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

2. 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. 5 IRIS. Survival Without AP/BC Worse If No Major CG Response at 12 mos Estimated rate at 60 months n= 86 93% n= 73 81% n= 350 97%  p<0.001  p=0.20 CCyR PCyR No MCyR Response at 12 months Rx aim: major CG response (Ph ≤ 35%)

6. Criteria for Failure and Suboptimal Response to Imatinib Time (mo) Response FailureSuboptimalOptimal 3No CHR No CG Response < 65% Ph+ 6 No CHR >95% Ph+ ≥35% Ph+≤35% Ph+ 12≥35% Ph+1-35% Ph+0% Ph+ 18≥5% Ph+ No MMRMMR Any Loss of CHR Loss of CCgR Mutation CE Loss of MMR Mutation Stable or improving MMR Baccarani. JCO 2009; 27: 6041-51

7. NCCN Treatment Recommendations 3-Month Follow-up Therapy BCR-ABL transcript levels ≤10% by QPCR International Scale (IS) or PCyR on bone marrow cytogenetics BCR-ABL transcript levels ≤10% by QPCR International Scale (IS) or PCyR on bone marrow cytogenetics BCR-ABL transcript levels >10% by QPCR using the IS or <PCyR on bone marrow cytogenetics BCR-ABL transcript levels >10% by QPCR using the IS or <PCyR on bone marrow cytogenetics Continue same dose of IM, DAS, or NIL Evaluate patient compliance and drug-drug interactions Mutational analysis Evaluate patient compliance and drug-drug interactions Mutational analysis Monitor with QPCR every 3 mo DAS 100 mg daily NIL 400 mg BID Evaluation and discussion of HSCT Clinical trial 3-mo evaluation 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. No relapse Relapse

8. Adherence Is the Most Important Factor Contributing to Molecular Responses Marin D et al. J Clin Oncol. 2010;28(14):2381-2388. 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. 0.1 12 Time Since Start of Imatinib Therapy (months) 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0 618243036424854606672 Probability of MMR Adherence >90% (n = 64) Adherence ≤90% (n = 23) P<0.001

9. EFS by Response to IM at 6 and 12 Mos 6 month response 12 month response 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) Alvarado. Cancer. 2009;115:3709-18.

10. MDACC Retrospective Analysis: MCyR at 6 Months Associated With OS Patients with MCyR have better OS than patients that do not Landmark analysis at 6 mos 0122436486072 Cytogenetic response at 6 mosTotalDeadP-value Complete2015 Partial391 Minor103 Others a 93 0.85 0.01 0.62 1.0 0.8 0.6 0.4 0.2 0 Proportion alive Months Kantarjian H. Cancer. 2008;112:837–845.

11. MDACC Retrospective Analysis: CCyR at 12 Months Associated With PFS Patients with CCyR have better PFS than patients that do not. Similar results were observed in patients achieving CCyR at 18 and 24 mos. Landmark analysis at 12 mos Proportion PFS 1.0 0.8 0.6 0.4 0.2 0 0122436486072 Months Cytogenetic response at 12 mosTotalFailureP-value Complete2147 Partial193 Minor52 Others85 0.02 0.2 0.22 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 848 pts randomized to IM 400mg, IM 800mg, or IM 400 + IFN Median FU: 40 months 12-month BCR-ABL/ABL (IS) N Percentage PFSOS <0.1%34199 0.1-1%2409798 >1%2679493 P value 0.00230.0011 Outcome independent of treatment arm Hehlman et al. JCO 2011;29:1634-42 CCyR

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

15. CML IV: Long-Term Impact of Response at 3 Months 1223 pts randomized to imatinib 400, imatinib + IFN, imatinib + ara-C, imatinib 800 3 month analysis: PCR in 692 pts, cytogenetics in 460 3 mo transcript levels predictive of achievement of CCyR and MMR % 5-year outcome Cytogenetics (% Ph+) Molecular [BCR-ABL/ABL (IS)] ≤35%>35%≤10%>10% PFS94879387 OS95879587 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 Imatinib Failure  Imatinib Second Generation TKI Ph 100% at 6 mos_+ Ph ≥ 35% at 12 mos ++ No CGCR in yr 2++ CG relapse++ Hematologic relapse _ +

19. Imatinib Dose Escalations % 2-yr Resistance 1,2 No.% CG CRTFSOS Cytogenetic63528090 Hematologic2155167 Similar results from IRIS 3 1 Kantarjian Blood 101:473, 2003 2 Jabbour Blood 113:2154, 2008 3 Kantarjian Cancer 115:551, 2008

20. 2 nd Generation TKI in CML ParameterDasatinibNilotinibBosutinib Potency (fold vs IM)3253020-50 TargetSrc & AblAblSrc & ABL BCR-ABL bindingActive + InactiveInactiveIntermediate Resistant mutationsT315I Mutations with intermediate sensitivity E255K/V, V299L, F317L E255K/V, Y253F/H, Q252H, F359V E255V/K, V299L, F317L Standard dose (CP)100mg QD400mg BID500mg QD Grade 3-4 neutropenia & thrombocytopenia 33% / 22%31% / 33%12% / 21% Other notable toxicities Pleural effusion, bleeding Bilirubin, lipase elevation Diarrhea, rash C-kit inhibition (vs imatinib) IncreasedSimilarNone PDGFR inhibition (vs imatinib) IncreasedSimilarNone Clinical activityHighly active

21. Phase II Studies of Dasatinib After Imatinib Failure Response Percent by Disease Stage CP n=387 AP n=174 MyBP n=109 LyBP n=48 ALL n=46 Hematologic9164503949 CHR9150262935 NEL-14767 Cytogenetic6240475862 Complete5333274654 Partial97762 Blood 110:abst 470 and 734, 2007.

22. Baccarani. Blood 112:abst 450, 2008 Optimal Dose and Schedule of Dasatinib IN CML CP after Imatinib Failure % Parameter 100mg QD N=166 50mg BID N=166 140mg QD N=163 70mg BID N=167 MCyR63616361 CGCR50 54 24-months PFS80767576 Neutropenia, G3-435474445 Thrombocytopenia, G3-423364138 Pleural effusion, G3-42455 Interruption58666971 Reduction33455457 Shah. Blood 112:abst 3225, 2008

23. Phase II Studies of Nilotinib After Imatinib Failure Response Percentage CP n =321 AP n =137 MyBP n =106 LyBP n =30 HR77542420 CHR76261213 Cytogenetic Major59313850 Complete44192833 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 OutcomePercent - CGCR46 - MMR28 (56% of CGCR) - 24-mos PFS64 - 24-mos OS87 Kantarjian. Blood 114:abst 1129; 2009

25. Nilotinib in CML Chronic Phase. Survival and PFS Kantarjian. Blood 112:abst 3238, 2008 % Progression-free survival

26. Summary of Bosutinib - Preclinical Activity Orally bioavailable Potent dual Src/Abl inhibitor Minimal inhibitory activity against PDGFR and c-KIT Inhibits Bcr-Abl signaling in CML cells Active against imatinib-resistant mutants of Bcr-Abl, except T315I Boschelli DH, et al. J Med Chem. 2005;48:3891-3902; Golas JM, et al. Cancer Res. 2003;63:375-381; Puttini M, et al. Cancer Res. 2006;66:11314-22.

27. Bosutinib in CML-CP post imatinib failure 288 pts Rx with bosutinib 500 mg/D: Imatinib resistant 200; intolerant 88 ParameterPercent -CHR86 -MCyR53 -CCyR41 -MMR if CCyR64 -2-yr PFS79 2-yr OS92 Side effects: diarrhea 9%, rash 9% Cortes. Blood 118: 4567;2012

28. Response to Bosutinib 3 rd Line Therapy Dual Src & Abl inhibitor, no effect over c-kit or PDGFR 118 pts who failed imatinib (600mg) & dasatinib or nilotinib Response, % IM + D resistant (n = 37) IM + D intolerant (n = 50) IM + NI resistant (n = 27) CHR508077 MCyR313032 CCyR142827 PCyR1728 MMR33511 2-yr PFS226150 2-yr OS6685100 IM, imatinib; D, dasatinib; NI, nilotinib. Khoury. Blood 119:3403;2012

29. 2 nd Generation TKI in CML CP Post-Imatinib Resistance Response Percentage DasatinibNilotinibBosutinib FU (mo)>24 24* CHR897786 MCyR595654 CCyR4441 24 mo PFS**80%64%79% 24 mo OS**91%87%92% * Median ** All patients Shah et al. Haematologica 2010; 95: 232-40 Kantarjian et al. Blood 2011; 117: 1141-45 Cortes et al. Blood 2011; 118; 4567-76

30. 2 nd -Generation TKI in CML CP Post- Imatinib Failure ToxicityDasatinibNilotinibBosutinib Pleural effusion++-- Liver+++ Transaminases++++ Bilirubin-++- Rash++++ Diarrhea--++ Lipase- (+)++- Glucose-++- Hypophosphatemia++ + Bleeding+-- QTc++ -

31. 2 nd -Generation TKI in CML CP Post- Imatinib Failure ToxicityDasatinibNilotinibBosutinib Anemia131113 Neutropenia353118 Thrombocytopenia233024 Shah et al. Haematologica 2010; 95: 232-40 Kantarjian et al. Blood 2011; 117: 1141-45 Cortes et al. Blood 2011; 118; 4567-76

32. Better Outcome on Dasatinib with Earlier Intervention Patients on dasatinib studies analyzed by failure status on imatinib: loss of MCyR vs loss of CHR Status at IM FailureNo. Percentage CCyR MMR Loss of MCyR1517260 Loss of CHR & MCyR334229 Loss of CHR (never MCyR)10926 Quintás-Cardama. Cancer 115: 2912-21, 2009

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

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

35. No MCyR (27) MCyR (59) 0 0.2 0.4 0.6 0.8 1 0122436 Months on second TKI PFS (%) PFS and Response to 2 nd TKI Response @ 12 mo % AP/BP/Death/CHR loss Next Year MCyR3% No MCyR17% 113 CML CP pts receiving nilotinib (n=43) or dasatinib (n=70) after imatinib failure Tam. Blood 112: 516-8, 2008 p = 0.003

36. Optimal Response to 2 nd TKIs. Survival % 3-month% 3-year ParameterCategoryNoCCyRp-valueEFSpOSp-value Clonal evolutionNo9430 0.35 54 0.46 87 0.22 Yes28414871 CML duration (year)0-32746 0.3 41 0.56 78 0.89 4-541325683 ≥655295587 CHR at the start of 2 nd TKINo3942 0.21 53 0.63 90 0.40 yes84295281 Best response to imatinibIntolerant875 0.001 50 <0.001 100 0.02 MCyR55446787 mCyR22185281 No CyR32133081 No data6334050 Performance status 08930 0.49 56 0.02 91 <0.001 ≥12938 59 %ph at the start ≤903558 0.001 66 0.03 91 0.41 >9082244580 Prior IFN No5341 0.12 54 0.76 79 0.85 Yes70285187 Mutation statusNone4236 0.09 55 0.22 81 0.09 Low IC50 23444587 Int IC50 1282550 Not done43NA % 3-month% 3-year ParameterCategoryNoCCyRp-valueEFSpOSp-value Clonal evolutionNo9430 0.35 54 0.46 87 0.22 Yes28414871 CML duration (year)0-32746 0.3 41 0.56 78 0.89 4-541325683 ≥655295587 CHR at the start of 2 nd TKINo3942 0.21 53 0.63 90 0.40 yes84295281 Best response to imatinibIntolerant875 0.001 50 <0.001 100 0.02 MCyR55446787 mCyR22185281 No CyR32133081 No data6334050 Performance status 08930 0.49 56 0.02 91 <0.001 ≥12938 59 %ph at the start ≤903558 0.001 66 0.03 91 0.41 >9082244580 Prior IFN No5341 0.12 54 0.76 79 0.85 Yes70285187 Mutation statusNone4236 0.09 55 0.22 81 0.09 Low IC50 23444587 Int IC50 1282550 Not done43NA 3-year survival (%) ParameterEvent-freeOverall CCyR by 3 monthsYes7498 No4379

37. 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 (?)

38. Ponatinib Phase 2 Study - PACE Response Characteristics CP-CML 93% failed ≥2 TKI, 58% failed ≥3 TKI Response Rate, n (%) N=267 Any Cytogenetic Response 180 (67) MCyR 149 (56) CCyR 124 (46) MMR 91 (34) MR 4.5 39 (15) BCR-ABL ≤10% at 3 months, n/N(%) 142/240 (59) 1 prior approved TKI 14/16 (88) Median Time to Response *, months [range] MCyR2.8 [1.6 – 11.3] MMR5.5 [1.8 – 19.2] 91% MCyR sustained at 12 months (K-M) Cortes J, et al. Blood. 2012;120: Abstract 163.

39. Ponatinib Phase 2 Study - PACE Response by Baseline Mutation CP-CML Baseline Mutations in at Least 2 Patients (Excluding T315I) P-LoopNon P-Loop Number of Patients MCyR CP-CML N=267 n/N (%) R/I, no mutation 66/136 (49) R/I, any non-T315I mutation 38/67 (57) T315I mutation 45/64 (70) Cortes J, et al. Blood. 2012;120: Abstract 163.

40. Ponatinib Phase 2 Study - PACE Response in Advanced Phase n (%) AP-CML N=83 BP-CML N=62 Ph+ ALL N=32 Myeloid N=52 Lymphoid N=10 MaHR*47 (57)15 (29)4 (40)13 (41) Any CyR** 46 (55)19 (37)5 (50)15 (47) MCyR 32 (39)10 (19)4 (40)15 (47) CCyR 20 (24)8 (15)3 (30)12 (38) MMR # 13 (16) N/A *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.

41. Omacetaxine for CML CP After Failure to ≥2 TKI 122 pts with CML CP (n=81) or AP (n=41) with ≥2 prior TKI Omacetaxine 1.25 mg/m 2 BID x14d, then x7d Response, % CP N=81 AP N=41 Primary endpointMCyR 20%MaHR 27% CCyR 10%CHR 24% Median duration, mo17.79 Median PFS, mo9.64.7 Median OS, mo33.916 11 pts (9 CP, 2 AP) ongoing response Median 35 cycles over median 39 months Median response duration: 14 mo CP, 24 mo AP Kantarjian HM, et al. Blood. 2012;120: Abstract 2767.

42. 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

43. 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

44. 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

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