Outcomes of Patients with Suboptimal /Warning Response to Tyrosine Kinase Inhibitors: A Comparison of the 2009 and 2013 Guidelines of the European Leukemianet

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