CHRONIC MYELOID LEUKEMIA (CML) Managing the Long and the Short of It

CHRONIC MYELOID LEUKEMIA (CML) Managing the Long and the Short of It Jeffrey H Lipton PhD MD Princess Margaret Cancer Centre Professor of Medicine University of Toronto CAGPO Annual Conference St. John s, NFLD October 24, 2014

Disclosure Research Support/P.I. Employee Consultant Stockholder Speakers Bureau Scientific Advisory Board Other BMS, Novartis, Roche, Pfizer (Wyeth), Merck (Schering), Teva (ChemGenex), Ariad BMS, Novartis, Roche, Merck, Teva, Pfizer, Alexion, Ariad, CSL Behring BMS, Novartis, Roche. Pfizer, Teva, Alexion, Ariad, CSL Behring

Disclosure This presentation is assisted by unrestricted sponsorship by Pfizer Canada Inc Under the guidance of the Rx&D Code of Canada Content is determined by the speaker Any off label uses of drugs will be indicated

Ice Breaker Just by Show of Hands How many of you will be involved in the diagnosis of new malignancies versus managing patients already diagnosed? How many of you in this room treat or will be treating leukemias? How many of you in this room treat or will be treating CML? How many of you feel comfortable with the concept of targeted therapy?

Goals of this Presentation Gain an understanding of CML, the disease Understand the concept of targeted therapy Know the options for first line therapy in CML Learn the importance of monitoring disease and side effects of patients on therapy Understand the principles of when to switch therapy, ie second or third line What to do when targeted therapy does not appear to be working

What is chronic myeloid leukemia? Biology and Epidemiology

The Philadelphia Chromosome (Ph) BCR-ABL gene structure Chromosome 22 bcr 1 Chromosome 9 2-11 abl 2-11 2-11 p210bcr-abl p185bcr-abl Exons Introns CML Breakpoints ALL Breakpoints Nowell PC, Hungerford DA. Science. 1960;132:1497-1501. Forrest et al, 2008; Bakshi et al, 2008; Nowell and Hungerford. JNCI. 1960;25. Rowley 1973.

Diagnosis of CML

Choosing a Treatment Path

Pre History or what we did in the days before targeted therapy

A walk through history Arsenic Lissauer, 1865 Radiotherapy Pusey, 1902 Busulfan Galton, 1953 Hydroxyurea Fishbein et al, 1964 Autografting Buckner et al, 1974 Allogeneic BMT (SD) Doney et al, 1978 Interferon Talpaz et al, 1983 Allogeneic BMT (UD) Beatty et al, 1989 Donor Leukocytes Kolb et al, 1990

CML Milestones 1 st description of pts w/ CML features Philadelphia chromosome identified Translocation identified as 22q to distal end of 9 BCR-ABL Kinase activity characterized TKI efficacy against BCR-ABL characterized 1840 1900 1940 1950 1960 1970 1980 1990 2000 2010 Arsenic RT Busulfan IFNa Allogeneic SCT Imatinib Nilotinib, Dasatinib Bosutinib, OM, 22 ponatinib

Proportion Surviving Improved Survival of Early Chronic Phase CML 1.0 0.8 0.6 95% Y ear T otal Dead Imatinib 230 7 1990-2000 960 334 1982-1989 365 265 1975-1981 132 127 1965-1974 123 122 0.4 0.2 0.0 0 2 4 6 8 10 12 14 Y ears from Referral Quintas-Cardama et al. Mayo Clin Proc. 2006; 81: 973-88

Probability of Survival CML Survival After Allogeneic SCT (FHCRC) 1.0 0.8 Chronic phase (n = 576) Accelerated phase (n = 125) Blast crisis/remission (n = 62) Blast crisis (n = 44) 0.6 0.4 0.2 0 0 2 4 6 8 10 12 14 16 Yrs After Transplantation *Includes both matched related and unrelated donors. Patients receiving allografts at the Fred Hutchinson Cancer Research Center from 1995 to the present. Figure is courtesy of Dr. Ted Gooley.

PMH CML Transplant Results Zaretsky 2007 Zaretsky, BMT (2007)

What is Targeted Therapy? Just the facts ma am

WWII ENOLA GAY AND HIROSHIMA 1944 AKA Conventional Chemotherapy

US PRECISION BOMBING OF IMPERIAL GUARD BUILDING IRAQ 2003 AKA Targeted Therapy

Therapy of Newly Diagnosed Patients with CML

What are the goals of CML therapy? Basically: to keep people from progressing from chronic phase to advanced phase. People rarely die from CML in chronic phase Ideally: To reduce the tumor load or molecular level of bcr-abl to undetectable disease To be able to maintain this response off therapy Cynically: To keep people alive with CML, so they can die from something else

Imatinib Dasatinib Nilotinib Tyrosine Kinase Inhibitors Currently Available and Approved in Canada for First-Line Therapy* brand Gleevec (Novartis) generic Apotex already problems with back orders! generic Teva generic Cobalt, just approved brand Sprycel (BMS) brand Tasigna (Novartis) * Health Canada approval and provincial reimbursement are not synonymous

IRIS R A N D O M I Z E Imatinib n = 553 IFN-a + Ara-C n = 553 14 (3%) 359 (65%) Crossover Discontinued study treatment 181 (33%) 364 (66%) 13 (2%) Hochhaus A. et al, Blood. 2007; 110, 11. Abstract 25. ASH 2007 Oral Presentation

% Responding Druker BJ, et al. N Engl J Med. 2006;355:2408-2417. Response with 1st-Line Imatinib at 60 Months 100 90 80 96% 85% 80% 84% 98% 92% 87% 70 69% 60 CHR 50 MCR 40 CCR 30 20 10 0 CCR IM = 68% IFN/Ara-c = 7% 0 6 12 18 24 30 36 42 48 54 60 66 Months since randomization to imatinib mesylate CCR = complete cytogenetic response.

Alive % OS on First-Line Imatinib (IRIS Study) 90 70 50 Estimated overall survival at 8 years was 85% (93%, considering only CML-related deaths) 30 10 Survival: deaths associated with CM L Overall Survival 12 24 36 48 60 72 84 Months Since Randomization 96 108 Deininger M, et al. ASH Annual Meeting Abstracts. 2009;114:1126.

With Event, % IRIS 8-Year Update Results: Annual Event Rates Imatinib Arm 8 7 6 5 7.5 4.8 Event Loss of CHR, Loss of MCyR, AP/BC, Death during treatment AP/BC 4 3 3.3 2.8 2 1.8 1.5 1.7 1.4 1.3 0.9 1 0.8 0.5 0.3 0.4 0 0 0 1 2 3 4 5 6 7 8 Estimated EFS at 8 years = 81% Year 1 progression to AP/BC and 2 non-cml related deaths occurred in year 8 Estimated rate of freedom from progression to AP/BC at 8 years = 92% Deininger, ASH 2009

% Alive Survival After Progression to AP/BP 100 90 80 70 60 50 40 30 20 10 Median Survival 10.5 months Progressed = 34 Died = 23 Alive = 11 0 0 6 12 18 24 30 36 Months Since Progression Saglio et al, 2011.

2nd Generation TKIs vs Imatinib Treatment-Naïve CP-CML ENESTnd N = 846 217 centers 35 countries Primary Endpoint: MMR at 12 Months *Stratified by Sokal risk score. Follow-up 5 years DASISION N = 519 108 centers 26 countries R A N D O M I Z E D Dasatinib 100 mg QD (N = 259) Imatinib 400 mg QD (N = 260) *Stratified by Hasford risk score. Follow-up 5 years Primary Endpoint: Confirmed CCyR at 12 Months 37

Patients With MR 4.5, % Second-Generation TKIs Produce Deeper 100 90 80 70 60 50 40 30 20 10 MRs Compared With Imatinib Nilotinib 300 mg BID (n = 282) Nilotinib 400 mg BID (n = 281) Imatinib 400 mg QD (n = 283) Δ 6% to 10% By 1 Year a 11%, P <.0001 7%, P <.0001 1% By 4 Years a 40%, P <.0001 37%, P =.0002 Δ 14% to 17% By 5 Years a 54%, P <.0001 52%, P <.0001 Δ 21% to 23% 0 0 1 2 3 4 5 6 Time Since Randomization, calendar years Rates of MR 4.5 by 5 years were consistently higher with nilotinib vs imatinib in patients with low, intermediate, or high Sokal risk scores a Cumulative response rates reported consider each year to consist of twelve 28-day cycles. Saglio G, et al. Blood. 2013;122(21) [abstract 92]. 23% 31% Data cutoff: May 22, 2013

Second-Generation TKIs Produce Deeper 60 MRs Compared With Imatinib P <.030 Dasatinib 100 mg QD n = 259 Imatinib 400 mg QD n = 260 50 % With MR 4.5 40 30 20 3% 18% 23% 34% 21% 37% 30% 10 9% 12% 0 2% 0 12 24 36 48 60 Months Cortes J, et al. Blood. 2013;122(21);[abstract 653].

MMR by 12 Months is Predictive of Undetectable BCR-ABL Transcript Levels Undetectable BCR-ABL, % 100 80 MMR by 12 months (n = 24) No MMR by 12 months (n = 29) 72% 60 40 P <.0001 20 0 Pre 1 2 3 4 5 6 Years on imatinib 5% Branford S, et al. Clin Cancer Res. 2007;13:7080-7085.

Number of Patients, n Progression to AP/BC: Including Events After Discontinuation (ITT Analysis)* ENESTnd 3-Year Update P =.0496 HR = 0.5 [0.2, 1.0] P =.0076 HR = 0.3 [0.1, 0.8] 19 9 6 3.2% 2.1% 6.7% On Core Treatment and After Discontinuation Nilotinib 300 mg BID Nilotinib 400 mg BID Imatinib 400 mg QD Off treatment progression information was prospectively collected for all patients every 3 months after discontinuation In the IRIS study, cumulative progression rates in the first 3 years of therapy were approximately 6% on imatinib 1 * Progression to AP/BC or death following progression. 1. Hochhaus A, et al. Leukemia. 2009;23(6):1054-1061. Data cut-off: 27Jul2011. 41 Saglio G, et al. Blood. 2011;118(21):208-209 [abstract 452].

DASISION: First-Line Dasatinib vs. Imatinib in CML-CP. Progression to AP/BP 15 Dasatinib 100 mg QD Imatinib 400 mg QD Progressed to AP/BP (n) 10 5 5 1.9% 9 3.5% 0 No patient who achieved MMR progressed to accelerated or blast phase 2 patients who achieved CCyR progressed to accelerated or blast phase (1 with dasatinib, 1 with imatinib)

It is difficult comparing drugs and outcomes outside of direct randomizations where the same language is spoken! Jabbour and Lipton, 2013

Efficacy Data from Studies Using Second Generation Drugs First Line Jabbour and Lipton, 2013 44

Importance of Achieving Deep Molecular Response Achievement of MMR is associated with Longer duration of CCyR 1-4 Higher rates of EFS 5 and PFS 6 Durable MMR is associated with improved PFS 7 Early, deep MR is associated with EFS, 5,8-10 PFS, 6,10,11 higher OS 11 and deeper MRs 12 MR 4.5 may predict survival better than CCyR 13 Deeper MR (MR 4 or MR 4.5 ) is a prerequisite for many treatment-free remission trials 14-17 1. Iacobucci I, et al. Clin Cancer Res; 2006:12,3037-3042. 2. Cortes J, et al. Clin Cancer Res. 2005;11:3425-3432. 3. Paschka P, et al. Leukemia. 2003;17:1687-1694. 4. Press RD, et al. Blood. 2006;107:4250-4256. 5. Press RD, et. al. Clin Cancer Res. 2007;13:6136-6143. 6. Hughes TP, et al. New Engl J Med. 2003;349:1423-1432. 7. Kantarjian H, et al. Cancer. 2008;112:837-845. 8. Müller MC, et al. Blood. 2008;112:129 [abstract 333]. 9. Osborn MP, et al. Blood. 2009;114:461-462 [abstract 1125]. 10. Marin D, et al. J Clin Oncol. 2012;30:232-238. 11. Hanfstein B, et al. Leukemia. 2012;26(9):2096-2102. 12. Branford S, et al. Clin Cancer Res. 2007;13:7080-7085. 13. Hehlmann et al. J Clin Oncol. 2014 Feb 10;32(5):415-23. 14. Mahon FX, et al. Lancet Oncol. 2010;11(11):1029-1035. 15. Rousselot P, et al. Blood. 2011;118(21) [abstract 3781]. 16. Matsuki E, et al. Blood. 2011;118(21) [abstract 3765]. 17. Ross M, et al. Haematologica. 2012;97(s1):74 [abstract 0189]. MR 4, molecular response 4-log reduction; MR 4.5, molecular response 4.5-log reduction.

So, you may ask, how do you choose which drug to use? Provincial or private payer guidelines and/or reimbursement may make this an easy choice A good initial history, physical and baseline bloodwork assessment may help define comorbidities which make one drug preferable over another Lifestyle review including shift work and eating habits may help define a preferable drug At diagnosis, there are no response/resistance criteria to help with the decision For many patients, it will be like

More drugs means more choices!

Monitoring

When we talk about monitoring It is usually assumed that we are dealing with response to therapy Although this is in part correct, it is also important to check for Compliance Side effects that may influence compliance Additional medications that may have been changed or added by other treaters

Decisions based on monitoring visits include Whether to continue with current management Whether to change management because of failed response Whether to change management because of side effects (INTOLERANCE) Dosing change Drug change Whether discontinuation of therapy on protocol for those with deepest responses

Therapy Efficacy Monitoring

Monitoring CML Hematological response (HR) Measure of blood count and differentials Cytogenetic response (CyR) Chromosome banding analysis of bone cell metaphases Molecular Response Measurement of BCR-ABL1 transcript levels 1. 2. 3. 1. Maslak P. ASH Image Bank. 2008; 8-0067. http://ashimagebank.hematologylibrary.org. Copyright American Society of Hematology 2008. 2. Quintas-Cardama A, et al. Leukemia. 2007;21:2394 2396. Image reprinted by permission from Macmillian Publishers Ltd. Copyright 2007. 3. Baccarani M, et al. J Clin Oncol. 200;27:6041 6051.

Defining Response Type of Response Definition CHR Complete Hematologic Response Normal differential, WBC, platelets ULN MCyR Major cytogenetic Response 0-35% Ph+ marrow metaphases CCyR Complete Cytogenetic Response 0% Ph+ marrow metaphases MMR Major Molecular Response BCR-ABL/ABL 0.1% (International Scale) CMR Complete Molecular Response Undetectable BCR-ABL (test of sensitivity 4.5 logs) 53

First-line Treatment Milestones Have Evolved The European LeukemiaNet (ELN) recommendations for optimal responses have shifted to deeper responses 3 to 6 months earlier in treatment Similarly, failure criteria occur 3 months earlier vs 2009 ELN recommendations 2009 ELN 2 ELN Definition of Optimal Response in Newly Diagnosed Patients 3 months 6 months 12 months Beyond 12 months 2013 ELN 3 BCR-ABL IS = 10% BCR-ABL IS = 1% a Platelet count < 450 10 9 /L, white blood cells (WBC) < 10 10 9 /L, differential count without immature granulocytes, and < 5% basophils; b 36% to 65% Ph+ metaphases; c 1% to 35% Ph+ metaphases; d No Ph+ metaphases; e BCR-ABL IS 0.1%; f BCR-ABL to ABL (or other housekeeping gene) ratio 0.1%. BCR-ABL IS = 0.1% BCR-ABL IS = 0.0032% 1. Baccarani M, et al. J Clin Oncol. 2009;27(35):6041-6051. 2. Baccarani M, et al. Blood. 2013;122(6):872-884. BCR-ABL IS, BCR-ABL transcripts measured on the International Scale; CCyR, complete cytogenetic response; mcyr, minor cytogenetic response; PCyR, partial cytogenetic response.

BCR-ABL1 transcripts (log 10 ) Correlation Between Response and Disease Burden: Molecular Response Number of leukaemic cells 10 12 10 11 10 10 10 9 10 8 Haematologic CHR (<1-log reduction) CCyR (2-log reduction) MMR (3-log reduction) Cytogenetic RQ-PCR 10 7 4.5-log reduction 10 6 Diagnosis Time Baccarani M, et al. Blood. 2006;108:1809 1820; Radich JP. Blood. 2009;114:3376 3381 RT-qPCR, reverse transcription - quantitative polymerase chain reaction

The Treatment Milestones in Ph+ CML Continue to Evolve: Earlier and Deeper 1960 1970 1980 1990 2000 Today Goal of Therapy CHR 1 MCyR 1,2 MMR 3 Deeper molecular responses 4 Leukemic Reduction 3,a 10% 1-log 1% 2-log 0.1% IS 3-log Leukemic Burden 0.0032% IS 4.5-log 1. Cortes JE, et al. Am J Med. 1996;100(5):555-570. 2. Rosti G, et al. Semin Hematol. 2003;40(2 suppl 2):56-61. 3. Baccarani M, et al. Blood. 2006;108(6):1809-1820. 4. Saglio G, et al. Blood. 2013;122(21):[abstract 92]. 5.Radich JP. Clin Lymphoma Myeloma. 2009;9(suppl 4):S391-S394. 6. Hughes TP, et al. Blood. 2010;116(19):3758-3765. 7. Press RD, et al. Clin Cancer Res. 2007;13(20):6136-6143. MR 4.5 and beyond 5-7 CHR, complete hematologic response; CML, chronic myelogenous leukemia; MCyR, major cytogenetic response; MMR, major molecular response; MR 4.5, molecular response with 4.5-log reduction below baseline; Ph+, Philadelphia chromosome positive.

Standardization of RQ-PCR for BCR-ABL: The International Scale (IS) Local Assay BCR - ABL / ABL BCR - ABL / BCR BCR - ABL / GUS 100% 10% International Scale IRIS standardised baseline 35% Ph+ Different primers/probes TaqMan LightCycler Rotorgene Others 1% 0.1% 0.01% 0.001% MMR = MR 3 MR 4 MR 5 0% Ph+ (CCyR) Hughes T, et al. Blood. 2006;108:28-37.

BCR-ABL/ABL % IS Apparent Fluctuating Levels of Residual Disease 100 10 1 0.1 MMR 0.01 0.001 MR 4.5 0.0001 0 6 12 18 24 30 36 42 48 54 60 Months

Definitions of Deep Molecular Deep MRs are defined as: 1 MR 4.0 : >4.0-log reduction in BCR-ABL1 transcripts either (i) detectable disease with <0.01 % BCR ABL1 IS or (ii) undetectable disease with >10,000 ABL1 or >24,000 GUSB transcripts Response MR 4.5 : >4.5-log reduction in BCR-ABL1 transcripts either (i) detectable disease with <0.0032% BCR ABL1 IS or (ii) undetectable disease in cdna with >32,000 ABL1 or >77,000 GUSB transcripts 10 12 10 11 10 10 10 9 10 8 10 7 10 6 CHR (<1-log) CCyR (2-log) MMR (3-log) MR 4.0 MR 4.5 5-log reduction 1.Baccarani et al. Blood. 2013;122:872 84. 2.Cross NCP, et al. Leukemia. 2012;26:2172 2175. IS, international scale.

What to do when you expect that the drug is not working Determine if this is an intolerance issue or a resistance issue If intolerance, see if the dosing, schedule, use of co-meds can be changed If resistance, first determine if it is a compliance issue If not compliance, check Mutation status Evidence of clonal progression

Microelectronic Monitoring System (MEMS 6 Trackcap) Records the time of opening the container Most reliable method of measuring adherence Our patients: not told about the chip Marin et al, Blood 2008

Marin et al, Blood 2008

Probability of MMR Six-year probability of MMR according to the measured adherence rate 1.0 0.9 0.8 p <0.0001 Adherence >90%, n= 64 0.7 0.6 0.5 0.4 0.3 0.2 Adherence 90%, n= 23 0.1 0.0 0 6 12 18 24 30 36 42 48 54 60 66 72 Marin et al, Blood 2008 Months from start of imatinib therapy

The 2013 ELN Recommendations Support Switching Treatments in Patients With Treatment Failures Optimal Responses 1 3 mo Ph+ 35% and/or BCR-ABL 10% 6 mo Ph+ 0% and/or BCR-ABL < 1% 12 mo BCR-ABL 0.1% (MMR) At any time BCR-ABL 0.1% (MMR) Failures 1 3 mo Ph+ > 95% 6 mo Ph+ > 35% and/or BCR-ABL > 10% 12 mo BCR-ABL > 1% At any time Loss of CCyR; CCA/Ph+; confirmed loss of MMR a ; mutations Per ELN recommendations, BCR-ABL > 10% at 6 months is considered treatment failure and the patient should receive another treatment 1. Baccarani M, et al. Blood. 2013;122(6):872-884. CCA, clonal chromosomal abnormalities.

Impact of 6 month versus 3 month assessment on outcome of molecular response Kim et al 2014

Tyrosine Kinase Sensitivity in CML bcr-abl Mutations BMS Canada, unpublished

Tyrosine Kinase Inhibitors Currently Available and Approved in Canada for Salvage Therapy* Imatinib brand Gleevec (Novartis) generic Apotex! generic Teva generic Cobalt, just approved Dasatinib brand Sprycel (BMS) Nilotinib brand Tasigna (Novartis) Bosutinib brand Bosulif (Pfizer) * Health Canada approval and provincial reimbursement are not synonymous

% Dasatinib dose and schedule optimization in CP-CML Hematologic and cytogenetic response 100 90 93 88 87 80 60 40 59 57 56 54 42 42 45 45 CHR MCyR CCyR 20 0 100 mg QD 50 mg BID 140 mg QD 70 mg BID Hochhaus, ASH 2006

Proportion progression-free Dasatinib dose and schedule optimization in CP-CML Progression-free survival 1.0 0.8 0.6 0.4 0.2 0 N No. progressed 100 mg QD 166 14 50 mg BID 166 13 140 mg QD 163 14 70 mg BID 167 18 0 2 4 6 8 10 12 Months Progression was defined as confirmed AP / BP, loss of CHR / MCyR, or increasing WBC count Hochhaus, ASH 2006

Without Progression, % Nilotinib - Phase II CML-CP Time to Progression 78% 64% Total = 321 Failed = 88 lll = Censored observations Months Since Start of Treatment Kantarjian, ASH 2007

Alive, % Nilotinib - Phase II CML-CP Survival 95% 91% Total = 321 Failed = 25 lll = Censored observations Kantarjian, ASH 2007 Months Since Start of Treatment

Probability of progression-free survival (%) 100 90 Bosutinib Progression-free Survival 80 70 60 50 40 30 20 10 0 Patients with any mutation CP 2L CP 3L ADV 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 54 56 58 60 62 64 66 68 Time to progression/death (months) Mutation status CP 2L CP 3L ADV No mutation, n 132 46 52 PFS rate at 1 year 92% (84.5% 95.6%) 80% (62.3% 90.2%) 43% (28.0% 57.5%) PFS rate at 2 years 86% (76.8% 91.3%) 80% (62.5% 90.2%) 34% (19.8% 48.9%) Any mutation, n 79 40 65 PFS rate at 1 year 87% (76.2% 92.9%) 82% (63.7% 91.9%) 42% (28.1% 54.3%) PFS rate at 2 years 70% (57.3% 80.0%) 77% (56.2% 88.9%) 30% (17.7% 44.1%) CP, chronic phase chronic myeloid leukemia; 2L, second-line setting; 3L, third-line setting; ADV, advanced leukemia; PFS rates at 1 year (48 weeks) and 2 years (96 weeks) were based on Kaplan-Meier estimates. PFS, progression-free survival.

Probability of overall survival (%) 100 90 80 70 60 50 Bosutinib Overall Survival 40 30 20 10 0 Time to death (months) Patients with any mutation CP 2L CP 3L ADV 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 54 56 58 60 62 64 66 68 Mutation status CP 2L CP 3L ADV No mutation, n 132 46 52 OS rate at 1 year 97% (92.0% 98.8%) 93% (79.6% 97.7%) 65% (51.2% 76.2%) OS rate at 2 years 95% (89.0% 97.4%) 88% (72.5% 94.6%) 55% (40.4% 67.4%) Any mutation, n 79 40 65 OS rate at 1 year 97% (90.0% 99.3%) 88% (72.5% 94.6%) 54% (41.3% 65.6%) OS rate at 2 years 82% (71.6% 89.4%) 79% (62.9% 89.2%) 46% (33.7% 58.0%) CP, chronic phase chronic myeloid leukemia; 2L, second-line setting; 3L, third-line setting; ADV, advanced leukemia; OS, overall survival. OS rates at 1 year (48 weeks) and 2 years (96 weeks) were based on Kaplan-Meier estimates.

BELA Trial: Bosutinib vs Imatinib Newly Diagnosed CML CP N = 502 R Bosutinib (500 mg QD), n = 250 Imatinib (400 QD), n = 252 Bosutinib, n = 250 Imatinib, n = 252 30-months CCyR 56% 61% Cumulative CCyR 70% 81% 30-month MMR 45% 43% Cumulative MMR 61% 50% Progression to AP or BP 1.6% 5.2% Deaths 3.6% 5.2% Bosutinib had a higher incidence of GI toxicities and similar rates of myelosuppression compared to imatinib Reduction of BCR-ABL:ABL transcript to 10% at 3, 6, and 9 months were associated with higher rates of MMR and CCyR for both bosutinib and imatinib Gambacorti-Passerini C, et al. ASCO Meeting Abstracts. 2012;6512.

So how do you chose which drug to use in salvage? All the criteria for front line choice PLUS Directed by a mutation Directed by a side effect of the front line drug that may also be present with one of the salvage drug

Side Effects

Short Term Usually defined by the fact that they show up early, are often short lived or can be controlled with co-medications or changes in administration Are usually mild, ie grade 1 or 2 and although annoying, usually do not interfere with taking the drug

Drug and Short Term Side Effects Imatinib Rash, GI symptoms, MSK symptoms, edema, LFT abnormalities Dasatinib Rash, abdominal discomfort, headache Nilotinib Abdominal discomfort, pancreatic and LFT abnormalities, increased blood sugars and cholesterol Bosutinib Abdominal discomfort, diarrhea, LFT abnormalities

Potential Long-Term Drug Toxicities and Choice of TKI

BACKGROUND 1 Significant side effects or adverse events that occur when a patient is started on a TKI can either be managed with simple options, dose changes or co-medications Occasionally a drug will have to be switched because of a severe or intractable AE Patients who get out a few years, tolerate their therapy and respond may be on their TKI for many years

BACKGROUND 2 Some patients will be eligible for discontinuing their therapy because of deep durable responses, the definition of which is still not standardized It is likely though that many patients will be on lifelong therapy and dealing with issues that may be associated with their particular therapy will need to be addressed

Fundamental Realities Generally, no specific medication is absolutely contraindicated, resistance aside Some TKIs in some people may pose a greater potential risk of side effects Choice of a TKI that has the potential for issues will therefore involve a risk/benefit analysis after getting full medical information, followed by a detailed discussion with the patient and more aggressive monitoring and possible intervention

Caveat I will look at problems that can continue to show up in patients even after years of therapy and at new late problems I will look at the red flags that have been raised with TKIs I will not comment on whether the definitions of these issues are correct or appropriate or whether studies were designed to collect this data accurately I am not going to talk about cause and effect, or patient risk going into treatment, just the observed associations that are likely significant and need thought and monitoring

Imatinib

Long Term AE s with Imatinib In general, after more than a decade of usage, there have been no new long term adverse advents identified with imatinib Persistence of low grade chronic side effects such as edema, gastrointestinal sensitivity and musculoskeletal problems continue Imatinib has continued to be a safe long term tolerated medication in those individuals who are responding

Dasatinib

Long Term AE s with Dasatinib Pleural Effusions Pleural effusions, likely of an immunologic etiology, and possibly of an innocent bystander effect, continue to be an issue Effusions can occur for the first time or recur years after starting the drug and constant vigilance is necessary Dose reductions do not necessarily prevent recurrence

Long Term AE s with Dasatinib The exact incidence of PAH with dasatinib is not known but is probably under reported Despite the severity, it is not a common side effect Symptoms including dyspnea in the absence of pleural effusions or evidence of congestive heart failure need to be investigated Confirmation of PAH requires aggressive work up with echocardiography and probably heart catheterization Early intervention with discontinuation of dasatinib is essential as PAH is essentially not reversible significantly in this scenario

Occurrence of PAH in Patients Treated With Dasatinib: Key Learnings Approximately 42,000 patients with CML or Ph+ ALL have received dasatinib worldwide 70 cases of PH identified 1-8 20 PAH cases confirmed by RHC and dasatinib was considered the most likely cause In most cases, patients had received previous treatment for CML PAH cases primarily identified via postmarketing surveillance In total, 2866 patients have been treated with dasatinib in clinical trials 8,9 3 cases of PAH determined by RHC have been identified 1 case in CA180-005 (START-A: 2 nd -line dasatinib in CML-AP) 2 cases in CA180-035 (2 nd -line dasatinib in CML-BP, CML-AP, Ph+ ALL) 1. Rasheed W, et al. Leuk Res 2009;33:861-864; 2. Mattei D, et al. Bone Marrow Transplant 2009;43:967-968; 3. Dumitrescu D, et al. Eur Respir J 2011;38:218-220; 4. Hennigs JK, et al. BMC Pulm Med 2011;11:30; 5. Orlandi EM, et al. Leuk Res 2012;36:e4-6; 6. Philibert L, et al. Fundam Clin Pharmacol 2011;25(suppl 1); 7. Montani D, et al. Circulation 2012;125:2128-2137; 8. Bristol-Myers Squibb. Sprycel (dasatinib) EMEA summary of product characteristics, revised December 2010; 9. Bristol-Myers Squibb. Sprycel (dasatinib) US prescribing information, revised October 2011

Nilotinib

Newly Acquired Alteration of Glucose Metabolism in the ENESTnd Study Glycemic Status by 3 Years in Patients With Normal Glycemic Status at Baseline Nilotinib 300 mg BID Nilotinib 400 mg BID Imatinib 400 mg QD (n = 91) a (n = 92) (n = 88) a Pre-diab. b Diabetes c Prediab. b Diabetes c Prediab. b Diabetes c Patients with newly acquired alteration of glucose metabolism, n (%) 34 (37.4) 16 (17.6) 43 (46.7) 16 (17.4) 34 (38.6) 1 (1.1) HbA 1c altered, 25 n (%) d (27.2) 4 (4.4) 42 (43.8) 6 (6.3) 27 (29.0) 0 a Patients with normal glycemic status at baseline who were evaluable for change in glycemic status by 3 years. b Patients with prediabetes by 3 years had either FGL 1.1 to < 1.26 g/l or HbA1c 5.7% to < 6.5%, or met both criteria. c Patients with diabetes by 3 years had either FGL > 1.26 g/l or HbA1c > 6.5%, or met both criteria. d Patients who met the HbA1c criterion for prediabetes or diabetes, respectively. Adapted from Rea D, et al: Blood 2012; 120(21):[abstract 1686].

Cardiac and Vascular Events by 4 Years in the ENESTnd Study (All Grades) Patients With an Event, n (%) Nilotinib 300 mg BID n = 279 Nilotinib 400 mg BID n = 277 Imatinib 400 mg QD n = 280 IHD 11 (3.9) 14 (5.1) 3 (1.1) PAOD 4 (1.4) 5 (1.8) 0 (0) IHD, ischemic heart disease; PAOD, peripheral arterial occlusive disease. Data cutoff: July 27 2012. Adapted from Kantarjian HM, et al: Blood 2012; 120(21):[abstract 1676].

Bosutinib

Long Term CV AE s with Bosutinib (Salvage and BELA Studies) Median (range) tx duration, mo Cardiac TEAEs (any grade), % Cardiac arrhythmia Pooled 2L/3L/4L 1L BOS* BOS * BOS (n=818) (n=570) * (n=248) 11.1 33.1 (0.03-83.4) (0.03-49.6) IM (n=251) 33.3 (0.5-46.9) 18.2 19.6 14.9 9.2 5.7 6.5 4.0 2.0 Coronary artery disorder 3.4 4.2 1.6 1.2 Heart failure 2.9 3.9 0.8 0.8 Myocardial disorder 2.1 2.8 0.4 0 Pericardial disorder 2.9 3.5 1.6 0 Vascular hypertensive disorder * 500 or 400 mg/d starting dose 6.7 6.8 6.5 4.4 Gambacorti-Passerini et, ASCO 2014

Tyrosine Kinase Inhibitors and Other Medications Currently Not Approved in Canada for Salvage Therapy Ponatinib brand Iclusig (Ariad) Omacetaxine brand Synribo (Teva)

When is a TKI not the treatment of choice for salvage? Persistent hematological toxicity Clonal progression Some clonal abnormalities in Ph-neg cells Unusual mutation such as t315i if ponatinib not available Uncontrolled heart failure

Survival Probability Allo SCT for CML in the Imatinib Era 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 Elective, n = 19, 3-yr survival: 88% Imatinib failure in 1 CP, n = 37, 3-yr survival: 94% Advanced phase, n = 28, 3-yr survival: 59% 0 6 12 18 24 30 36 42 48 Mos After Transplantation Saussele S, et al. Blood. 2010;115:1880-1885

What does a physician taking care of a patient with CML need to remember and need to do? Issues for the GPO

Most important things to remember Newly diagnosed chronic phase CML patients have a life expectancy virtually the same as age matched controls Monitoring the patient and the disease are equally important Since patients will likely not die from CML, making sure that they do not die from other diseases that are treatable is equally important

Necessary Information At starting therapy A good patient history, physical and baseline laboratory assessment is necessary to sort out best choice of drug given disease status and if choice is an option During monitoring Careful assessment in conjunction with primary physician and/or other specialist to identify, modify, or treat co-morbidities or side effects Monitoring must include more than just disease response assessments

Drug Choice Deciding on what TKI to use depends on a number of issues: Drug availability This varies from jurisdiction to jurisdiction Disease status First line or salvage Previous responses Presence of kinase mutations Patient status Co-morbidities Previous adverse events on therapy

Must knows if you are to manage CML Know the drugs, especially the potential side effects Know the disease, especially the aspects of response or resistance Know the milestones what to look for and when Know the options for management at any time point, including the non-tki options Know a mentor someone you can learn from and someone who is available to answer questions

The Future - Maybe

Survival Without Molecular Relapse Duration of Therapy: Is TKI Therapy Forever? Do patients need to stay on TKI therapy forever? STIM trial RFS after discontinuation of imatinib, N = 100 6-mo: 45%, 12 mo: 43%, 24 mo: 41% 100 80 60 40 20 0 Pts at Risk, n 100 57 36 28 27 23 20 16 6 Mahon FX, et al. Lancet Oncol. 2010;11(11):1029-1035. 106