Post ASH Actualités LMC

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1 Post ASH Actualités LMC

2 Actualités de première ligne LMC PC ENESTnd (6 ans) Dasision (5 ans) EPIC Spirit France (5 ans) Spirit 2 UK (5 ans)

3 ENESTnd: Mise à jour à 6 ans Design = 846 ults with wly agnosed 6 months) + CML-CP R A N D O M I Z E 1:1:1 Stratified by Sokal risk score Nilotinib 300 mg BID (n = 282) Nilotinib 400 mg BID (n = 281) Imatinib 400 mg QD (n = 283) Planned follow-up: 10 years a,b A, et al. Blood. 2014:[abstract 4541].

4 Patients disposition ENESTnd: Mise à jour à 6 ans Patient Status, n (%) Nilotinib 300 mg BID (n = 282) Nilotinib 400 mg BID (n = 281) Imatinib 400 mg QD (n = 283) Still on study a 231 (81.9) 238 (84.7) 224 (79.2) Still on core treatment 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 abnormalities 39 (13.8) 64 (22.8) 39 (13.8) Withdrawal of consent 19 (6.7) 22 (7.8) 22 (7.8) Suboptimal response/treatment failure b 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 reason c 29 (10.3) 21 (7.5) 19 (6.7) a On core or extension treatment or in posttreatment follow-up. b Per the 2009 European LeukemiaNet criteria (Baccarani M, et al. J Clin Oncol. 2009;27: ) or investigator assessment. c 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). A, et al. Blood. 2014:[abstract 4541].

5 umulative incidence of MR4.5 ENESTnd: Mise à jour à 6 ans Cumulative Incidence of MR 4.5, % Nilotinib 300 mg BID (n = 282) Nilotinib 400 mg BID (n = 281) Imatinib 400 mg QD (n = 283) By 1 Year 11%; P <.0001 a 7%; P <.0001 a 6% to 10% 1% By 5 Years 54%; P <.0001 a 52%; P <.0001 a 31% Months Since Randomization 21% to 23% By 6 Years 56%; P <.0001 a 55%; P <.0001 a 22% to 23% 33% A, et al. Blood. 2014:[abstract 4541].

6 ENESTnd: Mise à jour à 6 ans reedom from progression to AP/BC at 6 years Nilotinib 300 mg BID (n = 282) Nilotinib 400 mg BID (n = 281) Imatinib 400 mg QD (n = 283) Progression to AP/BC on core treatment, n KM-estimated 6-year freedom from progression to AP/BC (95% CI), % Hazard ratio vs imatinib (95% CI) 99.3 ( ) ( ) 98.7 ( ) ( ) 95.2 ( ) Nominal P value vs imatinib Progression to AP/BC on study, n KM-estimated 6-year freedom from progression to AP/BC (95% CI), % Hazard ratio vs imatinib (95% CI) 95.8 ( ) ( ) 97.8 ( ) ( ) 92.2 ( ) Nominal P value vs imatinib A, et al. Blood. 2014:[abstract 4541].

7 verall survival and deaths ENESTnd: Mise à jour à 6 ans Nilotinib 300 mg BID (n = 282) Nilotinib 400 mg BID (n = 281) Imatinib 400 mg QD (n = 283) Total deaths on study, n a KM-estimated 6-year OS on study (95% CI), % Hazard ratio vs imatinib (95% CI) ( ) 91.6 ( ) 95.8 ( ) 91.4 ( ) ( ) Nominal P value vs imatinib Deaths due to advanced CML, n KM-estimated 6-year freedom from death due to advanced CML (95% CI), % Hazard ratio vs imatinib (95% CI) 97.7 ( ) 98.5 ( ) 93.9 ( ) ( ) ( ) Nominal P value vs imatinib A, et al. Blood. 2014:[abstract 4541].

8 esign Dasision: Mise à jour à 5 ans Treatment-naïve CML-CP patients (N=519) 108 centers 26 countries Enrollment: September 2007 December 2008 Randomized a Dasatinib 100 mg QD (n=259) Imatinib 400 mg QD (n=260) 5-year final results Database lock of 24-Mar-2014 Primary end point: confirmed CCyR by 12 months 77% dasatinib vs. 66% imatinib (P=0.007) 1 et al. Blood. 2014:[abstract 152]. a Stratified by EURO (Hasford) risk score. 1. Kantarjian H et al. N Engl J Med 2010;362:22

9 atients disposition Dasision: Mise à jour à 5 ans Treated Patients, n (%) Dasatinib 100 mg QD (n=258) Imatinib 400 mg QD (n=258) On initial therapy at study end 158 (61) 162 (63) Discontinued Progression or treatment failure 28 (11) 36 (14) AE related to study treatment a 42 (16) 17 (7) AE unrelated to study treatment a 12 (5) 4 (2) Poor/nonadherence 1 (<1) 7 (3) Other 17 (7) b 31 (12) c et al. Blood. 2014:[abstract 152]. a As defined by investigator. b Includes withdrawal of consent and patient request (4 each), insufficient molecular response (3), pregnancy (2), and lost to follow-up, loss of CCyR, increased BCR-ABL, and relocation to the US (1 each). c Includes patient request (10), no molecular response/loss of molecular response (4), withdrawal of consent and suboptimal response (3 each), lost to follow-up, insufficient cytogenetic response, and investigator request (2 each), and pregnancy, recurrence of blasts in bone marrow, no CMR, no MMR, and appearance of mutation (1 each).

10 I MR Dasision: Mise à jour à 5 ans N Dasatinib 100 mg QD 259 Imatinib 400 mg QD 260 % With MR By 1 year 5% By 2 years 19% 8% By 3 years 24% 13% By 4 years 34% 23% By 5 years p= % 33% 0 3% Months Since Randomization et al. Blood. 2014:[abstract 152].

11 nsformation to AP/BC Dasision: Mise à jour à 5 ans On study During follow-up beyond discontinuation 7.3% Patients, n 4.6% Dasatinib n=259 Imatinib n=260 Dasatinib 100 mg QD (n=259) Imatinib 400 mg QD (n=260) BCR-ABL at 3 Months a 10% n=198 >10% n=37 10% n=154 >10% n=85 Transformation to AP/BP b, n (%) 6 (3) 5 (14) 5 (3) 13 (15) One imatinib patient and no dasatinib patients transformed between 4 and 5 years a One dasatinib and one imatinib patient transformed but did not have 3-month molecular assessments. b Including follow-up beyond discontinuation (intent to treat). et al. Blood. 2014:[abstract 152].

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

13 sign EPIC, et al. Blood. 2014:[abstract 519].

14 EPIC olecular results at 3, 6, 9 and 12 months (Evaluable patients), et al. Blood. 2014:[abstract 519].

15 atment-emergent vascular events EPIC = 14% emergent CV events in to, et al. Blood. 2014:[abstract 519].

16 rvie à 5 ans SPIRIT France Survie globale Survie sans progression F, et al. Blood. 2014:[abstract 1793].

17 SPIRIT 2 : Study Design Chronic phase CML within 3 months of diagnosis R Arm A Imatinib 400 N=407 n=814 Arm B Dasatinib 100 domised, open label ary endpoint: 5 year EFS ndary: cytogenetic, PCR response, toxicity N=407

18 Endpoints rimary 5 year event free survival (EFS) Assessed for all patients March 2018 econdary Rate of complete cytogenetic response (CCR) Rate of Major Molecular Response (MMR, MR 3, BCR-ABL1/ABL1 ratio<0.1%) Toxicity Treatment failure rates (TFR) after 5 years Rates of complete haematologic response (CHR) Overall survival at 2 and 5 years

19 Patients Who Stopped Study Drug Imatinib 406 (%) Dasatinib 406 (%) Total 812 (%) Reason for stopping study drug (exc. death) Consent withdrawn 7 (1.7) 9 (2.2) 16 (2.0) Disease progression - accelerated phase 1 (0.2) 2 (0.5) 3 (0.4) Disease progression - blast crisis 7 (1.7) 4 (1.0) 11 (1.4) Failure to achieve CCR after 24 months 4 (1.0) 1 (0.2) 5 (0.6) Failure to achieve MCR after 12 months 23 (5.7) 3 (0.7) 26 (3.2) Intolerance - non haem tox 53 (13.1) 80 (19.7) 133 (16.4) Intolerance - haem/lab tox 10 (2.5) 10 (2.5) 20 (2.5) Loss of CHR 5 (1.2) 0 5 (0.6) Loss of MCR 5 (1.2) 2 (0.5) 7 (0.9) Other reason 4 (1.0) 11 (2.7) 29 (3.6) Reason unknown - Lost to follow up 2 (0.5) 0 2 (0.2) Inadequate response (cytogenetic, haematological, molecular, mutation detected) 42 (10.3) 3 (0.7) 45 (5.5) Total 163 (40.1) 125 (30.8) 288 (35.5)

20 Cause of Death Imatinib 18/406 (2.2%) Total Deaths 38/812 (4.7%) Dasatinib 20/406 (2.5%) Unknown 3/18 (17%) CML related 6/18 (33%) Non CML related 9/18 (50%) Non CML related 10/20 (50%) CML related 5/20 (25%) Unknown 5/20 (25%) Other cancer 4/9 (44%) Non cancer 5/9 (56%) Other cancer 3/10 (30%) Non cancer 7/10 (70%) Bronchogenic Endometrial Rectal Gastric Left ventricular failure Bronchopneumonia secondary to emphysema Myocardial infarction Ruptured aortic aneurysm Bronchopneumonia Colon ca Lung ca Metastatic breast ca 11 Ischaemic heart disease, COPD, CCF Chest Infection, CCF, renal failure, diabetes Bowel perforation Cardiac failure and bronchopneumonia Liver disease COPD Chronic cardiac failure

21 Comparative AEs Fluid retention Oedema Difference Pleural effusion Myalgia Nausea 95% CIs Vomiting Diarrhoea Fatigue Headache Rash Pulmonary (arterial) hypertension Dyspnoea (exertional) with no pleural effusion ovember 2014 Favours dasatinib Favours imatinib

22 Cytogenetics at 12 Months Imatinib (%) Dasatinib (%) Difference (%) p value Major cytogenetic response (MCR) 209/406 (51.5) 228/406 (56.2) (4.7) 0.181* Complete cytogenetic response (CCR) 169/406 (41.6) 217/406 (53.4) (11.8) <0.001* Missing analyses 181/406 (44.6) 166/406 (40.9) ution required, missing analyses included in denominator

23 Imatinib n=406 On treatment 320/406 (78.8%) Off treatment 80/406 (19.7%) Unknown 6/406 (1.5%) 12 Month PCR Achieved MR3 Response 175/406 (43.1%) Achieved MR4.5 Response 24/406 (5.9%) Total Cohort n=812 = 15.3% p<0.001 = 7.4% P=0.001 Off treatment 59/406 (14.5%) Unknown 3/406 (0.7%) Dasatinib n=406 On treatment 344/406 (84.7%) Achieved MR3 Response 237/406 (58.4%) Achieved MR4.5 Response 54/406 (13.3%) vember 2014

24 Partial PCR Responses Imatinib Dasatinib Totals 3 month PCR samples available % % % PCR > 10% (MR1) at 3 months % % % PCR < 10% (MR1) at 3 months % % % 12 month PCR samples available % % % PCR > 1% (MR2) at 12 months* % % % PCR < 1% (MR2) at 12 months* % % % Total with 'less than ideal' progress 86/ % 30/ % 116/ %

25 PCR Data: All Patients, Both Arms PCR Ratio (BCR-ABL1/ABL1 Ratio) IS 7,431 data points, IS Months From Randomisation

26 11 Patients Who Died From CML PCR Ratio (BCR-ABL1/ABL1 Ratio) IS No follow up data 3 overt blast crisis 10.6 month interval to death 12.6 months 14.2 months 1 equivocal accelerated phase 42.4 months Months From Randomisation

27 Actualités de première ligne LMC PC Prognostic Significance of Early Predictors

28 Comparing the Prognostic Significance of Early Predictors of Survival in Chronic Myeloid Leukemia (CML) Treated with Imatinib - an Analysis of the Randomized CML-Study IV A156 Background Early prediction of outcome using response-related predictive landmarks has become a major paradigm in the clinical management of chronic myeloid leukemia (CML) Aims Compare the prognostic significance of early predictors of survival according to sensitivity and specificity of 3 Mo and 6 Mo landmarks Apply landmarks in patients with disease progression (AP, BP, deaths) within the CML study IV tein B, et al. Comparing the Prognostic Significance of Early Predictors of Survival in Chronic Myeloid mia (CML) Treated with Imatinib - an Analysis of the Randomized CML-Study IV.

29 Comparing the Prognostic Significance of Early Predictors of Survival in Chronic Myeloid Leukemia (CML) Treated with Imatinib - an Analysis of the Randomized CML-Study IV A156 A total of 967 newly diagnosed patients were assigned to an imatinib-based treatment arm of CML-Study IV Median follow-up: 7.1 years The number of molecular assessments: n= 789 (at 6 months) n= 692 (at 3 months) n= 301 (at 3 months and at diagnosis, without pretreatment) At 3 and 6 months, a BCR-ABL ratio was calculated using ABL as reference gene and standardized. At +3 mo a standardization was also made by GUS as a reference gene in order to ensure the linearity of the data n B, et al. Comparing the Prognostic Significance of Early Predictors of Survival in Chronic Myeloid a (CML) Treated with Imatinib - an Analysis of the Randomized CML-Study IV.

30 Applying early landmarks on patients with disease progression in CML-study IV A156 Patient sample 3-month and 6-month molecular assessment: n=513 Events defined by disease progression (accelerated phase, blastic phase or death) later than 7.5 months: Total: n= 45 Accelerated phase: n= 4 Blastic phase: n= 11 Death from any reason: n= 30 2 nd TKI: n= 21 SCT: n= 13 How could patients at risk be identified early and more precisely? Hanfstein B, et al. Comparing the Prognostic Significance of Early Predictors of Survival in Chronic Myeloid Leukemia (CML) Treated with Imatinib - an Analysis of the Randomized CML-Study IV.

31 Applying early landmarks on patients with disease progression in CML-study IV Conclusions The 3-month 10% BCR-ABL IS landmark identifies patients at risk of progression with a sensitivity of 41% and a specificity of 75% The 6-month 10% BCR-ABL IS landmark is less sensitive (18%) and more specific (94%) The most precise identification of patients at risk is allowed by a comparison of BCR-ABL IS at diagnosis and at 3 months A half-log reduction of BCR-ABL transcripts at 3 months is associated with an 8-year PFS of 94% vs 75% (43% sensitivity, 87% specificity) in B, et al. Comparing the Prognostic Significance of Early Predictors of Survival in Chronic Myeloid ia (CML) Treated with Imatinib - an Analysis of the Randomized CML-Study IV.

32 Applying early landmarks on patients with disease progression in CML-study IV A156 Progression-free survival (PFS) according to 0.5-log reduction of BCR-ABL at 3 months in B, et al. Comparing the Prognostic Significance of Early Predictors of Survival in Chronic Myeloid ia (CML) Treated with Imatinib - an Analysis of the Randomized CML-Study IV.

33 Essais d arrêt de traitement Euroski (3 ans) Stop TKI2G (7 ans)

34 Relapse defined as BCR-ABL > 0.1% (loss of MMR) on the IS at one time point Mahon FX, et al. Blood 2014:[abstract 151].

35 Molecular Relapse-free survival Relapses within 6 months, n=77 At 6 months : 63 % (95% CI : 55% - 69%) At 12 months: 56 % (95% CI : 49 % - 63 %) At 18 months : 55 % (95% CI : 47 % - 61 %) X, et al. Blood. 2014:[abstract #151]

36 Molecular Relapse-free survival 200 interim patients by TKI duration Pts treated > 8 y N = 86, loss MMR = 29 Pts treated < 8 y N = 114, loss MMR = 60 At 18 months : > 8 y : 65 % (95% CI : 53 % - 74%) < 8 y : 47 % (95% CI : 38 % - 56%) Overall p=0.007 X, et al. Blood. 2014:[abstract #151]

37 Molecular Relapse-free survival 200 interim patients by MR4 duration > 5 y : N = 92, loss MMR = 32 < 5 y : N = 108, loss MMR = 57 At 18 months : > 5 y : 65 % (95% CI : 54 % - 74%) < 5 y: 46 % (95% CI : 38 % - 56%) Overall p= X, et al. Blood. 2014:[abstract #151]

38 Study design and objectives - Adult CP-CML patients (n=100 planned) - TKI therapy for at least 3 years - 2G-TKI frontline or after intolerance/resistance to imatinib - Undetectable BCR-ABL* (CMR4.5) for at least 2 years STOP M12 M24 M36 M48 M60 Year 1 Year 2 Year 3-5 RQ-PCR monthly RQ-PCR q2-3 months RQ-PCR q3-6 months Primary objective: treatment-free survival in MMR. et al. Blood 2014; Abstract #811. *Major BCR. Molecular monitoring performed in local laboratories filling international standardization requirements. A 20000x2 copies of ABL control gene until 2012 then at least copies (Cross et al. Leukemia 2012; 26:

39 Treatment-free survival in MMR 24 patients lost MMR after a median time of 3.7 months ( ) % Treatment-free survival in MMR At 12 months: 59.6% (95% CI: ) At 24 months: 57.4% (95% CI: ) KM analysis Months after 2G TKI discontinuation et al. Blood 2014; Abstract 811.

40 Rea et al. Blood (ASH) 2014; Abstract 811. Treatment-free survival in MMR according to baseline factors No association between treatment-free survival without MMR loss and the following factors was found: age, gender, Sokal risk group, exposure to IFN, treatment/cmr duration and type of 2G-TKI. Only prior history of suboptimal response or resistance to imatinib was found to have a significant impact: % Treatment-free survival in MMR et al. Blood 2014; Abstract #811. KM analysis P= Months after 2G TKI discontinuation At 12 months: First line/imatinib intolerant: 65.6% (95% CI: 50,2-79.7). Suboptimal/resistant to imatinib: 41.6% (95% CI: ).

41 Rea et al. Blood (ASH) 2014; Abstract 811. Treatment-free survival in MMR according to BCR-ABL levels at 3 months Landmark analysis among 40 patients who remained treatment-free in MMR at 3 months. CMR at 3 months n=23 MR4.5 at 3 months n=30 No CMR at 3 months n=17 No MR4.5 at 3 months n=10 % Treatment-free survival in MMR 100 At 12 months: 91.3% (95%CI: ) At 12 months: 58.8% (95%CI: ) 20 P= % Treatment-free survival in MMR At 12 months: 93.3% (95%CI: ) At 12 months: 30% (95%CI: ) P= Months after 2G TKI discontinuation Months after 2G TKI discontinuation. et al. Blood 2014; KM analysis Abstract #811.

42 Early Disease Relapse after Tyrosine Kinase Inhibitor Treatment Discontinuation in CML Is Related Both to Low Number and Impaired Function of NK-Cells A812 Aim of the study: To identify predictive biomarkers for relapse/non relapse after TKI discontinuation CML-CP Nordic patients included in the EURO-SKI study (n=119) Basic lymphocyte immunophenotyping (number of NK-, T-, and B-cells) performed at baseline and 1, 6 and 12 months after TKI discontinuation Functional analyses (cytotoxicity of NK-cells, Th1 cytokines) were performed in some patients Patients with at least 6 months of follow-up after imatinib discontinuation (n=58) Baseline variables Patients without loss of MMR (n=36) Patients with loss of MMR (n=22) NK-cells count (10 9 cells/l) NK-cells proportion (%) NK-cells cytotoxic phenotype (1) Based on levels of expression of CD57, CD16, CD62L and IFN-ϒ/TNF-α secretion. ander MM, et al. Early Disease Relapse after Tyrosine Kinase Inhibitor Treatment Discontinuation in CML Is Related Both to Low Number and paired Function of NK-Cells. p

43 Early Disease Relapse after Tyrosine Kinase Inhibitor Treatment Discontinuation in CML Is Related Both to Low Number and Impaired Function of NK-Cells Early relapsing patients have lower proportion and number of Nkcells compared to nonrelapsing or late-relapsing patients 1) Based on levels of expression of CD57, CD16, CD62L and IFN-ϒ/TNF-α secretion. M, et al. Early Disease Relapse after Tyrosine Kinase Inhibitor Treatment Discontinuation in CML Is Both to Low Number and Impaired Function of NK-Cells.

44 Actualités de 2 ligne LMC PC PACE (3 ans) BMS 034 (7 ans)

45 tients disposition Essai PACE et al. Blood. 2014:[abstract 3135].

46 vival for CP CML Essai PACE et al. Blood. 2014:[abstract 3135]. Median follow-up: 38 months

47 vival Essai PACE et al. Blood. 2014:[abstract 3135]. Median follow-up: 34 months

48 verse Events Essai PACE = 49% emergent CV events in total et al. Blood. 2014:[abstract 3135].

49 CA Study Design N=670 randomized a CP-CML pts 18 years with Resistance Suboptimal response Intolerance to imatinib N=662 treated 100 mg QD (n=167) 50 mg BID (n=168) 140 mg QD (n=167) 70 mg BID (n=168) 7-year final results After 2 years, protocol allowed switching from BID to QD dosing Primary endpoint: To compare the MCyR rates of dasatinib when administered QD vs BID after a minimum follow-up of 6 months rollment period: July 13, 2005 March 13, atients were stratified by imatinib resistance vs. imatinib intolerance.

50 Duration of Therapy atients in the 100 mg QD arm: Remained on assigned therapy longer compared to other dose groups Maintained their assigned dose in a greater proportion of patients (38%) fter 2 years: The majority of patients on BID dosing arms were switched to QD dosing 19% of patients in the 140 mg QD arm treated after amendment switched to 100 mg QD dosing by last recorded dose 100 mq QD (n=165) 140 mg QD (n=163) 50 mg BID (n=167) 70 mg BID (n=167) Total (n=662) Median duration, m years dasatinib, % ta are reported according to dose assigned at study entry.

51 Reason for Discontinuation Prior to Study Closure Dasatinib Dose 100 mg QD (n=166) Number of Treated Patients (%) 140 mg QD (n=163) 50 mg BID a (n=166) 70 mg BID (n=167) rotocol-defined rogression b 35 (21) 42 (26) 29 (17) 27 (16) tudy drug toxicity 39 (24) 45 (28) 45 (27) 51 (31) E unrelated to study drug 10 (6) 4 (3) 10 (6) 8 (5) vestigator request 12 (7) 6 (4) 7 (4) 5 (3) atient request 14 (9) 19 (12) 18 (11) 16 (10) ther 16 (10) 15 (9) 19 (11) 22 (13) The majority of patients classified as other continued to receive dasatinib eason for discontinuation was not reported in one patient in the 50 mg BID arm. rotocol-defined progression included increasing WBC count, loss of CHR or MCyR, 30% increase in Ph+ metaphases, or transformation AP/BP.

52 Safety Dasatinib Dose 100 mg QD (n=165) Number of Patients (%) Other Dose Groups (n=497) Total (n=662) ug-related AE 150 (91) 471 (95) 621 (94) rade 3 drug-related AE 75 (46) 281 (57) 356 (54) rious drug-related AE 43 (26) 173 (35) 216 (33) ug-related AE leading to scontinuation 34 (21) 130 (26) 164 (25) ath 51 (31) 133 (27) 184 (28) tudy drug toxicity a 1 (1) 2 (<1) 3 (<1) isease progression 28 (17) 54 (11) 82 (12) fety and tolerability were assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events v3.0. eaths due to study drug toxicity include 1 due to sepsis; 1 due to pulmonary edema, congestive heart failure, neck pain, and pleural effusion; ue to necrosis of the colon.

53 Cumulative Incidence Rate of All-Cause Nonhematologic AEs of Special Interest Hemorrhage Pleural effusion Diarrhea Nausea/vomiting Fatigue Myalgias/arthralgias 100 mg QD (Any grade) Other Dose Groups (Any grade) 100 mg QD (Grade 3) Other Dose Groups (Grade 3) Rash Patients, % For 100 mg QD, most nonhematologic AEs (all grades) first occurred within 24 months of treatment

54 Efficacy Results: Cumulative Incidence of MMR Over 7 years of follow-up, cumulative incidence of MMR was similar across dose groups 100 mg QD (n=167) 140 mg QD (n=167) 50 mg BID (n=168) 70 mg BID (n=168) sessed treated patients, n (%) 160 (96) 153 (92) 160 (95) 151 (90) R in assessed treated ients, n (%) 73 (46) 68 (44) 70 (44) 69 (46)

55 % Alive OS is Similar Across Dose Groups mg QD 140 mg QD 50 mg BID 70 mg BID Months % 70% 68% 65% Imatinib-resistant Patients Imatinib-intolerant Patients Overall S, % (95% CI) 63 (53 71) 70 (52 82) 65 (56 72) FS, % (95% CI) 39 (29 49) 51 (32 67) 42 (33 51)

56 % Alive nts sk OS by 3-Month BCR-ABL Level: 100 mg QD Unstratified Log Rank P-Value = Months % >10% % 56% BCR-ABL 10% at 3 months (60%) BCR-ABL >10% at 3 months (40%) S, % (95% CI) 72 (60 81) 56 (42 68) FS, % (95% CI) 56 (43 67) 21 (10 34)

57 Other results.

58 The Experience of the International Registry for CML in Children and Adolescents (I-CML-Ped Study): Pronostic Consideration A521 Results-1 N=278 Age, Median (yrs) < 4 yrs (%) 12.4 (9-17.5) 6 Sex - Female (%) 43 Phase at diagnosis (%) Chronic Accelerated Blastique Sokal risk score (%) Low Intermediate High Splenomegaly (%) Median spleen size (below costal margin) (cm) (1-25) Median leucocyte count (x10 9 /L) 235 (5-1038) Additional chromosomal abnormalities in Ph+ cells (% pts.) 6 Median follow-up (mo) 39 ( ) et al. The Experience of the International Registry for Chronic Myeloid Leukemia (CML) in Children and Adolescents (I-CML-Ped Study): ic Consideration.

59 A521 The Experience of the International Registry for CML in Children and Adolescents (I-CML-Ped Study): Pronostic Consideration Children and adolescents with CML presented with clinical and biological differences compared to adult patients N=278 Estimated overall survival at 60 months (%) 95% (95%CI 89-97) Cumulative incidence of CCyR 1 73% CCyR Predictive factors 2 CCyR Predictive factors 3 Eutos score Spleen size Hematocrit level Lymphocyte count Immature cells in peripheral blood Sokal and medullary blast count 1) 169 pts. with available evaluation, CCyR in ) In univariate analysis. 3) Multivariate analysis., et al. The Experience of the International Registry for Chronic Myeloid Leukemia (CML) in Children and Adolescents (I-CML-Ped Study): ic Consideration.

60 Impairment of Longitudinal Growth By Tyrosine Kinase Inhibitor (TKI) Treatment 60 Data from a Large Pediatric Cohort with Chronic Myeloid Leukemia (CML) A522 CP-CML pediatric cohort Imatinib upfront N=102 Age, Median (yrs) at imatinib initiation 12 (1-18) Prepubertal (< 10 yrs), n (%) 27 (26.4) Pubertal (age:10-14 yrs), n (%) 46 (45) Postpubertal (age > 14 yrs), n (%) 29 (28.4) Sex - Female (%) 47 Median duration of imatinib exposure (mo) 9 (0-98) All cohort Aim: To determine the impact of sex, age, and pubertal stage on impaired growth in a pediatric cohort CP-CML treated with imatinib up-front Retrospective German study Pubertal (age:10-14 yrs), n (%) SDS: Standard deviation scores Change of SDS height on therapy Decrease of 0.48 SDS per year during the first 3 years of therapy 0.75 SDS per year during the first 3 years of therapy et al. Impairment of Longitudinal Growth By Tyrosine Kinase Inhibitor (TKI) Treatment Data from a Large Pediatric ith Chronic Myeloid Leukemia (CML).

61 Impairment of Longitudinal Growth By Tyrosine Kinase Inhibitor (TKI) Treatment Data from a Large Pediatric Cohort with Chronic Myeloid Leukemia (CML) Changes in SDS body height analyzed at 3 months intervals during TKI therapy n=102 pts (age at diagnosis: 12 years, range: 1-18 years; 54 male, 48 female) Growth retardation is a significant adverse effect of IMA in children with CML affecting predominantly prepubertal children T, et al. Impairment of Longitudinal Growth By Tyrosine Kinase Inhibitor (TKI) Treatment Data from Pediatric Cohort with Chronic Myeloid Leukemia (CML).

62 Combination of ABL001 and Nilotinib prevents the emergence of resistance Tumor Volume (mm 3 ) T315I detected * * Tumor Volume (mm 3 ) A337V detected KCL-22 CML Xeno Each line represents individual animals Nilotinib (75mg/kg) BID ABL001 (30mg/kg) BID Nilotinib (75mg/kg) BID + ABL001 (30mg/kg) BID Dosing stopped on day 77, all mice remain disease free >176 days * t al. Blood. 2014:[abstract 398].

63