-Year Results: Annual Rate of Events on Imatinib EFS = 81% Freedom from progression to AP/BC = 92% - 1 progression to AP/BC and 2 non-CML related deaths in year 8 Deininger et al. ASH Abs # AP/BC

% With CCyR

Dasatinib versus Imatinib Study in Treatment-Naïve CML: DASISION (CA ) Study 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 Shah et al. ASH 2010; abst #206.

DASISION: First-Line Dasatinib vs Imatinib in CML-CP CCyR Rate by 12 Months (ITT) CCyR (%) Confirmed CCyR by 12 months CCyR by 12 months P = P = Kantarjian. N Engl J Med 362: 2260, 2010.

DASISION: Progression to AP-BP (ITT) No patient who achieved MMR progressed to AP/BP CML 5 patients who achieved a CCyR progressed to AP/BP CML (2 dasatinib, 3 imatinib) Rates of progression-free survival at 18 mos: 94.9% for dasatinib and 93.7% for imatinib n/N 6/259 9/260 Shah N et al. Blood 2010;116: Abstract

DASISION: Confirmed CCyR (ITT) Shah N et al. Blood 2010;116: Abstract 206. P = P =

Definitions of PFS-EFS in CML Definitions of EFS/PFS vary in different studies Definitions applied to 435 pts treated with frontline TKI Occurrence EFS- IRIS TWP- ENEST PFS- DASISION EFS- MDACC AP-BP on TKI ++++ off TKI Death on TKI + CML-related <30 d off TKI Any cause + off TKI - CML-related <30 d off TKI <60 d off TKI + Loss of CHR/MCyR (also ↑WBC) + EFS-MDACC accounts for any event off TKI and any death on/off TKI Kantarjian et al. Blood 2010:116; Abst #672.

Outcome According to Different Definitions of EFS/PFS Kantarjian et al. Blood 2010:116;Abst #672. DefinitionsEvent5-yr (%) ENEST-TWP1596 IRIS-EFS4090 DASISION-PFS 4389 MDACC-EFS Because EFS and PFS are important in determining whether new TKIs are better than imatinib in front-line therapy, precise and common definitions of these endpoints are needed.

Data cut-off: 20Aug2010 Hughes TP, et al. ASH Abstract 207.

DASISION: Grade 3/4 Cytopenia 100 Grade 3/4 bleeding occurred in 2 patients on dasatinib and 3 patients on imatinib 6 patients on dasatinib and 3 patients on imatinib D/C Rx due to cytopenia Shah N et al. Blood 2010;116: Abstract 206.

Common Nonhematologic Drug-Related AEs (≥10%) AE, % Dasatinib 100 mg QD N = 258 Imatinib 400 mg QD N = 258 All GradesGrade 3/4All GradesGrade 3/4 Fluid retention Superficial edema*10036<1 Pleural effusion12<100 Myalgia † Nausea90210 Vomiting50100 Diarrhea18<1191 Fatigue8<1110 Headache Rash * Includes 11 MedDRA preferred terms † Includes myalgia, muscle inflammation and musculoskeletal pain

Copyright © 2011 Research To Practice. All rights reserved. What Clinicians Want to Know A Live CME Event Addressing the Most Common Questions and Controversies in the Current Clinical Management of Select Hematologic Cancers Sunday, June 5, :00 PM – 9:30 PM Chicago, Illinois Faculty Sergio Giralt, MD John P Leonard, MD Lauren C Pinter-Brown, MD Moderator Neil Love, MD Antonio Palumbo, MD Susan M O’Brien, MD Professor Michael Hallek

Copyright © 2011 Research To Practice. All rights reserved. What is your preferred initial systemic treatment for chronic-phase CML?

Copyright © 2011 Research To Practice. All rights reserved. Have you discontinued imatinib, dasatinib or nilotinib for patients responding with sustained molecular CR?

Copyright © 2011 Research To Practice. All rights reserved. What Clinicians Want to Know A Live CME Event Addressing the Most Common Questions and Controversies in the Current Clinical Management of Select Hematologic Cancers Sunday, June 5, :00 PM – 9:30 PM Chicago, Illinois Faculty Sergio Giralt, MD John P Leonard, MD Lauren C Pinter-Brown, MD Moderator Neil Love, MD Antonio Palumbo, MD Susan M O’Brien, MD Professor Michael Hallek