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T.P. Hughes et al.
Table 2. Hypertension by occurrence of drug-related pleural effusion in dasatinib-treated patients with CML-CP in DASISION and 034/Dose-optimization.
Patients with baseline hypertension With PE
Without PE
With anti-hypertensive medication
With PE
Without PE
Without anti-hypertensive medication
With PE
Without PE
Patients without baseline hypertension
With PE
Without PE
CML-CP: chronic myeloid leukemia in chronic phase; PE: pleural effusion.
DASISION (n=258)
28 (11) 13 (46) 15 (54) 20 (71) 9 (45) 11 (55) 8 (29) 4 (50) 4 (50) 230 (89) 60 (26) 170 (74)
034/Dose-optimization (n=662)
61 (9) 24 (39) 37 (61) 40 (66) 18 (45) 22 (55) 21 (34) 6 (29) 15 (71) 601 (91) 196 (33) 405 (67)
Dasatinib-treated patients, n (%)
Table 3. Age by occurrence of drug-related pleural effusion in dasatinib-treated patients with CML-CP in DASISION and 034/Dose-optimization.
Age, years
Mean (standard deviation) 95% CI (mean)
Median (range)
95% CI (median)
DASISION (n=258) No PE (n=185)
43 (14)
(41-45)
41 (18-84)
(41-45)
034/Dose-optimization (n=662)
With PE (n=73)
55 (13)
(52-58)
56 (24-82)
(52-58)
No PE (n=442)
52 (15)
(50-53)
53 (18-84)
(50-53)
With PE (n=220)
58 (13)
(57-60)
60 (22-84)
(57-60)
CI: confidence interval; CML-CP: chronic myeloid leukemia in chronic phase; PE: pleural effusion.
Events Version 3.032 in DASISION and 034/Dose-optimization. Additional description of assessments and statistical analyses can be found in the Online Supplementary Material.
Each study protocol was approved by all institutional review boards, ethics committees, and national competent authorities at participating sites.
Results
Incidence of pleural effusion
DASISION. With a minimum of 5 years of follow up, 73 (28%) patients in DASISION reported drug-related pleural effusion (Table 1). One case of pleural effusion was not attributed to dasatinib by the investigator (Grade 2) and occurred >30 days after the last study dose was given. Most drug-related pleural effusions were Grade 1 (8%) or Grade 2 (17%), and no Grade 4 events were reported. The median duration of all first cases of drug-related pleural effusion was 4 weeks. The median daily dose of dasatinib for patients who developed drug-related pleural effusion was 100 mg, similar to the overall dasatinib-treated popu- lation.19
New cases of pleural effusion (any grade) occurred in 8% of patients receiving dasatinib in the first year of the study, and 6-9% each remaining year up to 5 years, sug- gesting a steady but continuous risk over time (Table 1). The proportion of patients with a recurrent (>1) drug-
related pleural effusion (any grade) was 62% (n=45/73). Of these, 16 patients had 2 separate events, 6 had 3 sepa- rate events, 4 had 4 separate events, and 19 had ≥5 sepa- rate events. Twelve patients discontinued due to recurrent pleural effusion. Of these patients, 9 had ≥3 recurring events. Dose interruptions and dose reductions due to pleural effusion occurred in 62% and 41% of patients, respectively.
034/Dose-optimization. With a minimum follow up of 7 years, drug-related pleural effusion (any grade) occurred in 33% of patients (Table 1). Although the median dose of dasatinib for patients with drug-related pleural effusion (any grade) was 100 mg daily (range 0-180 mg), pleural effusion rates varied across dosing groups in 034/Dose- optimization, with 28% (n=46/165) of patients experienc- ing any-grade pleural effusion in the 100 mg QD group and 35% (n=174/497) in the other groups. The median duration of first pleural effusion was 4 weeks. The major- ity of drug-related pleural effusions were Grade 1/2, and Grade 3/4 drug-related pleural effusions were reported in 48 (7%) patients in the total treated population. Of these, 8 occurred in the 100 mg QD group and 40 in the remain- ing groups. First occurrences of pleural effusion (any grade) occurred in 15% of dasatinib-treated patients in the first year of the study, and in 5-10% per year up to 7 years. Recurrent (>1) drug-related pleural effusion (any grade) occurred in 61% (n=134/220). Of these, 54 patients had 2 separate events, 31 had 3 separate events, 16 had 4 sepa-
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