Phase III EURO-SKI: Cessation of TKI Therapy Safe, Feasible for Pts Who Achieve Deep Molecular Response New Findings in Hematology: Independent Conference Coverage of ASH 2016*; December 3-6, 2016; San Diego, California *CCO is an independent medical education company that provides state-of-the-art medical information to healthcare professionals through conference coverage and other educational programs. CML, chronic myeloid leukemia; TKI, tyrosine kinase inhibitor. This activity is supported by educational grants from Amgen, Celgene Corporation, Incyte, Merck, and Seattle Genetics.

EURO-SKI: TKI Cessation in CML—Background TKIs are standard of care in pts with CML[1] First generation: imatinib; second generation: nilotinib, dasatinib NCCN guidance currently recommends TKI therapy is continued indefinitely in CML pts who respond optimally[2] Whether TKIs may be discontinued in pts with DMR, and how to identify candidates for treatment cessation, is under investigation[3] Results from the STIM1 interventional study showed imatinib discontinuation to be safe in pts with a sustained DMR ≥ 2 yrs[4,5] To define preconditions for TKI discontinuation, current phase III EURO-SKI study assessed the effects of stopping TKI therapy in CML pts with DMR for ≥ 1 yr[6] CML, chronic myeloid leukemia; DMR, deep molecular responses; EURO-SKI, European Stop Kinase Inhibitor trial; TKI, tyrosine kinase inhibitor. 1. Rosti G, et al. Nat Rev Clin Oncol. 2016;[Epub ahead of print]. 2. NCCN. Clinical practice guidelines in oncology: chronic myelogenous leukemia. v.1.2015. 3. Mahon FX. Best Pract Res Clin Haematol. 2016;29:308-313. 4. Mahon FX, et al. Lancet Oncol. 2010;11:1029-1035. 5. Etienne G, et al. J Clin Oncol. 2016;[Epub ahead of print]. 6. Mahon FX, et al. ASH 2016. Abstract 787. Slide credit: clinicaloptions.com

EURO-SKI: Study Design Multicenter, open-label phase III interventional trial Adult pts recruited at multiple European sites in ELN May 2012 to Dec 2014 Eligible pts had CML with use of TKIs ≥ 3 yrs and MR4 for ≥ 1 yr MR4: DMR defined as 4-log reduction of BCR-ABL transcript n = 758 pts included in descriptive statistics (registered N = 821) Pts consenting to stop TKI monitored for molecular recurrence, defined as loss of MMR (BCR-ABL > 0.1%) on 1 assessment MR4 confirmed by central lab prior to stopping TKI Following TKI cessation, monitored by RQ-PCR Q4W, then Q6W during Yr 1; then every 3 mos in Yrs 2 and 3 CML, chronic myeloid leukemia; DMR, deep molecular response; ELN, European LeukemiaNet; EURO-SKI, European Stop Kinase Inhibitor trial; MR, molecular response; MMR, major molecular response; RQ-PCR, real-time quantitative PCR; MR4, 4-log reduction in BCR-ABL transcripts; TKI, tyrosine kinase inhibitor. Slide credit: clinicaloptions.com Mahon FX, et al. ASH 2016. Abstract 787.

EURO-SKI: Baseline Characteristics Pts (N = 758) Male, % 52.2 Median age at diagnosis, yrs (range) 52 (11-85) Median age at TKI cessation, yrs (range) 60 (19-90) Median time from diagnosis to TKI cessation, yrs (range) 7.7 (3.1-22.6) Median duration of TKI therapy, yrs (range) 7.5 (3.0-14.2) Median duration of MR4 prior to TKI cessation, yrs (range) 4.7 (1.0-13.3) EURO-SKI, European Stop Kinase Inhibitor trial; MR4, 4-log reduction in BCR-ABL transcripts; TKI, tyrosine kinase inhibitor. Slide credit: clinicaloptions.com Mahon FX, et al. ASH 2016. Abstract 787.

EURO-SKI: Molecular Recurrence Following TKI Cessation 755 pts were followed for a median of 14.9 mos (range: 0.9-36) 378 pts without events were followed for a median of 26.0 mos (range: 1.1-36.0) 78.3% (296/373) of pts with molecular recurrence lost MMR within 6 mos of TKI cessation Outcomes Following TKI Cessation, n Pts (n = 755) Loss of MMR 373 Death during remission 4 Total events 377 EURO-SKI, European Stop Kinase Inhibitor trial; MMR, major molecular response; TKI, tyrosine kinase inhibitor. Slide credit: clinicaloptions.com Mahon FX, et al. ASH 2016. Abstract 787.

EURO-SKI: MRFS and Cumulative MR Incidence Mos Since TKI Cessation (Pts at Risk, n = 755), % (95% CI) MRFS Cumulative MR 6 mos (n = 467) 61 (58-65) 39 (35-42) 12 mos (n = 396) 55 (51-58) 45 (41-48) 18 mos (n = 333) 52 (49-56) 47 (44-54) 24 mos (n = 219) 50 (47-54) 49 (45-52) 36 mos (n = 31) 47 (43-51) 52 (48-55) Likelihood of MRFS significantly predicted by duration of imatinib therapy (optimal ≥ 5.8 yrs), MR4 duration, duration of pretreatment IFN by univariate analysis, in 448 first-line imatinib pts (P < .001 for all) No significant association with age, sex, depth of MR, components of Sokal, EURO, EUTOS, or ELTS score ELTS, EUTOS Long-Term Survival score; EURO-SKI, European Stop Kinase Inhibitor trial; EUTOS, European Treatment Outcome Study; IFN, interferon; MR4, 4-log reduction in BCR-ABL transcripts; MR, molecular recurrence; MRFS, molecular recurrence-free survival; TKI, tyrosine kinase inhibitor. Slide credit: clinicaloptions.com Mahon FX, et al. ASH 2016. Abstract 787.

EURO-SKI: Safety Among pts restarting TKI therapy, 86% (321/373) achieved MMR and 80.1% (302/373) achieved MR4 at last assessment Outcomes Following TKI Cessation, n Pts BCR/ABL > 1% 72 Loss of CCR 11 Restarted TKI without loss of MMR 14 Progression to accelerated phase or blast crisis Total deaths on trial 10 CML-related deaths CCR, complete cytogenetic response; MMR, major molecular response; MR4, 4-log reduction in BCR-ABL transcripts; TKI, tyrosine kinase inhibitor. Slide credit: clinicaloptions.com Mahon FX, et al. ASH 2016. Abstract 787.

EURO-SKI: Conclusions Of CML pts receiving TKIs ≥ 3 yrs with DMR for ≥ 1 yr, 61% were free of MR at 6 mos and 55% were free of MR at 12 mos after TKI cessation In pts receiving imatinib, likelihood of MRFS 6 mos after TKI cessation was significantly predicted by Longer duration of imatinib therapy (optimal ≥ 5.8 yrs) Longer MR4 duration Longer duration of pretreatment IFN Investigators conclude that cessation of TKI therapy appears feasible, safe based on this large cohort of CML pts Among pts restarting TKI therapy after cessation and loss of MMR, 86% achieved MMR and 80.1% achieved MR4 at last assessment CML, chronic myeloid leukemia; DMR, deep molecular response; IFN, interferon; MMR, major molecular response; MR, molecular recurrence; MR4, 4-log reduction in BCR-ABL transcripts; MRFS, molecular recurrence-free survival; TKI, tyrosine kinase inhibitor. Slide credit: clinicaloptions.com Mahon FX, et al. ASH 2016. Abstract 787.

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