Analysis of Adverse Events of Dasatinib and Nilotinib in Chronic Phase Chronic Myeloid Leukemia Patients Treated Outside Clinical Trials

Background Patients with chronic myeloid leukemia (CML) encounter lifelong treatment. Incidence and severity of adverse events (AEs) of tyrosine kinase inhibitors (TKIs) are therefore one of the most important factors when making treatment decisions; yet studies focusing on AEs in "real life" setting and their impact on drug discontinuation and treatment outcomes are lacking.

Methods We retrospectively analyzed the rates and severity of AEs in 201 patients with chronic phase CML treated with nilotinib or dasatinib used as both first- and second-line therapy in two Korean tertiary care centers. AEs were graded according to Common Terminology Criteria for Adverse Events version 4.03. Event-free survival (EFS) was defined as the time from the start of the treatment to the earliest date of any of following event: treatment discontinuation due to AEs, loss of complete hematologic response (CHR), loss of major cytogenetic response (MCyR), loss of major molecular response (MMR), progression to accelerated phase (AP) or blastic phase (BP), discontinuation due to treatment failure as assessed by the clinician, and death from any cause on therapy. Progression-free survival (PFS) was defined as the time from the start of the treatment to the earliest date of any of following event: loss of CHR, MCyR, MMR, progression to AP or BP, discontinuation due to treatment failure as assessed by the clinician, and death from any cause on therapy.

Results There were 135 men (67%) and 66 women (33%). One-hundred and twenty (60%) received nilotinib (first line, n = 68; second line, n = 52) and 81 (40%) patients received dasatinib (first line, n = 37; second line, n = 44). For the majority of patients who received second line treatment with nilotinib and dasatinib, reason for imatinib discontinuation was resistance (81% in nilotinib group and 80% in dasatinib group). The median starting dose of nilotinib was 600mg/day (range 600 - 800mg/day) and dasatinib 100mg/day (range 100-140mg/day). During the median follow-up of 36.9 months (8.0 - 114.1) for nilotinib group and 37.2 months (2.2 - 95.0) for dasatinib group, 88.3% (106/120) of patients in nilotinib group and 86.4% (70/81) in dasatinib group experienced AEs. Dasatinib group had significantly higher grade 3-4 AEs compared to nilotinib group (21.7% vs. 54.3%, p < 0.001); however, rate of grade 3-4 non-hematological AEs were similar in both groups (13% vs. 14%, p = 0.960). Dasatinib group had more frequent dose reduction, interruption, and drug discontinuation (p < 0.001, p = 0.004, and p = 0.006, respectively).

At the time of analysis, 58 out of 201 (29%) discontinued treatment because of AEs (n = 47, 23%), resistance (n = 9, 5%), or other reasons (n = 2, 1%). Eighty one percent (47 out of 58) of drug discontinuation was due to AEs, and half of AE leading to drug discontinuation was grade 2. Treatment discontinuation occurred more rapidly in the first line setting than in the second line setting (duration of treatment, 2.9 months vs. 15.6 months, p = 0.015). Pleural effusion occurred in 35% (n = 28) in dasatinib group, and led to dasatinib discontinuation in 14 patients (Grade 2, n = 11; Grade 3, n = 3). One patient stopped dasatinib due to pulmonary artery hypertension. In nilotinib group, stroke, acute coronary syndrome and peripheral artery occlusive disease (PAOD) occurred in 5% (n = 6); only PAOD led to nilotinib discontinuation.

Dasatinib group had significantly shorter duration of EFS than nilotinib group (median EFS not reached [NR] vs. 48.7 months, p = 0.040 for first line treatment; NR vs. 50.5 months, p = 0.036 for second line treatment). However, PFS did not show statistically significant differences (p = 0.505 for first line and p = 0.179 for second line).

Conclusion AE was the main cause of nilotinib and dasatinib discontinuation in CML patients. Persistent grade 2 AEs, especially pleural effusion, were hard to manage and this translated into early discontinuation of drug especially in the first line setting and significantly shorter EFS in dasatinib treated patients compared to nilotinib treated patients. Large, prospective population based studies with long term follow-up are warranted to confirm our finding.