Practical Guidance for the Management of CML in 2016

Transcription

1 Practical Guidance for the Management of CML in 2016 Neil Shah, MD, PhD Edward S. Ageno Distinguished Professor in Hematology/Oncology Leader, Hematopoietic Malignancies Program Helen Diller Family Comprehensive Cancer Center at UCSF San Francisco, California

2 The Importance of CML to Molecular Oncology Chronic myeloid leukemia (CML) was the first malignancy shown to be associated with a particular genetic mutation CML was the first disease to be treated with small molecule tyrosine kinase inhibitors (TKIs) Lessons learned from TKI treatment have informed multiple other oncologic areas In 2016, the diagnosis, treatment, and monitoring of malignancies is increasingly molecular and personalized, and to a large extent CML has paved the way

3 1845 Timeline of Clinical Events in CML Early 1900s Late 1970s Early 1980s Busulfan 2 Radiotherapy 2 First description of leukemia 1 Hydroxyurea 3 Interferon 5 Imatinib approved for CML Hematopoietic stem cell transplantation (HSCT) 4 Dasatinib and nilotinib approved for second-line use in CML Nowell and Hungerford identify the Philadelphia (Ph) chromosome 1 Bosutinib, ponatinib approved in USA Dasatinib and nilotinib approved for first-line use in CML in USA 1. Patlak M. FASEB J. 2002;16: Bolin RW, et al. Cancer. 1982;50(9): Frame D. Am J Health-Syst Pharm. 2006;63(23 Suppl 8):S10-S Doti CA, et al. Leuk Lymphoma. 2009;50: Bonifazi F, et al. Blood. 2001;98(10):

4 Imatinib as Front-Line Therapy for CML 7-8 year update of newly-diagnosed chronic phase (CP) CML patients treated with 400 mg daily imatinib O Brien S, et al. Blood. 2008;112: Abstract 186.

5 % With Event Annual Event Rates: Imatinib Arm KM estimated event-free survival at 8 years = 81% KM estimated rate without accelerated-phase (AP) or blast crisis (BC) at 8 years = 92% Event Loss of complete hematologic response (CHR) Loss of major cytogenetic response (MCR) AP/BC, death during treatment AP/BC Year *Total events (n = 3), including two CML-unrelated deaths (n = 2), and one patient with progression to AP/BC Deininger D, et al. Blood. 2009;114: Abstract * 0.4

6 % Without Event Overall Survival (ITT Principle): Imatinib Arm Survival: Deaths associated with CML Overall survival Estimated overall survival (OS) at 8 years is 85% (93% considering only CML-related deaths) 0 Months Since Randomization Deininger D, et al. Blood. 2009;114: Abstract 1126.

7 Survival Probability (All Ph+ CML Disease Phases) Imatinib Has Revolutionized the Therapeutic Landscape for Patients With CML , IFN- or SCT *CML IV CML IIIA CML III , imatinib * Best available therapy 5-year OS, % Imatinib* 93 IFN- or SCT plus 2nd-line imatinib 71 IFN- or SCT 63 IFN- 53 Hydroxyurea 46 Busulfan , interferon-a (IFN- ) or stem cell transplantation (SCT) plus second-line imatinib , IFN , hydroxyurea , busulfan Years After Diagnosis Leitner AA, et al. Internist (Berl). 2011;52: Hochhaus A. In: Faderl S, Kantarjian H, eds. Leukemias: Principles and Practice of Therapy. 2010: Hehlmann R, et al. Haematologica. 2009;94(s2):193 (Abstract 478).

8 Imatinib: Conclusions Imatinib (400 mg daily) remains a front-line option for chronic phase CML patients 85% overall survival with imatinib exceeds that of all previous CML therapies, with 7% of patients dying from CML after 8 years 82% of patients treated with imatinib achieved a complete cytogenetic response (CCyR) 55% of all imatinib randomized patients are still on study treatment, and nearly all of these are in CCyR Responses are typically durable, and the annual risk of progression appears to decrease after 2-3 years No major new safety findings seen with long-term follow-up Many patients experience chronic lower grade toxicities

9 Monitoring Disease in Patients With CML

10 Treatment Response Level of response Complete hematologic response Minor cytogenetic response Partial cytogenetic response (PCyR) Complete cytogenetic response Major molecular response (MMR) Complete molecular response Definition Normal complete blood count and differential, no extramedullary disease >35% Ph-positive metaphases* 1%-35% Ph-positive metaphases* 0% Ph-positive metaphases* BCR-ABL1 transcripts 0.1% by qpcr or 3-log reduction Negativity by qpcr *Cytogenetic response is based on analysis of at least 20 metaphases PCyR + CCyR = major cytogenetic response (MCyR) National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Chronic Myelogenous Leukemia. V Available at: Accessed May 18, Adapted from: Deininger MW. Hematology Am Soc Hematol Educ Program. 2005;

11 CML (log 10 ) Monitoring Disease Burden in CML Cytogenetics FISH 1-2 log reduction MMR = 3 log RT-PCR ~ 5-6 log reduction Dx Radich JP. Blood. 2009;114: Treatment Time

12 Imatinib-Resistant Disease How is it defined?

13 Imatinib Resistance in Chronic Phase CML Definitions Primary resistance: Lack of an acceptable initial response Primary hematologic resistance: Rare Primary cytogenetic resistance: ~35% of patients Lack of PCyR ( 35% Ph) by 3 months Lack of CCyR (0% Ph) by months Primary molecular resistance: ~35% of patients Lack of BCR-ABL/ABL (IS) 10% by 3 months Lack of BCR-ABL/ABL (IS) 0.1%-1% by 12 months

14 Imatinib Resistance in Chronic Phase CML Definitions Primary resistance: Lack of an acceptable initial response Primary hematologic resistance: Rare Primary cytogenetic resistance: ~35% of patients Lack of PCyR ( 35% Ph) by 3 months Lack of CCyR (0% Ph) by months Primary molecular resistance: ~35% of patients Lack of BCR-ABL/ABL (IS) 10% by 3 months Lack of BCR-ABL/ABL (IS) 0.1%-1% by 12 months Secondary resistance: Loss of an established initial response (relapse despite treatment) Hematologic relapse: White cell blood count >normal and increasing or new immature forms/basophilia/accelerated or blast phase transformation Cytogenetic relapse: 30% increase in Ph+ metaphases Molecular relapse: Confirmed 1-log increase in BCR-ABL transcript level with lack/loss of MMR Primary resistance is a risk factor for the development of secondary resistance

15 Patients Without AP/BC (%) Importance of Achieving CCyR: IRIS Study Response at 18 months Estimated rate at 60 months CCyR with 3 log reduction n = % P =.11 CCyR with <3 log reduction No CCyR n = 54 n = 88 98% 87% P< Time (Months Since Randomization) Druker B et al. N Engl J Med. 2006;355:

16 Imatinib: IRIS 8-Year Update Shows 37% Have Unacceptable Outcome No CCyR: 17%* Sustained CCyR on study: 53% Lost CCyR: 15%* Safety: 5%* *Unacceptable outcome CCyR + other: 7% Lost regained CCyR: 3% Deininger D, et al. Blood. 2009;114: Abstract 1126.

17 Probability of Survival BCR-ABL/ABL After 3 Months of Imatinib Predicts OS Outcomes BCR-ABL/ABL >9.84% 8-yr OS: 56.9% BCR-ABL/ABL<9.84% 8-yr OS: 93.3% 0.4 P < Time From Onset of Imatinib Therapy (Years) Marin D, et al. J Clin Oncol. 2012;30:

18 NCCN: 3-Month Milestones National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Chronic Myelogenous Leukemia. V Available at: Accessed Accessed May 22, 2016.

19 NCCN: 3-Month Milestones National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Chronic Myelogenous Leukemia. V Available at: Accessed Accessed May 22, 2016.

20 NCCN: 3-Month Milestones National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Chronic Myelogenous Leukemia. V Available at: Accessed Accessed May 22, 2016.

21 NCCN: 3-Month Milestones National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Chronic Myelogenous Leukemia. V Available at: Accessed Accessed May 22, 2016.

22 CML: Monitoring Simplified Quantitative BCR-ABL PCR at diagnosis and every 3 months thereafter Achievement of 10% BCR-ABL (IS) or PCyR after 3 months of imatinib is associated with superior survival in multiple studies Bone marrow cytogenetics should be performed at diagnosis in all patients and at 3 and/or 12 months in select cases thereafter Achievement of a complete cytogenetic response remains the minimum acceptable level of response on TKI therapy Ideally achieved within months of TKI initiation

23 Imatinib-Resistant Disease What are its causes?

24 Acquired Clinical Resistance to Imatinib Is Most Often Associated With Restoration of BCR-ABL Kinase Activity

25 ATP-Binding Pocket of T315I Mutant BCR-ABL Cannot Accommodate Imatinib Wild type T315I mutant (model) Structural data provided by B Nagar and J Kuriyan UC Berkeley Gorre ME, et al. Science. 2001;293(5531):

26 (Incomplete) Map of BCR-ABL Kinase Domain Mutations Associated With Clinical Resistance to Imatinib L298V E292V P C A Gorre ME, et al. Science. 2001;293(5531): von Bubnoff N, et al. Lancet. 2002;359(9305): Branford S, et al. Br J Haematol. 2002;117(4): Hofmann WK, et al. Blood. 2003;102(2): Roche-Lestienne C, et al. Blood. 2002;100(3): Shah NP, et al. Cancer Cell. 2002;2(2): Hochhaus A, et al. Leukemia. 2002;16(11): Al-Ali HK, et al. Hematol J. 2004;5(1): Courtesy Tim Hughes

27 BCR-ABL Gene Amplification Associated With Clinical Imatinib Resistance MB13 Imatinib MB14 Imatinib Chemotherapy Gorre ME, et al. Science. 2001;293(5531):

28 Molecular Mechanisms of Resistance to Imatinib: Implications BCR-ABL kinase inhibitors that are: (1) More potent than imatinib and (2) Have activity against imatinib-resistant kinase domain mutations May be of significant therapeutic benefit to imatinibresistant and imatinib-intolerant patients

29 % Patients Achieving CCyR Dasatinib 70 mg BID in CP-CML: 24 Month Results CCyR Achieved for the First Time in Many Patients Prior CCyR on imatinib 100 (median duration treatments >3 years) CCyR on dasatinib Total Stone R, et al. Blood. 2007;110: Abstract 734.

30 Nilotinib Has a Better Fit to the Binding Pocket Imatinib IC nm Nilotinib IC 50 25nM Rationally designed highly specific inhibitor of BCR-ABL 30 X more potent than imatinib; maintains target specificity No significant effect on other kinases (Src, FLT3, VEGFR, EGFR, InsR, RET, MET, IGFR, etc) Swords R, et al. Drug Des Devel Ther. 2009;3:

31 Patients % Nilotinib in CP-CML: Response Rates With 24 Months of Follow-Up % 57% 44%* 41%* CHR Major CyR CCyR Imatinib resistant Median time to CHR 1 month, to MCyR 2.8 months 51%* Imatinib intolerant *When metaphases unavailable, response was measured by FISH alone Kantarjian H, et al. Blood. 2009;114: Abstract 1129.

32 Bosutinib in CP CML Response (Imatinib Resistant or Intolerant*) Response (N = 115) N / N evaluable (%) Hematologic Complete 34 / 38 (89) Cytogenetic Major 23 / 56 (41) Complete 17 / 56 (30) Molecular Major 19 / 58 (33) Complete 11 / 58 (19) *Patients had no prior exposure to kinase inhibitors other than imatinib Cortes J, et al. Blood. 2007;110: Abstract 733.

33 Ponatinib Oral pan-bcr ABL TKI with potent activity against native and mutated BCR-ABL and other kinases T315I gatekeeper residue Triple bond (yellow) unique structural feature evades the T315I gatekeeper mutation (blue) Cortes J, et al. Blood. 2012;120: Abstract 163. Extensive network of molecular contacts for optimal fit to the binding cavity of ABL

34 Ponatinib Phase II Study Responses at Any Time CP-CML AP- CML BP-CML Ph+ ALL R/I to das/nil MCyR CCyR MMR MaHR* MaHR MaHR 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 patients with baseline MaHR and 1 AP-CML patient with no baseline MaHR assessment counted as non-responders **Total comprises all eligible patients treated with ponatinib. It excludes 5 patients (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.

35 Treatment Options Based on BCR-ABL Kinase Domain Mutation Status Mutation T315I V299L T315A F317L/V/I/C Y253H, E255K/V, F359V/C/I Any other mutation Treatment options Ponatinib, omacetaxine, HSCT, or clinical trial Consider nilotinib, ponatinib or omacetaxine* Consider nilotinib, imatinib, bosutinib, ponatinib, or omacetaxine* Consider nilotinib, or bosutinib, ponatinib, or omacetaxine* Consider dasatinib, or bosutinib, ponatinib, or omacetaxine* Consider dasatinib, nilotinib, bosutinib, ponatinib, high dose imatinib, or omacetaxine* *Option for pts with resistance/intolerance to 2 TKIs If mutation detected following dasatinib treatment No sufficient dose escalation data indicating if mutations with low IC 50 are sensitive to high dose imatinib NCCN. Clinical practice guidelines in oncology: chronic myelogenous leukemia. v National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Chronic Myelogenous Leukemia. V Available at: Accessed May 18, 2016.

36 Frontline Therapy for CML How active are newer agents in the front-line management of CP-CML?

37 ENESTnd Study Design ENESTnd 5-year update Nilotinib 300 mg BID (n = 282) N = centers 35 countries R A N D O M I Z E 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. Data cutoff: May 22, 2013 Larson R, et al. J Clin Oncol. 2014;32(Suppl): Abstract 7073.

38 Patients With MMR, % Cumulative Incidence of MMR ENESTnd 5-year update By 1 Year a By 4 Years a By 5 Years a %, P < %, P < %, P <.0001 Δ 17% to 20% 77%, P < %, P <.0001 Δ 17% 60% 50 51%, P < % Δ 24% to 28% Nilotinib 300 mg BID (n = 282) Nilotinib 400 mg BID (n = 281) Imatinib 400 mg QD (n = 283) 20 27% 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. Data cutoff: May 22, 2013 Larson R, et al. J Clin Oncol. 2014;32(Suppl): Abstract Hochhaus A, et al. Leukemia. 2016;30(5):

39 Patients, % BCR-ABL Categories at 3 Months* 100 BCR-ABL 10% 91 Imatinib (n = 264) Nilotinib 300 mg BID (n = 258) ENESTnd 5-year update >1-10% 60 BCR-ABL >10% 40 >1-10% 1% % 9 0 n BCR-ABL Level at 3 Months Reasons for unevaluable samples included Atypical transcripts: 5 patients on nilotinib, 2 patients on imatinib Missing samples: 4 patients on nilotinib, 5 patients on imatinib Discontinuation: 15 patients (including 1 progression) on nilotinib, 12 patients (including 1 progression) on imatinib *Calculated from total number of evaluable patients with PCR assessments at 3 months Data cutoff: May 22, 2013 Larson R, et al. J Clin Oncol. 2014;32(Suppl): Abstract Hochhaus A, et al. Leukemia. 2016;30(5):

40 Patients, n 25 ENESTnd 5-year update Progression to AP/BC on Study a (Including After Treatment Discontinuation) P =.0588 Imatinib 400 mg QD (n = 283) 15 Nilotinib 300 mg BID (n = 282) New events in year % 3.5% Progressions on Study Two new progressions on study in year 5 (1 in the nilotinib 300 mg BID arm and 1 in the imatinib arm) Both patients had BCR-ABL >10% at 3 months a Includes progression to AP/BC (excluding clonal evolution) or deaths in patients with advanced CML occurring on study (on core or extension treatment or during follow-up after treatment discontinuation) Data cutoff: May 22, 2013 Larson R, et al. J Clin Oncol. 2014;32(Suppl): Abstract Hochhaus A, et al. Leukemia. 2016;30(5):

41 ENESTnd 5-year update PFS and OS on Study (Including After Treatment Discontinuation) a Imatinib 400 mg QD (n = 283) Nilotinib 300 mg BID (n = 282) Estimated 5-year PFS, % Progressions and deaths, n Hazard ratio (95% CI) 0.92 ( ) P value.77 Estimated 5-year OS, % Total deaths, n Deaths in patients with advanced CML, n b 15 6 Hazard ratio (95% CI) 0.84 ( ) P value.58 There were 6 newly reported deaths in year 5 Imatinib (n = 2): both due to study indication Nilotinib 300 mg BID (n = 3): study indication, rectal cancer, and pneumonia a Includes events occurring on core or extension treatment or during follow-up after treatment discontinuation b Patients for whom the principle cause of death was either study indication or unknown or not reported but occurred subsequent to a documented progression to AP/BC Data cutoff: May 22, 2013 Larson R, et al. J Clin Oncol. 2014;32(Suppl): Abstract Hochhaus A, et al. Leukemia. 2016;30(5):

42 Conclusions ENESTnd 5-year update At 5 years of follow-up, rates of event-free survival, progression-free survival, and overall survival rates are not significantly different in the two treatment arms Nilotinib demonstrated higher rates of early and deeper molecular response, including MR 4.5 By 5 years, more than half of nilotinib-treated patients had achieved MR 4.5, a key eligibility criterion for many treatmentfree remission studies Side effects that appear unique to nilotinib include pancreatitis, hyperglycemia, EKG changes, and peripheral arterial occlusive events Data cutoff: May 22, 2013 Larson R, et al. J Clin Oncol. 2014;32(Suppl): Abstract Hochhaus A, et al. Leukemia. 2016;30(5):

43 DASISION 5-year final study results DASISION (CA ) Study Design Treatment-naïve CML-CP patients (N = 519) 108 centers 26 countries Enrollment: September December 2008 Randomized a Dasatinib 100 mg QD (n = 259) Imatinib 400 mg QD (n = 260) 5-year final results Database lock of 24-Mar-2014 Primary end point: confirmed CCyR by 12 months 77% dasatinib vs. 66% imatinib (P =.007) 1 a Stratified by EURO (Hasford) risk score 1. Kantarjian H, et al. N Engl J Med. 2010;362:

44 % With MMR Cumulative MMR Rates Over Time DASISION 5-year final study results N Dasatinib 100 mg QD 259 Imatinib 400 mg QD 260 By 5 years By 4 years P =.0022 By 3 years 76% 73% By 2 years 67% 64% 64% 60% By 1 year 55% 46% 46% % Months Since Randomization Cortes J, et al. Blood. 2014;124: Abstract 152.

45 DASISION 5-year final study results Best 5-Year Responses by Molecular Response at 3 Months Dasatinib 100 mg QD (n = 259) Imatinib 400 mg QD (n = 260) BCR-ABL at 3 months 10% (84%) >10% (16%) 10% (64%) >10% (36%) CCyR, % MMR, % MR 4.5, % Cortes J, et al. Blood. 2014;124: Abstract 152.

46 5-Year Outcomes by Molecular Response at 3 Months DASISION 5-year final study results Dasatinib 100 mg QD (n = 259) Imatinib 400 mg QD (n = 260) BCR-ABL at 3 months 10% (84%) >10% (16%) P value 10% (64%) >10% (36%) P value Estimated 5-year OS, % Estimated 5-year PFS, % Estimated 5-year transformation-free survival, % < <.0001 On study treatment and in follow-up after discontinuation of randomized treatment Cortes J, et al. Blood. 2014;124: Abstract 152.

47 Patients, n On study 20 Overall transformations to AP/BP During follow-up beyond discontinuation 7.3% DASISION 5-year final study results Transformation to AP/BP CML by 5 Years % 5 0 Dasatinib n = 259 Imatinib n = 260 BCR-ABL at 3 months a 10% n = 198 Dasatinib 100 mg QD (n = 259) >10% n = 37 One imatinib patient and no dasatinib patients transformed between 4 and 5 years Imatinib 400 mg QD (n = 260) 10% n = 154 >10% n = 85 Transformation to AP/BP b, n (%) 6 (3) 5 (14) 5 (3) 13 (15) a One dasatinib and one imatinib patient transformed but did not have 3-month molecular assessments b Including follow-up beyond discontinuation (intent to treat) Cortes J, et al. Blood. 2014;124: Abstract 152.

48 Overall Survival and Progression-Free Survival Dasatinib 100 mg QD (n = 259) Imatinib 400 mg QD (n = 260) Hazard ratio (95% CI) Total number of deaths a, n Estimated 5-year OS a, % (95% CI) 91 (87-94) 90 (85-93) 1.01 ( ) Estimated 5-year PFS a, % (95% CI) 85 (80-89) 86 (80-89) 1.06 ( ) Causes of death were cardiovascular disease (2 dasatinib, 1 imatinib); disease progression (9 dasatinib, 17 imatinib); infection (11 dasatinib, 1 imatinib); other malignancy, septic shock and cardiac failure, multi-organ failure, and whole body swelling (1 each dasatinib); stem cell transplantation complications and unknown (2 each imatinib); severe chest pain, clinical deterioration and decrease in performance status, and fatal bleeding (1 each imatinib) a On study treatment and in follow-up after discontinuation of randomized treatment Cortes J, et al. Blood. 2014;124: Abstract 152.

49 5-Year follow-up demonstrates: Conclusions Deeper molecular responses with dasatinib versus imatinib More optimal molecular responses with dasatinib versus imatinib No significant difference in transformation-free or overall survival Achievement of BCR-ABL 10% at 3 months is associated with significantly higher PFS and OS by 5 years BCR-ABL 10% at 3 months: dasatinib 84% versus imatinib 64% By 5 years, 42% of dasatinib-treated patients had achieved MR 4.5, a key eligibility criterion for many treatment-free remission studies Side effects that appear unique to dasatinib include pleural effusion and pulmonary arterial hypertension. Cortes J, et al. Blood. 2014;124: Abstract 152.

50 BCR/ABL TKIs Focus on safety and tolerability

51 Treatment Options Based on Adverse Event Spectrum of TKIs in CML Ponatinib Pancreatic enzyme, hypertension, skin toxicity, thrombotic events Nilotinib Pancreatic enzyme, indirect hyperbilirubinemia, hyperglycemia QT prolongation, cardiovascular events Imatinib Edema/fluid retention, myalgia, hypophosphatemia, GI effects (diarrhea, nausea) Common Effects Myelosuppression Transaminase Electrolyte Δ Dasatinib Pleural effusions, bleeding risk, pulmonary arterial hypertension Bosutinib Diarrhea, nausea/emesis, rash In addition to grade 3/4 toxicities, it is reasonable to consider changing treatment for bothersome persistent grade 2 toxicities

52 BCR-ABL TKIs: Some Distinguishing Features TKI Pleural effusion Pulmonary arterial hypertension QT prolongation Hyper glycemia Pancreatitis Thrombotic events Diarrhea LFT abnormalities Twice daily schedule Imatinib Dasatinib Nilotinib Bosutinib Ponatinib

53 Management of Hematologic Toxicities With TKIs TKIs are not considered strongly myelosuppressive in the setting of a healthy bone marrow TKI-associated cytopenias are most common within 1-3 months after initiation, are typically transient, and likely reflect disease reduction prior to adequate hematologic recovery by normal stem/progenitor cells TKI dose interruption for platelet count <50K or absolute neutrophil count <1K should be considered; retreatment with lower doses is sometimes employed Note: Avoid CYP3A4 inducers/inhibitors in all patients on BCR-ABL TKIs

54 Management of Hematological Adverse Events (AEs): Summary In general, switch in TKI is not a solution to prolonged cytopenias. This is a feature of the patient s normal stem cell reserve and not the drug.

55 Imatinib Focus on safety and tolerability

56 Most Frequently Reported AEs: First-Line Imatinib Most common AEs (by 5 years) All grade AEs patients, % Grade 3/4 AEs patients, % Superficial edema 60 2 Nausea 50 1 Muscle cramps 49 2 Musculoskeletal pain 47 5 Diarrhea 45 3 Rash/skin problems 40 3 Fatigue 39 2 Headache 37 <1 Abdominal pain 37 4 Joint pain 31 3 Only serious adverse events (SAEs) were collected after 2005 Grade 3/4 adverse events decreased in incidence after years 1-2 O Brien S, et al. Blood. 2008;112: Abstract 186.

57 IRIS SAEs in Years 6 and 7 No unique, previously unreported AEs attributed to imatinib observed over the last 24 months (Exception: hepatitis B virus reactivation) In years 6 and 7 (n=545), 13 SAEs with suspected relationship to imatinib were reported: Congestive heart failure (n = 3): All of the patients had pre-existing cardiac disease prior to study entry Second malignancy (n = 3)* Myositis (n = 1); elevated CK (n = 1); multiple sclerosis (n = 1) Pancreatitis (n = 1); vomiting (n = 1) Renal failure (n = 1) Dermatitis (n = 1) *With >400,000 patient years of estimated imatinib exposure, the analysis of clinical safety data from clinical trials and spontaneous reports did not provide evidence for an increased incidence of malignancies for patients treated with imatinib compared to that of the general population O Brien S, et al. Blood. 2008;112: Abstract 186.

58 Management of Common Toxicities With Imatinib Gastrointestinal: Take imatinib with a full meal and a full glass of water Muscle cramping: Tonic water (quinine) Dose reduction (should not go below 300 mg daily under most circumstances)

59 Second-Line Dasatinib in CP- CML Focus on safety and tolerability

60 Second-Line Dasatinib: 7-Year Follow-Up N = 670 randomized a CP-CML patients 18 years with Resistance Suboptimal response Intolerance to imatinib N = 662 treated 100 mg QD (n = 167) 50 mg BID (n = 168) 140 mg QD (n = 167) 70 mg BID (n = 168) 7-year final results After 2 years, protocol allowed switching from BID to QD dosing Primary endpoint: To compare the MCyR rates of dasatinib when administered QD vs BID after a minimum follow-up of 6 months Enrollment period: July 13, 2005 March 13, a Patients were stratified by imatinib resistance vs imatinib intolerance Shah N, et al. Blood. 2014;124: Abstract 520.

61 Cumulative Incidence Rate of All-Cause Nonhematologic AEs of Special Interest Hemorrhage Pleural effusion Diarrhea Nausea/vomiting Fatigue 100 mg QD (Any grade) Other dose groups (any grade) 100 mg QD (Grade 3) Other dose groups (grade 3) Myalgias/arthralgias Rash Patients, % For 100 mg QD, most nonhematologic AEs (all grades) first occurred within 24 months of treatment Shah N, et al. Blood. 2014;124: Abstract 520.

62 Drug-Related Pleural Effusion and Pulmonary Hypertension Over Time (Any Grade) Dasatinib dose 100 mg QD (n = 165) Number of patients (%) Other dose groups (n = 497) 2-year 5-year 7-year 2-year 5-year 7-year Pleural effusion 23 (14) 40 (24) 46 (28) 118 (24) 158 (32) 174 (35) Pulmonary hypertension Pulmonary arterial hypertension 0 (0) 0 (0) 3 (2) 5 (1) 8 (2) 13 (3) -- 0 (0) 1 (<1) -- 0 (0) 0 (0) Shah N, et al. Blood. 2014;124: Abstract 520.

63 Arterial Ischemic Events Summary: All Treated Patients Number of patients (%) 100 mg QD (n = 165) Other dose groups (n = 497) Any grade Grade 3/4 Grade 5 Any grade Grade 3/4 Grade 5 Subjects with any cardiovascular 7 (4) 4 (2) 0 20 (4) 11 (2) 1 (<1) ischemic events a Myocardial infarction 3 (2) 3 (2) 0 4 (1) 3 (1) 1 (<1) Angina pectoris 2 (1) 1 (1) 0 12 (2) 6 (1) 0 Coronary artery disease 2 (1) (<1) 0 0 MedDRA Version 16.1 a Patients may have more than one event within a class Shah N, et al. Blood. 2014;124: Abstract 520.

64 Second-Line Nilotinib in CP- CML Focus on safety and tolerability

65 Imatinib-Resistant or Imatinib-Intolerant Patients 48-Month Follow-Up of Phase II Trial Hematologic Toxicity Giles FJ, et al. Leukemia. 2013;27(1):

66 Phase II CML-CP: Frequent (>10%) Drug-Related Nonhematologic AEs N = 321 All grades (%) Grades 3/4 (%) Rash 30 2 Pruritus 25 <1 Nausea 24 <1 Fatigue 20 1 Headache 18 2 Vomiting 12 <1 Constipation 12 0 Diarrhea 12 2 Kantarjian HM, et al. Blood. 2007;110: Abstract 735.

67 Phase II CML-CP: Grades 3/4 Biochemical Laboratory Abnormalities N = 321 Grades 3/4 (%) AST 2 ALT 4 Bilirubin (total) 8 Bilirubin (direct) 5 Creatinine 1 Hypocalcemia 1 Hypomagnesemia <1 Hypophosphatemia 14 Lipase elevation 15 Hyperglycemia 13 AST, aspartate aminotransferase, ALT alanine transaminase Kantarjian HM, et al. Blood. 2007;110: Abstract 735.

68 Phase II CML-CP: Incidence of Important Cardiac AEs N = 321 n (%) QTcF > 60 msec change from baseline 8 (2.5) QTcF prolongation (> 500 msec) 3 (0.9) Atrial arrhythmias 1 8 (2.5) Ventricular arrhythmias 2 3 (0.9) Cardiac failure 3 5 (1.6) Myocardial ischemia 4 22 (6.9) Myocardial infarction 5 6 (1.9) 1. Atrial fibrillation, atrial flutter, supraventricular tachycardia, arrhythmia supraventricular, supraventricular tachyarrhythmia, supraventricular extrasystoles 2. Ventricular tachyarrhythmia, ventricular flutter, ventricular extrasystoles; one case of ventricular arrhythmia reported in the originally MAA was later identified as having been reported in error (data entry error) 3. Cardiac failure, cardiac failure congestive, pulmonary oedema, left ventricular dysfunction, ejection fraction decreased 4. Angina pectoris, myocardial ischemia, coronary artery stenosis, coronary artery disease, Arteriosclerosis coronary artery 5. Myocardial infarction, acute myocardial infarction Kantarjian HM, et al. Blood. 2007;110: Abstract 735.

69 Second-Line Bosutinib in CP- CML Focus on safety and tolerability

70 Efficacy and Safety of Bosutinib (SKI-606) Among Patients With Chronic Phase Ph+ Chronic CML Cortes J, Brümmendorf TH, Kantarjian H, Khoury J, Rosti G, Fischer T, Tornaghi L, Hewes B, Martin EC, and Gambacorti-Passerini C Cortes J, et al. Blood. 2007;110: Abstract 733.

71 Bosutinib in CP CML: Non-Hematologic Adverse Events (N = 152) Event N (%) All grades Grade 3/4 Diarrhea 104 (68) 10 (7) Nausea 65 (43) 1 (1) Vomiting 42 (28) 4 (3) Abdominal pain 41 (27) 1 (1) Rash 37 (24) 10 (7) Other pain 27 (18) 0 Fatigue 26 (17) 2 (1) Any fluid retention 17 (11) 1(1) Cortes J, et al. Blood. 2007;110: Abstract 733.

72 Bosutinib in CP CML: Other Laboratory Abnormalities Abnormality No. (%) Grade 3/4 Hypophosphatemia 11 (7) Elevated ALT 10 (7) Elevated lipase 6 (4) Elevated glucose 4 (3) Elevated INR 4 (3) Elevated AST 2 (1) Elevated creatinine 2 (1) Hypocalcemia 2 (1) Cortes J, et al. Blood. 2007;110: Abstract 733.

73 Management of Bosutinib-Related Toxicities Diarrhea is common with bosutinib, particularly at the recommended starting dose of 500 mg daily Consider initiating mg daily and dose escalate as necessary and tolerated Educate patients that diarrhea is typically self-limited, and improves substantially within 4-6 weeks; encourage small meals and limited fluid intake Provide patients with prescription anti-diarrheal medications Perform monthly hepatic enzyme tests for the first 3 months of treatment with bosutinib and as clinically indicated; in patients with transaminase elevations, monitor liver enzymes more frequently; withhold, dose reduce, or discontinue bosutinib as necessary

74 Second-Line (and Beyond) Ponatinib in CP-CML Focus on safety and tolerability

75 Ponatinib in Patients With CML and Ph+ ALL Resistant or Intolerant to Dasatinib or Nilotinib, or With the T315I BCR ABL Mutation: 2-Year Follow Up of the PACE Trial Cortes J, Kim D-W, Pinilla-Ibarz J, le Coutre PD, Paquette R, Chuah C, Nicolini FE, Apperley JF, Khoury HJ, Talpaz M, DiPersio JF, DeAngelo DJ, Abruzzese E, Rea D, Baccarani M, Müller MC, Gambacorti-Passerini C, Lustgarten S, Rivera VM, Clackson T, Turner CD, Haluska FG, Guilhot F, Deininger MW, Hochhaus A, Hughes TP, Goldman JM, Shah NP, and Kantarjian HM on behalf of the PACE Study Group Cortes J, et al. Blood. 2013;122: Abstract 650.

76 Ponatinib Phase II Study: Hypertension Baseline blood pressure (BP) (mmhg), NCI CTCAE Increase in BP on study (single measurement) a Grade 1 Grade 2 Grade 3 Normal (<120/<80), N = 70 36% 30% 23% Grade 1 ( )/(80-89), N = % 34% Grade 2 ( )/(90-99), N = % Grade 3 ( 160/ 100), N = /449 (84%) patients had elevated BP at baseline ( 140/90, 47%) 301/449 (67%) patients experienced any increase in BP a on study AEs of hypertension were reported in 109/449 (24%) patients (SAEs in 8/449 [2%]) a Any shift to higher grade (NCI CTCAE v.4.0), based on single BP measurements Cortes J, et al. Blood. 2013;122: Abstract 650.

77 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 [340 patient-years] 24 months [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) 1.7-fold increase in exposure over additional 13 months of follow-up Incidence of serious AEs increased from 8% to 12% Median time to onset: 215 days (range days) SAE = AE reported as serious by the investigator, per standard criteria Cortes J, et al. Blood. 2013;122: Abstract 650.

78 Ponatinib Phase II Study: Incidence of Vascular Occlusive Events Over Time N = 449 n (%) Data as of: 23 July 2012 (USPI) 03 Sep 2013 Median follow-up [exposure] 12 months [340 patient-years] 24 months [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) In October 2013, inclusion of venous thromboembolism events (3 SAEs in intervening months) to create vascular occlusion category SAE = AE reported as serious by the investigator, per standard criteria Cortes J, et al. Blood. 2013;122: Abstract 650.

79 Management of Ponatinib-Related Toxicities Interrupt treatment for grade 3 pancreatitis and resume lower dose or switch to alternate TKI upon resolution of elevated serum lipase Stop treatment in any patient with a vaso-occlusive event suspected to be related to ponatinib; the use of anticoagulant therapy has not been investigated in this setting Consider an initial dose of 30 mg daily in patients with cardiovascular risk factors and dose escalate as tolerated/necessary to 45 mg daily

80 First-Line Nilotinib in CP-CML Focus on safety and tolerability

81 ENESTnd Update: Nilotinib vs Imatinib in Patients With Newly Diagnosed CML-CP and the Impact of Early Molecular Response and Sokal Risk at Diagnosis on Long-Term Outcomes ENESTnd 5-year update Saglio G, Hochhaus A, Hughes TP, Clark RE, Nakamae H, Kim DW, Jootar S, Etienne G, Flinn IW, Lipton JH, Pasquini R, Moiraghi B, Kemp C, Fan X, Menssen HD, Kantarjian HM, and Larson RA on behalf of the ENESTnd investigators Saglio G, et al. Blood. 2013;122: Abstract

82 ENESTnd Study Design ENESTnd 5-year update 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 Data cutoff: May 22, 2013 Saglio G, et al. Blood. 2013;122: Abstract 92. BID, twice daily; QD, once daily. 82

83 Patients, % ENESTnd 5-year update Newly Occurring or Worsening Grade 3/4 Hematologic and Selected Biochemical Abnormalities 25 Imatinib 400 mg QD (n = 280) Nilotinib 300 mg BID (n = 279) Nilotinib 400 mg BID (n = 277) 22 New events in year <1 <1 0 0 Anemia Neutropenia Thrombocytopenia Lipase AST Total bilirubin Glucose Cholesterol BID, twice daily; QD, once daily Data cutoff: May 22, 2013 Saglio G, et al. Blood. 2013;122: Abstract 92.

84 Patients with an Event, n Selected Cardiovascular Events by 5 Years (All Cause*, All Grades) 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, patients had longer exposure to nilotinib than imatinib Approximately 85% of patients with a cardiovascular event had at least 1 risk factor and were not optimally managed for hyperglycemia and hypercholesterolemia Y5, n Total, n ENESTnd 5-year update 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 Data cutoff: May 22, 2013 Saglio G, et al. Blood. 2013;122: Abstract 92.

85 Management of Nilotinib-Related Toxicities Interrupt treatment for elevated lipase in the setting of abdominal pain and resume lower dose or switch to alternate TKI upon resolution of elevated serum lipase Stop treatment in any patient with a vaso-occlusive event suspected to be related to nilotinib; the use of anticoagulant therapy has not been investigated in this setting QT prolongation and sudden deaths have been observed with nilotinib, and regular ECG monitoring is indicated; monitor and replete K and Mg levels as necessary; avoid nilotinib in patients with low K, low Mg or long QT syndrome

86 First-Line Dasatinib in CP-CML Focus on safety and tolerability

87 DASISION 5-year final study results Final Study Results of DASISION (Dasatinib Versus Imatinib in Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase [CML-CP]) Cortes J, Saglio G, Shah NP, Baccarani M, Kantarjian H, Mayer J, Nakamae H, Boqué C, Chuah C, Kim DW, Pavlovsky C, Shah S, Undurraga MS, Wang J, Ayala M, Casanova L, Bradley-Garelik B, Manos G, and Hochhaus A Cortes J, et al. Blood. 2014;124: Abstract 152.

88 DASISION 5-year final study results DASISION (CA ) Study Design Treatment-naïve CML-CP patients (N = 519) 108 centers 26 countries Enrollment: September December 2008 Randomized a Dasatinib 100 mg QD (n = 259) Imatinib 400 mg QD (n = 260) 5-year final results Database lock of 24-Mar-2014 Primary end point: confirmed CCyR by 12 months 77% dasatinib vs. 66% imatinib (P =.007) 1 a Stratified by EURO (Hasford) risk score 1. Kantarjian H, et al. N Engl J Med. 2010;362: Cortes J, et al. Blood. 2014;124: Abstract 152.

89 DASISION 5-year final study results On-Study Drug-Related Nonhematologic AEs (Frequency 10%) Pleural effusion Diarrhea Headache Musculoskeletal pain Skin rash Fatigue Abdominal pain Nausea Face edema Peripheral edema Myalgia Muscle spasms Vomitting Grade 1 2 Dasatinib2 Grade 3 4 Dasatinib Grade 1 2 Imatinib2 Grade 3 4 Imatinib Dasatinib 100 mg QD Imatinib 400 mg QD Patients, % No grade 5 AEs were reported for the nonhematologic AEs listed here Pulmonary hypertension was reported in 14 patients in the dasatinib group and 1 patient in the imatinib group No patients had pulmonary arterial hypertension per WHO definition Cortes J, et al. Blood. 2014;124: Abstract 152.

90 Characteristics and Management of Pleural Effusion Dasatinib 100 mg QD (n = 258) Total, n (%) 73 (28) Grade (26) Grade (3) Discontinuation due to pleural effusion, n (%) 15 (6) Dose interruptions due to pleural effusion, n (%) 45 (61) Dose reductions due to pleural effusion, n (%) 30 (41) Median time to first grade 1 2 pleural effusion, weeks (range) Median time to first grade 3 4 pleural effusion, weeks (range) 114 (4 299) 175 ( ) 9 (12%) dasatinib-treated patients had therapeutic thoracentesis DASISION 5-year final study results 9 out of 14 dasatinib-treated patients with pulmonary hypertension also had pleural effusion Cortes J, et al. Blood. 2014;124: Abstract 152.

91 Patients, % Pleural Effusion by Year of Treatment % DASISION 5-year final study results 6 4 5% 4% 5% 5% y >1 y 2 y >2 y 3 y >3 y 4 y >4 y 5 y At 5 years of follow-up in DASISION, recurrent pleural effusions were reported 46 out of 73 patients had recurrent pleural effusions Pleural effusion did not impair the ability of patients to obtain a response Of patients with pleural effusion, 96% had cccyr, 82% had MMR, and 50% had MR 4.5 BCR-ABL (IS) 0.1%; MR 4.5 = BCR-ABL (IS) % Cortes J, et al. Blood. 2014;124: Abstract 152.

92 Arterial Ischemic Events Regardless of Relationship to Study Therapy Any grade Dasatinib 100 mg QD (n = 258) Grade 3/4 Treated patients, n (%) Grade 5 Any grade Imatinib 400 mg QD (n = 258) Grade 3/4 Grade 5 Any ischemic event 12 (5) 7 (3) 2 (1) 6 (2) 3 (1) 1 (<1) Cardiovascular a 10 (4) 5 (2) 2 (1) 4 (2) 2 (1) 1 (<1) Transient ischemic attack Peripheral arterial occlusive disease 2 (1) 2 (1) (1) 1 (<1) 0 a Includes myocardial infarction, angina pectoris, coronary artery disease, and acute coronary syndrome. DASISION 5-year final study results Cardiovascular ischemic events occurred in 7 out of 10 patients within 1 year of dasatinib initiation Cortes J, et al. Blood. 2014;124: Abstract 152.

93 Management of Pleural Effusion With Dasatinib Pleural effusions can occur anytime following initiation of dasatinib More common in age >60 years Associated with higher trough levels of drug Tend to accumulate slowly Educate patients regarding concerning symptoms If chest X-ray confirms symptomatic pleural effusion, interrupt TKI; for severe effusions, refer for therapeutic thoracentesis; for mild/moderate effusions, short course of diuretics/steroids can be beneficial; after resolution, use lower dose of dasatinib or alternate TKI Cortes J, et al. Blood. 2014;124: Abstract 152.

94 Management of Pulmonary Arterial Hypertension (PAH) With Dasatinib Anecdotal reports of largely reversible pulmonary arterial hypertension with dasatinib have surfaced; incidence estimated to be ~0.5% If unexplained breathless develops on dasatinib, consider echocardiogram; if indicative of increased pulmonary arterial pressure, refer to cardiology for consideration of right heart catheterization (gold standard for diagnosis); discontinue dasatinib in individuals with confirmed PAH Cortes J, et al. Blood. 2014;124: Abstract 152.

95 Conclusions (I) BCR-ABL TKIs have transformed chronic phase CML to a manageable chronic condition in the vast majority of cases Excessive delays in diagnosis/treatment of chronic phase CML can be highly detrimental to long-term outcomes Effective monitoring is required to maximize therapeutic outcomes Better medical therapies are required for blast phase CML Timely recognition and treatment of TKI resistance is necessary to maximize therapeutic outcomes Certain BCR-ABL kinase domain mutants may respond preferentially to a particular TKI BCR-ABL TKIs have distinct AE profiles to be aware of Attempts to develop safer therapies for patients with the BCR-ABL/T315I mutation are ongoing (eg, ABL001)

96 Conclusions (II) CML represents a triumph of precision medicine, and the outlook for chronic phase CML patients is highly favorable as a result of TKI therapy As a consequence of dramatically improved long-term outcomes, the prevalence of CML has increased - With the favorable outlook, it is increasingly important to minimize serious and irreversible toxicities and maximize quality of life

97