1. Working Groups in Chronic Myelogenous Leukemia: Choice of Therapy After First-line Treatment Failure 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 Users are asked to honor this intent  These slides may not be published or posted online without permission from Clinical Care Options Disclaimer The materials published on the Clinical Care Options Web site reflect the views of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 Choice of Therapy After First-line Treatment Failure  Considering the established treatment options in second- line therapy: second-generation TKIs and other novel agents  Treatment recommendations and guidelines  Criteria to determine appropriate dosing of second- generation TKIs  Recent clinical trial data on approved second-generation TKIs  Ongoing or planned studies and research directions

6. clinicaloptions.com/oncology Treatment of CML: State of the Art Mechanisms of Resistance to Imatinib  BCR-ABL dependent –Amplification/overexpression –Mutations in ABL –Remigration of BCR-ABL to cytoplasm  BCR-ABL independent –Increased MDR expression –Increased alpha-1 acid glycoprotein –Overexpression of Src-related kinases  Quiescent stem cells (persistence) le Coutre P, et al. Blood. 2000;95:1758-1766. Weisberg E, et al. Blood. 2000;95:3498-3505. Mahon FX, et al. Blood. 2000;96:1070-1079. Gambacorti-Passerini C, et al. J Natl Cancer Inst. 2000;92:1641-1650. Vigneri P, et al. Nat Med. 2001;7:228-234.

7. clinicaloptions.com/oncology Treatment of CML: State of the Art Spectrum and Frequency of BCR-ABL KD Mutations Recovered After TKI Therapy This research was originally published in Blood. Cortes J, et al. Blood. 2007;110:4005-4011. © the American Society of Hematology. BCR-ABL Mutation (%) G250E 0 5 10 15 20 Nilotinib Dasatinib Imatinib Y253H/F E255K V299L F311I T315I F317L M351T E355G/A F359C/V H396R/P

8. clinicaloptions.com/oncology Treatment of CML: State of the Art Your Menu for BCR/ABL Mutants Redaelli S, et al, J Clin Oncol. 2009;27:469-471. BosutinibDasatinibImatinibNilotinib WT L248V G250E Q252H Y253F E255K E255V D276 G E279K V299L T315I F317L M351T F359V L384M H396P G398R F486S Resistant Moderately Resistant Sensitive Highly Resistant

9. clinicaloptions.com/oncology Treatment of CML: State of the Art Failure on Imatinib and My Recommended Strategies Imatinib FailureIncrease Imatinib Dose Second-Generation TKI Ph 100% at 6 mos–+ Ph ≥ 35% at 12 mos++ No CGCR in Yr 2++ CG relapse++ Hematologic relapse – +

10. clinicaloptions.com/oncology Treatment of CML: State of the Art When Does Imatinib Dose Escalation Work?  Imatinib dose escalation in 84 patients with imatinib failure –CG failure (n = 63):  imatinib associated with CGCR in 52% –MCyR durable at 2 yrs in 88% of patients –Hematologic failure (n = 21): only transient responses; CGCR in 5%  However, results of new TKIs better in CG relapse vs hematologic relapse Jabbour E, et al. Blood. 2009;113:2154-2160.

11. clinicaloptions.com/oncology Treatment of CML: State of the Art Phase II Studies of Dasatinib After Imatinib Failure *At least major. 1. Stone RM, et al. ASH 2007. Abstract 734. 2. Apperley JF, et al. J Clin Oncol. 2009;27:3472-3479. 3. Cortes J, et al. Leukemia. 2008;22:2176-2183. 4. Porkka K, et al. ASH 2007. Abstract 2810. Response, %CP [1] (n = 387) AP [2] (n = 174) MyBP [3] (n = 109) LyBP [3] (n = 48) ALL [4] (n = 46) Hematologic*9164343549  CHR9145272935  NEL--19767 Cytogenetic*6239335262  Complete5332264654  Partial97762

12. clinicaloptions.com/oncology Treatment of CML: State of the Art Dasatinib in Chronic-Phase CML After Imatinib Failure (START-C and START-R)  Pooled analysis of pts receiving 70 mg BID dasatinib in START-C (n = 387) and START-R (n = 101) –IM resistance: 80%; minimum follow-up: 24 mos Baccarani M, et al. ASH 2008. Abstract 450. OutcomePatients, % MCyR/CCyR at Mo 2460/51  IM resistant55/44  IM intolerant82/78 24-mo MMR40 24-mo duration of MCyR88 24-mo PFS81  MCyR at 12 mos94  No MCyR at 12 mos79

13. clinicaloptions.com/oncology Treatment of CML: State of the Art PFS and OS With Dasatinib in Chronic- Phase CML by Imatinib Failure Progression defined as increasing WBC count, loss of CHR/MCyR, AP/BP, or death. Imatinib Resistance Imatinib Intolerance Stone RM, et al. ASH 2007. Abstract 734. Reprinted with permission. 80 60 40 20 0 0 100 36 912 151821 2428 3033 Mos PFS OS 80 60 40 20 0 0 100 36 912 151821 2428 3033 Mos PFS OS 96% 92% 88% 75% 100% 98% 100% 94%

14. clinicaloptions.com/oncology Treatment of CML: State of the Art Optimal Dose and Schedule of Dasatinib in CP CML After Imatinib Failure Shah NP, et al. ASH 2008. Abstract 3225. Reprinted with permission. Parameter, % 100 mg QD (n = 166) 50 mg BID (n = 166) 140 mg QD (n = 163) 70 mg BID (n = 167) MCyR63616361 CGCR50 54 24-mo PFS80767576 Neutropenia, grade 3/435474445 Thrombocytopenia, grade 3/4 23364138 Pleural effusion, grade 3/4 2455 Interruption58666971 Reduction33455457

15. clinicaloptions.com/oncology Treatment of CML: State of the Art Nilotinib in Chronic-Phase CML Post- Imatinib Failure  N = 321 –Median duration of exposure to nilotinib: 18.4 mos –Patients on therapy for ≥ 12 months: 62% and ≥ 24 months: 42% –Patients requiring a dose interruption: 58% –median cumulative duration of interruption: 20 days Kantarjian HM, et al. Blood. 2011;117:1141-1145. OutcomePatients, % CGCR44 MMR28 (56% of CGCR) 24-mo PFS64 24-mo OS87

16. clinicaloptions.com/oncology Treatment of CML: State of the Art Nilotinib in Chronic-Phase CML: Major Cytogenetic Responses  MCyR –Overall: 59% –Imatinib-resistant patients: 56% –Imatinib-intolerant patients: 66% –Proportion of patients with baseline CHR significantly higher vs those who did not (73% vs 52%, respectively; P =.0002) Kantarjian HM, et al. Blood. 2011;117:1141-1145.

17. clinicaloptions.com/oncology Treatment of CML: State of the Art Nilotinib in Chronic-Phase CML: Complete Cytogenetic Responses  CGCR –Overall: 44% –Imatinib-resistant patients: 41% –Imatinib-intolerant patients: 51% –Proportion of patients with baseline CHR significantly higher vs those who did not (58% vs 36%, respectively; P =.0002) Kantarjian HM, et al. Blood. 2011;117:1141-1145.

18. clinicaloptions.com/oncology Treatment of CML: State of the Art Nilotinib Adverse Events Adverse Event, %All GradesGrade 3/4 Peripheral Edema60 Pericardial effusion< 1 Pleural effusion1< 1 Hematologic Anemia5311 Neutropenia5331 Thrombocytopenia5830 Kantarjian HM, et al. Blood. 2011;117:1141-1145.

19. clinicaloptions.com/oncology Treatment of CML: State of the Art Phase II Studies of Nilotinib After Imatinib Failure Kantarjian HM, et al. ASH 2008. Abstract 3238. le Coutre PD, et al. ASH 2008. Abstract 3229. Response, %CP (n = 321) AP (n = 137) MyBP (n = 106) LyBP (n = 30) HR 77542420  CHR 76261213 Cytogenetic  Major 59313850  Complete 44192833

20. clinicaloptions.com/oncology Treatment of CML: State of the Art Bosutinib (SKI–606) in CP CML: Phase I/II  Src-Abl inhibitor 30 x more potent than IM; minimal inhibition of PDGFR, c-kit  Bosutinib 400-600 mg/day (phase II: 500 mg/day) in 294 patients with chronic- phase CML and imatinib resistance/intolerance (no other previous TKIs); median follow-up: 23.8 mos  Grade 3/4 toxicity: thrombocytopenia 24%, neutropenia 16%, anemia 12%, diarrhea 9%, rash 9% Cortes J, et al. ASCO 2010. Abstract 6502. Response, %ResistantIntolerant Hematologic(n = 75)(n = 34)  CHR8897 Cytogenetic(n = 158)(n = 56)  MCyR6073  CCyR4659 Molecular(n = 108)(n = 43)  MMR5449  CMR3040

21. clinicaloptions.com/oncology Treatment of CML: State of the Art Survival by Response to Second TKI  113 CML patients (CP = 87; AP = 26) receiving nilotinib (n = 43) or dasatinib (n = 70) after imatinib failure This research was originally published in Blood. Tam CS, et al. Blood. 2008;112:516-518. © the American Society of Hematology. 1.0 0.8 0.6 0.4 0.2 0 Proportion Alive 0 12 24 36 Mos From 12-Mo Landmark PCyR or CCyR miCyR or CHR Hematologic failure PCyR/CCyR vs rest: P =.01 nDeaths PCyR/CCyR642 miCyR/CHR346 Hematologic failure92

22. clinicaloptions.com/oncology Treatment of CML: State of the Art EFS, OS, McyR With Second TKIs in CML  Adverse factors: EGOC PS ≥ 1 and lack of CG to imatinib Jabbour E, et al. Blood. 2011;117:1822-1827. Risk Factor, n P =.001 P =.002 P =.007 0 10 20 30 40 50 60 70 80 90 100 24 Month EFS 24 Month OS 12 Month MCyR 0 1 2

23. clinicaloptions.com/oncology Treatment of CML: State of the Art Prognosis With Second TKIs in CML: Application of EFS Model  Data suggest feasibility of a simple scoring system model –Easily applicable in the clinic  Outcome of patients after imatinib failure treated with second-generation TKIs, dependent on: –Cytogenetic response to imatinib –ECOG performance status at start of second therapy  Patients at high risk (ie, poor performance status and no previous CG response) have a low probability of responding to second-generation TKI Jabbour E, et al. Blood. 2011;117:1822-1827.

24. clinicaloptions.com/oncology Treatment of CML: State of the Art Allo SCT: Second or Third Salvage?  Imatinib failure in AP, BP: use new TKI as bridge to MRD, then allo SCT ASAP  T315I mutation in any CML phase: use AP 24534, other T315I inhibitors, HHT, HU, others as bridge to MRD, then allo SCT ASAP  Imatinib failure in chronic phase –If IC50 , clonal evolution, or no major CG in 12 mos  allo SCT (risk should also be reasonable: young, good match) –If not  TKI until failure –70 yrs of age or older or if poor match: may decide to forgo curative allo SCT option for several years of CML control

25. clinicaloptions.com/oncology Treatment of CML: State of the Art Ponatinib (AP24534) in CML  Oral TKI designed by computational drug design  IC 50 (nm): WT: 0.5; T315I: 11; F317V: 10; others: 1-35  Phase I: 2  60 mg daily; 74 pts  DLT: fatigue, QT , GI,  lipase/amylase  CP: CHR 95%; CGCR 53, CG major 66%, MMR 42%  T315I: CGCR 89%, CG major 100%, 2/2 AP Cortes. Blood 114: abst 643, 2009

26. clinicaloptions.com/oncology Treatment of CML: State of the Art Omacetaxine (HHT) in CML and T315I Post Imatinib Failure  90 pts, 66 evaluable: 40 CP, 16 AP, 10 BP  Median age 58 yrs; median CML 54 mos; 79% failed  2 TKIs  CP: T315I clones  57% in CP; 2-yr surv 88% Cortes. Blood 114:abst 644, 2009 CML phaseNo.%CHR/HR% CG response CP4085 27%; 15% major (2 CR, 2 PR) AP16371 CGCR BP1030

27. clinicaloptions.com/oncology Treatment of CML: State of the Art How Do You Choose the Second- Generation TKIs  Disease characteristics –AP/BP: favor dasatinib (?) and combinations –Chronic: see below  Mutations –T315I → none –Nilotinib IC50 > 150nM → avoid –Dasatinib IC50 > 3nM → avoid  Patient history –Hypertension, CHF, lung problems, COPD → avoid dasatinib –Severe diabetes, pancreatitis history → avoid nilotinib –QTc problems → be cautious with all (?)

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