IRIS 8-Year Update. Management of TKI Resistance Will KD mutations matter? Sustained CCyR on study. 37% Unacceptable Outcome 17% 53% 15%

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1 Management of TKI Resistance Will KD mutations matter? IRIS 8-Year Update 17% 53% 5% 15% 37% Unacceptable Outcome No CCyR Lost CCyR CCyR Other 3% 7% Safety Lost-regained CCyR Sustained CCyR on study Deininger et al; Blood 2009; 114: Abst#

2 IRIS. Survival Without AP/BC Worse If No Major CG Response at 12 mos without AP/BC % Rx aim: major CG response (Ph 35%) Response at 12 months Estimated rate at 60 months 30 CCyR 20 PCyR 10 No MCyR Months since randomization n= % n= 86 93% p<0.001 p=0.20 n= 73 81% IRIS. Survival Without AP/BC Worse If No CGCR In Year 2 But Not Related To MMR % without AP/BC Rx aim: CGCR in Year 2+; no need for MMR Response at 18 months CCyR with >=3 log red. CCyR with <3 log red. No CCyR Estimated rate at 60 months n= % n= 54 98% n= 89 87% p< Months since randomization p=0.11 2

3 CML. Criteria For Failure On Imatinib No CG response at 6 mos (Ph 100%) No major CG response at 12 mos (Ph>35%) No CGCR in Year 2+ CG relapse or hematologic relapse Not failure criteria - suboptimal CG response (most common reason for imatinib dose escalation in practice; no practice guideline for this) - QPCR in CGCR Baccarani et al. JCO 2009; 27: Criteria for Failure and Suboptimal Response to Imatinib Time (mo) 3 No CHR Response Failure Suboptimal Optimal No CG Response < 65% Ph+ 6 No CHR >95% 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. JCO 2009; 27:

4 Criteria for Failure and Suboptimal Response to Imatinib Time (mo) 3 No CHR Response Failure Suboptimal Optimal No CG Response <65% Ph+ 6 No CHR >95% 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. JCO 2009; 27: Suboptimal Response to Imatinib 400 mg/d in CP CML: GIMEMA CML WP Analysis of 423 Consecutive Patients 98% 98% 55% 63% p< p< % 33% p< % 51% p< Castagnetti. Hematologica 2009;94 abstract

5 EFS by Response to IM at 6 and 12 Mos 281 pts; imatinib frontline (400mg in 73, 800mg in 208) Suboptimal response at 6-12 months: 12-17% with 400mg, 1-4% with 800mg (p=0.002) month response month response No. Events (%) Failure 9 6 (67) 0.1 Suboptimal 10 5 (50) p< Optimal (6) Months 0.2 No. Evaluable (%) Failure 14 8 (57) 0.1 Suboptimal 19 3 (16) p< Optimal (4) Months Alvarado. Cancer. 2009;115: Outcome by 12-Month Response in CML CP 848 pts randomized to IM 400mg, IM 800mg, or IM IFN Median FU: 40 months 12-month BCR-ABL/ABL (IS) N Percentage PFS OS <0.1% CCyR 011% 0.1-1% >1% P value Outcome independent of treatment arm Hehlman et al. JCO 2011;29:

6 MDACC Retrospective Analysis: MCyR at 6 Months Associated With OS 1.0 Landmark analysis at 6 mos Proportion alive Cytogenetic response at 6 mos Total Dead P-value Complete Partial Minor Others a Months Patients with MCyR have better OS than patients that do not Kantarjian H. Cancer. 2008;112: MDACC Retrospective Analysis: CCyR at 12 Months Associated With PFS 1.0 Landmark analysis at 12 mos 0.8 Proportion PFS Cytogenetic response at 12 mos Total Failure P-value Complete Partial Minor 5 2 Others Months Patients with CCyR have better PFS than patients that do not. Similar results were observed in patients achieving CCyR at 18 and 24 mos. Kantarjian H. Cancer. 2008;112:

7 EFS and Survival by 12-month Response- CCyR vs Others with TKI Frontline Rx Jabbour E et al. Blood EFS and Survival by 12-month Response-CCyR with vs without MMR with TKI Frontline Rx Jabbour E et al. Blood

8 Hammersmith Experience. CCyR at 12 Months Associated With PFS Landmark analysis at 12 mos bability of PFS a % P = % Pro CCyR at 12 mos (n = 121) No CCyR at 12 mos (n = 72) Months de Lavallade. J Clin Oncol. 2008;26(20): Survival After Imatinib Therapy by Molecular Response Achieved at 3 Months Optimal PCR value determined by Receiver operating characteristic (ROC) curve Prob bability of survival BCR-ABL/ABL<9.8% OS= 93.3% BCR-ABL/ABL>9.8% OS= 54% p< Time from onset of imatinib therapy (years) Marin et al, JCO 2011; [Epub ahead of print] 8

9 CML IV: Long-Term Impact of Response at 3 Months 1223 pts randomized to imatinib 400, imatinib + IFN, imatinib + ara-c, imatinib month analysis: PCR in 692 pts, cytogenetics ti in mo transcript levels predictive of achievement of CCyR and MMR Cytogenetics Molecular % 5-year (% Ph+) [BCR-ABL/ABL (IS)] outcome 35% >35% 10% >10% PFS OS Hanfstein et al. ASH 2011; Abstract #783 CML. Criteria For Failure On Imatinib No major CG response at 6 mos (Ph 100%) (Ph > 35%) No major CG CR at 12 mos No CGCR in Year 2+ CG relapse or hematologic relapse Not failure criteria - suboptimal CG response - QPCR in CGCR Baccarani. Blood 108: ,

10 Failure On Imatinib And Strategies Imatinib Failure Imatinib Second Generation TKI Ph 100% at 6 mos _ + Ph 35% at 12 mos + + No CGCR in yr CG relapse + + Hematologic _ + relapse Imatinib Dose Escalations % 2-yr Resistance 1,2 No. %CGCR CR TFS OS Cytogenetic Hematologic Similar results from IRIS 3 1 Kantarjian Blood 101:473, Jabbour Blood 113:2154, Kantarjian Cancer 115:551,

11 When Does Imatinib Dose Escalation Work? CG relapse - imatinib associated with CGCR in 50%; durable at 2 yrs 85% Hematologic relapse only transient responses BUT results of new TKIs better in CG relapse vs hematologic relapse Response Phase II Studies of Dasatinib After Imatinib Failure Percent by Disease Stage CP AP MyBP LyBP ALL n=387 n=174 n=109 n=48 n=46 Hematologic CHR NEL Cytogenetic Complete Partial Blood 110:abst 470 and 734,

12 Optimal Dose and Schedule of Dasatinib IN CML CP after Imatinib Failure 100mg QD 50mg BID 140mg QD 70mg BID % Parameter N=166 N=166 N=163 N=167 MCyR CGCR months PFS Neutropenia, G Thrombocytopenia, G Pleural effusion, G Interruption Reduction Baccarani. Blood 112:abst 450, 2008 Better Outcome on Dasatinib with Earlier Intervention Patients on dasatinib studies analyzed by failure status on imatinib: loss of MCyR vs loss of CHR Status at IM Failure No. Percentage CCyR MMR Loss of MCyR Loss of CHR & MCyR Loss of CHR (never MCyR) Quintás-Cardama. Cancer 115: ,

13 Dasatinib Early Intervention EFS & OS Event-Free Survival Overall Survival Time to intervene: Loss of MCyR Quintás-Cardama. Cancer 115: , 2009 Nilotinib in Chronic Phase CML Post Imatinib Failure 321 pts; nilotinib 400 mg BID; median FU 19 mos; median nilotinib ib 788 mg/d; median days off 20 Outcome Percent -CGCR 46 - MMR 28 (56% of CGCR) - 24-mos PFS mos OS 87 Kantarjian. Blood 114:abst 1129;

14 Nilotinib in CML Chronic Phase. % Major CG Response by Status at Start 100 Patients, % n All Baseline CHR No Baseline CHR Kantarjian. Blood 112:abst 3238, Phase II Studies of Nilotinib After Imatinib Failure Percentage CP AP MyBP LyBP Response n =321 n =137 n =106 n =30 HR CHR Cytogenetic Major Complete Blood 112:abst 3229, 3238,

15 Bosutinib (SKI 606) in CML and Ph+ ALL Src-Abl inhibitor 30x more potent than IM No inhibition of PDGFR, c-kit 321 CP pts; median time from Dx 52 mos Bosutinib mg/d; Phase II 500 mg/d Median follow-up 7 months Response (%) in CP, prior imatinib only (N=102) Resistant N=69 Intolerant N=33 CHR MCyR CCyR MMR CMR G 3-4 toxicity: thrombocytopenia 21%, neutropenia 12%, diarrhea 8%, rash 7%, Cortes. Blood 112:abst 1098, 2008 Spectrum and frequency of BCR-ABL KD mutations recovered after TKI therapy Imatinib Dasatinib Nilotinib % G250E Y253F/H E255G/K V299L F311I/L T315I F317L/V M351T E355G/A F359C/V H396P/R BCR/ABL Mutation Cortes. Blood 110:4005,

16 Prognosis with 2 nd TKIs. Survival 16

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