Supplementary Online Content Douxfils J, Haguet H, Mullier F, Chatelain C, Graux C, Dogné J-M. Use of BCR-ABL tyrosine kinase inhibitors in chronic myeloid leukemia: a systematic review and metaanalysis of the risk of cardiovascular events, major molecular response, and overall survival. JAMA Oncology. Publish online February 4, 016. doi:10.1001/jamaoncol.015.593. emethods 1: Search strategy emethods : List of vascular occlusive adverse events efigure 1: Flow diagram of study selection according to PRISMA (preferr reporting items for systematic reviews and meta-analysis) statement etable 1: Characteristics of includ clinical trials and quality assessment efigure : Evaluation of publications bias etable : Rates of outcomes of interest across the includ studies stratifi by treatment efigure 3: One-way sensitivity analysis of the risk of vascular occlusive events in the leukemic population and stratifi by treatment efigure 4: One-way sensitivity analysis for the overall survival at 1 year and for the major molecular response rate. This supplementary material has been provid by the authors to give readers additional information about their work. 015 American Mical Association. All rights reserv.
emethods 1: Search strategy A. bosutinib Database: PubM: 1946 to September 1th 014 (5) update October 1th 014 1. bosutinib [Title] (60) Bosutinib [Title]. SKI-606 [Title] (17) SKI-606 [Title] 3. SKI606 [Title] (1) 4. ((#1) OR #) OR #3) (70) ((bosutinib[title]) OR SKI-606[Title]) OR SKI606[Title] 5. (#4) [and] "randomiz controll trial" (5) (#4) AND "randomiz controll trial"[all Fields] 6. (#4) [and] "randomiz trial" (0) (#4) AND "randomiz trial"[all Fields] 7. (#4) AND "randomiz clinical trial" (0) (#4) AND "randomiz clinical trial"[all Fields] 8. (#4) [and] "randomis controll trial" (0) (#4) AND "randomiz controll trial"[all Fields] 9. (#4) [and] "randomis trial" (0) (#4) AND "randomiz trial"[all Fields] 10. (#4) AND "randomis clinical trial" (0) (#4) AND "randomiz clinical trial"[all Fields] 11. (((((#5) OR #6) OR #7) OR #8) OR #9) OR #10 (5) (((((#5) OR #6) OR #7) OR #8) OR #9) OR #10 Database: Scopus: 1946 to September 1th 014 (14) update October 1th 014 1. TITLE (bosutinib) (73). TITLE (SKI-606) (18) 3. TITLE (SKI606) (1) 4. ( TITLE ( bosutinib ) ) OR ( TITLE ( ski-606 ) ) OR ( TITLE ( ski606 ) ) (83) 5. ( TITLE ( ski606 ) OR TITLE ( ski-606 ) OR TITLE ( bosutinib ) AND ALL ( "randomiz controll trial" ) ) (11) 6. ( TITLE ( ski606 ) OR TITLE ( ski-606 ) OR TITLE ( bosutinib ) AND ALL ( "randomiz trial" ) ) (3) 7. ( TITLE ( ski606 ) OR TITLE ( ski-606 ) OR TITLE ( bosutinib ) AND ALL ( "randomiz clinical trial" ) ) (1) 8. ( TITLE ( ski606 ) OR TITLE ( ski-606 ) OR TITLE ( bosutinib ) AND ALL ( "randomis controll trial" ) ) (11) 9. ( TITLE ( ski606 ) OR TITLE ( ski-606 ) OR TITLE ( bosutinib ) AND ALL ( "randomis trial" ) ) (3) 10. ( TITLE ( ski606 ) OR TITLE ( ski-606 ) OR TITLE ( bosutinib ) AND ALL ( "randomis clinical trial" ) ) (1) 11. #10 OR #9 OR #8 OR #7 OR #6 OR #5 ( ( TITLE ( ski606 ) OR TITLE ( ski-606 ) OR TITLE ( bosutinib ) AND ALL ( "randomis clinical trial" ) ) ) OR ( ( TITLE ( ski606 ) OR TITLE ( ski-606 ) OR TITLE ( bosutinib ) AND ALL ( "randomis trial" ) ) ) OR ( ( TITLE ( ski606 ) OR TITLE ( ski-606 ) OR TITLE ( bosutinib ) AND ALL ( "randomis controll trial" ) ) ) OR ( ( TITLE ( ski606 ) OR TITLE ( ski-606 ) OR TITLE ( bosutinib ) AND ALL ( "randomiz clinical trial" ) ) ) OR ( ( TITLE ( ski606 ) OR TITLE (
ski-606 ) OR TITLE ( bosutinib ) AND ALL ( "randomiz trial" ) ) ) OR ( ( TITLE ( ski606 ) OR TITLE ( ski-606 ) OR TITLE ( bosutinib ) AND ALL ( "randomiz controll trial" ) ) ) (14) Database: The Cochrane Library (all Cochrane product) : From 197 to September 1th 014 (8) update October 1th 014 1. bosutinib (17). SKI-606 (8) 3. SKI606 (0) 4. #1 or # or #3 (17) 5. #4 and «randomiz controll trial» (8) 6. #4 and «randomiz trials» (0) 7. #4 and «randomiz clinical trial» (0) 8. #4 and «randomis controll trials» (8) 9. #4 and «randomis trial» (0) 10. #4 and «randomis clinical trials» (0) 11. #5 or #6 or #7 or #8 or #9 or #10 (8) Then only «Trials» results were includ in the meta-analysis (8) B. dasatinib Database: PubM : 1946 to September, 15th 014 (3) update October 1th 014 1. Dasatinib [title] (680) Dasatinib[title]. BMS-35485 [title] (6) BMS-35485[title] 3. BMS35485 [title] (1) Search details : BMS35485[title] 4. ((#1) OR #) OR #3 (686) ((#1) OR #) OR #3) 5. (#4) [and] "randomiz controll trial" (19) (#4) AND "randomiz controll trial"[all Fields] 6. (#4) [and] "randomiz trial" (4) (#4) AND "randomiz trial"[all Fields] 7. (#4) AND "randomiz clinical trial" (0) (#4) AND "randomiz clinical trial"[all Fields] 8. (#4) [and] "randomis controll trial" (1) (#4) AND "randomiz controll trial"[all Fields] 9. (#4) [and] "randomis trial" (0) (#4) AND "randomiz trial"[all Fields] 10. (#4) AND "randomis clinical trial" (1) (#4) AND "randomiz clinical trial"[all Fields] 11. (((((#5) OR #6) OR #7) OR #8) OR #9) OR #10 (3) (((((#5) OR #6) OR #7) OR #8) OR #9) OR #10 Database: Scopus : 1946 to September 15th 014 (71) update October 1th 014 1. TITLE(dasatinib) (76) 3
. TITLE(BMS-35485) (8) 3. TITLE(BMS35485) () 4. (TITLE(dasatinib)) OR (TITLE(BMS-35485) OR (TITLE(BMS35485)) (770) 5. ( TITLE ( bms35485 ) OR TITLE ( bms-35485 ) OR TITLE ( dasatinib ) AND ALL ( "randomiz clinical trial" ) ) (4) 6. ( TITLE ( bms35485 ) OR TITLE ( bms-35485 ) OR TITLE ( dasatinib ) AND ALL ( "randomiz trial" ) ) (3) 7. ( TITLE ( bms35485 ) OR TITLE ( bms-35485 ) OR TITLE ( dasatinib ) AND ALL ( "randomiz controll trial" ) ) (49) 8. ( TITLE ( bms35485 ) OR TITLE ( bms-35485 ) OR TITLE ( dasatinib ) AND ALL ( "randomis clinical trial" ) ) (4) 9. ( TITLE ( bms35485 ) OR TITLE ( bms-35485 ) OR TITLE ( dasatinib ) AND ALL ( "randomis trial" ) ) (3) 10. ( TITLE ( bms35485 ) OR TITLE ( bms-35485 ) OR TITLE ( dasatinib ) AND ALL ( "randomis controll trial" ) ) (49) 11. ( ( TITLE ( bms35485 ) OR TITLE ( bms-35485 ) OR TITLE ( dasatinib ) AND ALL ( "randomiz clinical trial" ) ) ) OR ( ( TITLE ( bms35485 ) OR TITLE ( bms-35485 ) OR TITLE ( dasatinib ) AND ALL ( "randomiz controll trial" ) ) ) OR ( ( TITLE ( bms35485 ) OR TITLE ( bms-35485 ) OR TITLE ( dasatinib ) AND ALL ( "randomiz trial" ) ) ) OR ( ( TITLE ( bms35485 ) OR TITLE ( bms-35485 ) OR TITLE ( dasatinib ) AND ALL ( "randomis trial" ) ) ) OR ( ( TITLE ( bms35485 ) OR TITLE ( bms-35485 ) OR TITLE ( dasatinib ) AND ALL ( "randomis controll trial" ) ) ) OR ( ( TITLE ( bms35485 ) OR TITLE ( bms-35485 ) OR TITLE ( dasatinib ) AND ALL ( "randomis clinical trial" ) ) ) (71) Database : The Cochrane Library (all Cochrane product) : From 197 to 014 (34) update October 1th 014 1. dasatinib (108). BMS-35485 (1) 3. BMS35485 (0) 4. #1 or # or #3 (108) 5. #4 and «randomiz controll trial» (33) 6. #4 and «randomis controll trials» (1) 7. #4 and «randomiz clinical trial» (1) 8. #4 and «randomis clinical trials» (0) 9. #4 and «randomiz trial» (3) 10. #4 and «randomis trials» (0) 11. #5 or #6 or #7 or #8 or #9 or #10 (35) Then only «Trials» results were includ in the meta-analysis (34) C. nilotinib Database: PubM : 1946 to September 1th 014 (17) update October 1th 014 1. nilotinib [Title] (408) Nilotinib [Title]. AMN107 [Title] (33) AMN107 [Title] 3. ((#1) OR #) (45) (Nilotinib[Title]) OR AMN107[Title] 4. (#3) [and] "randomiz controll trial" (15) (#3) AND "randomiz controll trial"[all Fields] 5. (#3) [and] "randomiz trial" (1) (#3) AND "randomiz trial"[all Fields] 6. (#3) AND "randomiz clinical trial" (0) 4
(#3) AND "randomiz clinical trial"[all Fields] 7. (#3) [and] "randomis controll trial" (1) (#3) AND "randomiz controll trial"[all Fields] 8. (#3) [and] "randomis trial" (0) (#3) AND "randomiz trial"[all Fields] 9. (#3) AND "randomis clinical trial" (1) (#3) AND "randomiz clinical trial"[all Fields] 10. (((((#4) OR #5) OR #6) OR #7) OR #8) OR #9 (17) (((((#4) OR #5) OR #6) OR #7) OR #8) OR #9 Database: Scopus : 1946 to September 1th 014 (60) update October 1th 014 1. TITLE (nilotinib) (47). TITLE(AMN107) (37) 3. ( TITLE ( nilotinib ) ) OR ( TITLE ( amn107 ) ) (49) 4. ( TITLE ( amn107 ) OR TITLE ( nilotinib ) AND ALL ( "randomiz controll trial" ) ) (50) 5. ( TITLE ( amn107 ) OR TITLE ( nilotinib ) AND ALL ( "randomiz trial" ) ) () 6. ( TITLE ( amn107 ) OR TITLE ( nilotinib ) AND ALL ( "randomiz clinical trial" ) ) (1) 7. ( TITLE ( amn107 ) OR TITLE ( nilotinib ) AND ALL ( "randomis controll trial" ) ) (50) 8. ( TITLE ( amn107 ) OR TITLE ( nilotinib ) AND ALL ( "randomis trial" ) ) () 9. ( TITLE ( amn107 ) OR TITLE ( nilotinib ) AND ALL ( "randomis clinical trial" ) ) (1) 10. #9 OR #8 OR #7 OR #6 OR #5 OR #4 ( ( TITLE ( amn107 ) OR TITLE ( nilotinib ) AND ALL ( "randomis clinical trial" ) ) ) OR ( ( TITLE ( amn107 ) OR TITLE ( nilotinib ) AND ALL ( "randomis trial" ) ) ) OR ( ( TITLE ( amn107 ) OR TITLE ( nilotinib ) AND ALL ( "randomis controll trial" ) ) ) OR ( ( TITLE ( amn107 ) OR TITLE ( nilotinib ) AND ALL ( "randomiz clinical trial" ) ) ) OR ( ( TITLE ( amn107 ) OR TITLE ( nilotinib ) AND ALL ( "randomiz trial" ) ) ) OR ( ( TITLE ( amn107 ) OR TITLE ( nilotinib ) AND ALL ( "randomiz controll trial" ) ) ) (60) Database: The Cochrane Library (all Cochrane product) : From 197 to September 1th 014 (50) update October 1th 014 1. nilotinib (68). AMN107 () 3. #1 or # (70) 4. #3 and «randomiz controll trial» (68) 5. #3 and «randomiz trials» (68) 6. #3 and «randomiz clinical trial» (68) 7. #3 and «randomis controll trials» (68) 8. #3 and «randomis trial» (68) 9. #3 and «randomis clinical trials» (68) 10. #4 or #5 or #6 or #7 or #8 or #9 (68) Then only «Trials» results were includ in the meta-analysis (50) D. ponatinib Database: PubM : 1946 to September 1th 014 (1) update October 1th 014 1. ponatinib [Title] (69) Ponatinib [Title]. AP4534 [Title] (8) AP4534[Title] 5
3. ((#1) OR #) (71) Ponatinib[Title] OR AP4534[Title] 4. (#3) [and] "randomiz controll trial" (1) (#3) AND "randomiz controll trial"[all Fields] 5. (#3) [and] "randomiz trial" (0) (#3) AND "randomiz trial"[all Fields] 6. (#3) AND "randomiz clinical trial" (0) (#3) AND "randomiz clinical trial"[all Fields] 7. (#3) [and] "randomis controll trial" (0) (#3) AND "randomiz controll trial"[all Fields] 8. (#3) [and] "randomis trial" (0) (#3) AND "randomiz trial"[all Fields] 9. (#3) AND "randomis clinical trial" (0) (#3) AND "randomiz clinical trial"[all Fields] 10. (((((#4) OR #5) OR #6) OR #7) OR #8) OR #9 (1) (((((#4) OR #5) OR #6) OR #7) OR #8) OR #9 Database: Scopus : 1946 to September 1th 014 (3) update October 1th 014 1. TITLE (ponatinib) (87). TITLE(AP4534) (9) 3. ( TITLE ( AP4534 ) OR TITLE ( ponatinib ) ) (90) 4. ( TITLE ( ap4534 ) OR TITLE ( ponatinib ) AND ALL ( "randomiz clinical trial" ) ) (0) 5. ( TITLE ( ap4534 ) OR TITLE ( ponatinib ) AND ALL ( "randomiz trial" ) ) (1) 6. ( TITLE ( ap4534 ) OR TITLE ( ponatinib ) AND ALL ( "randomiz clinical trial" ) ) (0) 7. ( TITLE ( ap4534 ) OR TITLE ( ponatinib ) AND ALL ( "randomis controll trial" ) ) () 8. ( TITLE ( ap4534 ) OR TITLE ( ponatinib ) AND ALL ( "randomis trial" ) ) (1) 9. ( TITLE ( ap4534 ) OR TITLE ( ponatinib ) AND ALL ( "randomis clinical trial" ) ) (0) 10. #9 OR #8 OR #7 OR #6 OR #5 OR #4 ( ( TITLE ( ap4534 ) OR TITLE ( ponatinib ) AND ALL ( "randomis clinical trial" ) ) ) OR ( ( TITLE ( ap4534 ) OR TITLE ( ponatinib ) AND ALL ( "randomis trial" ) ) ) OR ( ( TITLE ( ap4534 ) OR TITLE ( ponatinib ) AND ALL ( "randomis controll trial" ) ) ) OR ( ( TITLE ( ap4534 ) OR TITLE ( ponatinib ) AND ALL ( "randomiz clinical trial" ) ) ) OR ( ( TITLE ( ap4534 ) OR TITLE ( ponatinib ) AND ALL ( "randomiz trial" ) ) ) OR ( ( TITLE ( ap4534 ) OR TITLE ( ponatinib ) AND ALL ( "randomiz clinical trial" ) ) ) (3) Database: The Cochrane Library (all Cochrane product) : From 197 to September 1th 014 (3) update October 1th 014 1. ponatinib (6). AP4534 (1) 3. #1 or # (6) 4. #3 and «randomiz controll trial» (6) 5. #3 and «randomiz trials» (6) 6. #3 and «randomiz clinical trial» (6) 7. #3 and «randomis controll trials» (6) 8. #3 and «randomis trial» (6) 9. #3 and «randomis clinical trials» (6) 10. #4 or #5 or #6 or #7 or #8 or #9 (6) Then only «Trials» results were includ in the meta-analysis (3) 6
emethods : list of vascular occlusive adverse events Acute myocardial infarction Angina pectoris Angina unstable Aortic stenosis Arterial occlusive disease Arterial stenosis limb Arteriosclerosis Arteriosclerosis coronary artery Atrial thrombosis Basilar artery stenosis Cardiac arrest Cardiac discomfort Cardiac infarction Cardiac ischaemia Cardiogenic shock Cardio-respiratory arrest Central nervous system lesion Cerebral infarction Cerebrovascular accident Cerebrovascular disorder Chest pain Coronary artery disease Coronary artery restenosis Coronary artery stenosis Deep vein thrombosis Dysarthria Electrocardiogram ST-segment depression Femoral arterial stenosis Hypoxic-ischemic encephalopathy Iliac artery stenosis Intermittent claudication Ischaemic heart disease Ischaemic stroke Mesenteric artery embolism Myocardial infarction Myocardial ischaemia Peripheral arterial occlusive disease Peripheral artery disease Peripheral artery thrombosis Peripheral vascular disorder Phlebitis Pulmonary embolism Retinal vein thrombosis Thrombophlebitis Thrombosis in device Transient ischaemic attack Varicose vein Vascular graft occlusion Vena cava thrombosis 7
efigure 1: Flow diagram of study selection according to PRISMA (preferr reporting items for systematic reviews and meta-analysis) statement. 8
etable 1: Characteristics of includ clinical trials and quality assessment Study ID BELA NCT005748 73 NCT000704 99 Study design Experimenta l Dosage Admin frequency bosutinib 500mg dasatinib 100mg Control Dosage Admin frequency 400 or 800mg No. of pt s 50 39 1 Populati on CP CML newly diagnose d CP CML untreat Age (mean ± SD) 46.53 ± 14. 6 % male Primary endpoint 56 CCyR at 1 50 61.40 MMR rate at 1 Secondary endpoint(s) MMR, MCyR, CHR at 1 Safety Duration of response Pharmacokine tics Time to transformatio n to AP/BP HR year OS year relapse free survival Toxicity Jada d scor e START R NCT001038 44 NCT00301 90 DASISION NCT00481 47 dasatinib 70mg twice daily dasatinib 100mg dasatinib 100mg twice daily 800mg 15 0 CP CML previousl y treat with 3 CML previousl y treat with 51 9 CP CML newly diagnose d 51 ± 13.6 50 MCyR at 1 weeks 48.6 ± 14.8 5 71.90 MMR rate at 1 46.7 ± 14. 59.40 CCyR rate by 1 MCyR at any time Duration of MCyR CHR, CCyR, MMR Duration of CHR AEs, SAEs, deaths QoL, PK Deaths, AEs, SAEs Mian time to treatment failure, to PFS Time to MMR CCyR Safety Time to CCyR and MMR OS PFS MMR 3 NordCML00 6 NCT00855 66 dasatinib 100mg 46 CP CML newly diagnose d dasatinib: 54 : 60 48 Proportion of Ph+ CD34+/CD 38 bone marrow cells at 6 Fraction of Ph+ cells at 1 and 3 Molecular and cytogenetic responses at 3, 6, 1 and 18 3 ENESTnd NCT004714 97 ENESTcmr NCT007608 77 nilotinib 300mg twice daily nilotinib twice daily nilotinib twice daily 400 or 600mg 84 6 0 7 CP CML newly diagnose d CP CML previousl y treat with nilotinib 300mg: 47 nilotinib : 47 Imatinib : 46 nilotinib: 46 : 5 nilotini b: 68 imatini b: 63 58 Rate of MMR at 1 Rate of confirm best cumulative CMR within the 1st year Rate of durable MMR by 4 Progression to AP/BP CCyR Rate ruction in BCR ABL transcript levels Kinetics of CMR PFS, EFS and OS 3 9
RE NICE NCT014000 74 nilotinib twice daily twice daily 43 CML early CP previousl y treat nilotinib: 45 : 35 74.40 Cumulative rate of MMR at 1 Time and duration of MMR and CMR Cumulative rate of CMR, MMR and MR4.0 PFS Safety 1 EPIC NCT016508 05 ponatinib 45mg 30 7 CP CML newly diagnose d 51.5 ± 15.4 1 61.50 MMR at 1 MR rate at 3,6,9 and 1 Time to MR CCyR rate Safety OS, PFS 10
efigure : Evaluation of publications bias A. Vascular occlusive events Funnel Plot of Standard Error by Log Peto odds ratio 0 1 Standard Error 3-3 - -1 0 1 3 Log Peto odds ratio 11
B. Overall survival Funnel Plot of Standard Error by Log Peto odds ratio 0 1 Standard Error 3-3 - -1 0 1 3 Log Peto odds ratio 1
C. Major molecular response Funnel Plot of Standard Error by Log Peto odds ratio 0,0 0, 0,4 Standard Error 0,6 0,8 1,0 -,0-1,5-1,0-0,5 0,0 0,5 1,0 1,5,0 Log Peto odds ratio 13
etable : Rates of outcomes of interest across the includ studies stratifi by treatment A. Vascular occlusive events Study No. of events/total No. (%) Fix effect model Random effect model New generation TKI ORPETO (95%CI) ORPETO (95%CI) NCT00574873 (BELA) 3/48 (1.1) 1/51 (0.40).77 (0.39 19.77).77 (0.39 19.77) Bosutinib 3/48 (1.1) 1/51 (0.40).77 (0.39 19.77).77 (0.39 19.77) NCT0070499 1/13 (0.81) 0/13 (0.00) 7.39 (0.15 37.38) 7.39 (0.15 37.38) NCT00103844 (START R) /101 (1.98) 0/49 (0.00) 4.46 (0.3 86.51) 4.46 (0.3 86.51) NCT0030190 0/19 (0.00) 1/13 (7.69) 0.09 (0.00 4.61) 0.09 (0.00 4.61) NCT0048147 (DASISION) 8/58 (3.10) 1/58 (0.39) 4.86 (1.30 18.1) 4.86 (1.30 18.1) NCT0085566 (NordCML006) 1/ (4.55) 0/4 (0.00) 8.09 (0.16 409.34) 8.09 (0.16 409.34) Dasatinib 1/53 (.30) /467 (0.43) 3.86 (1.33 11.18) 3.86 (1.33 11.18) NCT00471497 (ENESTnd) 61/556 (10.97) 6/80 (.14) 3.31 (1.95 5.61) 3.31 (1.95 5.61) NCT00760877 (ENESTcmr) 6/101 (5.94) 1/103 (0.97) 4.45 (0.99 0.0) 4.45 (0.99 0.0) Nilotinib 67/657 (10.0) 7/383 (1.83) 3.4 (.07 5.63) 3.4 (.07 5.63) NCT01650805 (EPIC) 1/154 (7.79) 3/15 (1.97) 3.47 (1.3 9.78) 3.47 (1.3 9.78) Ponatinib 1/154 (7.79) 3/15 (1.97) 3.47 (1.3 9.78) 3.47 (1.3 9.78) Overall 94/1,58 (5.94) 13/1,53 (1.04) 3.45 (.30 5.18) 3.45 (.30 5.18) B. Overall survival Study No. of events*/total No. (%) Fix effect model Random effect model New generation TKI ORPETO (95%CI) ORPETO (95%CI) NCT00574873 (BELA) 44/48 (98.39) 41/51 (96.0).38 (0.8 6.89).38 (0.8 6.89) bosutinib 44/48 (98.39) 41/51 (96.0).38 (0.8 6.89).38 (0.8 6.89) NCT0070499 1/13 (99.19) 13/13 (100.00) 0.14 (0.00 6.8) 0.14 (0.00 6.8) NCT0048147 (DASISION) 50/58 (97.00) 55/58 (99.00) 0.36 (0.11 1.4) 0.36 (0.11 1.4) NCT0085566 (NordCML006) / (100.00) 3/4 (95.83) 6.80 (0.13 343.88) 6.80 (0.13 343.88) dasatinib 394/403 (97.77) 397/405 (98.03) 0.4 (0.14 1.31) 0.46 (0.11.01) NCT00471497 (ENESTnd) 559/563 (99.9) 79/83 (98.59).1 (0.48 9.5).1 (0.48 9.5) NCT00760877 (ENESTcmr) 103/104 (99.04) 103/103 (100.00) 0.14 (0.00 6.89) 0.14 (0.00 6.89) nilotinib 66/667 (99.5) 38/386 (98.96) 1.51 (0.38 5.99) 1.01 (0.09 10.96) NCT01650805 (EPIC) 154/155 (99.35) 150/15 (98.68).00 (0.1 19.33).00 (0.1 19.33) ponatinib 154/155 (99.35) 150/15 (98.68).00 (0.1 19.33).00 (0.1 19.33) Overall 1,454/1,473 (98.71) 1,170/1,194 (97.99) 1.3 (0.67.3) 1.14 (0.46.81) * Number of events represents the number of patients alive after one or two years of treatment C. Major molecular response Study No. of events/total No. (%) Fix effect model Random effect model New generation TKI ORPETO (95%CI) ORPETO (95%CI) NCT00574873 (BELA) 103/50 (41.00) 68/5 (7.00) 1.86 (1.9.70) 1.86 (1.9.70) bosutinib 103/50 (41.00) 68/5 (7.00) 1.86 (1.9.70) 1.86 (1.9.70) NCT0070499 58/13 (47.15) 40/13 (3.5) 1.84 (1.10 3.06) 1.84 (1.10 3.06) NCT00103844 (START R) 9/101 (8.71) 6/49 (1.5).50 (1.1 5.58).50 (1.1 5.58) NCT0048147 (DASISION) 119/59 (45.95) 73/60 (8.08).15 (1.51 3.07).15 (1.51 3.07) NCT0085566 (NordCML006) 18/ (81.00) 11/4 (46.00) 4.33 (1.3 14.13) 4.33 (1.3 14.13) dasatinib 4/505 (44.36) 130/456 (8.51).17 (1.66.83).17 (1.66.83) NCT01400074 (RE NICE) 8/ (36.36) 7/1 (33.33) 1.14 (0.33 3.94) 1.14 (0.33 3.94) NCT00471497 (ENESTnd) 44/563 (43.34) 63/83 (.6).49 (1.85 3.34).49 (1.85 3.34) NCT00760877 (ENESTcmr) 0/4 (83.33) 15/8 (53.57) 3.77 (1.19 11.91) 3.77 (1.19 11.91) nilotinib 7/609 (44.66) 85/33 (5.60).45 (1.85 3.4).45 (1.84 3.6) NCT01650805 (EPIC) 8/10 (80.00) 5/13 (5.07) 4.95 (0.97 5.19) 4.95 (0.97 5.19) ponatinib 8/10 (80.00) 5/13 (5.07) 4.95 (0.97 5.19) 4.95 (0.97 5.19) Overall 607/1,374 (44.18) 88/1,053 (7.35). (1.87.63). (1.87.63) 14
efigure 3: One-way sensitivity analysis of the risk of vascular occlusive events in the leukemic population and stratifi by treatment 15
efigure 4: One-way sensitivity analysis for the overall survival at 1 year and for the major molecular response rate. A. Overall survival Overall survival Study name Tre atme nt ComparisonStatistics with study remov Peto odds ratio (95% Lower Upper CI) with study remov Point limit limit p-value NCT00574873- BELA bosutinib 0,80 0,36 1,8 0,600 NCT00070499 dasatinib 1,8 0,66,46 0,463 NCT0048147 - DASISION dasatinib 1,90 0,89 4,06 0,098 NCT0085566 - NordCML006 dasatinib 1,15 0,60,1 0,684 NCT00471497- ENESTnd nilotinib 1,05 0,51,16 0,891 NCT00760877- ENESTcmr nilotinib 1,8 0,66,46 0,463 NCT01650805- EPIC ponatinib 1,15 0,59,6 0,684 1,0 0,63,9 0,576 0,01 0,1 1 10 100 Imatinib New generation TKI B. Major molecular response Major molecular response Study name Treatment ComparisonStatistics with study remov Peto odds ratio (95% Lower Upper CI) with study remov Point limit limit p-value NCT00574873 - BELA bosutinib,3 1,9,81 0,000 NCT00070499 dasatinib,7 1,89,7 0,000 NCT00103844 - START-R dasatinib,0 1,85,6 0,000 NCT0048147 - DASISION dasatinib,4 1,84,7 0,000 NCT0085566 - NordCML006 dasatinib,19 1,84,60 0,000 NCT01400074 - RE-NICE nilotinib,4 1,89,67 0,000 NCT00471497 - ENESTnd nilotinib,09 1,70,58 0,000 NCT00760877 - ENESTcmr nilotinib,19 1,84,60 0,000 NCT01650805 - EPIC ponatinib,0 1,85,61 0,000, 1,87,63 0,000 0,01 0,1 1 10 100 Imatinib New generation TKI 16