Dosing Patterns of Dasatinib Use in Simplicity, an Observational Study in Chronic Phase Chronic Myeloid Leukemia (CP-CML) Patients (pts) in Routine Clinical Practice
Authors: Cortes Jorge E. , Chen Clara , Mauro Michael J. , Sen Ginny P , Gajavelli Srikanth , Davis Catherine , Goldberg Stuart L. 
Published: October 2019

Abstract
Introduction: Treatment dosing patterns have not been well documented among dasatinib-treated CP-CML pts outside of clinical trials. SIMPLICITY (NCT01244750) is an ongoing observational study of CP-CML adult pts in routine clinical practice receiving tyrosine kinase inhibitors (TKI) since 2010 in the US and Europe, exploring TKI use and management patterns in clinical practice. This analysis reports on dosing patterns of dasatinib and explores potential predictors of dose reductions.
Methods: Only pts enrolled in the SIMPLICITY observational study who received first-line (1L) and second-line (2L) dasatinib once daily (n=417) were reviewed to determine dosing patterns. Eleven pts were excluded from the analysis because they were not on a dasatinib once-daily regimen. Longitudinal data were used to determine dose changes. Results are presented according to the first change in dose. No restrictions or instructions regarding dosing were required per enrollment. Results are presented descriptively. Statistical comparisons were made using t-tests and the Mann-Whitney U test for continuous variables and chi-square for categorical variables. Logistic regression models were used to identify factors associated with dose reduction.
Results: Of the 406 pts treated with 1L dasatinib (QD), 374 (92.1%) started at 100 mg (Table 1); 318 (78%) remained on dasatinib at Year 1 and 259 (63.8%) at Year 2. The majority (64.4%) remaining on100 mg. Median follow-up was 59 months (IQR: 49, 61). Of the 25 (6.2%) pts who started on <100 mg, 12 started on 50 mg and 8 on 70 mg. Of the 7 (1.7%) who started at >100 mg, 6 started on 140 mg. Median age at start of 1L TKI differed between pts who started on 100 mg (55.2 yrs), <100 mg (73.7 yrs), and >100 mg (49.2 yrs; p<0.0001; Table 1). EU pts were more likely to start with a lower dose vs US pts (p<0.001): with 84.4% vs 95.0% starting on 100 mg; 13.8% vs 3.4% on <100 mg and 1.8% vs 1.7% on >100 mg, respectively. Of the 374 pts who started 1L dasatinib at 100 mg, 133 (35.6%) changed dose; 124 (33.2%) pts received a dose reduction and nine (2.4%) a dose increase (Table 1). Median time to dose reduction was 4.7 months (IQR: 1.5, 19.5): 51.6% pts (n=64) experienced a dose reduction in the first 6 months; 12.9% (n=16) between 6-12 months; 15.3% (n=19) between 12-24 months and 20.2% (n=25) after 24 months. Pts remained on a reduced dose for a median of 47.6 months (Table 2). Among the 33% that experienced dose reductions, the primary reasons for dose reduction were adverse events (63.7%; n=79), side effect/clinical complication (9.7%; n=12) and other clinical decisions, including stable MR4.5 (11.3%; n=9.7%; Table 1). Age (mean, p=0.003; median p=0.001) and male gender (p=0.02) at baseline were associated with dose reduction. Multivariate logistic regression analysis of the 1L dasatinib population, adjusted for covariates revealed that older age at start of 1L TKI (p=0.004) and fatigue at baseline (poorer performance status; p=0.02), were strong predictors for dose reduction (Table 1). Gender was a weak predictor for dose reduction (p=0.06; Table 1). Of the 202 pts receiving 2L dasatinib (QD), 25 (12.4%) started at <100 mg. Median follow-up was 57.4 months (IQR: 46.5, 60.8). Of these, 12 (48%) pts started on 50 mg and 10 (40%) on 70 mg. Of the 166 pts who started 2L dasatinib at 100 mg, 41 (24.7%) changed dose. Thirty-nine pts received a dose reduction (50 mg, n=18 [46.2%]; 70 mg, n=6 [15.4%]) and two a dose increase. Among the 23% receiving a dose reduction, intolerance (n=27; 69.2%) and other clinical decisions, including stable MR4.5 (n=6; 15.4%) were the primary reasons for dose reduction. There was a non-significant difference in median age between pts who started 2L dasatinib at 100 mg, <100 mg, and >100 mg, but otherwise they were similar in terms of other baseline characteristics.
Conclusions: Now that long-term survival has been achieved in pts with CML, the focus of clinical practice is shifting to dose optimization, with the goal of maintaining response while improving quality of life. Among the majority of pts who started dasatinib at 100 mg (QD) in 1L, 64.4% received only 100 mg; 33.1% received a dose reduction, and 2.4% received a dose increase; similar patterns were observed for 2L pts. Within the population experiencing a dose reduction, intolerance was the principal reason. Age at start of 1L TKI and fatigue in baseline (poorer performance status) were strong predictors of dose reduction, while gender was a weak predictor.

Disclosures
Cortes: Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding; Arog: Research Funding; Daiichi Sankyo: Consultancy, Research Funding. Chen:Bristol-Myers Squibb: Employment. Mauro:Pfizer: Consultancy; Bristol-Myers Squibb: Consultancy; Novartis: Consultancy, Research Funding; Takeda: Consultancy. Sen:ICON PLC: Employment. Gajavelli:Bristol-Myers Squibb: Employment. Davis:Bristol-Myers Squibb: Employment. Goldberg:COTA Inc.: Employment, Equity Ownership.