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Pleural effusion in dasatinib-treated CML patients
ular responses in the 034/Dose-optimization trial for patients who had drug-related pleural effusion events versus patients who did not were similar, although a trend showed slightly higher molecular responses for those who experienced pleural effusions. The duration of MMR was 34 months for those with 1 drug-related pleural effusion, and 42 months for those with >1 (Table 4). At the end of the 034/Dose-optimization 7-year study, PFS for dasa- tinib-treated patients who experienced drug-related pleu- ral effusion events was similar to PFS for patients who did not experience effusion events (Online Supplementary Figure S2A). Among patients who had drug-related pleural effusion, 93/220 (42%) progressed, compared with 220/442 (50%) patients who did not have pleural effusion but did progress. Seven-year OS in 034/Dose-optimiza- tion was similar across patients with and without drug- related pleural effusion (Online Supplementary Figure S2B).
As seen in DASISION, patients in 034/Dose-optimiza- tion were able to achieve responses prior to their first event, and these responses were maintained or improved following the pleural effusion in some patients (Online Supplementary Table S3). One hundred and sixteen patients (53% of patients with a drug-related pleural effusion evaluable for efficacy endpoints) had CCyR, 66 (30%) had MMR, and 15 (7%) had MR4.5 prior to experiencing a first case of pleural effusion. Following the effusion, 55 patients maintained or improved to CCyR and 9 patients lost CCyR. Changes in the depth of molecular response were also similar: 55 patients maintained/improved to MMR, and 31 patients maintained/improved to MR4.5. Three patients went from MMR to BCR-ABL1 0.1-≤1% following their first pleural effusion event. Of these patients, all had BCR-ABL1 >0.1% after their first event. Two patients in 034/Dose-optimization were excluded from the efficacy analysis because the date of onset of pleural effusion was not captured.
Discussion
Pleural effusion has been reported in dasatinib-treated patients at any time during the course of treatment, though the severity is generally mild to moderate. Grade 1 effusions are often asymptomatic and may not have been picked up in the absence of routine chest X-rays (only required in the DASISION trial), potentially reduc- ing the incidence of clinically significant effusions in this patient population. However, we cannot comment that Grade 1 pleural effusions would not progress with time. The risk of pleural effusion remains even after long-term dasatinib treatment in effusion-naive patients; thus, main- taining awareness of the risk is important.
As fluid retention events have been reported with most BCR-ABL1-targeted TKIs, it is tempting to attribute the occurrence of pleural effusion to a class effect on fluid overload. However, an immune-mediated mechanism is more likely for dasatinib-related pleural effusion, as exu- date containing high lymphocyte counts (predominantly natural killer cells) and chyle accumulate have been report- ed in pleural fluids and tissue from patients on dasa- tinib.15,33,34 Pleural effusion developed slightly more often in patients with lymphocytosis than in patients without lymphocytosis (33% with lymphocytosis vs. 26% with- out lymphocytosis) in the DASISION trial, although this difference was not statistically significant.35 We found that
lymphocytosis occurred during therapy, which appears to represent a risk factor for pleural effusion because it pre- ceded pleural effusion events.
Through multivariate analyses, we determined that race, sex, region, exposure to interferon, BCR-ABL1 levels at 3 months, lymphocytosis, colitis, history of autoim- mune disease, history of lung disease, history of skin rash, baseline smoking history, MMR at 12 months, average daily dose, line of therapy, baseline Euro risk scores, and duration of prior TKI therapy were not associated with an increased risk of pleural effusion. Other risk factors for pleural effusion previously described include advanced disease, heart disease, and hypercholesterolemia.10,12-14 It is difficult to analyze the association between the incidence of pleural effusion and the depth of molecular response achieved without correcting for the time of dasatinib exposure, given that most patients achieving deep molec- ular responses are typically on dasatinib longer and would therefore be expected to have a greater risk of developing pleural effusion. To address this, we evaluated MMR at 12 months as a potential risk factor; however, no associa- tion was observed. We found second-line patients with previous intolerance of imatinib to be at an increased risk of developing pleural effusion compared with first-line patients, although no association was observed for sec- ond-line imatinib-resistant patients. Finally, although effu- sions can develop in adults at any age, we determined that advanced age was the only significant patient risk factor for pleural effusion, particularly in those treated with 100 mg/day of dasatinib. Additional potential risk factors, such as a history of hypertension, can develop during treatment with dasatinib, and should be considered when evaluating individual patients, though the association between pleural effusion and hypertension was not sub- stantiated in this analysis.
Dasatinib dose, as a potential risk factor for pleural effu- sion, is of special interest. Wang et al. noted that pleural effusion was associated with trough drug concentrations, indicating that dasatinib pharmacokinetics may play a role in the development of pleural effusion.13 We did not find dasatinib dose to be a risk factor for the development of pleural effusion in the pooled population of patients ini- tially treated with 100 mg QD dasatinib. However, since patients with advanced disease in the pooled population of dasatinib-treated patients with Ph+ leukemia described here were treated with higher doses of dasatinib (up to 240 mg daily) than patients with CML-CP, dasatinib dose may still be associated with the increased rate of Grade 3/4 pleural effusions observed. Also, we reported that pleural effusion (any grade) was observed in a lower percentage of patients in the 100 mg QD arm versus the other dose groups in 034/Dose-optimization. A retrospec- tive study evaluating the toxicity-guided administration of a reduced-dose dasatinib regimen in similar imatinib-resis- tant/intolerant patients revealed that on/off treatment sig- nificantly reduced pleural effusions.36 Furthermore, recent sub-analyses of DASISION revealed that dose reductions for adverse events, including pleural effusion, did not affect dasatinib efficacy,37,38 suggesting that it may be pos- sible to administer lower doses to populations at higher risk for pleural effusion development. Moreover, we found that the achievement of MMR and MR4.5 was found to be correlated with a higher risk of developing pleural effusion. This may be because patients without MMR may have discontinued dasatinib treatment earlier than
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