Susan Branford_COLT 2014_Session2 - 3

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The importance of deep molecular response for patients with CML A/Prof Susan Branford, PhD Centre for Cancer Biology & Universities of Adelaide and South Australia

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May predict survival Gateway to treatment free remission (TFR) Deep molecular response is highly desirable discontinuation of TKI therapy without relapse

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10 9 6 months of therapy complete cytogenetic response Optimal Response 10 12 Number of Leukaemic cells (log) 0 10 3 10 11 10 10 10 8 10 7 10 6 10 5 10 4 10 2 10 0.10 1.0 0.01 10 100 0.001 0 3 1 2 4 5 100 35 0 Deep molecular response MMR deep molecular response – required for a trial of TKI discontinuation and TFR MR 5 CMR Cross et al, Leuk, 2012;26:2172 MCyR / 10% BCR-ABL1 - 3m CCyR / 1% BCR-ABL1 - 6m Real time quantitative PCR BCR-ABL1 mRNA levels MR 4 Many years to achieve MR 4.5 0.0032

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Response is reinstated by restarting imatinib Deep molecular response must be sustained ceased imatinib Nov ′03 Baseline 0.01 0.10 1.0 10 Years since the start of Imatinib PB BCR-ABL1% IS Pre 2 3 1 4 5 6 BCR-ABL1 detected BCR-ABL1 not detected Patient tested in Adelaide restarted imatinib ceased imatinib 7 MR 4 MR 4.5

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Some patients can cease imatinib and maintain response Response is reinstated by restarting imatinib BCR-ABL1 detected BCR-ABL1 not detected Baseline 0.01 0.10 1.0 10 Years since the start of Imatinib PB BCR-ABL1% IS Pre 2 3 1 4 5 6 Patient tested in Adelaide 7 ceased imatinib ceased imatinib maintained undetectable BCR-ABL1 for 9 years MR 4 MR 4.5

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Discontinuation trial criteria is evolving Imatinib ≥ 3 years Stable undetectable BCR-ABL1 for at least 2 years CML8 MR 4.5 STIM MR 5 Strict PCR sensitivity criteria CML8 (Aust) 40 patients July 2006 STIM (French) 100 patients July 2007 Undetectable BCR-ABL1 is no longer required in new discontinuation studies - BCR-ABL1 ≤0.0032% (MR 4.5 ) - BCR-ABL1 ≤0.01% (MR 4 ) Ross et al. Blood . 2013;122:515 Mahon et al. Lanc Onc . 2010;11:1029

Deep molecular response can take many years to achieve for some patients:

MR 3 Deep molecular response can take many years to achieve for some patients 1 4 8 Years Cumulative Incidence 2 3 5 6 7 100 80 40 20 0 60 MR 4 MMR MR 4.5 0 The rate of decline is not constant Confirmed response median time to response 10-fold decline 3.3-fold - even when a deep molecular response is achieved 528 first-line imatinib treated patients tested in Adelaide

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MMR MR 4 MR 4.5 German CML IV Study Hehlmann et al, JCO 2014;32:415 >1,500 patients imatinib 400, 800mg, IFN Many years may be required to reach a deep molecular response for patients treated with imatinib based therapies

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Studied 423 first line imatinib treated patients 0.01 0.001 0 3 1 2 4 5 Factors associated with deep molecular response MR 4 0.10 1.0 10 100 MR 5 MR 4.5 The initial rate of the BCR-ABL1 decline can lead to substantial differences in time to deep response Branford et al, Blood 2013;121:3818 <10% patients how many patients achieve deep responses? factors associated with deep responses? deep molecular response

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how many patients achieve deep responses? Branford et al, Blood 2013;121:3818 Years after commencing imatinib Cumulative Incidence % 0 20 40 60 80 100 0 4 5 6 7 8 1 2 3 Confirmed undetectable MR 4.5 52% (CI 43 - 60%) n=423 patients At 8 years ~ 12% of first line imatinib treated patients would maintain response if imatinib was stopped 37% Stable 2 years

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factors associated with deep responses? Branford et al, Blood 2013;121:3818 – strongest independent predictor was the 3 month BCR-ABL1 value, P < .001 Years after commencing imatinib 4 5 6 7 8 1 2 3 Cumulative Incidence % 0 20 40 60 80 100 0 MMR, 78% >10%, 9% >0.1-1.0%, 53% >1-10%, 29% Stable undetectable MR 4.5 for 2 years n=423

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Achieving MMR by 12 months of first-line imatinib is important for reaching the discontinuation criteria 0 20 40 60 80 100 Cumulative Incidence % 0 4 5 6 7 8 Years after commencing imatinib 1 2 3 MMR by 12 months No MMR by 12 months P < .001 Landmark analysis Justifies the focus of early achievement of MMR as a strategy to maximize recruitment to discontinuation studies Branford et al, Blood 2013;121:3818 n=423

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Switch to nilotinib leads to more patients reaching undetectable MR 4.5 Hughes et al. Blood 2014; 214:1353-1360 0.01 0.001 0 3 1 2 4 5 Deep molecular response 0.10 1.0 10 100 More patients have a rapid decline with first line nilotinib or dasatinib Saglio et al. NEJM 2010;362:2251 Kantarjian et al. NEJM 2010;362:2260

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ENESTcmr – BCR-ABL1 positive after at least 2 years of imatinib N = 207, 4 year study 1:1 randomization stratified by: Prior imatinib (≤ 36 m, > 36 m) and Prior interferon (None, ≤ 12 m, > 12 m) Imatinib continue same dose Nilotinib 400 mg BID R A N D O M I Z E Endpoints confirmed undetectable MR 4.5 by 12 and 24 months (formally known as CMR)

Cumulative Incidence of undetectable MR4.5 at 24 months of follow up :

50 Cumulative Incidence of undetectable MR 4.5 at 24 months of follow up % Months Since Randomization 40 30 20 10 0 0 6 12 18 Nilotinib, n=101 Imatinib, n=100 32% 17% 24 P = . 011 Hughes et al. Blood 2014;214:1353-1360

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Kantarjian et al., Lancet 2011; 12:841-851. Saglio et al. Blood. 2009;114 [LBA-1]. Hughes et al. Blood. 2010;116 [abstract 207]. Saglio et al. Blood. 2011;118 [abstract 452]. Kantarjian HM, et al. Blood . 2012;120(21):[abstract 1676]. 11 4 2 0 0 2 4 6 8 10 12 Less than CCyR CCyR MMR MR 4.5 Progression events ENESTnd – 4 years The greater the reduction of leukaemic cells, the greater the protection from progression deep molecular response

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Hehlmann et al, JCO 2014;32:415

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The aims of the MR 4.5 publication were to Analyse whether MR 4.5 is reached faster with optimised high dose imatinib IM 400+IFN n=434 CML IV study: 5 arm study that enrolled >1,500 patients since 2002 Hehlmann et al, JCO 2014;32:415 Determine the proportion of patients achieving MR 4.5 IM after IFN n=131 IM 400+Ara-C n=158 IM 400 n=406 IM 800 n=422 Determine whether the achievement of MR 4.5 results in better survival Imatinib 800 mg was administered after a run-in period of 6 weeks at 400 mg and then reduced according to tolerability to avoid grade 3 or 4 AEs

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– early MMR predicted MR 4.5 Determine the proportion of patients achieving MR 4.5 Years after commencing imatinib Branford et al, Blood 2013;121:3818 Cumulative Incidence % 0 20 40 60 80 100 0 4 5 6 7 8 1 2 3 Confirmed undetectable MR 4.5 52% (95% CI 43 - 60%) n=423 patients Hehlmann et al, JCO 2014;32:415 – confirmed MR 4.5 was 46% at 8 years – highest MR 4.5 level was reached for patients with MMR at 3 months Branford et al, Blood 2013;121:3818

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Hehlmann et al, JCO 2014;32:415 Maintaining an average daily dose of 600 mg imatinib leads to higher rates of MMR by 12 months versus <600 mg; 55% vs 32%, P = .037 Hughes et al, Blood. 2008;112:3965 Analyse whether MR 4.5 is reached faster with optimised high dose imatinib patients with optimized high-dose imatinib achieved MR 4.5 more quickly than with any other imatinib treatment arm – 48 months with imatinib 800 mg/day median time to MR 4.5 – 62 months with imatinib 400 mg/day “Important for countries where second generation TKI are not approved or not available due to high costs” Hehlmann et al, JCO 2014;32:415

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Landmark analyses of confirmed MR 4.5 at 4 years of therapy to evaluate the prognostic impact of different molecular response levels on survival Determine whether the achievement of MR 4.5 results in better survival 90% NS NS NS .047 OS at 8 years P .001 Hehlmann et al, JCO 2014;32:415 n MR 4 191 MMR 88% 260 0.1-1% 83% 55 >1% 78% 44 MR 4.5 92% 198

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American Journal of Hematology . 2013;88:1024 429 patients with 4 different treatment modalities -all achieved CCyR imatinib 400 and 800 mg, nilotinib, dasatinib assessed MMR, MR 4 , MR 4.5 , sustained MR 4.5 (2 years) and undetectable BCR-ABL1 Analysed the clinical outcome according to the depth of molecular response

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American Journal of Hematology . 2013;88:1024 Lower risk of losing CCyR, progression to AP/BC or death in patients with deeper molecular response Achieving a sustained MR 4.5 did not appear to further reduce the risk of transformation or death Small advantage in TFS if undetectable BCR-ABL1 achieved at any time compared to patients with no better than MMR, but not deeper responses The 6 year overall survival rate was superior for patients with undetectable BCR-ABL1 compared to those with no better than MMR, but not deeper responses When adjusting for the time to achieve the best MR, the clinical benefit of achieving undetectable BCR-ABL1 vanished, with no differences in TFS or OS even between the best and the worst MR category

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Haematologica . 2013;99:458 A random selection of 266 first line imatinib treated patients were analysed assessed the achievement of confirmed undetectable BCR-ABL1 (MR 4.5 ) at any time and its association with outcome

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Haematologica . 2013;99:458 Achieving CCyR within 12 months and MMR within 18 months were associated with undetectable BCR-ABL1 Multivariate analysis – baseline spleen enlargement, time to CCyR and MMR were strongly associated with undetectable BCR-ABL1

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Haematologica . 2013;99:458 Failure free survival CCyR, no MMR undetectable BCR-ABL1 MMR No difference in overall survival Concluded – achieving deeper molecular response is associated with a better FFS, and it clearly confers the best outcome and should be the main aim of therapy

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The importance of deep molecular response May be an advantage for failure free survival Gateway to treatment free remission (TFR) MMR by 3 months is associated with the highest rates of MR 4.5 More patients achieve MMR and MR 4.5 with nilotinib, dasatinib or higher dose imatinib ?overall survival?

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