1. 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

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

3. 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

4. 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)

5. 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:

6. 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

7. 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

8. 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

9. 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

10. 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. Revised September 13, 2012.

11. 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

12. 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?

13. 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

14. 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
44.3% of patients not switched because MD wanted to “wait and see”

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

16. 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 , 17 JUN 2009 DOI: /cncr

17. 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

18. 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 abstract 3780

19. 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

20. 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,

21. 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

22. 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 , 24 DEC 2012 DOI: /bjh

23. 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 , 24 DEC 2012 DOI: /bjh

24. 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.

25. 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

26. 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:
©2013 by American Society of Hematology

27. “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