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

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

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?

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; 113:6315-6321 Marin D et al JCO 2012; 30:232-238 Hanfstein B et al Leukemia 2012; 26:2096-2102 Saglio G et al Blood 2012 [abstract 1675] Saglio G et al JCO 2013 (abstract 7054) Jain P et al Blood 2013; 121:4687-4874

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;30:232-238

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

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

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

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

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

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

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

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

ABL kinase mutation analysis aids in 2nd (or 3rd or 4th) line drug selection www.ilte-cml.org/TKI-table.pdf.

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

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!