What Should Be Done for Patients Who Still Have >10% BCR/ABL after 3 months of Therapy? Ellen K. Ritchie Clinical Director, Richard T. Silver MPN Center Associate Professor of Medicine Weill Cornell Medical College

Don’t Be Too Late !! For this Important 3-month Date!! Switch Therapy

Survival After Imatinib Treatment is linked to the molecular response at 3 months Patients with a molecular response bcr/abl < 9.8% at three months had an 8-year OS of 93.3% Patients with a less optimal molecular response bcr/abl >9.8% had 8-year OS of 54% Marin et al, JCO 2012; 2012; 30: 232-8

Many Other Studies have confirmed this data Hanfstein et al, bcr-abl at 3 months correlated with PFS and OS at 5yrs (Leuk 2012, 26, 2096). Jain et al, bcr-abl at 3 months correlated with EFS at 3 yrs (Blood, 2013, 121, 24, 4867) Shah et al, Molecular and cytogenetic responses at 3 months were predictive of PFS and OS, (Blood, 2014, 123, 15, 2317)

Probability of MMR and Progression Free Survival at Fixed Time Points % Probability Outcome by Transcript Levels at Specified Times MMR Progression BCR/ABL Transcript Levels 3m 6m 12m <0.1 100 4 1 3 0.1-1 84 69 61 7 2 >1-10 53 44 20 11 9 8 >10 33 15 13 23 50 p<0.001 Quintas-Cardama et al. Blood 2009; 133:6315-21

Early Response in CML Event-Free Survival by Response at 3 months Cytogenetic Molecular 0% Similar results at 6 months landmark Event: loss of CHR, loss of MCyR, progression to AP, BP, or death from any cause while on study Jain P, et al. ASH 2012; Abstract #70

Molecular Response at 3 Months by Therapy >10% BCR-ABL/ABL 33-36% with Imatinib 9-16% with 2G TKI Hochhaus et al. ASH 2012: Abstract #167; Saglio et al. ASH 2012; Abstract #1675; Brummendorf et al. ASH 2012; Abstract #69

EFS by Molecular Response at 3 Months Hochhaus et al. ASH 2012: Abstract #167; Saglio et al. ASH 2012; Abstract #1675; Brummendorf et al. ASH 2012; Abstract #69 * Estimated

OS by Molecular Response at 3 Months Hochhaus et al. ASH 2012: Abstract #167; Saglio et al. ASH 2012; Abstract #1675; Brummendorf et al. ASH 2012; Abstract #69 * Estimated

NCCN Treatment Recommendations 3-Month Follow-up Therapy BCR-ABL transcript levels ≤10% by QPCR International Scale (IS) or PCyR on bone marrow cytogenetics Continue same dose of IM, DAS, or NIL Monitor with QPCR every 3 mo No relapse Relapse 3-mo evaluation BCR-ABL transcript levels >10% by QPCR using the IS or <PCyR on bone marrow cytogenetics Evaluate patient compliance and drug-drug interactions Mutational analysis DAS 100 mg daily NIL 400 mg BID Evaluation and discussion of HSCT Clinical trial National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: chronic myelogenous leukemia. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp. Revised September 13, 2012.

ELN Guidelines for Management of CML Time Optimal Response Warning Failure Baseline High Risk 3 months BCR-ABL < 10% Ph+ < 35% (PCyR) BCR-ABL >10% Ph+> 36—95% No CHR Ph+>95% 6 months BCR-ABL < 1% Ph+ 0% (CCyR) BCR-ABL 1-10% Ph+ 1-35% BCR-ABL > 10% Ph+ > 35% 12 months BCR-ABL <0.1% BCR-ABL 0.1-1% BCR-ABL> 1% Ph+ > 0% Then at any time MMR or better CCA/Ph- 9 (-7 or 7q-) Loss of CHR Loss of CCyR Loss of MMR confirmed Mutations Optimal: no change Rx. Warning: more monitoring. Failure: change treatment Baccarani et al, Blood 2013;122

Why not wait a little longer and see? Does Switching Therapy if response is suboptimal to 2nd generation TKI improve outcome? Why not wait a little longer and see? Why not just increase the dose of imatinib? Aren’t two measurements always better than one?

Impact of timely switching from imatinib to 2nd G TKI at 12m on CCyR Retrospective Chart Review Data collected form 108 heme/onc from across USA CP CML patients treated with imatinib and failed to achieve CCyR at 12 m 593 pts, 306 “timely” vs 287 “nonswitchers” Those who switched to 2nd G TKIs w/in 3 mos were “timely” switchers vs. those who did not switch. D’Angelo et al, Clin Lymph, Myeloma, Leuk 2013

Timely vs Non-Timely Switches Figure 1 Comparison of Outcomes Between Timely Switchers and Nonswitchers. Kaplan-Meier Curves Compared Timely Switchers and Nonswitchers for Time to CCyR Achievement. For These Graphs, Time is Measured in Months After the 10- to 14-Month Cytogenetic Test ... Daniel J. DeAngelo , Lei Chen , Annie Guerin , Amy Styles , Philippe Giguere-Duval , Eric Q. Wu Impact of Timely Switching From Imatinib to a Second-Generation Tyrosine Kinase Inhibitor After 12-Month Complete Cytogenetic Response Failure: A Chart Review Analysis Clinical Lymphoma Myeloma and Leukemia, 2013 http://dx.doi.org/10.1016/j.clml.2013.12.002 44.3% of patients not switched because MD wanted to “wait and see”

START-R: Dasatinib vs HD Imatinib for CP CML Resistant to Imatinib P2 open label study of 150 CP CML pts resistant to imatinib 400-600mg Randomized 2:1 to dasatinib 70mg bid (n=101) vs imatinib 800mg (n=49) 2 year follow up data

Dasatinib or high‐dose imatinib for chronic‐phase chronic myeloid leukemia resistant to imatinib at a dose of 400 to 600 milligrams daily Cancer Volume 115, Issue 18, pages 4136-4147, 17 JUN 2009 DOI: 10.1002/cncr.24504 http://onlinelibrary.wiley.com/doi/10.1002/cncr.24504/full#fig4

5 pts on nilotinib arm with MMR at 3m Efficacy of Nilotinib vs HD Imatinib in CP CML Pts with early suboptimal response to imatinib Small study of early CP CML pts who have achieved CCyR but no MMR after 18m treatment 13 treated with nilotinib, 17 with HD imatinib 800mg, 6 pts crossed over to nilotinib Cumulative MMR at 20m higher in nilotinib vs imatinib arm (59% vs 27%, p=0.047). 5 pts on nilotinib arm with MMR at 3m Goh, HG et al, Blood, 2011, 118, abstract 2765

Impact of 2nd gen TKR as 2nd line treatment in CP CML Retrospective study of 98 patients 60 with HD imatinib salvage, chemo, allo SCT 38 treated with 2nd gen TKI dasatinib/nilotinib CcyR 73% IM and 86% 2nd gen (p=0.09) MMR 41% IM and 71% 2nd gen (p=0.009) PFS 88% IM and 94% 2nd gen Garcia-Gutierrez, J et al. Blood 2011 118 abstract 3780

123 pts with CP CML treated with 2nd G TKI after imatinib failure 3 M CCyR to 2nd Gen TKI predicts survival in pts with CP CML after imatinib failure 123 pts with CP CML treated with 2nd G TKI after imatinib failure 78 pts treated with dasatinib 45 pts treated with nilotinib Imatinib failure as described by ELN criteria Jabbour, E et al. Clin Lymph, Myeloma, and Leuk, 2013, 13, p 302

In 2nd Gen Therapy After Imatinib Failure, CCyR at 3 months predicts OS Figure 2 Overall Survival by 3-Month Complete Cytogenetic Response (CCyR) Elias Jabbour , Hagop Kantarjian , Hady Ghanem , Susan O'Brien , Alfonso Quintas-Cardama , Guillermo Garcia-Manero... The Achievement of a 3-Month Complete Cytogenetic Response to Second-Generation Tyrosine Kinase Inhibitors Predicts Survival in Patients With Chronic Phase Chronic Myeloid Leukemia After Imatinib Failure Clinical Lymphoma Myeloma and Leukemia, Volume 13, Issue 3, 2013, 302 - 306 http://dx.doi.org/10.1016/j.clml.2012.12.005

112 pts CP CML receiving 2GTKI 80 pts dasatinib, 32 pts nilotinib BCR-ABL 1 transcript at 3m predicts LT outcomes following 2nd G TKI treatment in CP CML imatinib failures 112 pts CP CML receiving 2GTKI 80 pts dasatinib, 32 pts nilotinib 53% imatinib resistant 47% imatinib intolerant Median duration of f/u 24.6 m Kim, D et al, BJH 2013, 160, p.630

BCR‐ABL1 transcript at 3 months predicts long‐term outcomes following second generation tyrosine kinase inhibitor therapy in the patients with chronic myeloid leukaemia in chronic phase who failed Imatinib British Journal of Haematology Volume 160, Issue 5, pages 630-639, 24 DEC 2012 DOI: 10.1111/bjh.12187 http://onlinelibrary.wiley.com/doi/10.1111/bjh.12187/full#bjh12187-fig-0003

BCR‐ABL1 transcript at 3 months predicts long‐term outcomes following second generation tyrosine kinase inhibitor therapy in the patients with chronic myeloid leukaemia in chronic phase who failed Imatinib British Journal of Haematology Volume 160, Issue 5, pages 630-639, 24 DEC 2012 DOI: 10.1111/bjh.12187 http://onlinelibrary.wiley.com/doi/10.1111/bjh.12187/full#bjh12187-fig-0001

282 pts with CP CML on imatinib 400mg 118 pts with imatinib failure Imatinib 3m BCR-ABL transcript may be the most important outcome indicator 282 pts with CP CML on imatinib 400mg 118 pts with imatinib failure 8 year prob of CCyR whole population 76.6% HR pts 8-yr prob of CR 47% vs LR pts 91.1% based on 3m transcript levels Prognostic Value of early measurement of bcr-abl transcripts retains its value even for pats requiring treatment with 2GTKI Marin et al, JCO 2012, 30, p232.

Best to start out with TKI that gives the highest probability for 3m response If imatinib 400mg is used as initial treatment, 3m bcr-abl transcript data is a strong predictor of outcome to treatment Data suggests that switch may enhance response and lead to better outcomes If 3m data becomes important regardless of switch, it will significantly impact choice of initial TKI

Evaluable cytogenetic and molecular responses to different TKI modalities at 3- and 6-mo follow-up (imatinib 400, imatinib 800, nilotinib, and dasatinib). Jain P et al. Blood 2013;121:4867-4874 ©2013 by American Society of Hematology

“My dear, here we must run as fast as we can, just to stay in place “My dear, here we must run as fast as we can, just to stay in place. And if you wish to go anywhere you must run twice as fast as that.” ― Lewis Carroll, Alice in Wonderland