2015 Annual Hematology Meeting in Vienna 2015 Annual Hematology - - PowerPoint PPT Presentation

2015 Annual Hematology Meeting in Vienna 2015 Annual Hematology Meeting in Vienna

Canadian Clinical Spotlight: Clinical Perspectives in CML Important Updates

Reference Slide Deck Abstract S489 Abstract P228 Abstract P234 Abstract P601 Abstract P600

An NCRI Randomised Study Comparing Dasatinib With Imatinib in Patients With Newly Diagnosed CML: 2 Year Follow Up An NCRI Randomised Study Comparing Dasatinib With Imatinib in Patients With Newly Diagnosed CML: 2 Year Follow Up

O’Brien S, Osborne W, Hedgley C, Foroni L, Apperley J, Holyoake T, Pocock C, Byrne J, Gills G, Zwingers T, McCullough J, Copland M, Goldman J, Clark R

Abstract P489

SPIRIT 2: Background SPIRIT 2: Background

• Imatinib still commonly used as first-line therapy
• Second generation TKIs generally produce higher

rates of major molecular response (MMR)

• DASISION study* (n = 519) MR3 (MMR) at 5 years:

– Imatinib 64% (63% still on treatment) – Dasatinib 76% (61% still on treatment)

• No difference in OS at 5 years
• Concerns about long-term safety of second

generation

• SPIRIT 2 (n = 814) is largest dasatinib trial

*rates are Kalpan-Meier cumulative incidence

• 1. Kantarjian H, et al. N Engl J Med. 2010;362(24):2260-2270. 2. Jabbour E, et al. Blood. 2014;123(4):494-500. 3. Cortes J, et al. Blood.

2014;124: Abstract 154.

O’Brien S, et al. Haematologica. 2015;100(Suppl 1): Abstract S489.

SPIRIT 2: Study Design SPIRIT 2: Study Design

• Primary Endpoint

– 5-year event free survival (EFS), assessed for all patients March 2018

• Secondary

– Rate of complete cytogenetic response (CCR) – Rate of major molecular response (MMR, MR3, BCR-ABL1/ABL1 ratio <0.01%) – Toxicity – Treatment failure rates (TFR) after 5 years – Rates of complete hematologic response (CHR) – Overall survival at 2 and 5 years

Chronic-phase CML

Within 3 months of diagnosis

R Arm A Imatinib 400 Arm A Dasatinib 100

N = 814

Randomized, open label

n = 407 n = 407

O’Brien S, et al. Haematologica. 2015;100(Suppl 1): Abstract S489.

What Happened to All the Patients? What Happened to All the Patients?

Randomized n = 814

Allocated to imatinib – 407 1 exclusion: Protocol violation Received imatinib – 406 (100%) Allocated to dasatinib– 407 1 exclusion: Consent withdrawn Received dasatinib – 406 (100%)

Continued with imatinib – 197 (48.5%) Follow up complete – 41 (10.1%) Follow up ongoing – 156 (38.4%) Continued with dasatinib – 239 (58.9%) Follow up complete – 48 (11.8%) Follow up ongoing – 191 (47.0%) Stopped imatinib – 209 (51.5%) Death on study drug – 7 (1.7%) Finished study drug – 30 (7.4%) Decision to stop drug – 172 (42.4%) Stopped dasatinib – 167 (41.1%) Death on study drug – 6 (1.5%) Finished study drug – 28 (6.9%) Decision to stop drug – 133 (32.6%) Status of 172 patients who stopped imatinib: Subsequent death – 12 (2.9%) Follow up complete – 20 (4.9%) Follow up ongoing – 117 (28.8%) Declined follow up – 15 (3.7%) Unknown – 8 (1.9%) Status of 172 patients who stopped dasatinib: Subsequent death – 13 (3.2%) Follow up complete – 21 (5.2%) Follow up ongoing – 80 (19.7%) Declined follow up – 18 (4.4%) Unknown – 1 (0.2%)

O’Brien S, et al. Haematologica. 2015;100(Suppl 1): Abstract S489.

Reason for Stopping Study Drug (Excl Death)

Imatinib (N = 406), n (%) Dasatinib (N = 406), n (%) Total (N = 812), n (%)

Consent withdrawn 8 (1.9) 12 (2.9) 20 (2.5) Disease progression – accelerated phase 1 (0.2) 2 (0.5) 3 (0.3) Disease progression – blast crisis 7 (1.7) 4 (1.0) 11 (1.4) Failure to achieve CCR after 24 months 6 (1.5) 2 (0.5) 8 (1.0) Failure to achieve MCR after 12 months 22 (5.4) 3 (0.7) 25 (3.1) Intolerance – non hematologic toxicity 49 (12.0) 89 (21.9) 138 (16.9) Intolerance – hematologic/lab toxicity 21 (5.2) 9 (2.2) 30 (3.7) Loss of CHR 5 (1.3) 5 (0.6) Loss of MCR 5 (1.3) 2 (0.5) 7 (0.8) Other reason 2 (0.5) 3 (0.7) 5 (0.6) Reason unknown – lost to follow up 2 (0.5) 2 (0.5) 4 (0.5) ‘Inadequate reason’ (cytogenetic, hematologic, molecular, mutation detected) 44 (10.8) 5 (1.3) 49 (6.0)

Total 172 (42.4) 133 (32.6) 49 (6.0)

Patients Who Stopped Study Drug Patients Who Stopped Study Drug

O’Brien S, et al. Haematologica. 2015;100(Suppl 1): Abstract S489.

Cause of Death Cause of Death

Total deaths 38/812 (4.7%)

Imatinib 19/406 (2.3%) Dasatinib 19/406 (2.3%)

Unknown 4/19 (21%) CML related 6/19 (32%) Non-CML related 9/19 (47%) Non-CML related 10/19 (53%) CML related 5/19 (26%) Unknown 4/19 (21%) Other cancer 4/9 (44%) Noncancer 5/9 (56%) Other cancer 3/10 (30%) Noncancer 7/10 (70%)

• Lung
• Endometrial
• Rectal
• Gastric
• Left ventricular failure
• Bronchopneumonia

secondary to emphysema

• Myocardial infarction
• Ruptured aortic

aneurysm

• Bronchopneumonia
• 2 x Lung
• Breast
• Ischemic heart disease,

COPD, CCF

• Chest infection, CCR,

renal failure diabetes

• Bowel perforation
• Cardiac failure and

bronchopneumonia

• Liver disease
• COPD
• Chronic cardiac failure

O’Brien S, et al. Haematologica. 2015;100(Suppl 1): Abstract S489.

Comparative Adverse Events Comparative Adverse Events

Edema Diarrhea Dyspnea Anemia O’Brien S, et al. Haematologica. 2015;100(Suppl 1): Abstract S489.

Pleural Effusion & Dyspnea Pleural Effusion & Dyspnea

All Grades Imatinib N = 406, n (%) Dasatinib n = 406, n (%) Pleural effusion – number of patients 5 (1.2) 98 (24.1) Required drainage procedure 1 (20% of 5) 22 (22% of 98) Aspiration 0 (0) 10 (10) Chest drain 1 (20) 8 (8) Drainage procedure unknown 0 (0) 4 (4) Other treatment 1 (20) 8 (8) Dyspnea, no pleural effusion 32 (7.9) 63 (15.5) All grades 35 (8.6) 102 (25.1) Grades 2/3/4 8 (2.0) 50 (12.5)

O’Brien S, et al. Haematologica. 2015;100(Suppl 1): Abstract S489.

Cardiovascular Adverse Events Cardiovascular Adverse Events

Imatinib N = 406, n (%) Dasatinib N = 406, n (%) Cardiac serious AEs 9 (2.2) 17 (4.2)

AF x3, cardiac arrest x1, cardiac failure x3, MI x1, supraventricular tachycardia x1 ACS x2, AF x3, cardiac failure x5, MI x1, pericardial effusion x2, cardiac tamponade x1, AV block x1, cardiomegaly x1, palpitations x1

Vascular serious AEs

4 (1) 6 (1.5) AAA rupture x1, DVT x3 DVT x1, intermittent claudication x1, arterial stenosis x1, hematoma x1, thrombosis x1, lymphedema x1

Cerebovascular serious AEs

4 (1) 4 (1) Hemorrhagic stroke x1, ischemic stroke x3 Hemorrhagic stroke x3, ischemic stroke x1

Hypertension (nonserious AE) 4 (1) 8 (2)

O’Brien S, et al. Haematologica. 2015;100(Suppl 1): Abstract S489.

Cytogenetics at 24 Months Cytogenetics at 24 Months

Imatinib N = 406, n (%) Dasatinib N = 406, n (%) Difference, % P Value Major cytogenetic response (MCR) 12 months 211 (51.8) 228 (56.0) 4.2 .669 24 months 125 (30.7) 140 (34.4) 3.7 .787 Complete cytogenetic response (CCR) 12 months 171 (42.0) 217 (53.3) 11.3 .003 24 months 112 (27.5) 137 (33.7) 6.2 .189 Missing analyses 12 months 136 (33.5) 146 (35.9) 24 months 160 (39.4) 166 (40.9) Caution required, missing analyses included denominator

O’Brien S, et al. Haematologica. 2015;100(Suppl 1): Abstract S489.

PCR Data at 24 Months PCR Data at 24 Months

O’Brien S, et al. Haematologica. 2015;100(Suppl 1): Abstract S489.

Imatinib n = 406 Total Cohort n = 812 Dasatinib n = 406 On Treatment 246/406 (60.6%) Off Treatment 160/406 (39.4%) Off Treatment 116/406 (28.6%) On Treatment 290/406 (71.4%) Achieved MR3 Response 187/406 (46.0%) Achieved MR3 Response 234/406 (57.5%) Achieved MR4.5 Response 58/406 (14.3%) Achieved MR4.5 Response 82/406 (20.2%) ∆ = 11.5% P<.001 ∆ = 5.9% P = .026

SPIRIT 2: Two-Year Summary SPIRIT 2: Two-Year Summary

• Largest randomized trial of dasatinib vs imatinib
• N = 814
• Median follow up 3.5 years; 2 years follow up on all patients
• Both drugs generally well tolerated
• 436 of 812 (53.7%) continue on study medication
• Imatinib: GI toxicity; Dasatinib: Pleural effusions, headaches
• No differences in cardiovascular events
• MR3 rate at two years is: Imatinib 46.0%, dasatinib 57.5%
• ∆ = 11.5%P<.001
• 774/812 (95.3%) remain alive overall
• No difference in progression or overall survival
• 5-year event-free survival can be evaluated in 2018

O’Brien S, et al. Haematologica. 2015;100(Suppl 1): Abstract S489.

Efficacy and Safety of Nilotinib vs Imatinib in Patients With Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase: 6-Year Follow-Up of ENESTnd

Hughes TP, Larson RA, Kim D-W, Issaragrisil S, le Coutre PD, Lobo C, Dubruille V, Kuliczkowski K, Jootar S, Clark RE, Hochhaus A, Saglio G, Kemp CN, Deng W, Menssen HD, Kantarjian HM

Abstract P228

Introduction

• Evaluating nilotinib efficacy and safety in clinical trials-newly diagnosed

patients (ENESTnd) compared nilotinib (300 mg or 400 mg twice daily [BID]) with imatinib (400 mg once daily [QD]) in adult patients with newly diagnosed Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia in chronic phase (CML-CP).1-8 The 5-year follow-up data from this study7 showed that both doses of nilotinib resulted in – Higher rates of BCR-ABL ≤10% on the International Scale (IS) at 3 months – Higher rates of major molecular response (MMR; BCR-ABLIS ≤0.1%) and MR4-5 (BCR-ABLIS ≤0.0032%) – Lower risk of progression to accelerated phase/blast crisis (AP/BC) and death due to advanced CML

• The ENESTnd study protocol was amended in January 2012 to extend the follow-

up period 10 10 years, from the initial 5 years, to collect further data on efficacy parameters, including deep molecular response and survival, and safety

• The current analysis reports results based on a minimum 6-year follow-up
• 1. Saglio G, et al. N Engl J Med. 2010;362:2251-2259. 2. Kantarjian HM, et al. Lancet Oncol. 2011;12:841-851. 3. Larson RA, et al. Leukemia.

2012;26:2197-2203. 4. Hughes TP, et al. Blood. 2014;123:1353-1360. 5. Hochhaus A, et al. Blood. 2013;121:3703-3708. 6. Hughes TP, et al.

• Haematologica. 2014;99: Abstract S677. 7. Saglio G, et al. Blood. 2013;122:92. 8. Larson RA, et al. Blood. 2014;124:4541.

Hughes TP, et al. Haematologica. 2015;100(Suppl 1): Abstract P228.

Methods ENESTnd Study Design

Imatinib 400 mg QD (n = 283) Nilotinib 300 mg BID (n = 282)

R A N D O M I Z E

Nilotinib 400 mg BID (n = 281)

Planned follow-up: 10 yearsa

BID, twice daily; QD, once daily

aPatients randomized to nilotinib 300 mg BID or imatinib who experienced suboptimal response or treatment failure could discontinue core treatment and enter

an extension study in which they received nilotinib 400 mg BID. Patients randomized to nilotinib 400 mg BID were initially permitted to enter the extension study and receive imatinib 400 mg QD; however, a protocol amendment after the 36-month data cutoff removed this option. Survival and progression outcomes during extension study follow-up were included in the “on study” analyses for the core study.

N = 846 Adults with newly diagnosed (≤ 6 months) Ph+ CML-CP

1:1:1 Stratified by Sokal risk score

Hughes TP, et al. Haematologica. 2015;100(Suppl 1): Abstract P228.

Study Design (Cont)

• ENESTnd (NCT00471497) is an open-label, randomized phase III study
• The study design and methodology have been previously described1-5
• Data cutoff for the current analysis: July 18, 2014 (minimum follow-up
• f 72 cycles [28 days per cycle])
• Analyses of outcomes according to BCR-ABLIS levels at 3 months

were based on patients with evaluable 3-month assessments and without the evaluated outcome by 3 months

• Safety analyses included patients who received ≥1 dose of study drug
• Statistical analyses and nominal P values are provided for descriptive

purposes only and were not adjusted for multiple comparisons

• 1. Saglio G, et al. N Engl J Med. 2010;362:2251-2259. 2. Kantarjian HM, et al. Lancet Oncol. 2011;12:841-851. 3. Larson RA, et al.
• Leukemia. 2012;26:2197-2203. 4. Hughes TP, et al. Blood. 2014;123:1353-1360. 5. Hochhaus A, et al. Blood. 2013;121:3703-3708.

Hughes TP, et al. Haematologica. 2015;100(Suppl 1): Abstract P228.

Patient Disposition

Patient status, n (%) Nilotinib 300 mg BID (n = 282) Nilotinib 400 mg BID (n = 281) Imatinib 400 mg QD (n = 283) Still on studya 231 (81.9) 238 (84.7) 224 (79.2) Still on core treatmentb 151 (53.5) 155 (55.2) 127 (44.9) Discontinued core treatment and entered extension study 24 (8.5) 3 (1.1) 45 (15.9) Discontinued core treatment without entering extension study 107 (37.9) 123 (43.8) 111 (39.2) Adverse event/laboratory abnormality 39 (13.8) 64 (22.8) 39 (13.8) Withdrawal of consent 19 (6.7) 22 (7.8) 22 (7.8) Suboptimal response/treatment failurec 11 (3.9) 10 (3.6) 19 (6.7) Death 7 (2.5) 2 (0.7) 2 (0.7) Disease progression 2 (0.7) 4 (1.4) 10 (3.5) Other reasonsd 29 (10.3) 21 (7.5) 19 (6.7)

aOn-study analyses included all events occurring at any time during core or extension treatment or post-treatment follow-up. bOn–coretreatment analyses

included all events occurring during treatment with assigned study drug.C Per the 2009 European LeukemiaNet criteria (Baccarani M, et al. J Clin Oncol. 2009;27:6041-6051) or investigator assessment.d Included abnormal test procedure results (n = 0 [nilotinib 300 mg BID], 1 [nilotinib 400 mg BID], and 1 [imatinib]), condition no longer required study drug (n = 1, 0, and 0, respectively), lost to follow-up (n = 4, 2, and 3, respectively), administrative problems (n = 7, 6, and 7, respectively), treatment duration completed per protocol (n = 3, 1, and 2, respectively), and protocol deviation (n = 14, 11, and 6, respectively).

Hughes TP, et al. Haematologica. 2015;100(Suppl 1): Abstract P228.

Cumulative Incidence of MMR

6 12 18 24 30 36 42 48 54 60 20 40 60 80 100

Months Since Randomizationb Cumulative Incidence of MMR, %

Nilotinib 300 mg BID (n = 282) Nilotinib 400 mg BID (n = 281) Imatinib 400 mg QD (n = 283)

10 30 50 70 90 66 72 78

∆ 24% to 28% 55%; P<.0001a

By 1 Year 27% 77%; P<.0001a ∆ 16% to 18% 79%; P<.0001a By 6 Years 61% 60% 77%; P<.0001a 77%; P<.0001a ∆ 17% By 5 Years

51%; P<.0001a

aP values are nominal, were provided for descriptive purposes only, and were not adjusted for multiple comparisons. bFor each arm, the curve

stops at the latest timepoint at which a patient first achieved MMR.

Hughes TP, et al. Haematologica. 2015;100(Suppl 1): Abstract P228.

Cumulative Incidence of MR4.5

6 12 18 24 30 36 42 48 54 60 20 40 60 80 100 Months Since Randomization Cumulative Incidence of MR4.5, %

Nilotinib 300 mg BID (n = 282) Nilotinib 400 mg BID (n = 281) Imatinib 400 mg QD (n = 283)

10 30 50 70 90 66 72 78

11%; P<.0001a 7%; P<.0001a 1% ∆ 6% to 10% By 1 Year 56%; P<.0001a 55%; P<.0001a 33% ∆ 22% to 23% By 6 Years 31% By 5 Years 54%; P<.0001a 52%; P<.0001a

∆ 21% to 23%

aP values are nominal, were provided for descriptive purposes only, and were not adjusted for multiple comparisons.

Hughes TP, et al. Haematologica. 2015;100(Suppl 1): Abstract P228.

Treatment arm Kaplan Meier–estimated median time to first MR4.5, months Hazard ratio vs imatinib (95% Confidence Interval) P valuea Nilotinib 300 mg BID 45.5 months 2.0387 (1.5807-2.6295) <.0001 Nilotinib 400 mg BID 49.8 months 1.7770 (1.3780-2.2915) <.0001 Imatinib 400 mg QD 61.1 months

73.6 75.0 72.1 52.8 45.3 35.3 8.3 21.4 15.9

10 20 30 40 50 60 70 80

Nilotinib 300 mg BID Nilotinib 400 mg BID Imatinib 400 mg QD

Patients With MR4.5 by 6 Years,%

P = .0012b P<.0001b P<.0001b P = .0236b P<.0001b P = .0016b

n = 144 89 24 136 95 28 43 133 88

BCR-ABLIS ≤1% at 3 months BCR-ABLIS >1% to ≤10% at 3 months BCR-ABLIS >10% at 3 months

Rate of MR4.5 by 6 Years According to 3-Month BCR-ABLIS Levelsa

aAmong patients with evaluable 3-month assessments and without MR4.5 by 3 months. One patient in each nilotinib arm achieved MR4.5 by 3 months

and was excluded from this analysis. bP values are nominal, were provided for descriptive purposes only, and were not adjusted for multiple comparisons.

Hughes TP, et al. Haematologica. 2015;100(Suppl 1): Abstract P228.

2 3 12 11 6 21

5 10 15 20 25

Progression to AP/BC

Nilotinib 300 mg BID (n = 282) Nilotinib 400 mg BID (n = 281) Imatinib 400 mg QD (n = 283) New events reported since the 5-year data cutoff

On core treatment On study

P = .0059b P = .0185b P = .0030b P = .0661b

4.2% 1.1% 0.7% 7.4% 3.9% 2.1%

Patients With Progression to AP/BC, na

a Defined as progression to AP/BC or death due to advanced CML. b P values are nominal, were

provided for descriptive purposes only, and were not adjusted for multiple comparisons.

Hughes TP, et al. Haematologica. 2015;100(Suppl 1): Abstract P228.

OS and Deaths Due to Advanced CML

Hughes TP, et al. Haematologica. 2015;100(Suppl 1): Abstract P228. Nilotinib 300 mg BID (n = 282) Nilotinib 400 mg BID (n = 281) Imatinib 400 mg QD (n = 283) Total deaths on study, na 21 11 23 KM-estimated 6-year OS on study (95% CI), % 91.6 (88.0-95.1) 95.8 (93.4-98.2) 91.4 (88.0-94.7) Hazard ratio vs imatinib (95% CI) 0.8934 (0.4944-1.6143) 0.4632 (0.2258-0.9503) Nominal P value vs imatinib .7085 .0314 Deaths due to advanced CML, nb 6 4 16 KM-estimated 6-year freedom from death due to advanced CML (95% CI), % 97.7 (96.0-99.5) 98.5 (97.1-100) 93.9 (91.0-96.8) Hazard ratio vs imatinib (95% CI) 0.3694 (0.1445-0.9440) 0.2433 (0.0813-0.7279) Nominal P value vs imatinib .0302 .0061

KM, Kaplan-Meier

aDeath from any cause at any time (during study treatment or during post-treatment follow-up). bDeath due to advanced CML was defined as

any death for which the principal cause was reported as “study indication,” or, if death occurred subsequent to a documented progression to AP/BC, the cause of death was reported as “unknown” or not reported.

AEs Associated With TKI Therapy (All Cause, All Grade)

Nilotinib 300 mg BID (n = 279) Nilotinib 400 mg BID (n = 277) Imatinib 400 mg QD (n = 280) Peripheral edema 28 (10.0) 40 (14.4) 56 (20.0) Fluid retention 2 (0.7) 7 (2.5) Pleural effusion 5 (1.8) 3 (1.1) 3 (1.1) Pericardial effusion 2 (0.7) 2 (0.7) 3 (1.1) Pulmonary edema 1 (0.4) Pulmonary hypertension 2 (0.7) 1 (0.4) Retinal vein occlusion 1 (0.4) Thrombophlebitis 1 (0.4) 3 (1.1) Superficial thrombophlebitis 1 (0.4) Deep venous thrombosis 1 (0.4) 1 (0.4) 1 (0.4) Hughes TP, et al. Haematologica. 2015;100(Suppl 1): Abstract P228.

Cardiovascular Events

All grades Grades 3/4 Nilotinib 300 mg BID (n = 279) Nilotinib 400 mg BID (n = 277) Imatinib 400 mg QD (n = 280) Nilotinib 300 mg BID (n = 279) Nilotinib 400 mg BID (n = 277) Imatinib 400 mg QD (n = 280) Cardiovascular eventa 28 (10.0) 44 (15.9) 7 (2.5) 18 (6.5) 28 (10.1) 6 (2.1) Ischemic heart diseasea 14 (5.0) 28 (10.1) 6 (2.1) 7 (2.5) 20 (7.2) 5 (1.8) Ischemic cerebrovascular eventa 4 (1.4) 9 (3.2) 1 (0.4) 3 (1.1) 7 (2.5) 1 (0.4) Peripheral artery diseasea 12 (4.3) 9 (3.2) 8 (2.9) 3 (1.1) Othera,b 4 (1.4) 3 (1.1) 3 (1.1) 1 (0.4)

aIncludes predefined groupings of Medical Dictionary for Regulatory Activities (MedDRA) preferred terms or standardized MedDRA queries. Patients with multiple

events for a given AE term or category were counted only once for the AE term or category. bIncludes arteriosclerosis (nilotinib 300 mg BID, n = 4; nilotinib 400 mg BID, n = 2), arterial occlusive disease (nilotinib 300 mg BID, n = 1), and arterial stenosis (nilotinib 400 mg BID, n = 1); 5 of these patients (nilotinib 300 mg BID, n = 4; nilotinib 400 mg BID, n = 1) also had ischemic heart disease, ischemic cerebrovascular, and/or peripheral artery disease events.

Hughes TP, et al. Haematologica. 2015;100(Suppl 1): Abstract P228.

Conclusions

• Patients treated with nilotinib had higher rates of molecular response (both MMR and

MR4.5), fewer progressions to AP/BC, and fewer deaths due to advanced CML compared with those treated with imatinib

• Of patients who were evaluable for 3-month BCR-ABL levels, more achieved BCR-ABLIS

≤10% and BCR-ABLIS ≤1% with either dose of nilotinib than with imatinib – Patients with BCR-ABLIS ≤10% at 3 months in each arm had higher 6-year rates of MR4.5, PFS, and OS compared with patients with BCR-ABLIS >10% at 3 months

• The safety profile of nilotinib was consistent with that in previous reports1-3, 6

– Cardiovascular events were more common with nilotinib than imatinib, although few patients died within 3 months of a cardiovascular event in any arm of the study – Cardiovascular status should be evaluated and cardiovascular risk factors monitored and managed during treatment with nilotinib

• Pleural effusion, pericardial effusion, pulmonary edema, pulmonary hypertension, retinal

vein occlusion, thrombophlebitis, superficial thrombophlebitis, and deep vein thrombosis were infrequent in ENESTnd (<2% of patients in any arm)

• Results from the ENESTnd 6-year analysis continue to support use of frontline nilotinib

300 mg BID as a standard-of-care treatment option for patients with newly diagnosed Ph+ CML-CP1-8

Hughes TP, et al. Haematologica. 2015;100(Suppl 1): Abstract P228.

• 1. Saglio G, et al. N Engl J Med. 2010;362:2251-2259. 2. Kantarjian HM, et al. Lancet Oncol. 2011;12:841-851. 3. Larson RA, et al. Leukemia.

2012;26:2197-2203. 4. Hughes TP, et al. Blood. 2014;123:1353-1360. 5. Hochhaus A, et al. Blood. 2013;121:3703-3708. 6. Hughes TP, et al.

• Haematologica. 2014;99: Abstract S677. 7. Saglio G, et al. Blood. 2013;122:92. 8. Larson RA, et al. Blood. 2014;124:4541.

Ponatinib Efficacy and Safety in Heavily Pretreated Leukemia Patients: 3-Year Results of the PACE Trial Ponatinib Efficacy and Safety in Heavily Pretreated Leukemia Patients: 3-Year Results of the PACE Trial

Cortes JE, 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 M, Gambacorti-Passerini C, Lustgarten S, Rivera VM, Clackson T, Haluska FG, Guilhot F, Deininger MW, Hocchaus A, Hughes TP, Shah NP, Kantarjian HM

Abstract P234

Introduction Introduction

• Ponatinib, a potent oral tyrosine kinase inhibitor (TKI) with activity

against native BCR-ABL and resistant mutants, including the T315I mutant, is approved in the United States and European Union for use in adult patients with refractory chronic myeloid leukemia (CML)

• r Philadelphia chromosome–positive acute lymphoblastic leukemia

(Ph+ ALL) and those with the T315I mutation1-3

• The phase II PACE trial evaluated the efficacy and safety of ponatinib

(starting dose 45 mg once daily) in patients with CML or Ph+ ALL who were resistant or intolerant to dasatinib or nilotinib, or who had the T315I mutation4,5

• The primary publication of the PACE trial reported ponatinib efficacy in

patients with chronic-phase (CP)-CML, accelerated-phase (AP)-CML, blast-phase (BP)-CML, and Ph+ ALL with a median follow-up of 15 months; arterial occlusive events (AOEs) were observed4

• Dose reductions in the PACE trial were either used to manage adverse

events (AEs) as allowed by protocol, or implemented in response to prospective recommendations from ARIAD in October 2013 as part of the partial clinical hold6

• 1. O’Hare, et al. Cancer Cell. 2009;16:401-412. 2. Ponatinib [package insert]. Cambridge, MA: ARIAD Pharmaceuticals, Inc; 2014. 3. Ponatinib

[summary of product characteristics]. Leatherhead, UK: ARIAD Pharma Ltd; 2015. 4. Cortes JE, et al. N Engl J Med. 2013;369:1783-1796. 5. Cortes JE, et al. Blood. 2014;124: Abstract 3135. 6. ARIAD announces changes in the clinical development program of [ponatinib] [press release]. Cambridge, MA: ARIAD Pharmaceuticals, Inc; October 9, 2013.

Cortes JE, et al. Haematologica. 2015;100(Suppl 1): Abstract P234.

Cortes JE, et al. Haematologica. 2015;100(Suppl 1): Abstract P234.

Methods Methods

• The PACE trial design has been described previously1

– Primary endpoints were major cytogenetic response (MCyR) by 12 months for CP-CML and major hematologic response by 6 months for AP-CML, BP-CML, and Ph+ ALL patients – Secondary endpoints included major molecular response (MMR), time to and duration of response, progression-free survival (PFS), overall survival (OS), and safety

• The ponatinib starting dose was 45 mg once daily, and dose

reductions to 30 mg or 15 mg once daily were permitted to manage AEs

• 1. Cortes JE, et al. N Engl J Med. 2013;369:1783-1796.

Cortes JE, et al. Haematologica. 2015;100(Suppl 1): Abstract P234.

Methods Methods

• In October 2013, a partial clinical hold was placed on new patient

enrollment in ARIAD-sponsored ponatinib trials following an accumulation of AOEs with continued follow-up,1 and unless benefit-risk analysis justified treatment with a higher dose, the following dose reductions were recommended in PACE: – 15 mg/d for CP-CML patients with MCyR – 30 mg/d for CP-CML patients without MCyR – 30 mg/d for AP-CML or BP-CML patients

• Exposure-adjusted AE rates were calculated as: (number of first

events in interval)/(total exposure for interval in patient-years) x 100

• The results presented reflect data analysis as of 2 February 2015,

with a minimum follow-up (last patient first visit to cutoff date) of 40 months (3.3 years) and a median follow-up of 35.3 months (2.9 years) for all patients

• 1. ARIAD announces changes in the clinical development program of [ponatinib] [press release]. Cambridge, MA: ARIAD Pharmaceuticals,

Inc; October 9, 2013.

Totala,b N = 449 CP-CML n = 270 Median duration of treatment, months (range) 16.7 (0.03 – 52.4) 32.1 (0.1 – 52.4) Median follow-up, months (range) 35.3 (0.1 – 52.5) 42.3 (0.1 – 52.5) Remain on study, n (%) 139 (31) 114 (42) Discontinued, n (%) 310 (69) 156 (58) Primary reason for discontinuation, n (%) AE 70 (16) 49 (18) Disease progression 98 (22) 26 (10) Deathc 24 (5) 8 (3) Otherd 118 (26) 73 (27)

Cortes JE, et al. Haematologica. 2015;100(Suppl 1): Abstract P234.

Patient Disposition Patient Disposition

aIncludes 5 patients (3 CP-CML, 2 AP-CML) who were noncohort assigned (post-imatinib, nonT315I) but treated; 4 of 5 remain on study b44% of patients had no mutation (51% CP=CML), and 26% had mutations other than T315I (25% CP-CML) at study entry c7 deaths were assessed by investigators as possibly or probably related to ponatinib (CP-CM: pneumonia, acute myocardial

infarction; AP-CML: fungal pneumonia, gastrointestinal hemorrhage; BP-CML/Ph+ ALL: cardiac arrest, gastric hemorrhage, mesenteric arterial occlusion)

dIncludes withdrawl by patient (including for transplant; total, n = 41; CP-CML, n = 31), lack of efficacy (total, n = 28; CP-CML, n = 15),

and other reasons (total, n = 29; CP-CML, n = 14)

Response to Ponatinib in CP-CML: Response at Any Time Response to Ponatinib in CP-CML: Response at Any Time

59 53 39 28 23 55 48 33 23 19 72 70 58 44 34 10 20 30 40 50 60 70 80 MCyR CCyR MMR MR4 MR45 Total (n = 267) Resistant/intolerant (n = 203) T315I (n = 64) Patients, %

Cortes JE, et al. Haematologica. 2015;100(Suppl 1): Abstract P234.

MR4 = 4-log molecular response (≤0.01% BCR-ABLIS), MR4.5 = 4.5-log molecular response (≤0.0032% BCR-ABLIS

Response to Ponatinib in CP-CML: Duration of Response Response to Ponatinib in CP-CML: Duration of Response

100 90 80 70 60 50 40 30 20 10

12 24 36 48 60 Probability of Remaining in Response, %

83% of responders estimated to remain in MCyR at 36 months

Total Resistant/intolerant T315I Responders, n Lost MCyR, na Maintained MCyR at 3 Years, %b 148 20 83 103 16 82 45 4 86

Time, Months

Cortes JE, et al. Haematologica. 2015;100(Suppl 1): Abstract P234.

100 80 60 40 20

12 24 36 48 60

100 80 60 40 20

12 24 36 48 60 Time, Months Time, Months PFS at 36 months: 60% OS at 36 months: 81%

267 181 146 108 12 267 227 199 175 38 203 136 111 82 10 203 172 153 133 28 64 46 35 26 2 64 55 46 42 10 Total Res/intol T315I

• No. at risk
• No. at risk

Total PFS OS

aProgression from CP was defined as death, development of AP or BP, loss of CHR (in absence of cytogenetic response), loss of MCyR, or

increasing white blood cell count without CHR

Probability of PFS, % Probability of OS, %

Resistant/intolerant

T315I Total

Resistant/intolerant

T315I Cortes JE, et al. Haematologica. 2015;100(Suppl 1): Abstract P234.

PFS and OS in CP-CML PFS and OS in CP-CML

Treatment-Emergent AEs in ≥20% of All Patients Nonhematologic Treatment-Emergent AEs in ≥20% of All Patients Nonhematologic

Total N = 449 CP-CML n 270 Any Grade, n (%) Grade 3/4, n (%) Any Grade, n (%) Grade 3/4, n (%) Abdominal pain 191 (43) 40 (9) 124 (46) 27 (10) Rasha 186 (41) 18 (4) 125 (46) 10 (4) Constipation 168 (37) 10 (2) 111 (41) 7 (3) Headache 167 (37) 11 (2) 115 (43) 9 (3) Dry skin 163 (36) 11 (2) 112 (41) 9 (3) Fatigue 135 (30) 13 (3) 80 (30) 6 (2) Pyrexia 132 (29) 11 (2) 69 (26) 3 (1) Arthralgia 130 (29) 10 (2) 86 (32) 8 (3) Hypertensionb 130 (29) 50 (11) 89 (33) 34 (13) Nausea 128 (29) 3 (<1) 74 (27) 2 (<1) Diarrhea 95 (21) 7 (2) 52 (19) 2 (<1) Increased lipase 95 (21) 53 (12) 70 (26) 32 (12) Vomiting 95 (21) 5 (1) 48 (18) 4 (1) Myalgia 94 (21) 3 (<1) 64 (24) 3 (1)

aCombines the terms erythematous, macular, and papular rash b379/449 (84%) patients had elevated blood pressure at baseline (≥140/90 mm Hg, 47%); 306/449 (68%) patients experienced any increase

from baseline in blood pressure on study

Cortes JE, et al. Haematologica. 2015;100(Suppl 1): Abstract P234.

Treatment-Emergent AEs in ≥20% of All Patients Hematologic Treatment-Emergent AEs in ≥20% of All Patients Hematologic

Total N = 449 CP-CML n 270 Any Grade, n (%) Grade 3/4, n (%) Any Grade, n (%) Grade 3/4, n (%) Thrombocytopenia 196 (44) 160 (36) 121 (45) 95 (35) Neutropenia 133 (25) 100 (22) 53 (20) 45 (17) Anemia 108 (24) 69 (15) 49 (18) 25 (9)

Cortes JE, et al. Haematologica. 2015;100(Suppl 1): Abstract P234.

Cumulative and Exposure-Adjusted Incidences

• f Arterial Occlusive Events and Venous

Thromboembolic Eventsa Cumulative and Exposure-Adjusted Incidences

• f Arterial Occlusive Events and Venous

Thromboembolic Eventsa

Total N = 449 CP-CML n 270 AE SAE AE SAE Cumulative exposure, patient-years 826.0 615.7 AOEs, n (%) 101 (22)b 82 (18)c 75 (28) 62 (23) Cardiovascular 54 (12) 40 (9) 39 (14) 30 (11) Cerebrovascular 37 (8) 28 (6) 31 (11) 23 (9) Peripheral vascular 39 (9) 29 (6) 29 (11) 21 (8) Exposure-adjusted AOEs, number of patients with events per 100 patient-years 12.2 9.9 12.2 10.1 VYEs, n (%) 25 (6)b 22 (5)c 13 (5) 12 (4) Exposure-adjusted VTEs, number of patients with events per 100 patient-years 3.0 2.7 2.1 1.9

AE = total AEs (including SAEs); AOE, arterial occlusive event; SAE, serious AE only (designated as serious by the investigator, in accordance with standard regulatory criteria); VTE, venous thromboembolic event

aCategorization of AOEs is based on a broad collection of >400 Medical Dictionary for Regulatory Affairs (MedDRA) preferred terms related to

vascular ischemia or thrombosis

b47 patients had >1 AOE; 5 patients had >1 VTE c25 patients had >1 serious AOE; 2 patients had >1 serious VTE

Cortes JE, et al. Haematologica. 2015;100(Suppl 1): Abstract P234.

Exposure-Adjusted Yearly Incidence Rates for newly Occurring Arterial Occlusive Events and Venous Thromboembolic Events – All Patients Exposure-Adjusted Yearly Incidence Rates for newly Occurring Arterial Occlusive Events and Venous Thromboembolic Events – All Patients

14.5 3.5 14.1 1.8 10.5 1.7 7.2 0.9 2 4 6 8 10 12 14 16 AOEs VTEs 0 to <1 year 1 to <2 years 2 to <3 years ≥3 years*

• No. of Patients With Events per 100 Patient-Years

*Median follow-up is 35.3 months; analysis for ≥3 years does not cover a fourth full year for all patients Cortes JE, et al. Haematologica. 2015;100(Suppl 1): Abstract P234.

Relative Risk of Serious Arterial Occlusive Events by Risk Category (Univariate Analysis) Relative Risk of Serious Arterial Occlusive Events by Risk Category (Univariate Analysis)

Cortes JE, et al. Haematologica. 2015;100(Suppl 1): Abstract P234. Risk Catetory Rate of Serious AOEs in Patients With Risk Category,a % Rate of Serious AOEs in Patients Without Risk Category,b % Relative Risk (95% CI) Age ≥65 years (n = 115) 26 14 1.8 (1.2-2.7) Male (n = 238) 22 14 1.5 (1.0-2.3) History of diabetesc (n = 72) 32 16 2.0 (1.4-3.1) History of ischemic heart diseased (n = 101) 33 14 2.3 (1.6-3.4) History of hypertensione (n = 240) 25 10 2.5 (1.6-4.0) History of hypercholesterolemiaf (n = 228) 24 12 2.0 (1.3-3.0) History of nonischemic heart diseased (n = 193) 20 17 1.2 (0.8-1.8) History of obesityg (n = 109) 20 18 1.1 (0.7-1.8)

Risk category includes intrinsic factors (age, gender), widely accepted cardiovascular risk factors (diabetes, hypertension, hypercholesterolemia, and obesity), and history of disease

a Patients with risk category who had serious AOE divided by total number of patients with risk category b Patients without risk category who had serious AOE divided by the total number of patients without risk category c Includes medical history, prior concomitant medications, and/or baseline glucose grade ≥2 d Includes medical history and/or prior concomitant medication e Includes medical history, prior concomitant medication, and/or baseline blood pressure grade ≥2 f Includes medical history, prior concomitant medication, and/or baseline triglycerides grade ≥1 g Includes medical history and/or baseline body mass index ≥230 kg/m2

Maintenance of Response Following dose Reductions in October 2013 in CP-CML Patients Who Achieved MCyR or MMRa Maintenance of Response Following dose Reductions in October 2013 in CP-CML Patients Who Achieved MCyR or MMRa

MCyR MMR Patients in MCyR as of Oct 2013, n Maintained Response as of Feb 2015, n (%) Patients in MMR as of Oct 2013, n Maintained Response as

• f Feb 2015, n

(%) Dose reductions as of Oct 2013 64 61 (95) 47 44 (94) 45 mg/d to 30 mg/d 15 15 (100) 10 10 (100) 45 mg/d to 15 mg/d 18 17 (94) 17 16 (94) 30 mg/d to 15 mg/d 25 24 (96) 17 15 (88) Other reductions 6 5 (83) 24 23 (96)

• No. dose reduction as of October 2013

42 39 (93) 24 23 (96) 45 mg/d 6 5 (83) 2 2 (67) 30 mg/d 11 9 (82) 4 4 (100) 15 mg/d 25 25 (100) 17 17 (100)

*Maintenance of response was high, regardless of whether patients underwent dose reductions

Cortes JE, et al. Haematologica. 2015;100(Suppl 1): Abstract P234.

Patients With No AOEs Prior to Oct 2013 AOE After Oct 2013 No AOE After Oct 2013 Dose reductions as of Oct 2013 5 66 45 mg/d to 30 mg/d 1 26 45 mg/d to 15 mg/d 1 16 30 mg/d to 15 mg/d 3 18 Other reductions 6

• No. dose reduction as of October 2013

9 58 45 mg/d 2 7 30 mg/d 22 15 mg/d 7 29

• 5/71 (7%) patients without prior AOEs who had prophylactic dose reduction had a new AOE after

preoperative dose reductions

• 9/67 (13%) patients who maintained treatment at the same dose and did not have her prior AOEs

had a new AOE

Cortes JE, et al. Haematologica. 2015;100(Suppl 1): Abstract P234.

Occurrence and Arterial Occlusive Events Following Prospective Dose Reductions in All Ongoing Patients as of Oct 2013 Occurrence and Arterial Occlusive Events Following Prospective Dose Reductions in All Ongoing Patients as of Oct 2013

Summary Summary

Cortes JE, et al. Haematologica. 2015;100(Suppl 1): Abstract P234.

• Ponatinib continues to provide deep, durable responses in heavily pretreated

patients, particularly those with CP-CML, with longer (~3years) follow-up:

– 23% of patients achieved MR4.5 – The probability of remaining in MCyR at 3 years was 83% – The probability of PFS and OS at 3 years was 60% and 81%, respectively

• For AP-CML, BP-CML, and Ph+ ALL patients, the probability of OS at 3 years was

59%, 9%, and 16%, respectively

• The cumulative incidence of AOEs increased over time; there was a decrease in the

exposure-adjusted incidences of newly occurring AOEs and VTEs with longer duration of ponatinib treatment

• In October 2013, prospective dose reductions in the absence of AEs was

recommended for all patients, after 16 months of follow-up:

– 95% and 94% of CP-CML patients with dose reduction maintained MCyR and MMR, respectively; maintenance of response was high regardless of whether patients underwent dose reductions – 7% of patients without prior AOEs had a new AOE after prospective dose reductions

• The decision to initiate ponatinib therapy should be guided by benefits and risks,

particularly in patients who may be at increased risk of AOEs

• Enrollment will begin soon for a dose-ranging trial to evaluate benefits and risks of

ponatinib in refractory CML

Cardiovascular (CV) and Pulmonary Adverse Events (AEs) in Patients (pts) Treated With BCR-ABL Tyrosine Kinase Inhibitors (TKIs): Updated Analysis From the FDA Adverse Events Reporting System (FAERS) Cardiovascular (CV) and Pulmonary Adverse Events (AEs) in Patients (pts) Treated With BCR-ABL Tyrosine Kinase Inhibitors (TKIs): Updated Analysis From the FDA Adverse Events Reporting System (FAERS)

Cortes J, Mauro MJ, Steegmann JL, Saglio G, Soitkar A, Wallis N

Abstract P601

Background Background

• With the introduction of BCR-ABL TKIs, survival in CML has been extended

with most patients remaining on first-line or subsequent therapy for years using 1 of 5 TKIs: Imatinib (IMA), dasatinib (DAS), nilotinib (NIL), bosutinib (BOS), and ponatinib (PON)1-5

• Rare but serious CV and pulmonary AEs have been reported in patients

with CME treated with BCR-ABL TKIs, which vary amongst the therapies

– Pulmonary arterial hypertension (PAH) with DAS2 – Cardiac and arterial vascular occlusive events, including peripheral arterial

• cclusive disease (PAOD), with NIL and PON3,5
• Patients treating in the community setting may differ from clinical trials,

thus providing a rick source for information that may have escaped detection in clinical trials

• FAERS is one of the largest publically available and accepted post-

marketing surveillance AE databases6

– Provides consistent and reproducible data – Based on exposure in a more heterogeneous population than clinical trials – Includes both AEs reported to pharmaceutical manufacturers and voluntary report submitted by patients and healthcare providers

• 1. Imatinib [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2015. 2. Dasatinib [prescribing information]. Princeton, NJ:

Bristol-Myers Squibb Company; 2014. 3. Nilotinib [prescribing information]. East Hanover; NJ: Novartis Pharmaceuticals Corporation; 2015. 4.Bosutinib [prescribing information]. New York, NT: Pfizer Labs; 2014. 5. Ponatinib [prescribing information]. Cambridge, MA: Ariad Pharmaceuticals, Inc.; 2014. 6. US Food and Drug Administration. FDA Adverse Event Reporting System (FAERS) [formerly AERS) Website. Available at: www.fda.gov/drugs/guidancecomplianceregulatoryinformation/surveillance/adversedrugeffects. Accessed June 1, 2015.

Cortes J, et al. Haematologica. 2015;100(Suppl 1): Abstract P601.

Background (cont’d) Background (cont’d)

• On the basis of mathematical assessment of disproportional reporting,

potential associations between drugs and AEs (drug-event pairs) can be identified, although causality cannot be proven

• In a previous analysis, we assessed FAERS through Sept 2012 for CV and

pulmonary AE signals in patients treated with IMA, DAS, and NIL. Our findings are identified1 – Bone marrow necrosis, conjuctival hemorrhage, and peritoneal fluid retention events were uniquely associated with IMA – AEs most commonly associated with DAS related to fluid retention, including pleural effusion and pericardial effusion – Peripheral and cardiac vascular events were uniquely associated with NIL

• Due to the timing of the previous analysis, the more recently approved

TKIs, BOS and PON, were not included

• Here we report an updated analysis of the FAERS database for drug-event

pairs through Dec 2013, using the previous criteria and inclusive of BOS and PON

Cortes J, et al. Haematologica. 2015;100(Suppl 1): Abstract P601.

• 1. Cortes J, et al. Am J Hematol. 2015;90(4):E66-E72.

Methods Methods

• The FAERS database was analyzed up to and including Dec 2013

to identify the safety profile of IMA, DAS, NIL, BOS, and PON (including patients treated for any indication) in the post- marketing population

• Multi-item Gamma Poisson Shrinker (MGPS)1-2 was used to

calculate disproportionality, allowing identification of drug-event associations using large AE databases

• Empirical Bayesian Geometric Mean (EBGM), or

disproportionality measure (λ), was used to estimate the degree to which the reporting frequency of a drug-event pair is disproportionally higher than would be expected in cases with no drug-event association Observed frequency of drug-event pair “Expected” frequency of drug-event pair λ =

Cortes J, et al. Haematologica. 2015;100(Suppl 1): Abstract P601.

• 1. Harper R, et al. Clin Pharmacol Ther. 2013;93:539-546. 2. DuMouchel W. Am Statisticians. 1999;53:177-190.

Methods (cont’d) Methods (cont’d)

• Higher EBGM or EBO5 values indicate a higher probability
• f associated

– EBO5 is the lower bound of the 90% confidence interval for the EBGM – EBO5 ≥2 indicates a 95% chance an AE is reported ≥2x as frequently as expected and is commonly used for identifying drug-event pairs – EBO5 ≥24 was chosen for this analysis to identify events more likely to be clinically relevant and attributable to a drug

• All MedDRA preferred terms (PTs) in 3 system organ classes

(SOCs) were analyzed (MedDRA version 17)

– Cardiac – Vascular – Pulmonary, thoracic, and mediastinal

• In addition to the entire population of patients ≥18 years, MGPS

was utilized to assess the frequency of PTs for the following age cohorts: 18-45, 46-64, and ≥65 years

Cortes J, et al. Haematologica. 2015;100(Suppl 1): Abstract P601.

Drug-Event Pairs With EBO5 ≥4 in 2013 Drug-Event Pairs With EBO5 ≥4 in 2013

Cortes J, et al. Haematologica. 2015;100(Suppl 1): Abstract P601.

TKI MedDRA PT EBO5 2012 2013 Imatinib Gastric antral vascular ectasia 30.77 26.00 Imatinib Bone marrow necrosis 26.64 21.56 Imatinib Tumor necrosisa 15.50 16.09 Imatinib Tumor hemorrhage 14.23 11.73 Imatinib Conjunctival hemorrhage 8.78 8.07 Imatinib Pleural effusion 5.59 5.35 Imatinib Ascites 5.49 5.00 Imatinib Pericardial effusion 4.57 4.34 Imatinib Hemorrhagic ascites 4.09 4.09

EBO5 ≥2 - <4 EBO5 ≥5

aThe EBO5 for these terms increased from 2012 to 2013

Drug-Event Pairs With EBO5 ≥4 in 2013 Drug-Event Pairs With EBO5 ≥4 in 2013

Cortes J, et al. Haematologica. 2015;100(Suppl 1): Abstract P601.

TKI MedDRA PT EBO5 2012 2013 Dasatinib Cyclothoraxa 58.66 72.22 Dasatinib Pleural effusiona 30.77 30.95 Dasatinib Malignant pleural effusion 15.53 13.98 Dasatinib Pericardial effusion 11.75 11.40 Dasatinib Pulmonary edemaa 4.42 5.45 Dasatinib Pulmonary hypertensiona 3.48 4.96 Dasatinib Pleurisya 3.82 4.80

EBO5 ≥2 - <4 EBO5 ≥5

aThe EBO5 for these terms increased from 2012 to 2013

Drug-Event Pairs With EBO5 ≥4 in 2013 Drug-Event Pairs With EBO5 ≥4 in 2013

Cortes J, et al. Haematologica. 2015;100(Suppl 1): Abstract P601.

TKI MedDRA PT EBO5 2012 2013

Nilotinib Femoral arterial stenosis (peripheral artery stenosis)a,b 50.69 54.92 Nilotinib Intermittent claudicationa 23.16 40.55 Nilotinib Peripheral arterial occlusive diseasea 21.28 32.82 Nilotinib Arteritisa 2.86 20.68 Nilotinib Arterial stenosisa 3.25 17.17 Nilotinib Coronary artery stenosis 16.71 16.39 Nilotinib Arterial disordersa 3.65 14.88 Nilotinib Femoral artery occlusiona 6.16 12.27 Nilotinib Peripheral ischemiaa 5.12 7.79 Nilotinib Angina pectorisa 8=6.80 7.75 Nilotinib Acute coronary syndromea 4.93 5.96 Nilotinib Acute myocardial infarctiona 5.07 5.59 Nilotinib Pleur4al effusion 5.65 5.54 Nilotinib Arteriosclerosisa 3.71 4.73 Nilotinib Pericardial effusiona 3.86 4.69 Nilotinib Myocardial ischemiaa 3.75 4.28 Ponatinib Carotid artery stenosis N/A 4.55

EBO5 ≥2 - <4 EBO5 ≥5

aThe EBO5 for these terms increased from 2012 to 2013 bThe PT femoral arterial stenosis in 2012 had been reclassified as a lower-level term coding to the PT

peripheral artery stenosis

Results Results

• More drug-event pairs reached a threshold of EBO5

≥4 in older vs younger patients (≥65 years: n = 22; 46-64 years: n = 15; 18-45 years: n = 3)

• In all cohorts, pleural effusion with DAS and IMA, and

pericardial effusion with DAS, reached EBO5 ≥4

• Peripheral and cardiac vascular AEs with EBO5 ≥4

were observed in patients treated with NIL aged 46-46 years, including peripheral artery stenosis, intermittent claudication, PAOD, coronary artery stenosis, angina pectoris, ACS, and acute MI; similar events were observed in patients ≥65 years

Cortes J, et al. Haematologica. 2015;100(Suppl 1): Abstract P601.

Key Limitations Key Limitations

• The analysis does not confirm a causal relationship;

however, the higher the EBO5, the more likely the reported event is associated with the drug

• The FAERS database includes voluntary reports, and

thus likely under represents actual occurrence of AEs

• Possible impact of outside influences on reporting

frequency, including Weber effect, in which AE reports for a drug increase during the first 2 years after approval before decreasing,1,2 and notoriety bias3-6

• Data were not mature for BOS and PON due to limited

time from registration to date of analysis

Cortes J, et al. Haematologica. 2015;100(Suppl 1): Abstract P601.

• 1. Hartnell NR, et al. Pharmacotherapy. 2004;24:743-749. 2. Weiss-Smith S, et al. Arch Intern Med. 2011;171:591-593. 3. Pariente A, et
• al. Drug Saf. 2007;30:891-898. 4. Raschi E, et al. Acta Diabetol. 2013;50:569-577. 5. Moore N, et al. Pharmacoepidemiol Drug Saf.

2003;12:271-281. 6. Hauben M, et al. Pharmacoepidemiol Drug Saf. 2006;15:775-783.

Conclusions Conclusions

• Our updated findings continue to clarify the understandings of

AEs in patients treated with BCR-ABL TKIs in the community setting for all approved and nonapproved indications, suggesting drug-event pairs that warrant further investigation

• High EBO5 values for pleural effusion with DAS, and lower

values with IMA and NIL, were observed, consistent with the previous analysis. Additionally, BOS and PON reached EBO5 ≥2 - <4 for pleural effusion, suggestive of a class effect

• Numerous vascular events with EBO5 ≥4 were identified with

NIL in patients aged 46 years

• Due to limited exposure and potential bias for BOS and PON,

few signals (BOS: pleural effusion; PON: carotid artery stenosis, pleural effusion, hypertension, cerebral artery stenosis, pericardial effusion, PAOD, and cerebral infarction) reached EBO5 ≥2; such drug-event pairs should be monitored in future analyses as postregistrational follow-up

Cortes J, et al. Haematologica. 2015;100(Suppl 1): Abstract P601.

Real Life Analysis of CML Management Demonstrates That Second-Line Therapy Is Frequently Used but Is Prematurely Discontinued for Intolerance: Report on Behalf of the CML-MPN Quebec Research Group

Busque L, Gratton M-O, Harnois M, Mollica L, Laneuville P, Olney HJ, Delage R, Assouline S

Abstract P600

Background

Since the introduction of imatinib two decades ago, there has been a continual evolution in the management of CML. With the advent of second-generation tyrosine kinase inhibitors (TKI) and better molecular monitoring tools, the decision making for CML patients has become increasingly complex. A variety of treatment guidelines has emerged to help clinicians make decisions based on evidence

• btained from clinical trials. However, little is known about the utilization of these

guidelines in the real life setting, where patients have more co-morbidities than in clinical trials, and where clinical decision-making may deviate from the strict application of therapeutic guidelines due to diverse factors, such as drug availability, patient choice, and the definition of tolerance and resistance. The CML-MPN Quebec Research Group (gqr-lmc-nmp.ca), a non-profit organization, is the sponsor of a population based CML Registry that follows 620 CML patients in 18 oncology center across the Province of Quebec. The CML registry provides a global, accurate and complete perspective of real-life management of this

• population. All patients have provided informed consent to participate in this

registry.

Busque L, et al. Haematologica. 2015;100(Suppl 1): Abstract P600.

Methods

Busque L, et al. Haematologica. 2015;100(Suppl 1): Abstract P600.

Analysis criteria:

• Diagnosis of Philadelphia chromosome–positive

chronic myeloid leukemia (Ph+ CML) between January 1, 2002 and December 31, 2012

• 266 patients with complete clinical data are included in

this data analysis

• Data corresponds to the last follow-up recorded
• Treatment duration for patients varies from 12 to

143 months

First-Line Treatment

Busque L, et al. Haematologica. 2015;100(Suppl 1): Abstract P600.

First-line cumulative distribution (2002-2012) Imatinib Dasatinib Nilotinib Interferon

84% (n = 223) N = 266

9% (n = 23) 5% (n = 14) 2% (n = 6)

First-Line Discontinuation

Busque L, et al. Haematologica. 2015;100(Suppl 1): Abstract P600. Reasons for first-line imatinib discontinuation

Milestone failure Loss of response Intolerance/toxicity Death Stop trial Other DNK

45% (n = 45) N = 100

4% (n = 4) 1% (n = 1) 4% (n = 4)

42% (n = 42)

3% (n = 3) 1% (n = 1)

• A high proportion of first-line imatinib patients (45%) needed second-line treatment
• The two main causes of first-line imatinib discontinuation were resistance (45%)

and intolerance (42%)

Proportion of patients discontinuing imatinib as a first-line treatment

Kaplan-Meier survival estimate

2 4 6 8 10 Years Number at risk 222 154 108 62 25 7 Probability of remaining on imatinib .25 .5 .75 1 95% CI Survival function

Second-Line Treatment

Busque L, et al. Haematologica. 2015;100(Suppl 1): Abstract P600. Second-line cumulative distribution (2002-2012)

Imatinib Dasatinib Nilotinib SCT Bosutinib Other

47% (n = 49) N = 103

9% (n = 9) 2% (n = 2)

29% (n = 30)

4% (n = 4) 9% (n = 9)

Proportion of patients discontinuing a second-line treatment

0% 20% 40% 60% Dasatinib Nitotinib

53% (n = 16) N = 30 N = 49 47% (n = 23) P = 0.65

SCT, stem cell transplantation

Nilotinib

Milestone failure Loss of response Intolerance/toxicity Death

Reasons for Discontinuation of a Second-Line Treatment

Busque L, et al. Haematologica. 2015;100(Suppl 1): Abstract P600.

Dasatinib

N = 23

4% (n = 1) 4% (n = 1)

57% (n = 13)

9% (n = 2)

19% (n = 3)

N = 16 62% (n = 10)

13% (n = 2) 6% (n = 1)

9% (n = 2) 13% (n = 3) 4% (n = 1) Pre transplant Other DNK

Time Before the Patient Is Switched to a Third Line

Busque L, et al. Haematologica. 2015;100(Suppl 1): Abstract P600.

• Nilotinib was discontinued in 53% of patients after a mean of 13.6 months,

due mostly to intolerance (62%) and resistance (25%)

• Dasatinib was discontinued in 47% of patients after a mean of 11.9 months,

due mostly to intolerance (57%) and resistance (22%)

Time, months* Nilotinib (N = 16) Dasatinib (N = 23) P value Mean 13.6 11.9 .55 Median 4.5 7.0

• Range (min-max)

0-75 0-70

• *Calculated based on initiation of second-line TKI treatment

Third-Line Treatment

Busque L, et al. Haematologica. 2015;100(Suppl 1): Abstract P600. Third-line cumulative distribution (2002-2012)

Imatinib Dasatinib Nilotinib SCT Ponatinib Other

23% (n = 10) N = 44

5% (n = 2)

36% (n = 16)

7% (n = 3) 11% (n = 5)

Proportion of patients discontinuing a third-line treatment

0% 5% 10% 15% 20% 25% Dasatinib Nitotinib

25% (n = 4) N = 16 N = 10 10% (n = 1) P = 0.62

18% (n = 8)

Summary/Conclusion

Busque L, et al. Haematologica. 2015;100(Suppl 1): Abstract P600.

• Registry-based real life data indicate that intolerance is a predominant trigger for

switching therapy in first- and in second-line treatment of CML

• Results are in contrast with clinical trial data where resistance is the most

frequent cause of treatment discontinuation, particularly in second line

• There are proportionally fewer discontinuations in third than in second line
• We hypothesize that in the real-life setting:

– Selection of second generation TKI may be uncertain, leading to rapid change to alternate TKI in the presence of lower grade side effects – In third line, doctors and patients may be inclined to stay on treatment, despite adverse effects, unless resistance or progression occurs

2015 Annual Hematology Meeting in Vienna 2015 Annual Hematology Meeting in Vienna

Canadian Clinical Spotlight: Clinical Perspectives in CML Important Updates

Reference Slide Deck Abstract S489 Abstract P228 Abstract P234 Abstract P601 Abstract P600