HOW I TREAT CML. 4. KONGRES HEMATOLOGOV IN TRANSFUZIOLOGOV SLOVENIJE Z MEDNARODNO UDELEŽBO Terme Olimia, Podčetrtek,

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1 HOW I TREAT CML 4. KONGRES HEMATOLOGOV IN TRANSFUZIOLOGOV SLOVENIJE Z MEDNARODNO UDELEŽBO Terme Olimia, Podčetrtek, april, 2012 Gianantonio Rosti Dpt of Hematology and Oncological Sciences S. Orsola-Malpighi University Hospital Bologna - Italy

2 European LeukemiaNet: Definitions of Response to Imatinib Overall Response Definitions for Patients With CML-CP Treated With Frontline Imatinib (First 18 Months) Time Optimal Suboptimal Failure Warnings Diagnosis High risk CCA in Ph+ 3 months CHR, > minor CyR No CyR No CHR N/A 6 months PCyR < PCyR No CyR N/A 12 months CCyR < CCyR (PCyR) < PCyR < MMR 18 months MMR < MMR < CCyR N/A Baccarani et al. J Clin Oncol. 2009;27:

3 European LeukemiaNet: Definitions of Response to Imatinib Overall Response Definitions for Patients With CML-CP Treated With Frontline Imatinib (First 18 Months) Here The Milestones, 2009 Time Optimal Suboptimal Failure Warnings High risk Diagnosis 1) Are they still valid? CCA in Ph+ CHR, 3 months 2) Which No CyR No CHR N/A > minor CyR drug first? 6 months PCyR < PCyR No CyR N/A 3) How to monitor < CCyR response? 12 months CCyR < PCyR < MMR (PCyR) 18 months MMR < MMR < CCyR N/A 4) Is there anything appealing beyond the corner? Baccarani et al. J Clin Oncol. 2009;27:

4 European LeukemiaNet: Definitions of Response to Imatinib Overall Response Definitions for Patients With CML-CP Treated With Frontline Imatinib (First 18 Months) Time Optimal Suboptimal Failure Warnings Diagnosis High risk CCA in Ph+ 3 months CHR, > minor CyR No CyR No CHR N/A 6 months PCyR < PCyR No CyR N/A 12 months CCyR < CCyR (PCyR) < PCyR < MMR 18 months MMR < MMR < CCyR N/A Baccarani et al. J Clin Oncol. 2009;27:

5 % With MMR MMR by 3 Years According to Sokal Risk ENESTnd 3-Year Update P =.0264 P =.0020 P = n = Low Intermediate High Nilotinib 300 mg BID 5 Imatinib 400 mg QD Rates of MMR were consistently higher in patients treated with nilotinib vs imatinib across Low, Intermediate, or High Sokal risk scores Data cut-off: 27Jul2011. Saglio G, et al. Blood. 2011;118(21): [abstract 452].

6 Cytogenetics, (BM) MONITORING THE RESPONSE At 3 and 6 mo, then every 6 mo until a CCgR has been achieved and confirmed, then every 12 mo if a regular and reliable molecular monitoring cannot be assured * ELN, Baccarani et al, JCO 2009; 27:

7 European LeukemiaNet: Disease Monitoring and Definitions of Response Hematologic response (HR) Cytogenetic response (CyR) Molecular response (MR) Every 15 days until CHR Month 3 and 6 and every 6 months until CCyR Every 3 months until MMR Every 3 months thereafter Every year thereafter Every 4-6 months thereafter CCyR, complete cytogenetic response; CHR, complete hematologic response; CML, chronic myeloid leukemia; CP, chronic phase; MMR, major molecular response. 1. Gleevec (imatinib) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; Baccarani M, et al. J Clin Oncol. 2009;27:

8 559 Pts, Imatinib FL, Estimated OS, PFS, FFS, EFS Events Failures Progressions Deaths N GIMEMA, 2011 (data on file, unpublished) GIMEMA CML WP

9 2012: Key Objectives of Frontline Therapy Prevent Progression to AP/BP Maximize achievement of MMR MMR is the pre-requisite of CMR CMR is the basis of drug cessation Deininger et al. Blood. 2009;114. Abstract 1126.

10 Alive Following Progression, % % Alive Prevention of Progression Is the Goal of Therapy IRIS Estimated % alive at: months 43% months 30% Months Since AP/BC Treatment ENESTnd Progressed = 34 Died = 23 Alive = 11 Median survival 10.5 months Months Since Progression Novartis IRIS data on file. Saglio et al. Blood. 2011;118(21): [abstract 452].

11 GIMEMA Protocol CML 0307 Patients (18 Centres enrolled 1 pt between Jun 2007 and Feb 2008) N = 73 Age, years; median (range) 65 years or older 51 (18-83) 20 (27%) Relative Risk Low Intermediate High Variant Translocations CCA Ph+ Der(9) deletions Follow-up, months; median (range) Sokal Hasford 33 (45%) 29 (40%) 30 (41%) 43 (59%) 10 (14%) 1 (1%) 10 (14%) 3 (4%) 7 (10%) 38 (36-43) Rosti EHA 2011 GIMEMA CML WP

12 Study Design ENESTnd 3-Year Update N = centers 35 countries R A N D O M I Z E D * Nilotinib 300 mg BID (n = 282) Nilotinib 400 mg BID (n = 281) Imatinib 400 mg QD (n = 283) *Stratification by Sokal risk score Follow-up 5 years 12 Saglio G, et al. Blood. 2011;118(21): [abstract 452].

13 % With MMR Cumulative Incidence of MMR ENESTnd 3-Year Update n Nilotinib 300 mg BID Nilotinib 400 mg BID Imatinib 400 mg QD By 1 Year 55%, P < %, P <.0001 Δ 24%-28% By 3 Years 73%, P < %, P <.0001 Δ 17%-20% 53% % Months Since Randomization Data cut-off: 27Jul Saglio G, et al. Blood. 2011;118(21): [abstract 452].

14 Cumulative Incidence of MR 4* ENESTnd 3-Year Update Nilotinib 300 mg BID Nilotinib 400 mg BID Imatinib 400 mg QD n By 3 Years 50%, P < %, P <.0001 % With MR By 1 Year 20%, P < %, P =.0004 Δ 18%-24% 26% 10 Δ 9%-14% 0 6% Months Since Randomization * Equivalent to BCR-ABL transcript levels of 0.01% (IS). Data cut-off: 27Jul Saglio G, et al. Blood. 2011;118(21): [abstract 452].

15 GIMEMA Protocol CML 0307 Time to first CMR (CMR 4.0 : 0.01% BCR-ABL IS with 10,000 ABL transcripts ) 58% 72% 36% Rosti EHA 2011 GIMEMA CML WP

16 Cumulative Incidence of MR 4.5* n % With MR Nilotinib 300 mg BID Nilotinib 400 mg BID Imatinib 400 mg QD By 1 Year 11%, P < %, P <.0001 Δ 6%-10% By 3 Years 32%, P < %, P =.0003 Δ 13%-17% 15% 0 1% Months Since Randomization 36 * Equivalent to BCR-ABL transcript levels of % (IS). Data cut-off: 27Jul Saglio G, et al. Blood. 2011;118(21): [abstract 452].

Number of Patients, n Progression to AP/BC* on Core Treatment P =.0003 ENESTnd 3-Year Update P =.0059 P =.0185 12 P =.0085 17 2 3 0.7% 1.1% 4.2% 0.7% 1.8% 6.

17 Number of Patients, n Progression to AP/BC* on Core Treatment P =.0003 ENESTnd 3-Year Update P =.0059 P = P = % 1.1% 4.2% 0.7% 1.8% 6.0% Including Clonal Evolution Nilotinib 300 mg BID Nilotinib 400 mg BID Imatinib 400 mg QD No new progressions occurred on core treatment since the 2-year analysis * Progression to AP/BC or death following progression. Data cut-off: 27Jul Saglio G, et al. Blood. 2011;118(21): [abstract 452].

18 DASISION: First-Line Dasatinib vs Imatinib in CML-CP Transformation to Accelerated/Blast Phase (ITT) 20 Dasatinib 100 mg QD Imatinib 400 mg QD n % % 9 3.5% % 0 On study Including follow-up beyond discontinuation* 9 patients who achieved a CCyR transformed to AP/BP on study (3 dasatinib, 6 imatinib) No patient who achieved MMR transformed to AP/BP by data cut-off ELN 2006 criteria for transformation * Yearly evaluations after discontinuation are currently stipulated by the protocol; additional information on patient status may be provided by investigators at other times EHA

Study Drug-Related Adverse Events and Grade 3/4 Myelosuppression Fluid retention Diarrhea Headache Muscle cramps Rate difference (imatinib - nilotinib) with 95% CI Favors imatinib

20 Study Drug-Related Adverse Events and Grade 3/4 Myelosuppression Fluid retention Diarrhea Headache Muscle cramps Rate difference (imatinib - nilotinib) with 95% CI Favors imatinib Favors nilotinib (300 mg BID) Any grade Grade 3/4 Nausea Pruritus Rash Vomiting Anemia Neutropenia Thrombocytopenia Data cut-off: 20Aug2010.

21 Forest Plot Comparing Differences in AE Rates for Dasatinib and Imatinib Any grade Grade 3/4 Fluid retention Superficial edema Pleural effusion Myalgia Nausea Vomiting Diarrhea Fatigue Headache Rash Neutropenia Thrombocytopenia Anemia Rate Difference (dasatinib-imatinib) with 95% CI Favors dasatinib Favors imatinib

22 QOL in CML Patients (n. 456) Receiving Imatinib > 24 months with Compared with the General Population. Efficace et al, for GIMEMA Blood, 2011

23 Patient Disposition 23 Nilotinib 300 mg BID n = 282 Nilotinib 400 mg BID n = 281 Imatinib 400 mg QD n = 283 Still on active follow-up* or died, % Still on core treatment, % Discontinued core treatment and entered extension study, % Discontinued core treatment without entering extension study, % Disease progression < Suboptimal response / treatment failure Adverse events / lab abnormalities Death 1 < 1 < 1 Other reason * Patients are either on study drug or in follow-up after discontinuation of study drug. Patients with suboptimal response or treatment failure were allowed to discontinue core study and enter into extension study (allowed only for treatment failure in nilotinib 400 mg BID arm). Few patients discontinued treatment since the 2-year follow-up 4% on nilotinib 300 mg BID; 5% on nilotinib 400 mg BID; 6% on imatinib Data cut-off: 27Jul2011. Saglio G, et al. Blood. 2011;118(21): [abstract 452].

24 % of patients treated Laboratory Abnormalities Nilotinib 300 mg BID n = Nilotinib 400 mg BID n = 277 Imatinib 400 mg QD n = 280 All Grades Grade 3/4 All Grades Grade 3/4 All Grades Grade 3/4 Lipase Amylase 16 < ALT AST Total bilirubin < 1 Glucose Albumin Cholesterol < Phosphorous Alkaline phos < 1 Creatinine < 1 Calcium 3 < 1 5 < One patient in the imatinib arm and one in the nilotinib 400 mg BID arm discontinued the study due to acute pancreatitis Data cut-off: 2Jan2010

25 Discontinuation Due to Biochemical Adverse Events Number of patients Nilotinib 300 mg BID N = 279 Nilotinib 400 mg BID N = 277 Imatinib 400 mg QD N = 280 All Grade Grade 3/4 All Grade Grade 3/4 All Grade Grade 3/4 Transaminase and bilirubin increase Lipase increase Hyperglycemia Data cut-off: 20Aug2010

26 Sudden Deaths with Nilotinib is similar to that reported with other CML studies. TKI Study CML Patients n (%) Imatinib 0110 Late CP 3/532 (0.6%) 0109 AP 2/235 (0.9%) Dasatinib ODAC CP, AP, BC 3/511 (0.4%) Nilotinib 2101 All arms 5/940 (0.5%) 2101 CP & AP 2/447 (0.4%) 2109 CP, AP, BC 4/1100 (0.4%) FDA Data

27 Results: Change From Baseline in QTcF Over Time Mean change, ms (25 th 75 th percentiles) Nilotinib 300 mg BID n = 279 Nilotinib 400 mg BID n = 277 Imatinib 400 mg QD n = 280 Day 1 post-dose 4.9 ( ) 4.5 ( ) 0.8 ( ) Day 8 post-dose 6.8 ( ) 7.6 ( ) 3.1 ( ) Month 3 post-dose 10.4 ( ) 12.4 ( ) 7.3 ( ) Month 6 post-dose 7.9 ( ) 8.6 ( ) 4.7 ( ) Month 9 post-dose 8.6 ( ) 9.7 ( ) 6.2 ( ) Month 12 post-dose 5.8 ( ) 8.0 ( ) 5.1 ( ) The highest mean change from baseline in the QTcF interval was within 3 months of therapy in all 3 treatment arms There was no cumulative effect with increasing nilotinib treatment Larson RA, et al. Blood. 2010;116(21): [abstract 2291]. Data cut-off: 2Jan2010.

28 Results: Change From Baseline in LVEF (%) Over Time Mean change, % (25 th 75 th percentiles) Nilotinib 300 mg BID n = 279 Nilotinib 400 mg BID n = 277 Imatinib 400 mg QD n = 280 Month ( ) 0.89 ( ) 0.80 ( ) Month ( ) 1.19 ( ) 1.24 ( ) Month ( ) 1.31 ( ) 1.31 ( ) No decrease from baseline in mean LVEF anytime during treatment in any arm No patient in any arm with a LVEF < 45% during treatment No patient in any arm with an absolute reduction in LVEF of more than 15% No patient discontinued study due to LVEF changes Larson RA, et al. Blood. 2010;116(21): [abstract 2291]. Data cut-off: 2Jan2010.

29 GCT9310 Current European LeukemiaNet recommendations based on imatinib therapy define optimal response as 1 : Baseline Optimal Response NA 3 Months Complete hematologic response and at least minor cytogenetic response (Ph+ 65%) Are Goals of Therapy Changing? 6 Months At least partial cytogenetic response (Ph+ 35%) 12 Months Complete cytogenetic response (CCyR) 18 Months Major molecular response (MMR) a Any time Stable or improving MMR a a MMR indicates a ratio of BCR-ABL1 to ABL1 or other housekeeping genes of 0.1% on the international scale. With frontline nilotinib therapy: By 18 months, CCyR was achieved by 82%-85% of patients and MMR by 57%-66% of patients 2 By 3 years, MR 4 was achieved by 44%-50% of patients 3 1. Baccarani M, et al. J Clin Oncol. 2009;27(35): Hochhaus A, et al. Haematologica. 2010;95(s2):459 [abstract 1113]. 3.Saglio G, et al. Blood. 2011;118(21): [abstract 452]. 29

30 Criteria for Failure and Suboptimal Response to Imatinib Time (mo) 3 No CHR 6 Response Failure Suboptimal Optimal No CHR >95% Ph+ No CG Response <65% Ph+ 35% Ph+ 35% Ph % Ph+ 1-35% Ph+ 0% Ph+ 18 5% Ph+ No MMR MMR Any Loss of CHR Loss of CCgR Mutation CE Loss of MMR Mutation Stable or improving MMR Baccarani et al. JCO 2009; 27:

31 Criteria for Failure and Suboptimal Response to Imatinib Time (mo) 3 No CHR 6 Response Failure Suboptimal Optimal No CHR >95% Ph+ No CG Response <65% Ph+ 35% Ph+ 35% Ph % Ph+ 1-35% Ph+ 0% Ph+ 18 5% Ph+ No MMR MMR Any Loss of CHR Loss of CCgR Mutation CE Loss of MMR Mutation Stable or improving MMR Baccarani et al. JCO 2009; 27:

32 Criteria for Failure and Suboptimal Response to Imatinib Time (mo) 3 6 Response Failure Suboptimal Optimal No CG Response No CHR >35% Ph+ <65% Ph+ 35% Ph % Ph+ 0% Ph+ 18 5% Ph+ No MMR MMR Any Loss of CHR Loss of CCgR Mutation CE Loss of MMR Mutation Stable or improving MMR Baccarani et al. XXX, 2013

Treatment failure (%) Cumulative incidence of treatment failure according to BCR-ABL IS after 6 months BCR ABL IS < 1% (n = 426) BCR-ABL IS 1% and < 10% (n = 121) BCR-ABL IS 10% (n = 73) p=0.

33 Treatment failure (%) Cumulative incidence of treatment failure according to BCR-ABL IS after 6 months BCR ABL IS < 1% (n = 426) BCR-ABL IS 1% and < 10% (n = 121) BCR-ABL IS 10% (n = 73) p= total: n = p< months Less than PCgR (Ph+ >35%) 4 after 18 months Less than CCgR (Ph+ >0%) Hanfstein B, et al. ASH Annual Meeting 2010: Oral Presentation after 18 months Loss of CCgR and PCgR

34 Optimal Response To 2 nd TKIs-Frontline. Event-free by 3 mo Response Jabbour E et al. JCO

35 Probability of PFS Survival Probability Early and Deep Responses Are Predictive of Patient Outcomes GCT Progression-Free Survival (PFS) BCR-ABL IS at 3 Months 10% vs > 10% BCR-ABL IS n 5-y PFS 10% % P =.003 > 10% % Years After Diagnosis 10% > 10% Overall Survival (OS) BCR-ABL IS at 3 Months 10% vs > 10% BCR-ABL IS n 5-y OS 10% % P <.001 > 10% % Years After Diagnosis 10% > 10% Molecular and cytogenetic response after 3 months of imatinib treatment were predictive for the risk of disease progression and death in patients with newly diagnosed CML-CP in the CML IV study 1 Others studies have also shown the importance of month 3 as a response predictor Hanfstein B, et al. Blood. 2011;118(21): [abstract 783]. 2. Hochhaus A, et al. Blood. 2011;118(21): [abstract 2767]. 3. Marin D, et al. Blood. 2011;118(21):357 [abstract 785]. 4. Marin D, et al. J Clin Oncol. Epub ahead of print Nov 7,

36 % With MMR MMR by 3 Years According to Sokal Risk ENESTnd 3-Year Update P =.0264 P =.0020 P = n = Low Intermediate High Nilotinib 300 mg BID 36 Imatinib 400 mg QD Rates of MMR were consistently higher in patients treated with nilotinib vs imatinib across Low, Intermediate, or High Sokal risk scores Data cut-off: 27Jul2011. Saglio G, et al. Blood. 2011;118(21): [abstract 452].

37 % With MR MR 4.5 by 3 Years According to Sokal Risk Low Intermediate High Nilotinib 300 mg BID Imatinib 400 mg QD Rates of MR 4.5 were consistently higher in patients treated with nilotinib vs imatinib across Low, Intermediate, or High Sokal risk scores Data cut-off: 27Jul2011. P =.0468 n = P =.0003 P =.0099 Saglio G, et al. Blood. 2011;118(21): [abstract 452]. 9

% With MMR Cumulative Incidence of MMR ENESTnd 3-Year Update n 100 90 80 70 60 50 40 Nilotinib 300 mg BID Nilotinib 400 mg BID Imatinib 400 mg QD 282 281 283 By 1 Year 55%, P <.0001 51%, P <.

38 % With MMR Cumulative Incidence of MMR ENESTnd 3-Year Update n Nilotinib 300 mg BID Nilotinib 400 mg BID Imatinib 400 mg QD By 1 Year 55%, P < %, P <.0001 Δ 24%-28% By 3 Years 73%, P < %, P <.0001 Δ 17%-20% 53% % Months Since Randomization Data cut-off: 27Jul Saglio G, et al. Blood. 2011;118(21): [abstract 452].

39 Summary of Patients With Progression to AP/BC Nilotinib 300 mg BID Nilotinib 400 mg BID Imatinib 400 mg QD n Patients with mutations Secondary resistance Sokal, High Risk Sokal, Intermediate PD within 6 months PD within 6-12 months IM dose reduction (n) IM dose escalation (n) Dose Interruption (n) ENESTnd, ata cut-off: 2Sept2009

40 % With MMR MMR by 3 Years According to Sokal Risk ENESTnd 3-Year Update P =.0264 P =.0020 P = n = Low Intermediate High Nilotinib 300 mg BID 40 Imatinib 400 mg QD Rates of MMR were consistently higher in patients treated with nilotinib vs imatinib across Low, Intermediate, or High Sokal risk scores Data cut-off: 27Jul2011. Saglio G, et al. Blood. 2011;118(21): [abstract 452].

41 2012: Key Objectives of Frontline Therapy Prevent Progression to ABP Maximize achievement of MMR MMR is the pre-requisite of CMR CMR is the basis of drug cessation

42 Correlation Between Response and Disease Burden: Molecular Response BCR-ABL Transcripts (log10) Number of Leukemic Cells CHR (< 1-log) Hematologic Cytogenetics CCyR (2-log) MMR (3-log) RQ-PCR 10 7 ~5 log reduction 10 6 Baccarani M, et al. J Clin Oncol. 2009;27(35): Radich JP. Blood. 2009;114: Dx Months on Treatment Time

43 Phase 2 and 3 Trial CMR 4.5 Rates* at 18 mos Data from different trials 1-4 Phase 3* % 21% 2 1 6% 7% Phase 2 # 3 4 9% 20% * For phase 3 studies, results based on best cumulative responses with median follow-up of 18 months (ITT population). # For phase 2 studies, based on responses in evaluable patients at the given time point 1. Hughes T. et al. Blood (ASH Annual Meeting Abstracts), Nov 2010; 116: Shah N. et al. Blood (ASH Annual Meeting Abstracts), Nov 2010; 116: Cortes JE. et al. J Clin Oncol Jan 20;28(3): Cortes JE. et al. J Clin Oncol Jan 20;28(3):

44 STIM Study: Discontinuation of Therapy A select subset of patients who achieved CMR with imatinib therapy were able to discontinue therapy CMR, complete molecular response; STIM, stop imatinib. 1. Mahon FX, et al. Lancet Oncol. 2010; 11:

45 Design of EURO-SKI 45 TKI treatment at least 3 years CMR (MR 4 ) at least 1 year Screening phase (Confirming MR 4 ) QPCR QPCR q4w q6w every 3 months every 3 months Year 1 Year 2 Year 3 STOP Stop TKI (Restart TKI at molecular relapse)

2nd generation TKIs to first line therapy

New Horizons 2011 Newly diagnosed CML moving 2nd generation TKIs to first line therapy Gianantonio Rosti Dept. Of Hematology and Oncology St. Orsola-Malpighi University Hospital Bologna (Italy) GIMEMA