1. Michael J. Mauro, MD Associate Professor Knight Cancer Institute, Center for Hematologic Malignancies Oregon Health and Science University Portland, Oregon Practical Therapeutic Approaches for Patients With CML This program is supported by educational grants from

2. clinicaloptions.com/oncology Chronic Myeloid Leukemia: Translating State-of-the-Art Practice to Patient Care About These Slides  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 Users are asked to honor this intent  These slides may not be published or posted online without permission from Clinical Care Options (email permissions@clinicaloptions.com) Disclaimer The materials published on the Clinical Care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 Chronic Myeloid Leukemia: Translating State-of-the-Art Practice to Patient Care Agenda  3 review topics, each with case scenarios –Choice of First-line Therapy –Monitoring Response and Compliance to First-line Therapy –Choice of Second-line Therapy and Bone Marrow Transplantation

4. clinicaloptions.com/oncology Chronic Myeloid Leukemia: Translating State-of-the-Art Practice to Patient Care Choice of First-line Therapy

5. clinicaloptions.com/oncology Chronic Myeloid Leukemia: Translating State-of-the-Art Practice to Patient Care Case  48-yr-old bullpen catcher presents with fatigue, night sweats, increasing abdominal fullness, and bloating  Physical exam reveals splenomegaly ~ 6 cm below costal margin  CBC assessment –WBC count: 242,000 cells/mm 3 –Hematocrit: 38% –Platelet count: 518,000 cells/mm 3  BM aspiration shows hypercellular marrow (~ 100%) with 2% blasts  Cytogenetics identify Ph chromosome in all 20 cells assessed: 46,XX, t(9;22)(q34;q11.2)  BCR-ABL mRNA 94.2% by Q-RT-PCR

6. clinicaloptions.com/oncology Chronic Myeloid Leukemia: Translating State-of-the-Art Practice to Patient Care What would you recommend? A.Initiate therapy with imatinib 400 mg/day B.Initiate therapy with imatinib 800 mg/day C.Initiate therapy with dasatinib 100 mg/day D.Initiate therapy with nilotinib 300 mg twice daily E.Allogeneic BMT

7. clinicaloptions.com/oncology Chronic Myeloid Leukemia: Translating State-of-the-Art Practice to Patient Care CML “Historically”  Identification of Ph+ chromosome somewhat important  Response and progression monitored via marrow karyotype and pathology –Not regularly performed, given the small chance of response  BMT the only “cure”  Interferon could induce stable remission and prolong life in a minority of cases  Palliative therapy (HU, busulfan) common  “You have several yrs to live with your CML before it gets worse”

8. clinicaloptions.com/oncology Chronic Myeloid Leukemia: Translating State-of-the-Art Practice to Patient Care CML “Currently”  Intimate knowledge of Ph+ chromosome and related elements essential for drug development  Identifying presence of Ph+ chromosome essential for treatment start  Tracking initial response by marrow karyotype and pathology still important  Response tracked over time via sensitive, standardized Q-PCR  BMT reserved for select cases and used for rescue  “Functional cure” is the norm; quest for pharmacologic cure intensified  Patients have “normal” life span –Risk of other diseases/cancers increasingly important; long-term plan?

9. clinicaloptions.com/oncology Chronic Myeloid Leukemia: Translating State-of-the-Art Practice to Patient Care For Patients Newly Diagnosed With CML, Treatment Choice Driven by Many Factors Pretherapy issues  Access/cost  Physician preference/familiarity  Comorbidities and anticipated toxicity  Patient preference Issues during therapy  Tolerability  Response outcome –Remission rates –Duration –Relapse risk  Compliance with taking medication  Prospects/expectations for long- term maintenance therapy

10. clinicaloptions.com/oncology Chronic Myeloid Leukemia: Translating State-of-the-Art Practice to Patient Care Bosutinib Diarrhea/nausea/emesis, rash, pleural effusion Efficacy correlate? Toxicity Spectrum of TKIs in CML Nilotinib Pancreatic enzyme , indirect hyperbilirubinemia, QT prolongation Common Effects Myelosuppression Transaminase  Electrolyte Δ Dasatinib Pleural/pericardial effusions, bleeding risk Ponatinib Pancreatic enzyme  Imatinib Edema/fluid retention, myalgia, hypophosphatemia , GI effects (diarrhea, nausea)

11. clinicaloptions.com/oncology Chronic Myeloid Leukemia: Translating State-of-the-Art Practice to Patient Care Expectations on Imatinib: IRIS 8-Yr Update Shows 37% Have Unacceptable Outcome *Unacceptable outcome. Deininger M, et al. ASH 2009. Abstract 1126.

12. clinicaloptions.com/oncology Chronic Myeloid Leukemia: Translating State-of-the-Art Practice to Patient Care ENESTnd: Comparison of Nilotinib and Imatinib in Newly Diagnosed CP CML  Primary endpoint: MMR at 12 mos  Secondary endpoint: durable MMR at 24 mos  Other endpoints: time to MMR, CCyR by 12 mos, time to CCyR, EFS, PFS, OS, time to AP/BC on study treatment Patients diagnosed with Ph+ CP CML within 6 mos (N = 846) Nilotinib 300 mg BID (n = 282) Imatinib 400 mg QD (n = 283) Nilotinib 400 mg BID (n = 281) 5-yr follow-up Saglio G, et al. N Engl J Med. 2010;362:2251-2259. Stratified by Sokal risk

13. clinicaloptions.com/oncology Chronic Myeloid Leukemia: Translating State-of-the-Art Practice to Patient Care ENESTnd 3-Yr Update: Cumulative Molecular Responses Kantarjian HM, et al. ASCO 2012. Abstract 6509. *P <.0001 vs imatinib. † P =.0004 vs imatinib. ‡ P =.0003 vs imatinib. Outcome, %Nilotinib 300 mg BID (n = 282) Nilotinib 400 mg BID (n = 281) Imatinib 400 mg QD (n = 283) Cumulative MMR  1 yr55*5127  3 yrs73*70*53 Cumulative MR 4 (4.0 log reduction)  1 yr20*15 † 6  3 yr50*44*26 Cumulative MR 4.5 (4.5 log reduction in BCR-ABL)  1 yr11*7*1  3 yrs32*28 ‡ 15

14. clinicaloptions.com/oncology Chronic Myeloid Leukemia: Translating State-of-the-Art Practice to Patient Care ENESTnd 3-Yr Update: Progression to AP/BC  No new progressions since 2-yr analysis on core treatment 20 15 10 5 0 Patients (n) Nilotinib 300 mg BIDNilotinib 400 mg BIDImatinib 400 mg QD Including Clonal Evolution P =.0059 P =.0185 P =.0003 P =.0085 2 3 12 2 5 17 0.7%1.1%4.2%0.7%1.8%6.0% Kantarjian HM, et al. ASCO 2012. Abstract 6509. Excluding Clonal Evolution

15. clinicaloptions.com/oncology Chronic Myeloid Leukemia: Translating State-of-the-Art Practice to Patient Care ENESTnd 3-Yr Update: Hematologic AEs and Biochemical Abnormalities Kantarjian HM, et al. ASCO 2012. Abstract 6509. Grade 3/4 AEs, %Nilotinib 300 mg BID (n = 282) Nilotinib 400 mg BID (n = 281) Imatinib 400 mg QD (n = 283) Neutropenia121121 Thrombocytopenia10129 Anemia456 Lipase increase884 ALT increase493 Total bilirubin increase48< 1 Hyperglycemia650

16. clinicaloptions.com/oncology Chronic Myeloid Leukemia: Translating State-of-the-Art Practice to Patient Care Patients newly diagnosed with CP CML (N = 519) Dasatinib 100 mg QD (n = 259) Imatinib 400 mg QD (n = 260) DASISION: Comparison of Dasatinib and Imatinib in Newly Diagnosed CP CML 5-yr follow-up  Primary endpoint: confirmed CCyR at 12 mos  Key secondary endpoints: MMR, time in confirmed CCyR, time to confirmed CCyR and MMR, PFS, OS Stratified by Hasford risk score Kantarjian HM, et al. N Engl J Med. 2010;362:2260-2270.

17. clinicaloptions.com/oncology Chronic Myeloid Leukemia: Translating State-of-the-Art Practice to Patient Care DASISION 3-Yr Update: Cumulative Molecular Responses Hochhaus A, et al. ASCO 2012. Abstract 6504. Outcome, % Dasatinib 100 mg QD (n = 259) Imatinib 400 mg QD (n = 260) Cumulative MMR  1 yr 46*23  2 yrs 64*46  3 yrs 68*55 Cumulative MR 4  3 yrs 35 † 22 Cumulative MR 4.5  3 yrs 22 ‡ 12 *P <.0001 vs imatinib. † P =.00635 vs imatinib. ‡ P =.00069 vs imatinib.

18. clinicaloptions.com/oncology Chronic Myeloid Leukemia: Translating State-of-the-Art Practice to Patient Care DASISION 3-Yr Update: Progression to AP/BC 100 6 4 0 Progressed to AP/BP (%) 3.1 5.0 Hochhaus A, et al. ASCO 2012. Abstract 6504. n/N = 8/259 13/260 Imatinib 400 mg QD Dasatinib 100 mg QD

19. clinicaloptions.com/oncology Chronic Myeloid Leukemia: Translating State-of-the-Art Practice to Patient Care DASISION 3-Yr Update: Hematologic AEs and Biochemical Abnormalities Hochhaus A, et al. ASCO 2012. Abstract 6504. Grade 3/4 AEs, %Dasatinib 100 mg BID (n = 281) Imatinib 400 mg QD (n = 283) Neutropenia24.020.9 Thrombocytopenia19.411.2 Anemia11.68.5 Decreased phosphorus7.028.3 Decreased calcium3.11.9 Elevated creatinine1.20.8 Elevated total bilirubin1.20 Elevated ALT0.41.6 Elevated AST0.41.2 Decreased potassium02.3

20. clinicaloptions.com/oncology Chronic Myeloid Leukemia: Translating State-of-the-Art Practice to Patient Care ENESTnd [1] DASISION [2] OS Nilotinib 300 mg BID (n = 282) Nilotinib 400 mg BID (n = 281) Imatinib 400 mg QD (n = 283) 3-yr OS, %95.197.094.0  HR (95% CI) vs imatinib0.8 (0.4-1.6)0.5 (0.2-1.1)--  P value vs imatinib.44.064-- OS and PFS 1. Kantarjian HM, et al. ASCO 2012. Abstract 6509. 2. Hochhaus A, et al. ASCO 2012. Abstract 6504. 3-Yr Survival OutcomeDasatinib (n = 259) Imatinib (n = 260) HR (95% CI) PFS, %91.090.91.00 (0.55-1.80) OS, %93.793.20.86 (0.45-1.65) Deaths, n1720-

21. clinicaloptions.com/oncology Chronic Myeloid Leukemia: Translating State-of-the-Art Practice to Patient Care Monitoring Response and Compliance to First-line Therapy

22. clinicaloptions.com/oncology Chronic Myeloid Leukemia: Translating State-of-the-Art Practice to Patient Care Case  Patient received imatinib 400 mg/day and has peripheral blood BCR-ABL/ABL ratio of 1% IS at 3 mos  Achieves CCyR at 12 mos  Patient’s peripheral blood BCR-ABL/ABL ratio monitored with PCR every 3 mos –12 mos: 0.12% IS –15 mos: 0.15% IS –18 mos: 0.18% IS

23. clinicaloptions.com/oncology Chronic Myeloid Leukemia: Translating State-of-the-Art Practice to Patient Care Based on these PCR findings, what do you recommend? A.Send sample for mutation studies B.Check compliance and continue imatinib 400 mg/day C.Increase imatinib dose to 800 mg/day D.Switch to dasatinib 100 mg/day E.Switch to nilotinib 400 mg twice daily

24. clinicaloptions.com/oncology Chronic Myeloid Leukemia: Translating State-of-the-Art Practice to Patient Care Expert Insight: 5 CML Experts’ Clinical Recommendation

25. clinicaloptions.com/oncology Chronic Myeloid Leukemia: Translating State-of-the-Art Practice to Patient Care Disease Burden and Diagnostic Tests Time Dx Cytogenetics FISH RT-PCR Treatment CML (log 10 ) 1-2 log reduction ~ 5-6 log reduction MMR = 3 log

26. clinicaloptions.com/oncology Chronic Myeloid Leukemia: Translating State-of-the-Art Practice to Patient Care ResponseDescription of Monitoring HematologicAt diagnosis, then every 15 days until CHR has been achieved and confirmed, then at least every 3 mos or as required CytogeneticAt diagnosis, 3 mos, and 6 mos; then every 6 mos until CCyR has been achieved and confirmed; then every 12 mos if regular molecular monitoring cannot be assured; always for occurrences of treatment failure (primary or secondary resistance) and for occurrences of unexplained anemia, leukopenia, or thrombocytopenia Molecular by Q-RT-PCR Every 3 mos until MMR has been achieved and confirmed, then at least every 6 mos Molecular by mutational analysis In occurrences of suboptimal response or failure; always required before changing to other TKI or other treatments Baccarani M, et al. J Clin Oncol. 2009;27:6041-6051. Let’s make it 14 to be more practical … 2009 ELN Recommendations for Monitoring Response to CML Therapy

27. clinicaloptions.com/oncology Chronic Myeloid Leukemia: Translating State-of-the-Art Practice to Patient Care IRIS: Survival Without AP/BC Worse if No Major Cytogenetic Response at 12 Mos Druker BJ, et al. N Engl J Med. 2006;355:2408-2417. Without AP/BC (%) 0 20 40 60 80 100 Mos Since Randomization 0612182430364248546066 CCyR PCyR No major CyR Response at 12 Mos n = 350 97% n = 86 93% n = 73 81% Estimated Rate at 60 Mos P <.001 P =.20

28. clinicaloptions.com/oncology Chronic Myeloid Leukemia: Translating State-of-the-Art Practice to Patient Care IRIS: Response to Imatinib at 18 Mos and Outcome at 60 Mos Druker BJ, et al. N Engl J Med. 2006;355:2408-2417. CCyR with ≥ 3 log reduction CCyR with < 3 log reduction No CCyR Response at 18 Mos n = 139 100% n = 54 98% n = 88 87% Estimated Rate at 60 Mos P <.001 P =.11 100 80 60 40 20 0 Patients Without Progression (%) 0122436486072 Mos

29. clinicaloptions.com/oncology Chronic Myeloid Leukemia: Translating State-of-the-Art Practice to Patient Care IRIS: EFS at 84 Mos by Molecular Response to Imatinib at 12 Mos Hughes TP, et al. Blood. 2010;116:3758-3765. 100 80 60 40 20 0 01224364860728496 Estimated % Without Event BCR-ABL/ABL Ratio (IS) at 12 Mos ≤ 0.1% > 0.1% to ≤ 1.0% > 1.0% to ≤ 10% > 10% Mos Since Start of Treatment Event = loss of CHR or MCyR, progression to AP/BC, or death due to any cause. n = 15391.0% n = 90 91.7% n = 36 64.1% n = 2552.5% Estimated Rate at 84 Mos P =.001 P = NS

30. clinicaloptions.com/oncology Chronic Myeloid Leukemia: Translating State-of-the-Art Practice to Patient Care IRIS: Progression to AP/BC at 84 Mos by Molecular Response to Imatinib at 18 Mos 100 80 60 40 20 0 01224364860728496 Mos Since Start of Treatment Estimated % Without AP/BC BCR-ABL/ABL Ratio (IS) at 18 Mos ≤ 0.1% > 0.1% to ≤ 1.0% > 1.0% to ≤ 10% > 10% Hughes TP, et al. Blood. 2010;116:3758-3765. n = 16499.1% n = 48 95.7% n = 25 82.6% n = 1681.5% Estimated Rate at 84 Mos P <.001 P =.054

31. clinicaloptions.com/oncology Chronic Myeloid Leukemia: Translating State-of-the-Art Practice to Patient Care 2009 ELN Recommendations for Response Assessment Response Evaluation Time, Mos OptimalSuboptimalFailureWarning BaselineNA High risk; CCA/Ph+ 3CHR and at least minor CyR (Ph+ ≤ 65%) No CyR (Ph+ > 95%) < CHRNA 6At least partial CyR (Ph+ ≤ 35%) 35%) No CyR (Ph+ > 95%) NA 12CCyRPartial CyR (Ph+ 1% to 35%) < Partial CyR (Ph+ > 35%) < MMR 18MMR< MMR< CCyRNA Any time during treatment Stable or improving MMR Loss of MMR; mutations Loss of CHR, loss of CCyR, mutations, CCA/Ph+ Increase in transcript levels, CCA/Ph- Baccarani M, et al. J Clin Oncol. 2009;27:6041-6051.

32. clinicaloptions.com/oncology Chronic Myeloid Leukemia: Translating State-of-the-Art Practice to Patient Care Probability of Survival Yrs From Onset of Imatinib Therapy BCR-ABL/ABL< 9.84% 8-yr OS: 93.3% BCR-ABL/ABL > 9.84% 8-yr OS: 56.9% Marin D, et al. J Clin Oncol. 2012;30:232-238. P <.001 BCR-ABL/ABL Cutoff ~ 10% IS at 3 Mos Predicts OS Outcomes 1.0 0.8 0.6 0.4 0.2 0 013458762

33. clinicaloptions.com/oncology Chronic Myeloid Leukemia: Translating State-of-the-Art Practice to Patient Care Mos CCyR (%) 100 80 60 40 20 0 0612182430 DASISION: Cumulative Incidence of CCyR According to BCR-ABL Level at 3 Mos  Phase III RCT conducted in 519 patients with newly diagnosed CML in chronic phase [1]  Cumulative 2-yr CCyR with dasatinib vs imatinib: 86% vs 82% [1] Mos CCyR (%) Dasatinib 100 mg QD [2] Imatinib 400 mg QD [2] ≤ 1% > 1% to 10% > 10% 3-Mo BCR-ABL/ABL Ratio (IS) 1. Kantarjian HM, et al. Blood. 2012;119:1123-1129. 2. Hochhaus A, et al. ASH 2011. Abstract 2767. 100 80 60 40 20 0 0612182430

34. clinicaloptions.com/oncology Chronic Myeloid Leukemia: Translating State-of-the-Art Practice to Patient Care Kantarjian H, et al. ASH 2008. Abstract 445. 1.0 0.8 0.6 0.2 0 0122436486072 Mos From Q-PCR Increase Proportion With PFS 0.4  PFS by Q-PCR increase (excluded 4 non-CML deaths) P =.0001 Q-PCR ↑ > 1 log With Loss or Never MMRTotal, nProgression, n No Yes 72 44 1 10 Significance of Q-PCR Increase in CML

35. clinicaloptions.com/oncology Chronic Myeloid Leukemia: Translating State-of-the-Art Practice to Patient Care Long-term Adherence to Imatinib Is Critical for Achieving Molecular Response  Adherence to imatinib tracked for 3 mos in 87 consecutive CML patients with CCyR using microelectronic monitoring devices Marin D, et al. J Clin Oncol. 2010;28:2381-2388. MMRCMR Probability of MMR 0 0.8 1.0 Mos Since Start of Imatinib Therapy 0.6 0.4 0.2 061218243036424854606672 P <.001 Adherence > 90% (n = 64) Adherence ≤ 90% (n = 23) Probability of CMR 0 0.8 1.0 Mos Since Start of Imatinib Therapy 0.6 0.4 0.2 061218243036424854606672 P =.002 Adherence > 90% (n = 64) Adherence ≤ 90% (n = 23)

36. clinicaloptions.com/oncology Chronic Myeloid Leukemia: Translating State-of-the-Art Practice to Patient Care Choice of Second-line Therapy and Bone Marrow Transplantation

37. clinicaloptions.com/oncology Chronic Myeloid Leukemia: Translating State-of-the-Art Practice to Patient Care Case  Patient has now received imatinib 400 mg for 24 mos  At Mo 24 –BCR-ABL Q-RT-PCR positive at 2.23% –Bone marrow analysis consistent with chronic-phase disease –Cytogenetics show t(9;22)(q34;q11.2) in 3 out of 20 cells –F317L mutation identified in ABL

38. clinicaloptions.com/oncology Chronic Myeloid Leukemia: Translating State-of-the-Art Practice to Patient Care What would you recommend? A.Escalate to imatinib 800 mg/day B.Switch to dasatinib 100 mg/day C.Switch to nilotinib 400 mg twice daily D.Allogeneic BMT ASAP

39. clinicaloptions.com/oncology Chronic Myeloid Leukemia: Translating State-of-the-Art Practice to Patient Care Parameters to Consider When Deciding Whether to Change TKIs  Why are you considering a change? –Toxicity? –1º resistance (ie, suboptimal response)? –2º resistance (ie, loss of response)?

40. clinicaloptions.com/oncology Chronic Myeloid Leukemia: Translating State-of-the-Art Practice to Patient Care Options When BCR-ABL Transcripts Are Rising  If there is a 1 log increase in BCR-ABL transcript level –Evaluate patient compliance –If transcript levels are below defined MMR  repeat Q-PCR in 1-3 mos –If transcript levels are above defined MMR  obtain bone marrow cytogenetics –Consider ABL kinase domain mutation analysis NCCN. Clinical practice guidelines in oncology: chronic myelogenous leukemia. v.2.2012.

41. clinicaloptions.com/oncology Chronic Myeloid Leukemia: Translating State-of-the-Art Practice to Patient Care When to Test for BCR-ABL Mutations?  Probability of finding ABL kinase domain mutations [1] –Very low in patients with stable or declining BCR-ABL transcript levels –Low in treatment-naive patients with CP CML –Low in patients in stable CCyR  International consensus group devised clinical criteria for mutational testing, adopted by NCCN [2] 1. Hughes TP, et al. Blood. 2006;108:28-37. 2. NCCN. Clinical practice guidelines in oncology: chronic myelogenous leukemia. v.2.2012.

42. clinicaloptions.com/oncology Chronic Myeloid Leukemia: Translating State-of-the-Art Practice to Patient Care When to Consider Mutation Testing  ABL kinase domain mutation screening is recommended for patients with CP CML after inadequate initial response –Failure to achieve CHR at 3 mos –Failure to achieve minor CyR at 6 mos –Failure to achieve major CyR at 12 mos  ABL kinase domain mutation screening is recommended for patients in CP CML if there is any sign of loss of response –Hematologic relapse –Cytogenetic relapse –1 log increase in BCR-ABL transcript ratio and loss of MMR NCCN. Clinical practice guidelines in oncology: chronic myelogenous leukemia. v.2.2012.

43. clinicaloptions.com/oncology Chronic Myeloid Leukemia: Translating State-of-the-Art Practice to Patient Care 1. Hughes T, et al. J Clin Oncol. 2009;27:4204-4210. 2. Müller MC, et al. Blood. 2009;114:4944-4953. Mutational Summary for Resistance to Nilotinib and Dasatinib Nilotinib [1] Dasatinib [2] Specific mutations E255K/V Y253F/H F359C/V F317L Q252H 12 mo CCyR (n/N)0/26 1/14 (F317L) 1/6 (Q252H)  T315I: resistant to all currently (as of June 2012) approved TKIs

44. clinicaloptions.com/oncology Chronic Myeloid Leukemia: Translating State-of-the-Art Practice to Patient Care Phase II PACE Trial: Ponatinib in Second- Generation TKI-Resistant CML  Ponatinib: experimental oral BCR-ABL TKI –Active in multiple mutations including T315I  Heavily pretreated study population –≥ 2 TKIs: 93% –≥ 3 TKIs: 58% Cortes JE, et al. ASCO 2012. Abstract 6503. Patients with CML or Ph-positive ALL resistant or intolerant to dasatinib or nilotinib or with emergent T315I mutation Ponatinib 45 mg/day (n = 444)

45. clinicaloptions.com/oncology Chronic Myeloid Leukemia: Translating State-of-the-Art Practice to Patient Care PACE Trial: Efficacy, Safety Outcomes (Median Follow-up: 10.1 Mos for CP CML)  Ponatinib active in all patient subsets with CP CML  Generally well tolerated: grade ≥ 3 AEs in ≥ 10% of patients: elevated lipase (10%), thrombocytopenia (28%), neutropenia (17%) Cortes JE, et al. ASCO 2012. Abstract 6503. *CHR for CP CML, MaHR for AP CML and BP CML/ALL. Response, % CP CML (n = 271) AP CML (n = 79) BP CML/ALL (n = 94) R/IT315IR/IT315IR/IT315I CHR or MaHR* 9491 60503533 MCyR 4970 34562735 CCyR 3766 20332326 MMR 2350 917194

46. clinicaloptions.com/oncology Chronic Myeloid Leukemia: Translating State-of-the-Art Practice to Patient Care 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 ponatinib, other T315I inhibitors, HHT, HU, others as bridge to MRD, then allo SCT ASAP  Imatinib failure in chronic phase –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 yrs of CML control

47. clinicaloptions.com/oncology Chronic Myeloid Leukemia: Translating State-of-the-Art Practice to Patient Care Response at 12 Mos on Second- Generation TKIs Predicts Survival Tam CS, et al. Blood. 2008;112:516-518. 1.0 0.8 0.6 0.4 0.2 0 Proportion Alive 0 122436 Mos From 12-Mo Landmark on a Second-Generation TKI (N = 113; nilotinib: n = 43; dasatinib n = 70) PCyR or CCyR (= MCyR) miCyR or CHR Hematologic failure NDeaths, n PCyR/CCyR642 miCyR/CHR346 Hematologic failure 92 Alive at 12 Mos, % MCyR97 miCyR/CHR84 H. failure88 MCyR vs rest: P =.01

48. clinicaloptions.com/oncology Chronic Myeloid Leukemia: Translating State-of-the-Art Practice to Patient Care 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. Reprinted with permission. 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)

49. clinicaloptions.com/oncology Chronic Myeloid Leukemia: Translating State-of-the-Art Practice to Patient Care CML Treatment Paradigm: 2012 Advanced-phase CML CHEMO + TKI vs TKI alone Imatinib 400 mg BID Dasatinib 70 mg BID Nilotinib 400 mg BID CP CML Complete diagnostic workup Tumor burden by Q-RT-PCR Imatinib 400 mg/day Nilotinib 300 mg BID Dasatinib 100 mg/day Goals Heme CR in 1-2 mos Cyto response in 3-6 mos CCyR in 12-15 mos MMR in ~ 12 mos Allogeneic BMT @ progression Dasatinib Nilotinib No

50. clinicaloptions.com/oncology Chronic Myeloid Leukemia: Translating State-of-the-Art Practice to Patient Care Summary  Second-generation TKIs demonstrate significant short- term efficacy as first-line therapy  Unique toxicity profiles are seen with the different TKIs  Patient monitoring is important for optimal disease management  Second-generation TKIs are effective for some BCR-ABL mutations that mediate imatinib resistance  Ponatinib potential future option for CML resistant or intolerant to dasatinib or nilotinib or with emergent T315I mutation  ASCT is effective following TKI failure

51. Go Online for More CML Educational Programming! Optimal Clinical Management of Patients With Chronic Myeloid Leukemia: Proceedings of an Independent Expert Panel Interactive Decision Support Tool (Coming Soon) Online Presentation: The Importance of Patient Compliance to TKI Therapy clinicaloptions.com/TreatingCML