SWITCHING OF TKI IN CML
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SWITCHING OF TKI IN CML

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  • 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.
  • EFS by PCR 3 month responseP=0.003
  • EFS by PCR 3 month responseP=0.003
  • EFS by CG 12 month response P=0.009OS by CG 12 month response P=0.037

SWITCHING OF TKI IN CML SWITCHING OF TKI IN CML Presentation Transcript

  • Elias Jabbour, MD Chronic Myeloid Leukemia: Treatment Success and Milestones
  • 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
  • 4 IRIS. Survival Without AP/BC Worse If No Major CG Response at 12 mos Estimated rate at 60 months n= 86 93% n= 73 81% n= 350 97% p<0.001 p=0.20CCyR PCyR No MCyR Response at 12 months %withoutAP/BC 0 10 20 30 40 50 60 70 80 90 100 Monthssince randomization 0 6 12 18 24 30 36 42 48 54 60 66 Rx aim: major CG response (Ph ≤ 35%)
  • %withoutAP/BC 0 10 20 30 40 50 60 70 80 90 100 Months since randomization 0 6 12 18 24 30 36 42 48 54 60 66 IRIS. Survival Without AP/BC Worse If No CGCR In Year 2 But Not Related To MMR n= 139 100% n= 54 98% n= 89 87% Estimated rate at 60 months p<0.001 p=0.11 Response at 18 months CCyR with >=3 log red. CCyR with <3 log red. No CCyR Rx aim: CGCR in Year 2+; no need for MMR
  • 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 6054481260 Time From Start of Imatinib Therapy (months) 4236302418 Survival PFS EFS CHR Loss of MCyR 63% de Lavallade H et al. J Clin Oncol. 2008; 26:3358-3363 • EFS: death, progression to AP/BP, loss of CHR, loss of MCyR, or  WBC, failure to achieve MCyR, intolerance (88% per IRIS definition)
  • MDACC Retrospective Analysis: MCyR at 6 Months Associated With OS Patients with MCyR have better OS than patients that do not Landmark analysis at 6 mos 0 12 24 36 48 60 72 Cytogenetic response at 6 mos Total Dead P-value Complete 201 5 Partial 39 1 Minor 10 3 Othersa 9 3 0.85 0.01 0.62 1.0 0.8 0.6 0.4 0.2 0 Proportionalive Months Kantarjian H et al. Cancer. 2008;112:837–845.
  • MDACC Retrospective Analysis: CCyR at 12 Months Associated With PFS Patients with CCyR have better PFS than patients that do not. Similar results were observed in patients achieving CCyR at 18 and 24 mos. Landmark analysis at 12 mos ProportionPFS 1.0 0.8 0.6 0.4 0.2 0 0 12 24 36 48 60 72 Months Cytogenetic response at 12 mos Total Failure P-value Complete 214 7 Partial 19 3 Minor 5 2 Others 8 5 0.02 0.2 0.22 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 98% 55% 98% 63% 79% 33% 85% 51% p<0.0001 p<0.0001 p<0.0001p<0.0001 98% 55% 98% 63% 79% 33% 85% 51% p<0.0001 p<0.0001 p<0.0001p<0.0001 Castagnetti. Hematologica 2009;94 abstract 0528
  • EFS by Response to IM at 6 and 12 Mos 0 12 24 36 48 60 72 Months 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Failure Suboptimal Optimal p<0.0001 No. 9 10 240 Events (%) 6 (67) 5 (50) 14 (6) 0 12 24 36 48 60 72 Months 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Failure Suboptimal Optimal p<0.0001 No. 14 19 213 Evaluable (%) 8 (57) 3 (16) 8 (4) 6 month response 12 month response •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) 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 de Lavallade. J Clin Oncol. 2008;26(20):3358-3363. ProbabilityofPFSa CCyR at 12 mos (n = 121) No CCyR at 12 mos (n = 72) 0 0.2 0.4 0.6 0.8 1.0 12 24 48 600 36 Months 96% 74% Landmark analysis at 12 mos P = .007
  • 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 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 CCyR
  • 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 87 OS 95 87 95 87 Hanfstein et al. ASH 2011; Abstract #783
  • Months on therapy Response Total (%) 3 (N=160) Optimal 160 (100) Sub-optimal 0 Failure 0 6 (N=155) Optimal 152 (98) Sub-optimal 3 (2) Failure 0 12 (N=129) Optimal 128 (99) Sub-optimal 1 (1) Failure 0 18 (n=119) Optimal 99 (84) Sub-optimal 14 (12) Failure 5 (4) • Median follow-up 33 months (range, 3 to 66 months) Optimal Response To 2nd TKIs-Frontline. Response (N=167) 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 0 20 40 60 80 100 84% 64% %ofpatients ≤10% BCR-ABL at 3 Months n//N 198/235 154/239 171/210 148/221 >1-10% ≤1% >1-10% ≤1% P<0.0001 CCyR CCyR PCyR PCyR PCyR/CCyR at 3 Months 81% 67% P<0.0001 Dasatinib 100 mg QD Imatinib 400 mg QD  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 Imatinib 400 mg QD 67% of patients had PCyR/CCyR Dasatinib 100 mg QD 81% of patients had PCyR/CCyR 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% P<0.0001 P<0.0026 < PCyR, N=73 CCyR, N=79 PCyR, N=68 Months 100 80 60 40 20 0 0 6 12 24 36 42 100 80 60 40 20 0 0 6 12 24 36 42 Months %NotProgressed <PCyR, N=39 CCyR, N=139 PCyR, N=31 PCyR CCyR P=0.2185 PCyR CCyR P=0.8062 Jabbour E et al. EHA. 2012.
  • Dasatinib 100 mg QD Imatinib 400 mg QD PFS According to Response at 12 Months Months Months <CCyR, N=50 MMR, N=64 CCyR (no MMR), N=87 100 80 60 40 20 0 0 6 12 24 36 42 100 80 60 40 20 0 0 6 12 24 36 42 <CCyR, N=26 MMR, N=95 CCyR (no MMR), N=85 %NotProgressed MMR and/or CCyR <CCyR P<0.0001 MMR and/or CCyR <CCyR P<0.0001 Jabbour E et al. EHA. 2012.
  • OS According to Response at 12 Months Dasatinib 100 mg QD Imatinib 400 mg QD MMR, N=95 CCyR (no MMR), N=86 <CCyR, N=28 < CCyR, N=52 MMR, N=64 CCyR (no MMR), N=89 Months Months 100 80 60 40 20 0 0 6 12 24 36 42 100 80 60 40 20 0 0 6 12 24 36 42 %Alive MMR and/or CCyR <CCyR P=0.0503 MMR and/or CCyR <CCyR P=0.0041 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
  • TKI Frontline Therapy in CML EFS and OS by CG Response AT 6 Mo Event-Free Survival Overall Survival
  • 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
  • Criteria for Failure and Suboptimal Response to Imatinib Time (mo) Response Failure Suboptimal Optimal 3 No CHR 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 et al. JCO 2009; 27: 6041-51
  • Criteria for Failure and Suboptimal Response to Imatinib Time (mo) Response Failure Suboptimal Optimal 3 No CHR 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 et al. JCO 2009; 27: 6041-51
  • No MCyR (27) MCyR (59) 0 0.2 0.4 0.6 0.8 1 0 12 24 36 Months on second TKI PFS(%) PFS and Response to 2nd TKI Response @ 12 mo % AP/BP/Death/CHR loss Next Year MCyR 3% No MCyR 17% • 113 CML CP pts receiving nilotinib (n=43) or dasatinib (n=70) after imatinib failure Tam. Blood 112: 516-8, 2008 p = 0.003
  • Optimal Response to 2nd TKIs- Secondline. Survival Adverse features H.R. p-value For overall survival No CCyR at 3 months 5.4 0.03 For event-free survival No CCyR at 3 months 4.5 <0.001 Jabbour. Blood 116: abstract 2289, 2011
  • Optimal Response to 2nd TKIs. Survival 3-year survival (%) Parameter Event-free Overall CCyR by 3 months Yes 74 98 No 43 79
  • 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
  • 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
  • 36 My Desk On A Good Day! JC
  • Leukemia Questions? •Pager 713-606-1307 •ejabbour@mdanderson.org Elias Jabbour, M.D.