Dose Adjustment and Treatment Interruptions Associated with Second-Line Nilotinib or Dasatinib In Real-World Treatment of Chronic Myeloid Leukemia

Nilotinib and dasatinib are second-generation tyrosine kinase inhibitors (TKI) indicated for the treatment of chronic phase (CP) and accelerated phase (AP) Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) patients resistant to or intolerant of first-line therapy with imatinib. Dasatinib is also indicated for treatment of blast crisis (BC) patients. The recommended dose of nilotinib for treatment of resistant or intolerant Ph+ CML-CP is 400 mg twice daily. The current recommended starting dose of dasatinib for second-line therapy of Ph+ CML-CP is 100 mg once daily, and for Ph+ CML-AP or BC is 140 mg once daily. Some patients may experience treatment-related adverse events at the recommended doses of nilotinib or dasatinib, necessitating a dose reduction or interruption of treatment. Therefore, patients may not be receiving the full approved therapeutic doses. There is no available information comparing dose modifications or interruption of treatment between nilotinib and dasatinib. The objective of this study was to compare the frequency of dose adjustments and treatment interruptions between nilotinib and dasatinib in second-line therapy in CML patients from a clinical practice setting perspective.

Two claims databases were combined (MarketScan and Ingenix Impact, 01/2002-12/2008) to identify patients diagnosed with CML (ICD-9 code 205.1x) and who had received ≥1 prescription of nilotinib or dasatinib. Patients were required to have continuous enrollment ≥1 month prior to and after the index date. The index date was defined as the first prescription for nilotinib or dasatinib. Two patient cohorts were created based on patient's index treatment. Dasatinib data prior to the 100 mg once daily approval date were excluded from the analysis. Patients were followed for up to 6 months from the index date to the earliest of the termination of health care plan enrollment, or end of data availability. Dosage characteristics, including any dose changes from index prescription, defined as either an increase or decrease in the delivered dose and average dose were calculated during the study period. A ≥15% dose decrease in average dose is selected for comparison between the two groups as it is the mean of the lowest absolute dose change. Dose adjustments were further characterized in relation to the incidence and frequency of hematological and non-hematological events during the study period.

Data were analyzed for 514 patients receiving a second-line TKI (67 nilotinib, 447 dasatinib). Baseline characteristics were similar between the groups. Seven patients (2 nilotinib, 5 dasatinib) were excluded due to missing dosage information. Patients treated with dasatinib had more follow-up days in the study period than nilotinib-treated patients (mean ± standard deviation [SD], 162 ± 39 days versus 143 ± 51 days; P = 0.0003). There were no differences between the number of patients treated with nilotinib or dasatinib who had any dose adjustments over the study period (P = 0.8424). Stratification of the data by percent of adjustment revealed statistically significant differences between the two treatment groups. Eighty-nine (19.9%) patients treated with dasatinib had at least one dose reduction of at least 15% compared with 4 patients (6.0%) treated with nilotinib (P = 0.0057). Dasatinib-treated patients with at least 15% dose reduction experienced a mean ± SD of 0.24 ± 0.52 dose decreases compared with 0.06 ± 0.24 dose decreases for patients who received nilotinib (P = 0.0055). However the time to first dose reduction was longer for dasatinib users than for nilotinib users (15.1 ± 37.5 days vs. 7.5 ± 31.5 days, P = 0.0194). Dose decreases occurred within 30 days of a hematological or non-hematological event in 49.5% of patients.

These data demonstrate that more CML patients treated second-line with dasatinib experienced dose reductions of at least 15% than patients treated second-line with nilotinib, and that fewer dose reductions were required by the nilotinib users. Although this study did not assess the specific reasons for dose change, dose reductions are frequently associated with hematological or non-hematological events. Future studies may also investigate the relationship between response to treatment and dose reduction for the two TKIs.

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