Chronic Myeloid Leukemia: Treatment Success and Milestones Elias Jabbour, MD

Are Surrogate Endpoints Predictive of Outcome in CML? 12-mo CCyR on IFN Rx associated with better EFS and survival 12-mo CCyR on imatinib Rx associated with better EFS and survival 12-mo MMR on imatinib Rx associated with better EFS and (?) survival Early CCyR (3 and 6-mo) on 2nd TKI Rx associated with better EFS

Results with Imatinib in Early CP CML – The IRIS Trial at 8-Years 304 (55%) patients on imatinib on study Projected results at 8 years: CCyR 83% 82 (18%) lost CCyR, 15 (3%) progressed to AP/BP Event-free survival 81% Transformation-free survival 92% If MMR at 12 mo: 100% Survival 85% (93% CML-related) Annual rate of transformation: 1.5%, 2.8%, 1.8%, 0.9%, 0.5%, 0%, 0%, & 0.4% Deininger. Blood 114:1126; 2009

IRIS. Survival Without AP/BC Worse If No Major CG Response at 12 mos Rx aim: major CG response (Ph ≤ 35%) Response at 12 months Estimated rate at 60 months   CCyR n= 350 97% p=0.20 PCyR n= 86 93% p<0.001 n= 73 81% No MCyR 4 4

IRIS. Survival Without AP/BC Worse If No CGCR In Year 2 But Not Related To MMR Rx aim: CGCR in Year 2+; no need for MMR Response at 18 months Estimated rate at 60 months n= 139 100% n= 54 98% n= 89 87% CCyR with >=3 log red. p=0.11 CCyR with <3 log red. p<0.001 No CCyR 5

Long-Term Outcome With Imatinib in ECP CML (ITT) Probability 1.0 0.8 0.6 0.4 0.2 0.1 0.9 0.7 0.5 0.3 60 54 48 12 6 Time From Start of Imatinib Therapy (months) 42 36 30 24 18 Survival PFS EFS CHR Loss of MCyR 63% (88% per IRIS definition) EFS: death, progression to AP/BP, loss of CHR, loss of MCyR, or  WBC, failure to achieve MCyR, intolerance de Lavallade H et al. J Clin Oncol. 2008; 26:3358-3363 6

MDACC Retrospective Analysis: MCyR at 6 Months Associated With OS Landmark analysis at 6 mos 1.0 0.8 0.6 0.4 0.2 Proportion alive Cytogenetic response at 6 mos Total Dead P-value Complete 201 5 Partial 39 1 Minor 10 3 Othersa 9 0.85 0.01 0.62 0 12 24 36 48 60 72 Months Patients with MCyR have better OS than patients that do not Kantarjian H et al. Cancer. 2008;112:837–845.

MDACC Retrospective Analysis: CCyR at 12 Months Associated With PFS Landmark analysis at 12 mos 1.0 0.8 0.6 0.4 0.2 Proportion PFS Cytogenetic response at 12 mos Total Failure P-value Complete 214 7 Partial 19 3 Minor 5 2 Others 8 0.02 0.2 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 et al. Cancer. 2008;112:837–845.

Suboptimal Response to Imatinib 400 mg/d in CP CML: GIMEMA CML WP Analysis of 423 Consecutive Patients The data shown on this slide highlight the relationship between the degree of early cytogenetic response and prognostic outcomes. For example, for patients with suboptimal cryptogenic response at 6 months of imatinib treatment, the probability of achieving event-free survival at 4 years is less than 35% compared to almost 80% in those who achieve early CCR. Reference: Castagnetti F, Gugliotta G, Breccia M et al. Suboptimal response to imatinib 400mg daily for chronic myeloid leukemia in early chronic phase: A GIMEMA CML WP analysis of 423 consecutive patients. Haematologica 2009; 94[suppl.2]:255 abstract 0628. Castagnetti. Hematologica 2009;94 abstract 0528 9

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) 6 month response 12 month response Alvarado. Cancer. 2009;115:3709-18.

EFS and Survival by 12-month Response- CCyR vs Others with TKI Frontline Rx Jabbour. Blood. 2011;118:4541-6.

EFS and Survival by 12-month Response-CCyR with vs without MMR with TKI Frontline Rx Jabbour. Blood. 2011;118:4541-6.

Hammersmith Experience. CCyR at 12 Months Associated With PFS Landmark analysis at 12 mos 1.0 96% 74% P = .007 0.8 0.6 Probability of PFSa 0.4 0.2 CCyR at 12 mos (n = 121) No CCyR at 12 mos (n = 72) 12 24 36 48 60 Months de Lavallade. J Clin Oncol. 2008;26(20):3358-3363.

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 0.1-1% 240 97 98 >1% 267 94 93 P value 0.0023 0.0011 Outcome independent of treatment arm CCyR Hehlman et al. JCO 2011;29:1634-42

CML IV: Long-Term Impact of Response at 3 Months 1223 pts randomized to imatinib 400, imatinib + IFN, imatinib + ara-C, imatinib 800 3 month analysis: PCR in 692 pts, cytogenetics in 460 3 mo transcript levels predictive of achievement of CCyR and MMR % 5-year outcome Cytogenetics (% Ph+) Molecular [BCR-ABL/ABL (IS)] ≤35% >35% ≤10% >10% PFS 94 87 93 OS 95 Hanfstein et al. ASH 2011; Abstract #783

Optimal Response To 2nd TKIs-Frontline. Response (N=167) Months on therapy Response Total (%) 3 (N=160) Optimal 160 (100) Sub-optimal Failure 6 (N=155) 152 (98) 3 (2) 12 (N=129) 128 (99) 1 (1) 18 (n=119) 99 (84) 14 (12) 5 (4) In summary, the outcome of patients with CML in chronic phase post imatinib failure treated with second generation TKIs is mainly dependent on the previous cytogenetic response to imatinib therapy and performance status. Patients with poor performance status and no previous cytogenetic response to imatinib therapy have a low likelihood of responding to second generation TKI with poor event-free survival, and therefore should be offered additional treatment options. The achievement of a 12-month MCyR after therapy with second generation TKI may compensate for the presence of one or two unfavorable baseline factors. Thank you for your attention Median follow-up 33 months (range, 3 to 66 months) Jabbour E et al. JCO. 2011.

Optimal Response To 2nd TKIs-Frontline. Event-free by 3 mo Response Jabbour E et al. JCO. 2011.

Optimal Response To 2nd TKIs-Frontline. Event-free by 6 mo Response Jabbour E et al. JCO. 2011.

Molecular and Cytogenetic Response at 3 Months Dasatinib 100 mg QD 84% 81% Imatinib 400 mg QD 64% PCyR 67% >1-10% % of patients PCyR >1-10% CCyR ≤1% CCyR ≤1% n//N 198/235 154/239 171/210 148/221 ≤10% BCR-ABL at 3 Months PCyR/CCyR at 3 Months BCR-ABL of <10% and ≤1% are not fully concordant with ≥PCyR and CCyR, respectively 96% and 83% of dasatinib and imatinib pts with ≥PCyR had <10% BCR-ABL, respectively 68% and 26% of dasatinib and imatinib pts with CCyR had ≤1% BCR-ABL, respectively Jabbour E et al. EHA. 2012.

PFS According to Cytogenetic Response at 3 Months Dasatinib 100 mg QD 81% of patients had PCyR/CCyR Imatinib 400 mg QD 67% of patients had PCyR/CCyR 100 80 60 40 20 6 12 24 36 42 100 80 60 40 20 6 12 24 36 42 P<0.0026 P<0.0001 % Not Progressed PCyR CCyR P=0.2185 PCyR CCyR P=0.8062 CCyR, N=139 CCyR, N=79 PCyR, N=31 PCyR, N=68 <PCyR, N=39 < PCyR, N=73 Months Months For ≥PCyR vs <PCyR at 3 months 3-year PFS rates were 93.9% vs 71.3% For ≥PCyR vs <PCyR at 3 months 3-year PFS rates were 93.7% vs 77.3% Jabbour E et al. EHA. 2012.

PFS According to Response at 12 Months Dasatinib 100 mg QD Imatinib 400 mg QD 100 80 60 40 20 6 12 24 36 42 100 80 60 40 20 6 12 24 36 42 MMR and/or CCyR <CCyR P<0.0001 MMR and/or CCyR <CCyR P<0.0001 % Not Progressed MMR, N=95 MMR, N=64 CCyR (no MMR), N=85 CCyR (no MMR), N=87 <CCyR, N=26 <CCyR, N=50 Months Months Jabbour E et al. EHA. 2012.

OS According to Response at 12 Months Dasatinib 100 mg QD Imatinib 400 mg QD 100 80 60 40 20 6 12 24 36 42 100 80 60 40 20 6 12 24 36 42 MMR and/or CCyR <CCyR P=0.0503 MMR and/or CCyR <CCyR P=0.0041 % Alive MMR, N=95 MMR, N=64 CCyR (no MMR), N=86 CCyR (no MMR), N=89 <CCyR, N=28 < CCyR, N=52 Months Months Jabbour E et al. EHA. 2012.

TKI Frontline Therapy in CML EFS and OS by CG Response AT 3 Mo Event-Free Survival Overall Survival EFS by PCR 3 month response P=0.003

TKI Frontline Therapy in CML EFS and OS by CG Response AT 6 Mo Event-Free Survival Overall Survival EFS by PCR 3 month response P=0.003

TKI Frontline Therapy in CML EFS and OS by MCyR AT 6 Mo Event-Free Survival Overall Survival

TKI Frontline Therapy in CML EFS and OS by CG Response AT 12 Mo Event-Free Survival Overall Survival

TKI Frontline Therapy in CML EFS and OS by MCyR AT 12 Mo Event-Free Survival Overall Survival EFS by CG 12 month response P=0.009 OS by CG 12 month response P=0.037

Criteria for Failure and Suboptimal Response to Imatinib Time (mo) Response Failure Suboptimal Optimal 3 No CHR No CG Response <65% Ph+ 6 >95% Ph+ ≥35% Ph+ ≤35% Ph+ 12 1-35% Ph+ 0% Ph+ 18 ≥5% Ph+ No MMR MMR Any Loss of CHR Loss of CCgR Mutation CE Loss of MMR Stable or improving MMR Baccarani et al. JCO 2009; 27: 6041-51

Criteria for Failure and Suboptimal Response to Imatinib X Criteria for Failure and Suboptimal Response to Imatinib Time (mo) Response Failure Suboptimal Optimal 3 No CHR No CG Response <65% Ph+ 6 >95% Ph+ ≥35% Ph+ ≤35% Ph+ 12 1-35% Ph+ 0% Ph+ 18 ≥5% Ph+ No MMR MMR Any Loss of CHR Loss of CCgR Mutation CE Loss of MMR Stable or improving MMR Baccarani et al. JCO 2009; 27: 6041-51

PFS and Response to 2nd TKI 113 CML CP pts receiving nilotinib (n=43) or dasatinib (n=70) after imatinib failure No MCyR (27) MCyR (59) 0.2 0.4 0.6 0.8 1 12 24 36 Months on second TKI PFS (%) Response @ 12 mo % AP/BP/Death/CHR loss Next Year MCyR 3% No MCyR 17% p = 0.003 Achieving a major cytogenetic response is a known major determinant of outcome in previous generations of therapy including interferon alpha and imatinib. In a previous report from our institution, patients who achieved a major cytogenetic response after 12 months of therapy with second generation TKI had at least a better progression-free survival. Tam. Blood 112: 516-8, 2008 30

Optimal Response to 2nd TKIs-Secondline. Survival % 3-month % 3-year Parameter Category No CCyR p-value EFS p OS Clonal evolution 94 30 0.35 54 0.46 87 0.22 Yes 28 41 48 71 CML duration (year) 0-3 27 46 0.3 0.56 78 0.89 4-5 32 56 83 ≥6 55 29 CHR at the start of 2nd TKI 39 42 0.21 53 0.63 90 0.40 yes 84 52 81 Best response to imatinib Intolerant 8 75 0.001 50 <0.001 100 0.02 MCyR 44 67 mCyR 22 18 No CyR 13 No data 6 33 40 Performance status 89 0.49 91 ≥1 38 59 %ph at the start ≤90 35 58 66 0.03 0.41 >90 82 24 45 80 Prior IFN 0.12 0.76 79 0.85 70 51 Mutation status None 36 0.09 Low IC50 23 Int IC50 12 25 Not done 43 NA Adverse features H.R. p-value For overall survival No CCyR at 3 months 5.4 0.03 For event-free survival 4.5 <0.001 % 3-month % 3-year Parameter Category No CCyR p-value EFS p OS Clonal evolution 94 30 0.35 54 0.46 87 0.22 Yes 28 41 48 71 CML duration (year) 0-3 27 46 0.3 0.56 78 0.89 4-5 32 56 83 ≥6 55 29 CHR at the start of 2nd TKI 39 42 0.21 53 0.63 90 0.40 yes 84 52 81 Best response to imatinib Intolerant 8 75 0.001 50 <0.001 100 0.02 MCyR 44 67 mCyR 22 18 No CyR 13 No data 6 33 40 Performance status 89 0.49 91 ≥1 38 59 %ph at the start ≤90 35 58 66 0.03 0.41 >90 82 24 45 80 Prior IFN 0.12 0.76 79 0.85 70 51 Mutation status None 36 0.09 Low IC50 23 Int IC50 12 25 Not done 43 NA In the univariate analysis for event-free survival, factors associated with poor event-free survival were older age (> 55 years), lack of any cytogenetic response to previous imatinib therapy, an ECOG performance status ≥1 at the start of second generation TKI therapy, and more than ≥ 90% Philadelphia-positive metaphases at the start of second generation TKI therapy. Kinase domain sequencing was performed in only 88 patients. When added to the analysis, the presence of KD mutations with intermediate IC50 at the start of second generation TKI was associated with poor event-free survival. In the subsequent multivariate analysis, the lack of any cytogenetic response to previous imatinib therapy (p<0.001), and an ECOG performance status ≥1 at the start of second generation TKI therapy (p=0.007) were selected as independent factors associated with poor event-free survival. Jabbour. Blood 116: abstract 2289, 2011 31

Optimal Response to 2nd TKIs. Survival % 3-month % 3-year Parameter Category No CCyR p-value EFS p OS Clonal evolution 94 30 0.35 54 0.46 87 0.22 Yes 28 41 48 71 CML duration (year) 0-3 27 46 0.3 0.56 78 0.89 4-5 32 56 83 ≥6 55 29 CHR at the start of 2nd TKI 39 42 0.21 53 0.63 90 0.40 yes 84 52 81 Best response to imatinib Intolerant 8 75 0.001 50 <0.001 100 0.02 MCyR 44 67 mCyR 22 18 No CyR 13 No data 6 33 40 Performance status 89 0.49 91 ≥1 38 59 %ph at the start ≤90 35 58 66 0.03 0.41 >90 82 24 45 80 Prior IFN 0.12 0.76 79 0.85 70 51 Mutation status None 36 0.09 Low IC50 23 Int IC50 12 25 Not done 43 NA % 3-month % 3-year Parameter Category No CCyR p-value EFS p OS Clonal evolution 94 30 0.35 54 0.46 87 0.22 Yes 28 41 48 71 CML duration (year) 0-3 27 46 0.3 0.56 78 0.89 4-5 32 56 83 ≥6 55 29 CHR at the start of 2nd TKI 39 42 0.21 53 0.63 90 0.40 yes 84 52 81 Best response to imatinib Intolerant 8 75 0.001 50 <0.001 100 0.02 MCyR 44 67 mCyR 22 18 No CyR 13 No data 6 33 40 Performance status 89 0.49 91 ≥1 38 59 %ph at the start ≤90 35 58 66 0.03 0.41 >90 82 24 45 80 Prior IFN 0.12 0.76 79 0.85 70 51 Mutation status None 36 0.09 Low IC50 23 Int IC50 12 25 Not done 43 NA In the univariate analysis for event-free survival, factors associated with poor event-free survival were older age (> 55 years), lack of any cytogenetic response to previous imatinib therapy, an ECOG performance status ≥1 at the start of second generation TKI therapy, and more than ≥ 90% Philadelphia-positive metaphases at the start of second generation TKI therapy. Kinase domain sequencing was performed in only 88 patients. When added to the analysis, the presence of KD mutations with intermediate IC50 at the start of second generation TKI was associated with poor event-free survival. In the subsequent multivariate analysis, the lack of any cytogenetic response to previous imatinib therapy (p<0.001), and an ECOG performance status ≥1 at the start of second generation TKI therapy (p=0.007) were selected as independent factors associated with poor event-free survival. 3-year survival (%) Parameter Event-free Overall CCyR by 3 months Yes 74 98 No 43 79 32

CML. Criteria For Failure On Any TKI No major CG response at 6 mos (Ph > 35%) No CG CR at 12 mos CG relapse or hematologic relapse Not failure criteria - QPCR  in CGCR

CML 2013. Frontline Therapy: New Proposed Algorithm Start TKI Check CG at 3/6 and 12 mos: At 3/6 mo - CCyR → Home free - PCyR → Recheck at 12 mo - Less than MCyR → Careful monitoring; ? New generation TKIs At 12 mo - Less than CCyR → Careful monitoring; ? New generation TKIs/ASCT

New Proposed Algorithm CML 2013. Salvage Therapy: New Proposed Algorithm Start 2nd TKI Check CG at 3 and 12 mos: At 3 mo - CCyR → Home free - Less than CCyR → Careful monitoring; ? New generation TKIs vs ASCT At 12 mo - Less than CCyR → ? New generation TKIs versus ASCT

My Desk On A Good Day! JC 36

Leukemia Questions? Pager 713-606-1307 ejabbour@mdanderson.org Elias Jabbour, M.D.