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

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Presentation on theme: "Elias Jabbour, MD Chronic Myeloid Leukemia: Treatment Success and Milestones."— Presentation transcript:

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

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 Early CCyR (3 and 6-mo) on 2 nd 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 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= %  p<0.001  p=0.20 CCyR PCyR No MCyR Response at 12 months Rx aim: major CG response (Ph ≤ 35%)

5 IRIS. Survival Without AP/BC Worse If No CGCR In Year 2 But Not Related To MMR n= % 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

6 Long-Term Outcome With Imatinib in ECP CML (ITT) de Lavallade H et al. J Clin Oncol. 2008; 26: EFS: death, progression to AP/BP, loss of CHR, loss of MCyR, or  WBC, failure to achieve MCyR, intolerance (88% per IRIS definition)

7 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 Cytogenetic response at 6 mosTotalDeadP-value Complete2015 Partial391 Minor103 Others a Proportion alive Months Kantarjian H et al. Cancer. 2008;112:837–845.

8 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 Proportion PFS Months Cytogenetic response at 12 mosTotalFailureP-value Complete2147 Partial193 Minor52 Others 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 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:

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

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

13 Hammersmith Experience. CCyR at 12 Months Associated With PFS de Lavallade. J Clin Oncol. 2008;26(20): Probability of PFS a CCyR at 12 mos (n = 121) No CCyR at 12 mos (n = 72) Months Landmark analysis at 12 mos P =.007

14 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 PFSOS <0.1% % >1% P value Outcome independent of treatment arm Hehlman et al. JCO 2011;29: CCyR

15 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 in 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 OS Hanfstein et al. ASH 2011; Abstract #783

16 Months on therapyResponseTotal (%) 3 (N=160) Optimal160 (100) Sub-optimal0 Failure0 6 (N=155) Optimal152 (98) Sub-optimal3 (2) Failure0 12 (N=129) Optimal128 (99) Sub-optimal1 (1) Failure0 18 (n=119) Optimal99 (84) Sub-optimal14 (12) Failure5 (4) Median follow-up 33 months (range, 3 to 66 months) Optimal Response To 2 nd TKIs-Frontline. Response (N=167) Jabbour E et al. JCO

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

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

19 Molecular and Cytogenetic Response at 3 Months 84% 64% % of patients ≤10% BCR-ABL at 3 Months n//N 198/ / / /221 >1-10% ≤1% >1-10% ≤1% P< CCyR PCyR PCyR/CCyR at 3 Months 81% 67% P< 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

20 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

21 Dasatinib 100 mg QDImatinib 400 mg QD PFS According to Response at 12 Months Months

22 OS According to Response at 12 Months Dasatinib 100 mg QDImatinib 400 mg QD MMR, N=95 CCyR (no MMR), N=86

23 TKI Frontline Therapy in CML EFS and OS by CG Response AT 3 Mo Event-Free SurvivalOverall Survival

24 TKI Frontline Therapy in CML EFS and OS by CG Response AT 6 Mo Event-Free SurvivalOverall Survival

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

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

27 TKI Frontline Therapy in CML EFS and OS by MCyR AT 12 Mo Event-Free SurvivalOverall Survival

28 Criteria for Failure and Suboptimal Response to Imatinib Time (mo) Response FailureSuboptimalOptimal 3No 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 MMRMMR Any Loss of CHR Loss of CCgR Mutation CE Loss of MMR Mutation Stable or improving MMR Baccarani et al. JCO 2009; 27:

29 Criteria for Failure and Suboptimal Response to Imatinib Time (mo) Response FailureSuboptimalOptimal 3No 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 MMRMMR Any Loss of CHR Loss of CCgR Mutation CE Loss of MMR Mutation Stable or improving MMR Baccarani et al. JCO 2009; 27: X

30 No MCyR (27) MCyR (59) Months on second TKI PFS (%) PFS and Response to 2 nd TKI 12 mo % AP/BP/Death/CHR loss Next Year MCyR3% No MCyR17% 113 CML CP pts receiving nilotinib (n=43) or dasatinib (n=70) after imatinib failure Tam. Blood 112: 516-8, 2008 p = 0.003

31 Optimal Response to 2 nd TKIs- Secondline. Survival % 3-month% 3-year ParameterCategoryNoCCyRp-valueEFSpOSp-value Clonal evolutionNo Yes CML duration (year) ≥ CHR at the start of 2 nd TKINo yes Best response to imatinibIntolerant < MCyR mCyR No CyR No data Performance status <0.001 ≥ %ph at the start ≤ > Prior IFN No Yes Mutation statusNone Low IC Int IC Not done43NA % 3-month% 3-year ParameterCategoryNoCCyRp-valueEFSpOSp-value Clonal evolutionNo Yes CML duration (year) ≥ CHR at the start of 2 nd TKINo yes Best response to imatinibIntolerant < MCyR mCyR No CyR No data Performance status <0.001 ≥ %ph at the start ≤ > Prior IFN No Yes Mutation statusNone Low IC Int IC Not done43NA Adverse featuresH.R.p-value For overall survival No CCyR at 3 months For event-free survival No CCyR at 3 months4.5<0.001 Jabbour. Blood 116: abstract 2289, 2011

32 Optimal Response to 2 nd TKIs. Survival % 3-month% 3-year ParameterCategoryNoCCyRp-valueEFSpOSp-value Clonal evolutionNo Yes CML duration (year) ≥ CHR at the start of 2 nd TKINo yes Best response to imatinibIntolerant < MCyR mCyR No CyR No data Performance status <0.001 ≥ %ph at the start ≤ > Prior IFN No Yes Mutation statusNone Low IC Int IC Not done43NA % 3-month% 3-year ParameterCategoryNoCCyRp-valueEFSpOSp-value Clonal evolutionNo Yes CML duration (year) ≥ CHR at the start of 2 nd TKINo yes Best response to imatinibIntolerant < MCyR mCyR No CyR No data Performance status <0.001 ≥ %ph at the start ≤ > Prior IFN No Yes Mutation statusNone Low IC Int IC Not done43NA 3-year survival (%) ParameterEvent-freeOverall CCyR by 3 monthsYes7498 No4379

33 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 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 CML Salvage Therapy: New Proposed Algorithm Start 2 nd 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 - CCyR → Home free - Less than CCyR → ? New generation TKIs versus ASCT

36 36 My Desk On A Good Day! JC

37 Leukemia Questions? Pager Elias Jabbour, M.D.


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