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# 1126 1
IRIS. Survival Without AP/BC Worse If No Major CG Response at 12 mos without AP/BC % 100 90 80 70 60 Rx aim: major CG response (Ph 35%) 50 40 Response at 12 months Estimated rate at 60 months 30 CCyR 20 PCyR 10 No MCyR 0 0 6 12 18 24 30 36 42 48 54 60 663 Months since randomization n= 350 97% 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 100 90 80 70 60 50 40 30 20 10 0 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= 139 100% n= 54 98% n= 89 87% p<0.001 0 6 12 18 24 30 36 42 48 54 60 66 Months since randomization p=0.11 2
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: 6041-51 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+ 12 35% 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: 6041-51 3
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+ 12 35% 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: 6041-51 Suboptimal Response to Imatinib 400 mg/d in CP CML: GIMEMA CML WP Analysis of 423 Consecutive Patients 98% 98% 55% 63% p<0.0001 p<0.0001 79% 33% p<0.0001 85% 51% p<0.0001 Castagnetti. Hematologica 2009;94 abstract 0528 4
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) 1.0 1.0 0.9 0.9 0.8 0.8 0.7 0.6 0.5 0.7 6 month response 0.6 12 month response 0.5 0.4 0.4 0.3 0.3 0.2 No. Events (%) Failure 9 6 (67) 0.1 Suboptimal 10 5 (50) p<0.0001 Optimal 240 14 (6) 0.0 0 12 24 36 48 60 72 Months 0.2 No. Evaluable (%) Failure 14 8 (57) 0.1 Suboptimal 19 3 (16) p<0.0001 Optimal 213 8 (4) 0.0 0 12 24 36 48 60 72 Months Alvarado. Cancer. 2009;115:3709-18. Outcome by 12-Month Response in CML CP 848 pts randomized to IM 400mg, IM 800mg, or IM 400 + IFN Median FU: 40 months 12-month BCR-ABL/ABL (IS) N Percentage PFS OS <0.1% 341 99 99 CCyR 011% 0.1-1% 240 97 98 >1% 267 94 93 P value 0.0023 0.0011 Outcome independent of treatment arm Hehlman et al. JCO 2011;29:1634-42 5
MDACC Retrospective Analysis: MCyR at 6 Months Associated With OS 1.0 Landmark analysis at 6 mos Proportion alive 0.8 0.6 0.4 Cytogenetic response at 6 mos Total Dead P-value Complete 201 5 0.85 02 0.2 Partial Minor 39 10 1 3 001 0.01 0.62 Others a 9 3 0 0 12 24 36 48 60 72 Months Patients with MCyR have better OS than patients that do not Kantarjian H. Cancer. 2008;112:837 845. MDACC Retrospective Analysis: CCyR at 12 Months Associated With PFS 1.0 Landmark analysis at 12 mos 0.8 Proportion PFS 0.6 0.4 02 0.2 0 Cytogenetic response at 12 mos Total Failure P-value Complete 214 7 0.02 Partial 19 3 0.2 Minor 5 2 Others 8 5 0.22 0 12 24 36 48 60 72 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;112:837 845. 6
EFS and Survival by 12-month Response- CCyR vs Others with TKI Frontline Rx Jabbour E et al. Blood. 2011. EFS and Survival by 12-month Response-CCyR with vs without MMR with TKI Frontline Rx Jabbour E et al. Blood. 2011. 7
Hammersmith Experience. CCyR at 12 Months Associated With PFS Landmark analysis at 12 mos bability of PFS a 1.0 0.8 0.6 0.4 96% P =.007 74% Pro 0.2 0 CCyR at 12 mos (n = 121) No CCyR at 12 mos (n = 72) 0 12 24 36 48 60 Months de Lavallade. J Clin Oncol. 2008;26(20):3358-3363. 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<0.0001 Time from onset of imatinib therapy (years) Marin et al, JCO 2011; [Epub ahead of print] 8
CML IV: Long-Term Impact of Response at 3 Months 1223 pts randomized to imatinib 400, imatinib + IFN, imatinib + ara-c, imatinib 800 33 month analysis: PCR in 692 pts, cytogenetics ti in 460 3 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 94 87 93 87 OS 95 87 95 87 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 108:1809-20, 2006 18 9
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 2 + + CG relapse + + Hematologic _ + relapse Imatinib Dose Escalations % 2-yr Resistance 1,2 No. %CGCR CR TFS OS Cytogenetic 63 52 80 90 Hematologic 21 5 51 67 Similar results from IRIS 3 1 Kantarjian Blood 101:473, 2003 2 Jabbour Blood 113:2154, 2008 3 Kantarjian Cancer 115:551, 2008 10
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 91 64 50 39 49 CHR 91 50 26 29 35 NEL - 14 7 6 7 Cytogenetic 62 40 47 58 62 Complete 53 33 27 46 54 Partial 9 7 7 6 2 Blood 110:abst 470 and 734, 2007. 11
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 63 61 63 61 CGCR 50 50 50 54 24-months PFS 80 76 75 76 Neutropenia, G3-4 35 47 44 45 Thrombocytopenia, G3-4 23 36 41 38 Pleural effusion, G3-4 2 4 5 5 Interruption 58 66 69 71 Reduction 33 45 54 57 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 151 72 60 Loss of CHR & MCyR 33 42 29 Loss of CHR (never MCyR) 109 26 26 Quintás-Cardama. Cancer 115: 2912-21, 2009 12
Dasatinib Early Intervention EFS & OS Event-Free Survival Overall Survival Time to intervene: Loss of MCyR Quintás-Cardama. Cancer 115: 2912-21, 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 64-24-mos OS 87 Kantarjian. Blood 114:abst 1129; 2009 13
Nilotinib in CML Chronic Phase. % Major CG Response by Status at Start 100 Patients, % 80 60 40 59 73 51 20 n 0 321 114 207 All Baseline CHR No Baseline CHR Kantarjian. Blood 112:abst 3238, 2008. Phase II Studies of Nilotinib After Imatinib Failure Percentage CP AP MyBP LyBP Response n =321 n =137 n =106 n =30 HR 77 54 24 20 CHR 76 26 12 13 Cytogenetic Major 59 31 38 50 Complete 44 19 28 33 Blood 112:abst 3229, 3238, 2008. 14
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 400-600 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 81 82 MCyR 45 51 CCyR 32 40 MMR 42 39 CMR 22 32 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 20 15 Imatinib Dasatinib Nilotinib % 10 5 0 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, 2007 15
Prognosis with 2 nd TKIs. Survival 16