Current State of CML Management. Phillip le Coutre, MD Charité-University Medicine Berlin Berlin, Germany

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2 Current State of CML Management Phillip le Coutre, MD Charité-University Medicine Berlin Berlin, Germany

3 1845 R. Virchow J. Bennett Berlin Edinburgh Geary CG. Br J Haematol. 2000;110(1):2-11.

4 QoL, quality of life; TKI, tyrosine kinase inhibitor Bjorkholm M, et al. J Clin Oncol. 2011;29(18): Mahon FX, et al. Lancet Oncol. 2010;11(11): Huang X, et al. Cancer. 2012;118(12): Cumulative Relative Survival Challenges in CML Bjorkholm et al. J Clin Oncol Time Since Diagnosis, Years Prevalence of CML in the USA, adapted from M. Talpaz Huang et al. Cancer , , Discontinuation of Imatinib CMR 60 Mahon et al. Lancet Oncol T315I (clonal evolution, compound mutations) Accelerated phase/blast crisis TKI intolerance/toxicities QoL (adherence, pregnancies, etc) Cost of therapy Months Since Discontinuation of Imatinib

5 CML: Evolution of Therapy Survival Probability Imatinib, (CML IV) 5-year survival 90% 10-year survival 84% n = 3682 IFN-α or SCT, (CML IIIA) 5-year survival 71% 10-year survival 61% IFN-α or SCT, (CML III) 5-year survival 63% 10-year survival 48% IFNα, ± HU, (CML I,II) 5-year survival 53% 10-year survival27% Hydroxyurea, , 5-year survival 44%, 10-year survival 18% Busulfan, , 5-year survival 38%, 10-year survival 11% Years After Diagnosis 1960 acml IV; bcml IIIA; ccml III. HU, hydroxyurea; IFN-α, Interferon-alpha; SCT, stem cell transplant German CML Study Group, Update 2013.

6 TKI Efficacy

7 ENESTnd Study Design N = centers 35 countries R A N D O M I Z E Nilotinib 300 mg BID (n = 282) Nilotinib 400 mg BID (n = 281) Imatinib 400 mg QD (n = 283) Follow-up: 5 years; extended to 10 years after protocol amendment Patients were stratified according to Sokal risk score at diagnosis BID, twice daily; QD, once daily Saglio G, et al. Blood. 2013;122: Abstract 92.

8 DASISION (CA ) Study Design Treatment-naïve CML-CP patients (N = 519) 108 centers 26 countries Enrollment: September 2007 December 2008 Dasatinib 100 mg QD (n = 259) Long-term Randomized a follow-up Imatinib 400 mg QD (n = 260) a Stratified by EURO (Hasford) risk score Primary endpoint: confirmed CCyR by 12 months 77% dasatinib versus 66% imatinib (P =.007) 1 CCyR, complete cytogenetic response, CP, chronic phase 1. Kantarjian H, et al. N Engl J Med. 2010;362(24): DASISION (CA ): NCT Cortes J, et al. Blood. 2013;112: Abstract 653.

9 ENESTnd Cumulative Incidence of MMR Nilotinib 300 mg BID (n = 282) Nilotinib 400 mg BID (n = 281) Imatinib 400 mg QD (n = 283) By 1 Year a By 4 Years a By 5 Years a Patients With MMR, % %, P< %, P<.0001 Δ 24% to 28% 27% 76%, P< %, P<.0001 Δ 17% to 20% 56% 77%, P< %, P<.0001 Δ 17% 60% Time Since Randomization, Calendar Years MMR, major molecular response (BCR-ABL IS 0.1%). a Cumulative response rates reported consider each year to consist of twelve 28-day cycles. Hughes T, et al. Haematologica ;99(Suppl 1): Abstract S677.

DASISION Cumulative Rate of MMR 100 P<.0001 Dasatinib 100 mg QD Imatinib 400 mg QD % With MMR 80 60 40 1.6-fold higher likelihood of achieving MMR with dasatinib; HR = 1.55 (1.26-1.

10 DASISION Cumulative Rate of MMR 100 P<.0001 Dasatinib 100 mg QD Imatinib 400 mg QD % With MMR fold higher likelihood of achieving MMR with dasatinib; HR = 1.55 ( ) 46% 64% 46% 69% 55% 74% 60% 76% 63% 20 23% Months MMR, major molecular response; BCR-ABL (IS) 0.1%; IS, International Scale Cortes J, et al. Blood. 2013;122: Abstract 653. Hasford Risk Score MMR 4-Year Cumulative Rates Low Intermediate High Dasatinib 90% 70% 65% Imatinib 69% 63% 52%

11 ENESTnd Cumulative Incidence of MR Nilotinib 300 mg BID (n = 282) Nilotinib 400 mg BID (n = 281) Imatinib 400 mg QD (n = 283) Patients With MR 4.5, % Δ 6% to 10% By 1 Year a 11%, P< %, P< % By 4 Years a 40%, P< %, P =.0002 Δ 14% to 17% 23% By 5 Years a 54%, P< %, P<.0001 Δ 21% to 23% % Time Since Randomization, Calendar Years MR 4.5, molecular response 4.5-logs (BCR-ABL IS %). a Cumulative response rates reported consider each year to consist of twelve 28-day cycles. Saglio G, et al. Blood. 2013;122: Abstract 92.

12 DASISION Cumulative Rate of MR 4 and MR 4.5 Dasatinib 100 mg QD Imatinib 400 mg QD % With MR P = % 5% MR 4 MR % 53% 35% 42% 28% 35% 22% 17% % With MR P = % 18% 3% 12% 9% 2% 34% 21% 37% 30% Months Months MR 4 = BCR-ABL (IS) 0.01%; MR 4.5 = BCR-ABL (IS) % Cortes J, et al. Blood. 2013;122: Abstract 653.

ENESTnd Progression to AP/BC on Core Treatment a P =.0185 P =.0085 P =.0059 P =.0009 4.2% 0.7% 1.1% 6.0% 1.1% 1.

13 ENESTnd Progression to AP/BC on Core Treatment a P =.0185 P =.0085 P =.0059 P = % 0.7% 1.1% 6.0% 1.1% 1.8% Imatinib 400 mg QD (n = 283) Nilotinib 300 mg BID (n = 282) Nilotinib 400 mg BID (n = 281) No new progressions on core treatment (excluding or including clonal evolution) in year 5 a Includes progression to AP/BC or deaths in patients with advanced CML occurring on core treatment. AP, acute phase; BC, blast crisis Saglio G, et al. Blood. 2013;122: Abstract 92.

14 DASISION Transformation to AP/BP CML by 4 Years Patients, n Dasatinib 100 mg QD 8 (3.1%) On Study 14 (5.4%) Imatinib 400 mg QD 18 (6.9%) 12 (4.6%) Including Follow-Up Beyond Discontinuation (ITT) a One patient (on imatinib) transformed on study between 3 and 4 years a Yearly evaluations after discontinuation are currently stipulated per protocol; additional information on patient status may be provided by investigators at other times. ITT, intent to treat Cortes J, et al. Blood. 2013;122: Abstract 653.

DASISION BCR-ABL Level at 3 Months a 84% Dasatinib 100 mg QD Imatinib 400 mg QD 64% % of Patients >1-10% >1-10% 36% 1% 16% 1% n/n 198/235 154/239 37/235 85/239 10%

15 DASISION BCR-ABL Level at 3 Months a 84% Dasatinib 100 mg QD Imatinib 400 mg QD 64% % of Patients >1-10% >1-10% 36% 1% 16% 1% n/n 198/ /239 37/235 85/239 10% >10% a Calculated from total number of evaluable patients with PCR assessments at 3 months. Cortes J, et al. Blood. 2013;122: Abstract 653. BCR-ABL Level at 3 Months

PFS BCR-ABL IS at 3 Months 10% vs >10% (Imatinib-Based Therapy) 1.0 0.9 0.8 10% >10% Probability of PFS 0.7 0.6 0.5 0.4 0.3 0.

16 PFS BCR-ABL IS at 3 Months 10% vs >10% (Imatinib-Based Therapy) % >10% Probability of PFS BCR-ABL IS n 5-Year PFS 10% % >10% % P Value Hanfstein B, et al. Leukemia. 2012;26(9): Years After Diagnosis

17 OS BCR-ABL IS at 3 Months 10% vs >10% (Imatinib-Based Therapy) Survival Probability BCR-ABL IS n 5-Year OS 10% % >10% % P Value < % >10% Years After Diagnosis Hanfstein B, et al. Leukemia. 2012;26(9):

DASISION PFS According to BCR-ABL Levels at 3 Months a Dasatinib 100 mg QD 84% had 10% BCR-ABL Imatinib 400 mg QD 64% had 10% BCR-ABL 100 100 % Not Progressed 80 60 40 20 0 4-year PFS 10% = 91.

18 DASISION PFS According to BCR-ABL Levels at 3 Months a Dasatinib 100 mg QD 84% had 10% BCR-ABL Imatinib 400 mg QD 64% had 10% BCR-ABL % Not Progressed year PFS 10% = 91.8% >10% = 67.1% BCR-ABL at 3 months 1% >1-10% >10% P = year PFS 10% = 95.2% >10% = 70.3% BCR-ABL at 3 months 1% >1-10% >10% P< Months Months a Calculated from total number of evaluable patients with PCR assessments at 3 months. Cortes J, et al. Blood. 2013;122: Abstract 653.

ENESTnd PFS (AP/BC or Death) on Study by BCR-ABL Levels at 3 Months Nilotinib 300 mg BID Imatinib 400 mg QD EMR Failure: 9% of pts EMR Failure: 33% of pts Patients Without Progression, % 100 90 80 70

19 ENESTnd PFS (AP/BC or Death) on Study by BCR-ABL Levels at 3 Months Nilotinib 300 mg BID Imatinib 400 mg QD EMR Failure: 9% of pts EMR Failure: 33% of pts Patients Without Progression, % BCR-ABL Level 1% >1% to 10% >10% Censored Observations Pts Evt Cen PFS by 5 Years a 94.6% 95.3% 78.3% Time Since Randomization, Calendar Years P =.9814 P =.0010 Patients Without Progression, % BCR-ABL Level 1% >1% to 10% >10% Censored Observations Pts Evt Cen PFS by 5 Years a 98.5% P = % P< % Time Since Randomization, Calendar Years Overall rates of BCR-ABL 10% at 3 months by treatment arm: Imatinib 400 mg QD, 67% Nilotinib 300 mg BID, 91% Cen, censored; EMR, early molecular response; Evt, events; Pts, patients a PFS rates reported consider each year to consist of twelve 28-day cycles. Saglio G, et al. Blood. 2013;122: Abstract 92.

20 Therapeutic Goals

21 Criteria for Response/Failure and Change of Therapy ELN 2013 Time Optimal Warning Failure Diagnosis 3 Months 6 Months _ PCgR and/or <10% CCyR and/or <1% High risk CCA in Ph+ Ph % and/or >10% Ph+ 1-35% and/or 1-10% 12 Months MMR <0.1 1% any time ELN2013: Definitions of Response to TKIs First-Line Less than MMR CCA/Ph- (-7 or 7q-) _ No CHR and/or 95% Ph+ Ph+ >35% and/or >10% >0% Ph+ and/or >1% Loss of CHR, Loss of CCyR, Confirmed loss of MMR, Mutations, CCA/Ph+ CCA, clonal chromosomal abnormality; PCgR, partial cytogenetic response Baccarani M, et al. Blood. 2013;122(6):

22 Standardization of PCR Local Assay BCR-ABL/ABL BCR-ABL/BCR BCR-ABL/GUS International Scale 100% IRIS Standardized Baseline 10% 35% Ph+ 1% 0% Ph+ (CCyR) Taqman LightCycler Rotorgene Andere 0.1% MMR = MR % MR % MR 5 Hughes T, et al. Blood. 2006;108(1):28-37.

23 Therapy Versus Therapeutic Goals Busulfan IFN-α Imatinib 2nd Gen. TKIs (CHR) (CCyR) (MMR) (MR 4,5 ) Tumor Reduction a 10% 1-log 1% 2-log Tumor load 0,1% IS 3-log 0,01% IS 4-log 0,0032% IS 4,5-log 0,001% IS 5-log a Compared to the initial level CMR 4,5 and beyond

24 RNA vs DNA-Based PCR BCR-ABL DNA detected BCR-ABL DNA not detected PCR, polymerase chain reaction Ross DM, et al. Blood. 2013;122(4): N = 13 patients in TFR

25 Can We Achieve a Cure?

26 Normal vs Malignant Hematopoesis Normal CML Courtesy of A. Burchert Nowell P, et al. Science. 1960;142:1497. Rowley JD. Nature. 1973;243(5405): Ben-Neriah Y, et al. Science. 1986;233(4760): Daley GQ, et al. Science. 1990;247;(4944):

27 Normal vs Malignant Hematopoesis Normal Reversibility? CML Courtesy of A. Burchert Nowell P, et al. Science. 1960;142:1497. Rowley JD. Nature. 1973;243(5405): Ben-Neriah Y, et al. Science. 1986;233(4760): Daley GQ, et al. Science. 1990;247;(4944):

No Induction of CML In Mice Survival Rate, % 100 80 60 40 20 0 P<.0001 Lin + (n = 10) Lin - (n = 10) KLS - (n = 10) KLS + (n = 16) Courtesy of A.

28 No Induction of CML In Mice Survival Rate, % P<.0001 Lin + (n = 10) Lin - (n = 10) KLS - (n = 10) KLS + (n = 16) Courtesy of A. Burchert Time Post-BMT, day Huntly BJ, et al. Cancer Cell. 2004;6(6): Naka K, et al. Nature. 2010;463(7281): Biernaux C, et al. Blood. 1995;86(8): Bose S, et al. Blood. 1998;92(9)

29 Kaplan-Meier Estimates of CMR After Discontinuation of Imatinib Mahon FX, et al. Lancet Oncol. 2010;11(11):

30 Discontinuation by Predictive Factors Survival Without Molecular Relapse At 24 Months: Sokal Low + IM >5 years: 68% (95% CI: 45-88) Others: 68% (95% CI: 45-88) P = Months Since Discontinued of Imatinib

31 Discontinuation After Second-Line TKI? Following 2G-TKI cessation, median follow-up was 17 months (7-38) 16/39 patients lost MMR Median time to MMR loss was 3 months (1-25) Delphine R, et al. Blood. 2012;120: Abstract 1686.

32 TFR Trials: Path to Cure Strategy Induction Consolidation Phase Treatment-Free Remission ENESTFreedom >3 years on Nilotinib BCR-ABL Monitoring De Novo Patients MR 4.5 with 2 years Nilotinib Nilotinib 1 year sustain MR 4.5 Treatment-free Maintain MR 3.0 Study period ENESTop Imatinib >4 weeks not achieved MR 4.5 SWITCH MR 4.5 with 2 years Nilotinib 3 years on Nilotinib Nilotinib 1 year sustain MR 4.5 Study period BCR-ABL Monitoring Treatment-free Maintain MR 4.0 ENESTPath 2 or 3 years on Nilotinib BCR-ABL Monitoring Imatinib 2 years not achieved MR 4.5 SWITCH 1 year Nilotinib Induction Nilotinib 1 or 2 years sustain MR 4.0 Study period Treatment-free Maintain at least MMR for 2 or 3 years

33 DASFREE Study Design Prescreening Dasatinib induced CMR (MR 4.5 ) for a minimum of 9 months must be documented by at least 3 assessments, conducted months apart at a local lab. Enrollment (N = 78) Key Eligibility Criteria CP-CML patients on dasatinib treatment for a minimum of 2 years Stable dasatinib-induced CMR (MR 4.5 ) for a minimum of 12 months prior to entry, confirmed by prescreening and 2 assessments for central lab 1-log reduction in BCR- ABL transcript levels compared to baseline as determined by local standards or less than or equal to 10% IS at 3 months for current dasatinib therapy (first or second line) No prior AP/BC, SCT or patients eligible for SCT Discontinue dasatinib If Loss of MMR Restart dasatinib at the dose received before discontinuation at study entry Patients will be followed for up to 5 years Mercury Activity: 729HQ13NP08330; Approved September 2013; Expires September 2015 US National Institutes of Health. Available at: Accessed November 10, 2014.

34 How Many Patients Can Stop Therapy? ~45% of patients achieve sustained undetectable transcripts (Falchi L, et al. Blood. 2012;120: Abstract 164.) ~39% sustained CMR 24 months after discontinuation (Mahon F-X, et al. Blood. 2011;118: Abstract 603.).45 x.39 =.17 ~18% of patients may discontinue therapy and maintain CMR

Discontinuation of Imatinib Optimizing Therapy With IFNα 100 80 PFS, % 60 40 20 0 1 2 3 4 Time Since Imatinib Withdrawl, Years * Relapse : increase BCR-ABL (IS) to >1% at any time after settling.

35 Discontinuation of Imatinib Optimizing Therapy With IFNα PFS, % Time Since Imatinib Withdrawl, Years * Relapse : increase BCR-ABL (IS) to >1% at any time after settling. #The Treatment with pegylated INFα found in combination with imatinib or as monotherapy after discontinuation of imatinib rather than in clinical trials and is not part of the drug approval for pegylated INFα Burchert A, et al. J Clin Oncol. 2010;28(8):

36 Discontinuation of Imatinib Optimizing Therapy With IFNα * Relapse: increase BCR-ABL (IS) to >1% at any time after settling. #The Treatment with pegylated INFα found in combination with imatinib or as monotherapy after discontinuation of imatinib rather than in clinical trials and is not part of the drug approval for pegylated INFα Burchert A, et al. J Clin Oncol. 2010;28(8):

37 Mechanisms of Resistance to Imatinib Apperley JF. Lancet Oncol. 2007;8(11):

38 Kinase Targets for TKIs Manley PW, et al. Proc Am Assoc Cancer Res. 2007;48:772. Weisberg E, et al. Cancer Cell. 2005;7(2): Remsing Rix LL, et al. Leukemia. 2009;23(3): O Hare T, et al. Cancer Cell. 2009;16(5):

39 TKI Adverse Event Profile and Management

Toxicity Spectrum of TKIs in CML Imatinib Edema/fluid retention, myalgia, hypophosphatemia, GI effects (diarrhea, nausea) Ponatinib Pancreatic enzyme Nilotinib Pancreatic enzyme,

40 Toxicity Spectrum of TKIs in CML Imatinib Edema/fluid retention, myalgia, hypophosphatemia, GI effects (diarrhea, nausea) Ponatinib Pancreatic enzyme Nilotinib Pancreatic enzyme, indirect hyperbilirubinemia Common Effects Myelosuppression Transaminase Electrolyte Δ Bosutinib Diarrhea/nausea/emesis, rash Dasatinib Pleural/pericardial effusions, bleeding risk

41 Severe PAOD and Nilotinib Author Study n/n % Aichberger et al 2011 Am J Hematol (Retrospective study) 3 / 24 (12.5%) Tefferi et al 2011 Am J Hematol (Case report) 2 patients Le Coutre et al 2011 JNCI (Retrospective study) 11 / 179 (6.1%) Quintás-Cardama et al Levato et al Larson et al Rosti et al 2012 Clin Lymphoma Myeloma Leuk (Retrospective study) Abstract # 1679 ASH 2012 (Retrospective study) 2012 Leukemia (Phase III, first line) (ENESTnd: 2:1 nilotinib vs imatinib. 0 PAOD cases in imatinib arm) Abstract # 3784 ASH 2012 (Phase II, first line) 5 / 233 (2.1%) 2 / 27 (7.4%) 8 / 556 (1.4%) 3 / 73 (4.1%) Severe cases of PAOD in early recruiters and large centers and no control arm PAOD, peripheral arterial occlusive disease Aichberger KJ, et al. Am J Hematol. 2011;86(7): Tefferi A, et al. Am J Hematol. 2011;86(7): Le Coutre P, et al. J Natl Cancer Inst. 2011;103(17): Quintás-Cardama A, et al. Clin Lymphoma Myeloma Leuk. 2012;12(5): Levato L, et al. Blood. 2012;120: Abstract Larson RA, et al. Leukemia. 2012:26(10): Rosti G, et al. Blood. 2012;120: Abstract 3784.

42 Selected Cardiovascular Events by 5 Years (All Cause*, All Grades) Patients With an Event, n Total, n Imatinib 400 mg QD n = 280 Y1-4, n Y5, n Total, n Nilotinib 300 mg BID n = 279 Y1-4, n Nilotinib 400 mg BID n = 277 Due to the discontinuation rate, more patients were exposed to nilotinib than imatinib Approximately 85% of patients with a cardiovascular event had at least 1 risk factor and were suboptimally managed The following events were reported in year 5 Nine new cases of IHD (imatinib, n = 2; nilotinib 400 mg BID, n = 7) Four new ICVEs (nilotinib 300 mg BID, n = 1; nilotinib 400 mg BID, n = 3) One new PAD event (nilotinib 400 mg BID) Y5, n Total, n Y1-4, n IHD ICVE PAD Y5, n *All cause indicates all events, not only those deemed study drug-related by the investigator. IHD, ischemic heart disease; ICVE, ischemic cerebrovascular events; PAD, peripheral arterial disease Saglio G, et al. Blood. 2013;122: Abstract 92.

43 Arterial Occlusive Events of Interest (Any Cause) Dasatinib (n = 259) Imatinib (n = 260) Adverse Event Grade 1/2 Grade 3/4 Grade 5 Total n (%) Grade 1/2 Grade 3/4 Grade 5 Total n (%) Cardiac ischemia 10 (3.9%) 3 a (1.2%) Myocardial infarction b (1.9%) (0.8%) Angina c (1.2%) (0.4%) Coronary artery disease, myocardial ischemia (0.8%) (0.4%) PAOD Patients with a history of cardiac disease were included in DASISION, except those who had angina within 3 months, myocardial infarction within 6 months, congestive heart failure within 3 months, significant arrhythmias, or QTc prolongation 9 of 10 dasatinib and 2 of 3 imatinib patients with cardiac ischemia had at least 1 baseline risk factor for cardiovascular disease (eg, diabetes, hypertension, hyperlipidemia, left ventricular dysfunction, coronary artery disease) a 4 events in 3 imatinib patients b MedDRA preferred terms: myocardial infarction, acute myocardial infarction, and silent myocardial infarction c MedDRA preferred terms: angina pectoris and unstable angina Cortes J, et al. Blood. 2013;112: Abstract 653.

44 Cardiovascular Effect of Imatinib vs Atherosclerotic Effects of Nilotinib Cardiovascular Protection of Imatinib Clinical beneficial effect on glucose metabolism Mouse model: Attenuation of diabetes driven atherosclerosis Atherosclerotic Effects of Nilotinib Clinical evidence of glucose elevation Clinical evidence of cholesterol and LDL elevation No cases of PAOD in DASISION, BELA and SWOG trials Comparable frequencies of PAOD in imatinib treated patients as compared to historical control Agostino NM, et al. J Oncol Pharm Pract. 2011;17(3): Lassila M, et al. Arterioscler Thromb Vasc Biol. 2004;24(5): Delphine R, et al. Blood. 2012;120; Abstract Labussière-Wallet H, et al. Blood. 2012;120; Abstract Schwaiger JP, et al. Am J Kidney Dis. 2006;47(5): Cortes J, et al. Blood. 2013;112: Abstract 653.

45 Methods Screening for PAOD in all CP CML Charité, Berlin Questionnaire for: Tobacco, Hypertension, Previous PAOD, Diabetes mellitus, Dyslipidemia, Obesity Ankle brachial index (ABI) Duplex ultrasonography if ABI <0.9 or by discretion of cardiovascular expert Chemistry: Glucose, Hba 1c, HDL, LDL, Cholesterol, TG N = 159 I. Imatinib 1st n = 54 II. Nilotinib 1st n = 33 III. Nilotinib 2nd n = 33 IV. After Nilotinib n = 25 V. Never Nilotinib* n = 14 * First-ine imatinib excluded Kim TD, et al. Leukemia. 2013:27(6):

46 CML-Associated Baseline Parameters First-Line Imatinib First-Line Nilotinib Second-Line Nilotinib After Nilotinib Never Nilotinib n = 54 n = 33 n = 33 n = 25 n = 14 Male, % Prior HU, % Prior IFN, % Duration of CML, months (range) 102 (16-250) 30 (7-62) 78 (27-240) 116 (10-269) 14.5 (4-248) P value <.0001 SNS SNS SNS Duration of firstline TKI, months (range) 97.5 (8-146) 29 (6-59) 27 (0,5-103) 26 (2-89) 26.5 (2-110) P value < SNS, statistically not significant Kim TD, et al. Leukemia. 2013:27(6): One-way ANOVA (Bonferroni Post-Test)

47 Age, years (range) Clinical Risk Factors Assessment First-Line Imatinib First-Line Nilotinib Second-Line Nilotinib After Nilotinib Never Nilotinib n = 54 n = 33 n = 33 n = 25 n = (25-81) 60 (22-85) 52 (31-78) 70 (21-78) 43 (26-68) P value SNS SNS SNS SNS Tobacco, % P value SNS SNS SNS =.0149 HTN, % P value SNS SNS SNS SNS IHD, % P value SNS SNS SNS SNS DM, % P value SNS SNS SNS SNS BMI P value SNS SNS SNS SNS HTN, hypertension; IHD, ischemic heart disease; DM, diabetes mellitus; BMI, body mass index Kim TD, et al. Leukemia. 2013:27(6): Fisher s exact test; One-way ANOVA (Bonferroni Post-Test)

ABI N = 159 patients II. Nilotinib 1st n = 33 IV. After Nilotinib n = 25 I. Imatinib 1st n = 54 III. Nilotinib 2nd n = 33 V. Never Nilotinib n = 14 ABI : 129 / 159 (81%) Pathologic ABI 24 / 129 (18.

48 ABI N = 159 patients II. Nilotinib 1st n = 33 IV. After Nilotinib n = 25 I. Imatinib 1st n = 54 III. Nilotinib 2nd n = 33 V. Never Nilotinib n = 14 ABI : 129 / 159 (81%) Pathologic ABI 24 / 129 (18.6%) n = 3/48 (6.3%) n = 7/27 (26%) n = 10/28 (35.7%) n = 3/18 (16.6%) n = 1/8 (12.5%) P =.0297 P =.0029 Historical data on non-cml population Lamina et al Age 45 64: % Kim TD, et al. Leukemia. 2013:27(6):

6%) n = 1/8 (12.5%) P =.0297 P =.0029 n = 7 ABI @ mo: 21, 27, 37, 40, 45, 51, 56 Response: 1x CCyR, 6x CMR Kim TD, et al. Leukemia.

49 ABI N = 159 patients II. Nilotinib 1st n = 33 IV. After Nilotinib n = 25 I. Imatinib 1st n = 54 III. Nilotinib 2nd n = 33 V. Never Nilotinib n = 14 ABI : 129 / 159 (81%) Pathologic ABI 24 / 129 (18.6%) n = 3/48 (6.3%) n = 7/27 (26%) n = 10/28 (35.7%) n = 3/18 (16.6%) n = 1/8 (12.5%) P =.0297 P =.0029 n = 7 mo: 21, 27, 37, 40, 45, 51, 56 Response: 1x CCyR, 6x CMR Kim TD, et al. Leukemia. 2013:27(6): Historical data on non-cml population Lamina et al Age 45 years to 64 years: 1.3 % to 6.7% Fisher s exact test, two-sided, alpha < 0.05

50 Event / Duplex N = 159 patients II. Nilotinib 1st n = 33 IV. After Nilotinib n = 25 I. Imatinib 1st n = 54 III. Nilotinib 2nd n = 33 V. Never Nilotinib n = 14 PAOD event: n = 5 Event: n = 0 Event: n = 1 Event: n = 3 Event: n = 1 Event: n = 0 Duplex : n = 30 Pathological Duplex: n = 8 DS: n = 1 DS: n = 2 DS: n = 2 DS: n = 3 DS: n = 0 n = 1/54 (1.9%) n = 3/33 (9.1%) n = 5/33 (15.2%) n = 4/25 (16.0%) n = 0/7 p = p = p = Fisher s exact test, two-sided, alpha < 0.05 Levato L, et al. Blood. 2012;120: Abstract Kim TD, et al. Leukemia. 2013:27(6):

51 Event / Duplex N = 159 patients II. Nilotinib 1st n = 33 IV. After Nilotinib n = 25 I. Imatinib 1st n = 54 III. Nilotinib 2nd n = 33 V. Never Nilotinib n = 14 PAOD event: n = 5 Event: n = 0 Event: n = 1 Event: n = 3 Event: n = 1 Event: n = 0 Duplex : n = 30 Pathologic Duplex: n = 8 DS: n = 1 DS: n = 2 DS: n = 2 DS: n = 3 DS: n = 0 n = 1/54 (1.9%) n = 3/33 (9.1%) n = 5/33 (15.2%) n = 4/25 (16.0%) n = 0/7 P =.1507 P =.0276 P =.0327 Fisher s exact test, two-sided, alpha < 0.05 Levato L, et al. Blood. 2012;120: Abstract Kim TD, et al. Leukemia. 2013:27(6):

52 Glucose, mg/dl Hba 1c, % Cholesterol, g/dl Biochemistry Assessment: Cholesterol & LDL Elevation First-Line Imatinib 90 (74-279) 5.4 (4.5-8) 164 ( ) First-Line Nilotinib 89.5 (68-178) 5.7 ( ) 209 ( ) Second-Line Nilotinib 84 (57-285) 5.7 ( ) 222 ( ) After Nilotinib 94.5 (66-152) 5.7 ( ) 193 ( ) Never Nilotinib 80 (43-102) 5.4 ( ) 194 ( ) P <.0001 <.0001 <.034 <.7 LDL, mg/dl 95 (47-152) 135 (33-215) 139 (77-210) 117 (56-234) 124 (56-160) P <.0003 <.0001 <.03 <.5 TG, mg/dl HDL, mg/dl (50-407) 48 (16-107) 98 (37-500) 62.5 (30-111) 108 (44-290) 58 (15-90) (75-280) 48.5 (31-74) 119 (59-246) 52.2 (28-109) Laboratory parameters were taken after 4 weeks of drug exposure One-way ANOVA (Bonferroni Post-Test) HDL, high-density lipoprotein; LDL, low-density lipoprotein; TG, triglyceride Delphine R, et al. Blood. 2012;120: Abstract Labussière-Wallet H, et al. Blood. 2012;120: Abstract Kim TD, et al. Leukemia. 2013:27(6):

53 Prevalence of Cardiovascular Disease in Adults National Health and Nutrition Examination Survey Percent of Population Go A, et al. Circulation. 2013;127:e6-e245. Age, Years

54 Cardiovascular Medicine Over the Last 50 Years Declining Lethality Marsh B. NY Times. Source: Centers for Disease Control and Prevention; National Vital Statistics System. Available at: Accessed November 10, 2014.

55 PACE: Ponatinib Phase II Study Responses at Any Time CP-CML AP-CML BP-CML Ph+ ALL MCyR CCyR MMR MaHR* MaHR MaHR R/I to das/nil 56% 48% 31% 62% 32% 50% T315I 72% 70% 58% 61% 29% 36% Total 60% 54% 38% 61% 31% 41% Median time to response, months *14 AP-CML pts with baseline MaHR and 1 AP-CML pt with no baseline MaHR assessment counted as non-responders **Total comprises all eligible pts treated with ponatinib. It excludes 5 pts (3 CP-CML, 2 AP-CML) who were non-cohort assigned (post-imatinib, non-t315i), but treated; all 5 achieved MCyR Cortes J, et al. Blood. 2013;122: Abstract 650.

56 PACE Ponatinib Phase II Study Incidence of Arterial Thrombotic Events Over Time N = 449 n (%) Data as of: 23 July 2012 (USPI) 03 Sep 2013 Median follow-up [exposure] 12 months 24 months [340 patient-years] [578 patient-years] Category SAE AE SAE AE Cardiovascular 21 (5) 29 (6) 28 (6) 41 (9) Cerebrovascular 8 (2) 13 (3) 18 (4) 25 (6) Peripheral vascular 7 (2) 17 (4) 16 (4) 28 (6) Total arterial thrombosis 34 (8) 51 (11) 53 (12) 77 (17) Venous thromboembolism 10 (2) 15 (3) 13 (3) 23 (5) Vascular occlusion a Method 1 b 41 (9) 62 (14) 62 (14) 91 (20) Method 2 c 47 (10) 81 (18) 67 (15) 109 (24) a Combined incidence of cardiovascular, cerebrovascular, peripheral vascular, venous thromboembolism events; b EMA press release, Nov 22, 2013; c FDA drug safety communication, Oct 31, 2013; SAE = AE reported as serious by the investigator, per standard criteria AE, adverse event; EMA, European Medicines Association; SAE, serious AE Cortes J, et al. Blood. 2013;122: Abstract 650.

57 PACE: Overall Survival by Presence or Absence of Arterial Thrombotic Events Probability of OS (%) Arterial Thrombotic Event (N = 77) (N = 372) OS at 2 years: 73% with event (95% CI: 62, 82) Months 5 patients died of a grade 5 vascular event No Arterial Thrombotic Event 69% without event (95% CI: 64, 74) 5 additional patients died with vascular events possibly contributing to death Cortes J, et al. Blood. 2013;122: Abstract 650.

58 About causality.

59 Atherothrombotic Risk and TKIs Treatment in CML Patients: A Role for Genetic Predisposition and Pro-Inflammatory/Pro-Oxidative Status? Nilotinib (36 Patients) Imatinib (39 Patients) OxLDL, UI/L P =.021 TNFα, pg/ml IL6, pg/ml IL10 (pg/ml) P = TNFα/IL P = IL6/IL P = scd40l, pg/ml P = 0014 ETP, % P = ETP, endogenous thrombin potenital; IL, interleukin; TNF, tumor necrosis factor Aprile L, et al. Blood. 2013;122(21):1482.

60 Nilotinib Inhibits In Vitro Proliferation and Survivial of Endothelial Cells: Comparison to Imatinib 3 H-Thymidine Uptake, % of Control n=3 n = 3 Imatinib Nilotinib Co Drug Concentration (μm) HUVEC 3 H-Thymidine Uptake, % of Control HCAEC Imatinib Nilotinib Co Drug Concentration (μm) 3 H-Thymidine Uptake, % of Control n = 3 n=3 Imatinib Nilotinib HMEC-1 HCAEC, human coronary artery derived endothelial cells; HMEC-1, human microvascular endothelial cell line; HUVEC, human umbilical vein endothelial cells Hadzijusufovic E, et al. Blood. 2013;122(21):257. n=3 HCAEC Co Control Control Imatinib Nilotinib Drug Concentration (μm) 1μM 1μM Rel. Apoptosis Caspase [3/7] n = 3 T T T +50 ng VEGF * T

61 Mechanism of Impaired Glucose Metabolism During Nilotinib Therapy in Patients With CML Racil Z, et al. Haematologica. 2013;98(10):e Start Median (Range) Month 3 Median (Range) Fasting glucose, mmol/l 5.25 ( ) 5.8 ( ).009 Fasting insulin, µiu/ml 16.6 ( ) 27.8 ( ).049 Fasting C-peptide pmol/ml 0.87 ( ) 0.94 ( ).275 Fasting HbA1c, % 3.80 ( ) 3.9 ( ).725 Incretins Fasting GLP-1, pm 5.4 ( ) 5.3 ( ) hour stimulated GLP-1, pm 6.3 ( ) 6.4 ( ).160 Fasting GIP, pg/ml 49.5 ( ) 58.5 ( ) hour stimulated GIP, ph/ml ( ) ( ).232 Adipokines Fasting FABP, ng/ml 15.7 ( ) 17.3 ( ).241 Fasting adiponectin, mg/l 13.8 ( ) 7.8 ( ).027 Serum lipids Total cholesterol, mmol/l 4.75 ( ) 5.35 ( ).013 Triglycerides, mmol/l 1.03 ( ) 1.29 ( ).432 HDL cholesterol, mmol/l 1.50 ( ) 1.45 ( ).152 LDL cholesterol, mmol/l 2.55 ( ) 2.80 ( ).020 Non-HDL cholesterol, mmol/l 2.90 ( ) 3.45 ( ).011 P

62 10-Year OS San Diego Artery Study 1.00 Overall OS survival Normal normal Asymptomatic asymptomatic PAD PAD Symptomatic symptomatic PAD PAD Severe PAD PAD Years PAD, peripheral arterial disease Criqui MH, et al. N Engl J Med. 1992;326(6): Courtesy of P Kuhlencordt, LMU München

63 Pulmonary Arterial Hypertension in Patients Treated by Dasatinib Improvement of clinical, functional and hemodynamic parameters after discontinuation of dasatinib A: NYHA B: 6-min walking distance C: mpap D: PVR ERA CCB No treatment mpap, mmhg mpap, mean pulmonary artery pressure; NYHA, A Number of Patients C IV III II 2 Baseline Baseline New York Heart Association; PVR, pulse volume recording Montani D, et al. Circulation. 2012;125(17): P<.01 P<.05 III II I Last Evolution Normal mpap is 14 ± 3 mmhg, PH is defined as mpap 25 mmhg Last Evolution 6-MWD, m PVR, mmhg/l/min B 700 D Baseline Baseline P<.05 P<.05 Last Evolution Last evolution

Cardiovascular Risk Assessment ABI Normal 0.9-1.

sex, smoking, BP and cholesterol BP, blood pressure; CVE,

64 Cardiovascular Risk Assessment ABI Normal Risk of fatal CVE to 10 years in the general population by age, sex, smoking, BP and cholesterol BP, blood pressure; CVE, cardiovascular event Joint ESC Guidelines: Perk J, et al. Eur Heart J. 2012;33(13):

65 Provisional Algorithm of PAOD Prevention and Management In collaboration with cardiovascular experts at Charité American College of Cardiology Foundation and the American Heart Association Task Force on Practice Guidelines: ABI in otherwise healthy individuals >65 years Risc score: Baseline ABI/Duplex: Baseline and once per year while in nilotinib Labchemistry (Hba1c, glucose, cholesterol, LDL, HDL, TG): Baseline and once per year while on nilotinib

Preliminary Algorithm for Management PAOD in nilotinibtreated patients Severe PAOD

TKI Reexpose to alternative TKI in case of relapse Dose reduction (50%) and close

66 Preliminary Algorithm for Management PAOD in nilotinibtreated patients Severe PAOD Mild to moderate PAOD Stable MR 4,5 < stable MR 4,5 Stable MR 4,5 < stable MR 4,5 Permanently discontinue nilotinib. Re-expose to alternative TKI in case of relapse Immediately switch to alternative TKI Permanently discontinue nilotinib. Reexpose to alternative TKI in case of relapse Dose reduction (50%) and close follow-up Switch to alternative TKI Severe PAOD: Requirement of invasive treatment Stable MR 4,5 : 18 months

67 Take Home Messages 1. Excellent second generation TKIs (dasatinib, nilotinib, ponatinib) 2. Early responses are predictive for survival 3. Deeper molecular responses improve eventfree survival 4. Potential for effective discontinuation of therapy (improved QoL) 5. Patient comorbidities and the AE profile of individual TKIs should be considered at the time of treatment initiation

CML: Living with a Chronic Disease

CML: Living with a Chronic Disease Jorge Cortes, MD Chief, CML and AML Sections Department of Leukemia M. D. Anderson Cancer Center Houston, Texas Survival in Early Chronic Phase CML TKI Interferon Chemotherapy