Elias Jabbour, MD University of Texas – M. D. Anderson Cancer Center

1. CML and Imatinib Resistance: Which TKI and When? Elias Jabbour, MD University of Texas – M. D. Anderson Cancer Center

2. CML and Imatinib Resistance: Which TKI and When? Marcos de Lima, MD Stem Cell Transplantation Program Case Western Reserve University University Hospitals Seidman Cancer Center Cleveland - OH

3. 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 et al; Blood 2009; 114: Abst# 1126

4. IRIS 8-Year Update 37% Unacceptable Outcome Deininger et al; Blood 2009; 114: Abst# 1126

5. IRIS. Survival Without AP/BC Worse If No Major CG Response at 12 mos Rx aim: major CG response (Ph ≤ 35%) Response at 12 months Estimated rate at 60 months   n= 350 97% CCyR p=0.20 p<0.001 n= 86 93% PCyR n= 73 81% No MCyR 5

6. Criteria for Failure and Suboptimal Response to Imatinib Baccarani. JCO 2009; 27: 6041-51

7. NCCN Treatment Recommendations3-Month Follow-up Therapy No relapse Monitor with QPCR every 3 mo BCR-ABL transcript levels ≤10% by QPCR International Scale (IS) or PCyR on bone marrow cytogenetics Continue same dose of IM, DAS, or NIL Relapse 3-moevaluation DAS 100 mg daily BCR-ABL transcript levels >10% by QPCR using the IS or <PCyR on bone marrow cytogenetics • Evaluate patient compliance and drug-drug interactions • Mutational analysis NIL 400 mg BID Evaluation and discussion of HSCT Clinical trial National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: chronic myelogenous leukemia. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp. Revised September 13, 2012.

8. Adherence Is the Most Important Factor Contributing to Molecular Responses 1.0 Adherence >90% (n = 64) 0.9 Adherence ≤90% (n = 23) 0.8 P<0.001 0.7 0.6 Probability of MMR 0.5 0.4 0.3 0.2 0.1 0 6 12 18 24 30 36 42 48 54 60 66 72 Time Since Start of Imatinib Therapy (months) Adherence monitored over a period of 3 months using a microelectronic monitoring device in the imatinib bottle cap. Patients were not aware of the device. Marin D et al. J Clin Oncol. 2010;28(14):2381-2388.

9. EFS by Response to IM at 6 and 12 Mos • 281 pts; imatinib frontline (400mg in 73, 800mg in 208) • Suboptimal response at 6-12 months: 12-17% with 400mg, 1-4% with 800mg (p=0.002) 6 month response 12 month response Alvarado. Cancer. 2009;115:3709-18.

10. MDACC Retrospective Analysis: MCyR at 6 Months Associated With OS Landmark analysis at 6 mos 1.0 0.8 0.6 0.4 0.2 0 Proportion alive 0.85 0.01 0.62 0 12 24 36 48 60 72 Months Patients with MCyR have better OS than patients that do not Kantarjian H. Cancer. 2008;112:837–845.

11. MDACC Retrospective Analysis: CCyR at 12 Months Associated With PFS Landmark analysis at 12 mos 1.0 0.8 0.6 0.4 0.2 0 Proportion PFS 0.02 0.2 0.22 0 12 24 36 48 60 72 Months Patients with CCyR have better PFS than patients that do not. Similar results were observed in patients achieving CCyR at 18 and 24 mos. Kantarjian H. Cancer. 2008;112:837–845.

12. EFS and Survival by 12-month Response-CCyR with vs without MMR with TKI Frontline Rx Jabbour E et al. Blood. 2011.

13. Outcome by 12-Month Response in CML CP CCyR Hehlman et al. JCO 2011;29:1634-42

14. Survival After Imatinib Therapy by Molecular Response Achieved at 3 Months • Optimal PCR value determined by Receiver operating characteristic (ROC) curve BCR-ABL/ABL<9.8% OS= 93.3% Probability of survival BCR-ABL/ABL>9.8% OS= 54% p<0.0001 Time from onset of imatinib therapy (years) Marin et al, JCO 2011; [Epub ahead of print]

15. CML IV: Long-Term Impact of Response at 3 Months Hanfstein et al. ASH 2011; Abstract #783

16. OS by Response to TKI at 3 Months at MDACC Naqvi et al. ASH 2011; Abstract #3784

17. EFS by Response to TKI at 3 Months at MDACC Naqvi et al. ASH 2011; Abstract #3784

18. Failure On Imatinib And Strategies

19. Imatinib Dose Escalations • Similar results from IRIS 3 1Kantarjian Blood 101:473, 2003 2Jabbour Blood 113:2154, 2008 3Kantarjian Cancer 115:551, 2008

20. 2nd Generation TKI in CML

21. Phase II Studies of Dasatinib After Imatinib Failure Blood 110:abst 470 and 734, 2007.

22. Optimal Dose and Schedule of Dasatinib IN CML CP after Imatinib Failure Shah. Blood 112:abst 3225, 2008

23. Phase II Studies of Nilotinib After Imatinib Failure Blood 112:abst 3229, 3238, 2008.

24. Nilotinib in Chronic Phase CML Post Imatinib Failure 321 pts; nilotinib 400 mg BID; median FU 19 mos; median nilotinib 788 mg/D; median days off 20 Kantarjian. Blood 114:abst 1129; 2009

25. Nilotinib in CML Chronic Phase. Survival and PFS 95% 91% 88% 10 0 84% 9 0 73% 8 0 64% 7 0 6 0 5 0 4 0 3 0 2 0 1 0 0 0 3 6 9 12 15 18 21 24 27 30 33 Time in mos % Progression-free survival Kantarjian. Blood 112:abst 3238, 2008

26. Bosutinib in CML-CP post imatinib failure • 288 pts Rx with bosutinib 500 mg/D: Imatinib resistant 200; intolerant 88 • ParameterPercent -CHR 86 -MCyR 53 -CCyR 41 -MMR if CCyR 64 -2-yr PFS 79 2-yr OS 92 • Side effects: diarrhea 9%, rash 9% Cortes. Blood 118: 4567;2012

27. Response to Bosutinib 3rd Line Therapy Khoury. Blood 119:3403;2012

28. 2nd Generation TKI in CML CP Post-Imatinib Resistance Shah et al. Haematologica 2010; 95: 232-40 Kantarjian et al. Blood 2011; 117: 1141-45 Cortes et al. Blood 2011; 118; 4567-76

29. 2nd-Generation TKI in CML CP Post- Imatinib Failure

30. 2nd-Generation TKI in CML CP Post- Imatinib Failure Shah et al. Haematologica 2010; 95: 232-40 Kantarjian et al. Blood 2011; 117: 1141-45 Cortes et al. Blood 2011; 118; 4567-76

31. Better Outcome on Dasatinib with Earlier Intervention Patients on dasatinib studies analyzed by failure status on imatinib: loss of MCyR vs loss of CHR Quintás-Cardama. Cancer 115: 2912-21, 2009

32. Dasatinib Early InterventionEFS & OS Event-Free Survival Overall Survival Time to intervene: Loss of MCyR Quintás-Cardama. Cancer 115: 2912-21, 2009

33. Prognosis with 2nd TKIs. Survival • Adverse factors: PS ≥1 and lack of CyR to imatinib Jabbour. Blood 117: 1822-7, 2011

34. PFS and Response to 2nd TKI 1 0.8 0.6 No MCyR (27) PFS (%) 0.4 0.2 MCyR (59) 0 0 12 24 36 Months on second TKI • 113 CML CP pts receiving nilotinib (n=43) or dasatinib (n=70) after imatinib failure p = 0.003 Tam. Blood 112: 516-8, 2008

35. Optimal Response to 2nd TKIs. Survival

36. 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 Hx - Hypertension, CHF, lung problems, COPD → avoid dasatinib, consider bosutinib/nilotinib - Severe diabetes, pancreatitis Hx, atherosclerosis → avoid nilotinib, consider bosutinib/dasatinib - QTc problems → be cautious with all (?)

37. Ponatinib Phase 2 Study - PACE Response Characteristics CP-CML Cortes J, et al. Blood. 2012;120: Abstract 163.

38. Ponatinib Phase 2 Study - PACE Response by Baseline Mutation CP-CML Number of Patients P-Loop Non P-Loop Baseline Mutations in at Least 2 Patients (Excluding T315I) Cortes J, et al. Blood. 2012;120: Abstract 163.

39. Ponatinib Phase 2 Study - PACE Response in Advanced Phase *MaHR = primary endpoint; 14 AP-CML patients with baseline MaHR and 1 AP-CML patient with no baseline MaHR assessment counted as non-responders **CCyR + PCyR + minor CyR + minimal CyR #MMR was assessed on the International Scale using peripheral blood; Patients missing a valid baseline MMR assessment , or who met the criteria for MMR at baseline, were counted as non-responders Kantarjian HM, et al. Blood. 2012;120: Abstract 915.

40. Omacetaxine for CML CP After Failure to ≥2 TKI Kantarjian HM, et al. Blood. 2012;120: Abstract 2767.

41. Allo SCT. Second or Third Salvage? • Imatinib failure in AP, BP: use new TKI as bridge to MRD, then alloSCT 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 CP: • 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 • Age  70 yrs or if poor match: may decide to forgo curative allo SCT option for several years of CML control; • Young patient (?) • Financial considerations

42. Monitoring Patients with CML While on TKI Therapy • Adequate monitoring required to optimize outcome / Not too much, not too little • CCyR is associated with survival benefit • MMR is associated with durable CCyR and may therefore decrease probability of relapse • CMR offers hope for treatment discontinuation (clinical trials only) • Results should be interpreted in the context of alternative options • Not failure criterion / QPCR  in CCyR

43. CML in 2013 Imatinib,nilotinib,dasatinib are standard frontline Rx (except p190 CML) Dose optimization and adequate monitoring Sub-optimal response  dose imatinib (400mg → 800mg) New TKI Failure Dasatinib, nilotinib, bosutinib Allogeneic SCT T315I: ponatinib, omacetaxine

44. Questions? ejabbour@mdanderson.org Marcos.delima@uhhospitals.org