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 An NCRI Randomised Study Comparing Dasatinib With Imatinib in Comparing Dasatinib With Imatinib in Patients With Newly Diagnosed CML: Patients With Newly Diagnosed CML: 2 Year Follow Up 2 Year Follow Up Abstract P489 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

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 Arm A Randomized, open label Imatinib 400 n = 407 Chronic-phase CML R Within 3 months of diagnosis Arm A Dasatinib 100 N = 814 n = 407 • 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, MR 3 , 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 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n = 814 Allocated to imatinib – 407 Allocated to dasatinib– 407 1 exclusion: Protocol violation 1 exclusion: Consent withdrawn Received imatinib – 406 (100%) Received dasatinib – 406 (100%) Continued with dasatinib – 239 (58.9%) Continued with imatinib – 197 (48.5%) Follow up complete – 41 (10.1%) Follow up complete – 48 (11.8%) Follow up ongoing – 156 (38.4%) Follow up ongoing – 191 (47.0%) Stopped imatinib – 209 (51.5%) Stopped dasatinib – 167 (41.1%) Death on study drug – 7 (1.7%) Death on study drug – 6 (1.5%) Finished study drug – 30 (7.4%) Finished study drug – 28 (6.9%) Decision to stop drug – 172 (42.4%) Decision to stop drug – 133 (32.6%) Status of 172 patients who stopped imatinib: Status of 172 patients who stopped dasatinib: Subsequent death – 12 (2.9%) Subsequent death – 13 (3.2%) Follow up complete – 20 (4.9%) Follow up complete – 21 (5.2%) Follow up ongoing – 117 (28.8%) Follow up ongoing – 80 (19.7%) Declined follow up – 15 (3.7%) Declined follow up – 18 (4.4%) Unknown – 8 (1.9%) Unknown – 1 (0.2%) O’Brien S, et al. Haematologica. 2015;100(Suppl 1): Abstract S489.

Patients Who Stopped Study Drug Patients Who Stopped Study Drug Reason for Stopping Study Drug Imatinib Dasatinib Total (Excl Death) (N = 406), n (%) (N = 406), n (%) (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) 0 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, 44 (10.8) 5 (1.3) 49 (6.0) hematologic, molecular, mutation detected) Total 172 (42.4) 133 (32.6) 49 (6.0) 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 Dasatinib 19/406 (2.3%) 19/406 (2.3%) Unknown CML related Non-CML related Non-CML related CML related Unknown 4/19 (21%) 6/19 (32%) 9/19 (47%) 10/19 (53%) 5/19 (26%) 4/19 (21%) Other cancer Noncancer Other cancer Noncancer 4/9 (44%) 5/9 (56%) 3/10 (30%) 7/10 (70%) • Lung • Ischemic heart disease, • Left ventricular failure • 2 x Lung COPD, CCF • Endometrial • Breast • Bronchopneumonia • Rectal • Chest infection, CCR, secondary to • Gastric renal failure diabetes emphysema • Bowel perforation • Myocardial infarction • Cardiac failure and • Ruptured aortic bronchopneumonia aneurysm • Liver disease • Bronchopneumonia • 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 Imatinib Dasatinib All Grades N = 406, n (%) 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 Dasatinib N = 406, n (%) N = 406, n (%) 9 (2.2) 17 (4.2) Cardiac serious ACS x2, AF x3, cardiac failure x5, MI AF x3, cardiac arrest x1, cardiac AEs x1, pericardial effusion x2, cardiac failure x3, MI x1, tamponade x1, AV block x1, supraventricular tachycardia x1 cardiomegaly x1, palpitations x1 4 (1) 6 (1.5) Vascular serious DVT x1, intermittent claudication x1, AEs AAA rupture x1, DVT x3 arterial stenosis x1, hematoma x1, thrombosis x1, lymphedema x1 4 (1) 4 (1) Cerebovascular serious AEs Hemorrhagic stroke x1, Hemorrhagic stroke x3, ischemic stroke x3 ischemic stroke x1 Hypertension 4 (1) 8 (2) (nonserious AE) O’Brien S, et al. Haematologica. 2015;100(Suppl 1): Abstract S489.

Cytogenetics at 24 Months Cytogenetics at 24 Months Imatinib Dasatinib N = 406, n N = 406, n Difference, P (%) (%) % Value Major 12 months 211 (51.8) 228 (56.0) 4.2 .669 cytogenetic response 24 months 125 (30.7) 140 (34.4) 3.7 .787 (MCR) Complete 12 months 171 (42.0) 217 (53.3) 11.3 .003 cytogenetic response 24 months 112 (27.5) 137 (33.7) 6.2 .189 (CCR) 12 months 136 (33.5) 146 (35.9) Missing analyses 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 On Treatment Achieved MR3 Achieved MR4.5 Response 246/406 Response (60.6%) 187/406 58/406 Imatinib (46.0%) (14.3%) n = 406 Off Treatment 160/406 (39.4%) Total Cohort ∆ = 11.5% ∆ = 5.9% n = 812 P <.001 P = .026 Off Treatment 116/406 (28.6%) Dasatinib n = 406 Achieved MR3 Achieved MR4.5 On Treatment Response Response 290/406 234/406 82/406 (71.4%) (57.5%) (20.2%) O’Brien S, et al. Haematologica. 2015;100(Suppl 1): Abstract S489.

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 MR 3 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 Abstract P228 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