1. Great Debates in Hematology
New York City – April 2014
Switch therapy for a CML patient at 3 months because of failure to achieve an Early Molecular Response? Not so fast.
David Steensma, MD FACP
Associate Professor of Medicine, Harvard Medical School
Adult Leukemia Program, Dana-Farber Cancer Institute
Hematological Oncology Service, Brigham & Women’s Hospital

2. Disclosures
Data monitoring committee: Amgen, Novartis Scientific advisory board or consulting: Genoptix, Janssen-Cilag, Celgene, Boehringer Ingelheim, Incyte Stock equity: Ariad Off-label / experimental use will be discussed

3. But if your patient doesn’t get there… is the sky falling?
It is clear that achieving an early molecular response (<10% BCR-ABLIS) in chronic-phase CML with TKI therapy is a good thing.
But if your patient doesn’t get there… is the sky falling?

4. 3 month landmark matters…
Importance of 1 log reduction in transcript by 3 months first established in subset analysis of IRIS trial
Better OS, EFS, and PFS also seen in study by Marin et al of 282 pts with CP-CML
CML IV study from Germany (n=1303 with CP-CML on imatinib) showed 5 year OS of 87% vs 95% and PFS of 87% vs 92% for not meeting vs meeting 3 month 10% landmark
Landmark analyses from DASISION and ENESTnd showed same applies to second gen TKI in CP-CML
Quintas-Cardama A et al Blood 2009; 113:
Marin D et al JCO 2012; 30:
Hanfstein B et al Leukemia 2012; 26:
Saglio G et al Blood 2012 [abstract 1675]
Saglio G et al JCO 2013 (abstract 7054)
Jain P et al Blood 2013; 121:

5. Eight-year probability of overall survival (OS) and current complete cytogenetic response survival (c-CCyRS) in the whole population and with patients stratified by risk group defined by BCR-ABL1 transcript level at 3 months.
Marin D et al. JCO 2012;30:

6. 6 month time point was critical
But even patients who do not achieve a 3 month early molecular response <10% can do well… if they get there by 6 months
6 month time point was critical
361 patients with CP-CML on imatinib (320 with all data) reviewed at Princess Margaret Hosp. in Toronto
Kim D et al Am J Hematol 2014 ePub Mar 12

7. Slow and steady…
Kim D et al Am J Hematol 2014 ePub Mar 12

8. Does changing drugs at 3 months actually help?
210 CML-CP patients in 23 Australasian centers
All started on imatinib 600 mg
Series of time dependent MR targets (BCR-ABL IS):
≤10% at 3 months
≤1% at 6 months
≤0.1% at 12 months
If patients did not meet targets, either escalated to imatinib 800 mg QD or switched to nilotinib 400 mg BID
No difference in blast crisis between cohorts; small difference in proportion of pts achieving deep MR

9. NCCN guidelines have too many ‘ors’ to be helpful…
Panel achieved consensus about switching from imatinib at 3 months
No consensus about patients started on second generation TKIs

10. What to do instead of switching drugs
Step 1: Assess adherence
Which is the most important cell type
in determining relapse/progression of CML?

11. What to do instead of switching drugs
Step 1: Assess adherence
Step 2: Check for drug or food interactions

12. A surprising number of foods and drugs interact with the 3 first line TKIs: absorption, metabolism
Imatinib is metabolized mainly by CYP3A4; CYP2C9, CYP2C19, CYP2D6, and CYP3A5 have a minor role; it is a substrate of hOCT1, Pgp, and BCRP
Dasatinib is metabolized by CYP3A4 is a substrate of BCRP and Pgp
Nilotinib is metabolized by CYP3A4 and is a substrate of BCRP
All 3 are highly protein bound
Haouala A et al
Blood 2011; 117:e75-e87

13. What to do instead of switching drugs
Step 1: Assess adherence
Step 2: Check for drug interactions
Step 3: Consider ABL kinase mutation assay

14. ABL kinase mutation analysis aids in 2nd (or 3rd or 4th) line drug selection

15. So, if your patient doesn’t meet criteria for EMR at 3 months…

17. DFCI Adult Leukemia Clinical Program:
Richard Stone MD
Daniel Deangelo MD PhD
Martha Wadleigh MD
Gregory (Goyo) Abel MD MPH
R. Coleman Lindsley MD PhD
And other research collaborators
Sarah Cahill PA-C
Katherine Edmonds NP
Adriana Penicaud PA-C
Susan Buchanan PA-C
Ilene Galinsky NP &
Clinical Research Coordinators
Regulatory Team
Dana-Farber Cancer Institute
Thank you!