Outcomes of Patients with Suboptimal /Warning Response to Tyrosine Kinase Inhibitors: A Comparison of the 2009 and 2013 Guidelines of the European Leukemianet
Authors: Ahaneku Hycienth O , Kantarjian Hagop M. , Nogueras González Graciela M. , Borthakur Gautam M. , Verstovsek Srdan , Kadia Tapan M. , Pemmaraju Naveen , Garcia-Manero Guillermo , Konopleva Marina Y , DiNardo Courtney D. , Naqvi Kiran , Sasaki Koji , Issa Ghayas C. , Jabbour Elias , Cortes Jorge E. 
Published: November 2019

Introduction
Since the advent of tyrosine kinase inhibitors (TKIs) in 2001, the treatment goals in the management of chronic myeloid leukemia (CML) have evolved according to international recommendations. The 2009 European LeukemiaNet (ELN) proposed a category of "suboptimal response". The 2013 recommendations introduced a "warning response" category that saw some "suboptimals" in 2009 becoming failures in 2013. The clinical implications of this intermediate category and the difference in categorizations has not been fully explored. As new recommendations are being prepared, we seek to compare the outcomes of patients with suboptimal/warning using 2009 and 2013 guidelines.
Methodology
We analyzed 730 patients treated with front-line TKIs in various clinical trials and identified patients who meet the criteria for suboptimal response at 3, 6 and 12 months according to the 2009 ELN guidelines and/or warning criteria according to 2013 ELN criteria. We computed descriptive statistics for patients at each of the above criteria at the 3 time points. Kaplan-Meier product limit method, was used to estimate the median for overall survival (OS), event-free survival (EFS), failure-free survival (FFS) and transformation-free survival (TFS).
Results
Of the 730 CML patients evaluated, using the 2009 ELN guidelines, 2%, 3% and 5% of the patients met the 3, 6 and 12 months definition of suboptimal response, respectively. Analysis of baseline characteristics show a median age of 44.1, 42.1 and 44.4 years, respectively for the three time lines with a predominantly male and white population. Using the 2013 guidelines 4%, 10% and 17% of the patients met the 3, 6 and 12 months definition of warning, respectively. Patients were again predominantly male and white with a median age at diagnosis of 41.5, 44.1 and 47 years respectively.
With regard to achieving complete cytogenetic response (CCyR), a higher percentage of patients achieved CCyR using the 2013 guidelines (55.2%, 80.8% and 98%, for warning cohorts at 3, 6 and 12 months, respectively) compared to using the 2009 guidelines (35.3%, 56.5% and 81.1%, respectively). Similarly, for best molecular response, a higher percentage of patients achieved MR4.5 using the 2013 guidelines (10.7%, 20.8% and 44.2%, for warning cohorts at 3, 6 and 12 months, respectively) compared to using the 2009 guidelines (13.3%, 4.5% and 24.2%, for suboptimal cohorts respectively).
With respect to survival outcomes, patients classified as warning per the 2013 guidelines had better outcomes than those with suboptimal response using the 2009 guidelines. For example, for EFS, median survival was longer for the 2013 warning cohort compared to the 2009 suboptimal cohort (29 months vs. 18 months, by 3 months assessment). For FFS, the median survival was longer for the 2013 warning cohort compared to the 2009 suboptimal cohort (68 months vs. 11 months, by 6 months assessment). Using the 2013 guidelines median survival could not be reached for most of the survival outcomes.
Conclusion
Our assessment reveal that survival outcomes were better for the warning cohort using the ELN 2013 recommendations compared to the suboptimal cohort of the 2009 recommendations. This represents a stage migration by moving the subset of patients with the worse outcome away from this intermediate category and into the failure. An important, still unanswered question, is the optimal management of patients in this intermediate category or of those that migrate from one category to the next based on a change in definitions.

Disclosures
Kantarjian: Ariad: Research Funding; Amgen: Honoraria, Research Funding; Immunogen: Research Funding; AbbVie: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Astex: Research Funding; Cyclacel: Research Funding; Pfizer: Honoraria, Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Research Funding; BMS: Research Funding; Daiichi-Sankyo: Research Funding; Takeda: Honoraria; Novartis: Research Funding. Borthakur:Eli Lilly and Co.: Research Funding; NKarta: Consultancy; PTC Therapeutics: Consultancy; Cyclacel: Research Funding; Eisai: Research Funding; Janssen: Research Funding; Agensys: Research Funding; Oncoceutics: Research Funding; Tetralogic Pharmaceuticals: Research Funding; Bayer Healthcare AG: Research Funding; BMS: Research Funding; AbbVie: Research Funding; Merck: Research Funding; GSK: Research Funding; Incyte: Research Funding; Arvinas: Research Funding; BioTheryX: Membership on an entity's Board of Directors or advisory committees; Xbiotech USA: Research Funding; Novartis: Research Funding; AstraZeneca: Research Funding; Argenx: Membership on an entity's Board of Directors or advisory committees; Polaris: Research Funding; Cantargia AB: Research Funding; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Oncoceutics, Inc.: Research Funding; Strategia Therapeutics: Research Funding. Verstovsek:Blueprint Medicines Corp: Research Funding; Celgene: Consultancy, Research Funding; Gilead: Research Funding; Promedior: Research Funding; CTI BioPharma Corp: Research Funding; Genetech: Research Funding; Sierra Oncology: Research Funding; Pharma Essentia: Research Funding; Roche: Research Funding; NS Pharma: Research Funding; Incyte: Research Funding; Astrazeneca: Research Funding; Ital Pharma: Research Funding; Protaganist Therapeutics: Research Funding; Constellation: Consultancy; Pragmatist: Consultancy; Novartis: Consultancy, Research Funding. Kadia:BMS: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bioline RX: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Research Funding. Pemmaraju:abbvie: Consultancy, Honoraria, Research Funding; samus: Research Funding; celgene: Consultancy, Honoraria; cellectis: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; novartis: Consultancy, Research Funding; plexxikon: Research Funding; Daiichi-Sankyo: Research Funding; sagerstrong: Research Funding; affymetrix: Research Funding; mustangbio: Consultancy, Research Funding; incyte: Consultancy, Research Funding. Garcia-Manero:Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. Konopleva:Agios: Research Funding; Ablynx: Research Funding; Astra Zeneca: Research Funding; Kisoji: Consultancy, Honoraria; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Ascentage: Research Funding; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Cellectis: Research Funding; Amgen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Eli Lilly: Research Funding; Forty-Seven: Consultancy, Honoraria; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Calithera: Research Funding. DiNardo:notable labs: Membership on an entity's Board of Directors or advisory committees; jazz: Honoraria; medimmune: Honoraria; syros: Honoraria; daiichi sankyo: Honoraria; abbvie: Consultancy, Honoraria; celgene: Consultancy, Honoraria; agios: Consultancy, Honoraria. Sasaki:Otsuka: Honoraria; Pfizer: Consultancy. Jabbour:Takeda: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Cyclacel LTD: Research Funding. Cortes:Immunogen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Sun Pharma: Research Funding; Biopath Holdings: Consultancy, Honoraria; BiolineRx: Consultancy; Pfizer: Consultancy, Honoraria, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Merus: Consultancy, Honoraria, Research Funding; Forma Therapeutics: Consultancy, Honoraria, Research Funding.