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Elias Jabbour, MD

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

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Elias Jabbour, MD

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

  2. 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 • EarlyCCyR (3 and 6-mo) on 2nd TKI Rx associated with better EFS

  3. 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

  4. 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   n= 350 97% CCyR p=0.20 p<0.001 n= 86 93% PCyR n= 73 81% No MCyR 4

  5. 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 p<0.001 CCyR with <3 log red. No CCyR

  6. Long-Term Outcome With Imatinib in ECP CML (ITT) 1.0 0.9 0.8 0.7 0.6 Probability 0.5 Survival 63% PFS 0.4 (88% per IRIS definition) CHR 0.3 EFS Loss of MCyR 0.2 0.1 0 6 12 18 24 30 36 42 48 54 60 Time From Start of Imatinib Therapy (months) • 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 ClinOncol. 2008; 26:3358-3363

  7. 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 0 Proportion alive 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.

  8. 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 0 Proportion PFS 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.

  9. Suboptimal Response to Imatinib 400 mg/d in CP CML: GIMEMA CML WP Analysis of 423 Consecutive Patients Castagnetti. Hematologica 2009;94 abstract 0528

  10. 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.

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

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

  13. 96% 74% Hammersmith Experience. CCyR at 12 Months Associated With PFS Landmark analysis at 12 mos 1.0 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) 0 0 12 24 36 48 60 Months de Lavallade. J Clin Oncol. 2008;26(20):3358-3363.

  14. Outcome by 12-Month Response in CML CP CCyR Hehlman et al. JCO 2011;29:1634-42

  15. CML IV: Long-Term Impact of Response at 3 Months Hanfstein et al. ASH 2011; Abstract #783

  16. Optimal Response To 2nd TKIs-Frontline. Response (N=167) • Median follow-up 33 months (range, 3 to 66 months) Jabbour E et al. JCO. 2011.

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

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

  19. Molecular and Cytogenetic Response at 3 Months P<0.0001 P<0.0001 Dasatinib 100 mg QD 84% 81% Imatinib 400 mg QD PCyR 67% 64% >1-10% PCyR % of patients >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.

  20. PFS According to Cytogenetic Response at 3 Months Dasatinib 100 mg QD 81% of patients hadPCyR/CCyR Imatinib 400 mg QD 67% of patients hadPCyR/CCyR 100 80 60 40 20 0 100 80 60 40 20 0 P<0.0026 P<0.0001 PCyR CCyR PCyR CCyR % Not Progressed P=0.8062 P=0.2185 CCyR, N=79 CCyR, N=139 PCyR, N=68 PCyR, N=31 0 0 6 6 12 12 24 24 36 36 42 42 < PCyR, N=73 <PCyR, N=39 Months Months For ≥PCyRvs <PCyR at 3 months3-year PFS rates were 93.9% vs 71.3% For ≥PCyRvs <PCyR at 3 months3-year PFS rates were 93.7% vs 77.3% Jabbour E et al. EHA. 2012.

  21. PFS According to Response at 12 Months Dasatinib 100 mg QD Imatinib 400 mg QD 100 80 60 40 20 0 100 80 60 40 20 0 % Not Progressed MMR, N=95 MMR, N=64 MMR and/or CCyR <CCyR MMR and/or CCyR <CCyR CCyR (no MMR), N=85 P<0.0001 P<0.0001 CCyR (no MMR), N=87 42 42 0 0 6 6 12 12 24 24 36 36 <CCyR, N=26 <CCyR, N=50 Months Months Jabbour E et al. EHA. 2012.

  22. OS According to Response at 12 Months Dasatinib 100 mg QD Imatinib 400 mg QD 100 80 60 40 20 0 100 80 60 40 20 0 % Alive MMR, N=64 MMR, N=95 MMR and/or CCyR <CCyR MMR and/or CCyR <CCyR CCyR (no MMR), N=89 CCyR (no MMR), N=86 P=0.0503 P=0.0041 42 42 0 0 6 6 12 12 24 24 36 36 < CCyR, N=52 <CCyR, N=28 Months Months Jabbour E et al. EHA. 2012.

  23. TKI Frontline Therapy in CMLEFS and OS by CG Response AT3 Mo Event-Free Survival Overall Survival

  24. TKI Frontline Therapy in CMLEFS and OS by CG Response AT6 Mo Event-Free Survival Overall Survival

  25. TKI Frontline Therapy in CMLEFS and OS by MCyRAT6 Mo Event-Free Survival Overall Survival

  26. TKI Frontline Therapy in CMLEFS and OS by CG Response AT12 Mo Event-Free Survival Overall Survival

  27. TKI Frontline Therapy in CMLEFS and OS by MCyRAT12 Mo Event-Free Survival Overall Survival

  28. Criteria for Failure and Suboptimal Response to Imatinib Baccarani et al. JCO 2009; 27: 6041-51

  29. X Criteria for Failure and Suboptimal Response to Imatinib Baccarani et al. JCO 2009; 27: 6041-51

  30. PFS and Response to 2nd TKI 1 0.8 0.6 No MCyR (27) PFS (%) 0.4 0.2 MCyR (59) 0 0 12 24 36 Months on second TKI • 113 CML CP pts receiving nilotinib (n=43) or dasatinib (n=70) after imatinib failure p = 0.003 Tam. Blood 112: 516-8, 2008

  31. Optimal Response to 2nd TKIs-Secondline. Survival Jabbour. Blood 116: abstract 2289, 2011

  32. Optimal Response to 2nd TKIs. Survival

  33. 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

  34. 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 • - CCyR → Home free • - Less than CCyR → Careful monitoring; • ? New generation TKIs/ASCT

  35. My Desk On A Good Day! JC 36

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

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