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Pleural effusion in dasatinib-treated CML patients
rate events, and 33 had ≥5 separate events. In all 034/Dose-optimization dose groups, discontinuation due to recurrent pleural effusion occurred in 46 (7%) patients.
The cumulative incidence rate of pleural effusion was lower in the 100 mg QD group than in dose groups and increased over time (at 2 years 15% vs. 24%, respectively; at 7 years 27% vs. 36%, respectively). Similarly, the cumu- lative incidence rate of Grade 3/4 pleural effusion was lower in the 100 mg QD group than in the other dose groups (at 7 years 5% vs. 9%, respectively), and increased over time (at 2 years 2% vs. 4%, respectively; at 5 years 4% vs. 7%, respectively). Within year 7 of the study, new cases of pleural effusion occurred in 5% (2/42) of patients at risk treated with dasatinib 100 mg QD and in 8% (7/91) of patients at risk in the other treatment arms. The cumu- lative rates of drug-related pleural effusion over time for the 100 mg QD arm were 14% at 2 years, 24% at 5 years, and 28% at 7 years. For the other treatment arms, the cumulative rates of drug-related pleural effusion over time were 24% at 2 years, 32% at 5 years, and 35% at 7 years.
The incidence of pleural effusion was also lower in ima- tinib-intolerant and imatinib-resistant patients receiving 100 mg QD than in the other dose groups. Pleural effusion (any grade) was reported in 19% of patients who were imatinib-intolerant in the 100 mg QD arm and in 43% of imatinib-intolerant patients in the other dose groups, while pleural effusion (any grade) was reported in 31% of imatinib-resistant patients in the 100 mg QD arm and in 35% in the other dose groups. Pleural effusions were man- aged with dose interruptions in 44% of patients.
Pooled population of patients with Ph+ leukemia. Eleven dasatinib clinical trials of patients with Ph+ leukemia, including the DASISION and 034/Dose-optimization tri- als, were pooled for this analysis to include the largest number of dasatinib-treated patients possible. Pleural effu- sion of any grade from any cause occurred in 946 patients (35%), 553 (34%) with CML-CP and 393 (36%) with CML-AP/BP or Ph+ ALL. Grade 3/4 pleural effusions were reported in 223 (8.2%) patients, 119 (7%) with CML-CP, and 104 (10%) with CML-AP/BP or Ph+ ALL. Deaths due to pleural effusion were reported in 5 (<1%) patients, all with CML-AP/BP or Ph+ ALL (4 were not receiving the cur- rently approved dose of 140 mg QD dasatinib1). Drug- related pleural effusion of any grade occurred in 538 (33%) patients with CML-CP and 345 (32%) with CML-AP/BP or Ph+ ALL (883 [33%] patients total). Grade 3/4 drug- related pleural effusion episodes were reported in 114 (7%) patients with CML-CP and 93 (9%) patients with CML-AP/BP or Ph+ ALL (207 [8%] patients in total). One drug-related death was reported (<1%) in a patient with CML-AP/BP or Ph+ ALL.
Risk factors for pleural effusion
Based on risk factors for pleural effusion in dasatinib- treated patients described in literature,9,11-13 retrospective multivariate analyses were performed to investigate the association between pleural effusion and baseline hyper- tension, age, and lymphocytosis in patients treated with dasatinib, as well as additional variables of interest includ- ing sex, region, dosing schedule (034/Dose-optimization only), baseline Euro (Hasford) risk scores (DASISION only), exposure to interferon alpha (034/Dose-optimiza- tion only), BCR-ABL1 levels, baseline parameters, major molecular response (MMR) at 12 months, line of therapy, duration of prior TKI therapy, and depth of MR at any
time. Average daily dose, prior skin rash, and prior autoimmune or lung disease were assessed in the DASI- SION/034/Dose-optimization pooled population only.
DASISION. In DASISION, 28 (11%) patients had hyper- tension, and 13 of 28 (46%) patients with hypertension developed drug-related pleural effusion (Table 2). Of the 13 patients who developed pleural effusion, 9 were taking antihypertensive medications. When the relation between hypertension and pleural effusion was assessed in a mul- tivariate analysis, there was no significant association found (Figure 1A). Pulmonary hypertension was reported in 14 (5%) dasatinib-treated patients, 9 of whom had pleu- ral effusion. One patient with pulmonary hypertension underwent right heart catheterization in order to confirm pulmonary arterial hypertension (PAH); however, the pro- cedure did not support a diagnosis of PAH. Twelve of the 14 pulmonary hypertension diagnoses were drug related.19 In DASISION, the correlation between pulmonary hyper- tension and pleural effusion was not confirmed.
The median age of patients who developed drug-related pleural effusion in DASISION was 56 years, whereas for patients who did not develop pleural effusions it was 41 years (Table 3). Of significance, older age was found to be a risk factor for developing pleural effusion (odds ratio [OR] 1.067; 95% confidence interval [CI] 1.041-1.094; Figure 1A). These results were confirmed using a reduced model multivariate analysis.
In DASISION, 29 (11%) patients had lymphocytosis at any time prior to pleural effusion, and 0 patients devel- oped lymphocytosis after. However, lymphocytosis was not found to be a significant risk factor for the develop- ment of pleural effusion by multivariate analysis (Figure 1A).
Of the patients receiving 100 mg QD dasatinib in the DASISION trial, 86 (33%) patients had low-risk Euro scores, 124 (48%) had intermediate-risk Euro scores, and 49 (19%) had high-risk Euro scores.16 Using a reduced model multivariate analysis, patients with intermediate- risk Euro scores were not found to be at an increased risk of developing pleural effusion compared with patients with low-risk Euro scores. Similarly, no association was observed between pleural effusion and patients with high- risk Euro scores compared with patients with low-risk Euro scores.
The remaining variables investigated via multivariate analysis were found not to have an association with pleu- ral effusion (Figure 1A).
034/Dose-optimization. Similar to DASISION, no signifi- cant association between pleural effusion and hyperten- sion was found for patients in 034/Dose-optimization treated with dasatinib 100 mg QD, the currently approved dose for CML-CP1 (Figure 1B). Twenty-four of 61 (39%) patients from any treatment arm with hypertension devel- oped drug-related pleural effusion (Table 2). Of these 24 patients, 18 were taking antihypertensive medication. Pulmonary hypertension (any grade) was reported in 3 (2%) patients in the 100 mg QD dose group and in 13 (3%) patients in the other dose groups.23 One patient (<1%) in the 100 mg QD dose group reported severe drug- related PAH, confirmed with a right heart catheterization procedure.23 Similar to DASISION, the association between pulmonary hypertension and pleural effusion was not confirmed in these patients.
In 034/Dose-optimization, the median age of all patients who developed drug-related pleural effusion was
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