1. Working Groups in Chronic Myelogenous Leukemia: Choice of First-line Therapy This program is supported by an educational grant from

2. clinicaloptions.com/oncology Treatment of CML: State of the Art About These Slides  Our thanks to the presenters who gave permission to include their original data  Users are encouraged to use these slides in their own noncommercial presentations, but we ask that content and attribution not be changed. Users are asked to honor this intent  These slides may not be published or posted online without permission from Clinical Care Options Disclaimer The materials published on the Clinical Care Options Web site reflect the views of the authors of the CCO material, not those of Clinical Care Options, LLC, the CME providers, or the companies providing educational grants. The materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or using any therapies described in these materials.

3. clinicaloptions.com/oncology Treatment of CML: State of the Art Faculty Elias Jabbour, MD Assistant Professor Department of Leukemia University of Texas M. D. Anderson Cancer Center Houston, Texas

4. clinicaloptions.com/oncology Treatment of CML: State of the Art Disclosure Elias Jabbour, MD, has disclosed that he has received fees for non-CME/CE services from Bristol-Myers Squibb and Novartis.

5. clinicaloptions.com/oncology Treatment of CML: State of the Art Choosing First-line Therapy for Newly Diagnosed Chronic-Phase CML  Role of allogeneic SCT  Which TKI is the best choice in this setting? –Imatinib –Dasatinib –Nilotinib –Bosutinib

6. clinicaloptions.com/oncology Treatment of CML: State of the Art CML: Overview of Historical vs Modern Perspective ParameterHistorical Perspective (Until 2000) Modern Perspective (Since 2000) CourseFatalIndolent PrognosisPoorExcellent 10-yr survival10%84% to 90% Frontline treatmentAllogeneic SCT, interferon alfa Imatinib or dasatinib or nilotinib Second-line treatmentNot establishedAllogeneic SCT or novel TKIs Faderl S, et al. Ann Intern Med. 1999;131:207-219. Druker BJ, et al. N Engl J Med. 2001;344:1031-1037.

7. clinicaloptions.com/oncology Treatment of CML: State of the Art Survival in Early Chronic-Phase CML Yrs From Referral The University of Texas M. D. Anderson Cancer Center database. Reprinted with permission. 1.0 0.8 0.6 0.4 0.2 0 0369121518212427 Proportion Alive YearTotalDead Imatinib 302 15 Imatinib 1990-2000 1982-1989 1975-1981 1965-1974 (censored for non-CML death) 302 963 364 132 123 31 425 273 129 123 93% 84%

8. clinicaloptions.com/oncology Treatment of CML: State of the Art CML Survival After Allogeneic SCT* *Includes both matched related and unrelated donors. Patients receiving allografts at the Fred Hutchinson Cancer Research Center from 1995 to the present. Figure is courtesy of Dr. Ted Gooley. 1.0 0.8 0.6 0.4 0.2 0 Probability of Survival 0246810121416 Yrs After Transplantation Chronic phase (n = 576) Accelerated phase (n = 125) Blast crisis/remission (n = 62) Blast crisis (n = 44)

9. clinicaloptions.com/oncology Treatment of CML: State of the Art CML Survival After Allogeneic SCT Years Probability of Survival 0.0 0.2 0.4 0.6 0.8 1.0 Sib + CP1 (n = 3,372) Sib + Not CP1 (n = 1,141) Other Donor + CP1 (n = 1,302) Other Donor + Not CP1 (n = 725) All Patients (N = 6,548) 45% 60% Imatinib 048121820 The University of Texas M. D. Anderson Cancer Center database. Reprinted with permission.

10. clinicaloptions.com/oncology Treatment of CML: State of the Art The IRIS Study Design IFN-  + Ara-C (n = 553) Imatinib (n = 553) Crossover RANDOMIZERANDOMIZE Crossover for: Lack of response Loss of response Intolerance of treatment Druker BJ, et al. N Engl J Med. 2006;355:2408-2417.

11. clinicaloptions.com/oncology Treatment of CML: State of the Art IRIS Study in Chronic-Phase CML  553 patients randomized to imatinib 400 mg/day; 8-yr follow-up  Transformation to AP/BP at Yrs 4-8: 0.9%, 0.5%, 0%, 0%, 0.4%  Only 15 patients in CGCR (3%) progressed to AP/BP  No patients in MMR at 12 mos progressed to AP/BP Outcome at 8 YrsPatients, % On study55 EFS81 PFS92 OS85 OS (CML deaths + deaths before SCT)93 MMR86 Deininger M, et al. ASH 2009. Abstract 1126. Reprinted with permission.

12. clinicaloptions.com/oncology Treatment of CML: State of the Art ENESTnd: Nilotinib vs Imatinib in Newly Diagnosed Chronic Phase CML  Primary endpoint: MMR at 12 mos; secondary endpoint: CCyR by 12 mos  Other endpoints: time/duration of MMR and CGCR, EFS, PFS, time to AP/BP, OS  Stratification by Sokal risk; MMR defined as ≤ 0.1% BCR-ABL(/ABL ratio) on the International Scale Imatinib 400 mg QD (n = 283) Nilotinib 300 mg BID (n = 282) RANDOMIZERANDOMIZE Nilotinib 400 mg BID (n = 281) Newly diagnosed CML-CP (N = 846) 217 centers; 35 countries Saglio G, et al. N Engl J Med. 2010;362:2251-2259.

13. clinicaloptions.com/oncology Treatment of CML: State of the Art Outcome at 24 mos, % Nilotinib 300 mg BID (n = 282) Nilotinib 400 mg BID (n = 281) Imatinib 400 mg QD (n = 283) MMR62*59*37 CMR26*21 † 10 CCyR87 ‡ 85 § 77 Estimated OS97.497.896.3 Hughes TP, et al. ASH 2010. Abstract 207. ENESTnd: Outcomes at 24 Months *P <.0001 vs imatinib. † P =.0004 vs imatinib. ‡ P =.0018 vs imatinib. § P =.016 vs imatinib.

14. clinicaloptions.com/oncology Treatment of CML: State of the Art ENESTnd: Progression to AP/BC and Death at 24 Months Outcome, n Nilotinib 300 mg BID (n = 282) Nilotinib 400 mg BID (n = 281) Imatinib 400 mg QD (n = 283) Progression to AP/BC2*3†3† 12 Progression to AP/BC+CE2‡2‡ 5§5§ 17 Deaths96║6║ 11  CML unrelated431  CML related5310 Hughes TP, et al. ASH 2010. Abstract 207. *P =.0059 vs imatinib. † P =.0196 vs imatinib. ‡ P =.0003 vs imatinib. § P =.0089 vs imatinib. ║ P <.0485 vs imatinib.

15. clinicaloptions.com/oncology Treatment of CML: State of the Art 100 80 60 40 20 0 MMR (%) At 12 MosAt 24 Mos ENESTnd: MMR Rates at 12 and 24 Mos 44 43 22 P <.0001 Nilotinib 300 mg BIDNilotinib 400 mg BIDImatinib 400 mg QD P <.0001 62 59 37 Hughes TP, et al. ASH 2010. Abstract 207.

16. clinicaloptions.com/oncology Treatment of CML: State of the Art All Grade Nonhematologic Drug-Related Adverse Events, % Nilotinib 300 mg BID (n = 279) Nilotinib 400 mg BID (n = 277) Imatinib 400 mg QD (n = 280) Nausea142134 Diarrhea8726 Vomiting5918 Peripheral edema5615 Facial edema< 1211 Eyelid edema< 1216 Periorbital edema< 1114 Muscle spasms8727 Rash323713 Headache14229 ENESTnd: Study Drug-Related Adverse Events (≥ 10% in Any Group) Hughes TP, et al. ASH 2010. Abstract 207.

17. clinicaloptions.com/oncology Treatment of CML: State of the Art Dasatinib vs Imatinib in Treatment-Naive CML: DASISION (CA180-056)  Primary endpoint: confirmed CCyR by 12 mos  Secondary/other endpoints: rates of CCyR and MMR; times to confirmed CCyR, CCyR, and MMR; time in confirmed CCyR and CCyR; PFS; OS Follow-up 5 yrs Imatinib 400 mg QD (n = 260) Dasatinib 100 mg QD (n = 259) N = 519 108 centers 26 countries Stratified by Hasford risk score Kantarjian H, et al. N Engl J Med. 2010;362:2260-2270.

18. clinicaloptions.com/oncology Treatment of CML: State of the Art DASISION: Confirmed CCyR Rate (ITT) 100 80 60 40 20 0 Confirmed CCyR (%) By 12 MosBy 18 Mos P =.0086 P =.0366 77 67 78 70 Dasatinib 100 mg QD Imatinib 400 mg QD Shah N, et al. ASH 2010. Abstract 206. Reprinted with permission.

19. clinicaloptions.com/oncology Treatment of CML: State of the Art 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 9/260 100 Shah N, et al. ASH 2010. Abstract 206. Reprinted with permission. 6 4 0 Progressed to AP/BP, % 2.3 3.5 Dasatinib 100 mg QD Imatinib 400 mg QD

20. clinicaloptions.com/oncology Treatment of CML: State of the Art DASISION: Differences in Adverse Event Rates With Dasatinib vs Imatinib No. of pts DASIM 60111 2592 310 5699 2355 1227 4750 2128 3227 2944 5752 4927 2918 Anemia Thrombocytopenia Neutropenia Rash Headache Fatigue Diarrhea Vomiting Nausea Myalgia Pleural effusion Superficial edema Fluid retention -0.4-0.20.00.20.4 Any grade Grade 3/4 Rate difference (dasatinib-imatinib) with exact 95% CI Favors Dasatinib Favors Imatinib Shah N, et al. ASH 2010. Abstract 206. Reprinted with permission.

21. clinicaloptions.com/oncology Treatment of CML: State of the Art S0325 Intergroup Trial: Phase II Study of Frontline Dasatinib vs Imatinib in CP CML Radich JP, et al. ASH 2010. Abstract LBA-6. Patients with previously untreated chronic-phase CML (N = 246) Dasatinib 100 mg/day (n = 123) Imatinib 400 mg/day (n = 123) Stratified by Hasford risk score

22. clinicaloptions.com/oncology Treatment of CML: State of the Art Patient Characteristics CharacteristicImatinib 400 mg/day (n = 123) Dasatinib 100 mg/day (n = 123) Median age, yrs (range)51 (20-89)48 (19-91) Sex (male/female), %59/4161/39 Hasford (low/int/high), %36/37/2736/33/32 WBC,* 10 9 /L (range)51.9 (0.3-401.0)89.0 (3.0-410.0) Platelets, 10 9 /L (range)378 (109-1390)363 (100-1810) BM blasts, n (range)1 (0-9)2 (0-12) Radich JP, et al. ASH 2010. Abstract LBA-6. Reprinted with permission. *P <.01.

23. clinicaloptions.com/oncology Treatment of CML: State of the Art Removal From Protocol Treatment Reason for Removal From TreatmentImatinib 400 mg/day (n = 123) Dasatinib 100 mg/day (n = 123) Toxicity, n (%) By 12 mos, n Heme/nonhem, n/n 13 (11) 12 0/12 18 (15) 14 1/13 Refusal, n (%) By 12 mos, n 8 (7) 6 3 (2) 3 Other, n (%) By 12 mos, n 20 (16) 11 11 (9) 5 Progression AP/BC, n (%)4 (3)1 (1) Total, n (%)45 (37)33 (27) Radich JP, et al. ASH 2010. Abstract LBA-6. Reprinted with permission.

24. clinicaloptions.com/oncology Treatment of CML: State of the Art Hematologic Toxicities Imatinib 400 mg/day (n = 123) Dasatinib 100 mg/day (n = 122) All GradesGrades 3-4All GradesGrade 3-4 Hemoglobin, % 68 47010 Neutrophils, % 37123715 Platelets, % 3385718 Maximum Grade of Any Hematologic Toxicity, % 01234 Imatinib 400 mg/day254328252 Dasatinib 100 mg/day2534302112 Radich JP, et al. ASH 2010. Abstract LBA-6. Reprinted with permission.

25. clinicaloptions.com/oncology Treatment of CML: State of the Art Nonhematologic Toxicities Events, nImatinib 400 mg/day (n = 123) Dasatinib 100 mg/day (n = 122) All GradesGrades 3-4All GradesGrades 3-4 Fluid retention Edema (any) Pleural effusion 59 2 3131 24 14 1212 Diarrhea492416 Nausea590320 Vomiting230191 Muscle pain441120 Rash342400 Headache192343 Fatigue631611 Prolonged QTc 10 21 Radich JP, et al. ASH 2010. Abstract LBA-6. Reprinted with permission.

26. clinicaloptions.com/oncology Treatment of CML: State of the Art Treatment Outcomes Response Imatinib 400 mg/day (n = 123) Dasatinib 100 mg/day (n = 123) 2-Sided P Value* Molecular response at 12 mos 3.0 log reduction39/90 (43%)58/99 (59%).042 4.0 log reduction18/90 (20%)27/99 (27%).31 4.5 log reduction13/90 (14%)21/99 (21%).26 Hematologic CR within 12 mos111/123 (90%)104/123 (86%).25 Cytogenetic CR within 12 mos40/58 (69%)55/67 (82%).097 OS at 12 mos99%100%.65 PFS at 12 mos96%99%.20 *Fisher’s exact test (response); log rank test (OS, PFS). Radich JP, et al. ASH 2010. Abstract LBA-6. Reprinted with permission.

27. clinicaloptions.com/oncology Treatment of CML: State of the Art S0325: Deaths Event, nImatinib 400 mg/day (n = 123) Dasatinib 100 mg/day (n = 122) Total deaths43 CML21 Cardiac10 Other cancer01 Other11 Radich JP, et al. ASH 2010. Abstract LBA-6. Reprinted with permission.

28. clinicaloptions.com/oncology Treatment of CML: State of the Art Overall and Progression-Free Survival 80 60 40 20 0 0 100 1 2 3 4 Yrs After Registration Dasatinib Imatinib 400 mg/day 80 60 40 20 0 0 100 1 2 3 4 Yrs After Registration 123 3 4 97% 98% nDeaths 2-Yr Estimate OS by Treatment ArmPFS by Treatment Arm Dasatinib Imatinib 400 mg/day 123 4 8 96% 95% nDeaths 2-Yr Estimate Radich JP, et al. ASH 2010. Abstract LBA-6. Reprinted with permission. OS (%) PFS, (%)

29. clinicaloptions.com/oncology Treatment of CML: State of the Art Comparison of S0325 With DAISISION DAISISIONS0325 12 Mo Outcome, %ImatinibDasatinibImatinibDasatinib CCyR72836982 MMR (3-log)284643 (32*)59 (47*) PFS3.51.94.3 † 0.8 † *Calculated as ITT, where a missing test is counted as a negative. † KM probability of relapse, progression or death with 12 mos; raw numbers 3% and 1%, respectively. Radich JP, et al. ASH 2010. Abstract LBA-6. Reprinted with permission.

30. clinicaloptions.com/oncology Treatment of CML: State of the Art BELA: Randomized Phase III Trial of Bosutinib vs Imatinib in Chronic-Phase CML  Primary endpoint: CCyR at 12 mos; secondary endpoints: MMR at 12 mos, duration of CCyR, MMR, and CHR, time to and rate of AP and BP, safety and tolerability Gambacorti-Passerini C, et al. ASH 2010. Abstract 208. Patients with previously untreated chronic-phase CML (N = 502) Bosutinib 500 mg/day (n = 250) Imatinib 400 mg/day (n = 252) 5-yr follow-up Stratified by Sokal risk score and geographic region

31. clinicaloptions.com/oncology Treatment of CML: State of the Art BELA: Response at 12 Mos Response*, %Bosutinib (n = 250) Imatinib (n = 252) P Value CCyR (ITT)7068.601 MMR (ITT)3926.002 CCyR (eval)7868.026 MMR (eval)4327<.001 Gambacorti-Passerini C, et al. ASH 2010. Abstract 208. *Median follow-up 14 mos.

32. clinicaloptions.com/oncology Treatment of CML: State of the Art BELA: Disease Progression (ITT) Gambacorti-Passerini C, et al. ASH 2010. Abstract 208. Disease Progression, n (%)BosutinibImatinibP Value Treatment failure7 (3) 25 (10)<.001 Transformation to AP/BP4 (2) 10 (4).053 Death due to CML progression3 (1) 8 (3).056

33. clinicaloptions.com/oncology Treatment of CML: State of the Art Frontline Rx With Imatinib vs Second- Generation TKIs Saglio G, et al. N Engl J Med. 2010;362:2251-2259. Kantarjian H, et al. N Engl J Med. 2010;362:2260-2270. ParameterImatinibSecond-Generation TKIs Efficacy ExcellentEven better 12-mo outcome, %  CGCR 65-7080-85  MMR 20-2540-45  AP-BP 3.50.4-2.0 Tolerance ExcellentEven better Follow-up, yrs 106-7 Cost, $/yr 54,00090,000-96,000

34. clinicaloptions.com/oncology Treatment of CML: State of the Art Summary  Second generation TKIs in the frontline setting: –Less progression to AP/BC than with imatinib –Faster, deeper, and more durable molecular and cytogenetic responses –The superior rate of responses compared with imatinib has been maintained over time –Second generation TKI therapy was generally well tolerated and manageable

35. Go Online for More Downloadable Slidesets on CML! Working Groups in Chronic Myelogenous Leukemia: Monitoring First-line Therapy, Resistance, and Considering Second-line Therapy Working Groups in Chronic Myelogenous Leukemia: Choice of Therapy After First-line Treatment Failure clinicaloptions.com/oncology