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Journal of Clinical Oncology, Vol 25, No 25 (September 1), 2007: pp. 3908-3914 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.12.0329 Pleural Effusion in Patients With Chronic Myelogenous Leukemia Treated With Dasatinib After Imatinib Failure
From the Department of Leukemia and Department of Radiology, The University of Texas M.D. Anderson Cancer Center, Houston, TX. Address reprint requests to Alfonso Quintás-Cardama, MD, M.D. Anderson Cancer Center, Department of Leukemia, Unit 428, 1515 Holcombe Blvd, Houston, TX 77030; e-mail: aquintas{at}mdanderson.org
Purpose We investigated the risk factors and management of pleural effusion associated with dasatinib therapy for chronic myelogenous leukemia (CML) after failure of imatinib. Patients and Methods We analyzed 138 patients with CML treated with dasatinib from November 2003 to January 2006 in one phase I (n = 50) and four phase II (n = 88) studies for the development of pleural effusion. Results Pleural effusion occurred in 48 patients (35%; grade 3/4 in 23 [17%]), including 29% of those treated in chronic phase (CP), 50% in accelerated phase (AP), and 33% in blast phase (BP). By multivariate analysis, history of cardiac disease, hypertension, and use of a twice-daily schedule (v once daily) were identified as factors associated with development of pleural effusions. Effusions were exudative in 78% of the assessable cases. In some patients, effusions were associated with reversible increments of right ventricular systolic pressure. Management included transient dasatinib interruption in 83%, diuretics in 71%, pulse steroids in 27%, and thoracentesis in 19% of patients. Conclusion Pleural effusions occur during dasatinib therapy, particularly among patients in AP or BP. A twice-daily schedule may result in a higher incidence of pleural effusion. Close monitoring and timely intervention may allow patients to continue therapy and achieve the desired clinical benefit.
Imatinib induces complete cytogenetic responses (CCyR) in more than 80% of patients with chronic myeloid leukemia (CML) in chronic phase (CP).1 Although responses are usually durable, some patients eventually develop resistance.2-4 Dasatinib is an oral inhibitor of abl and Src family of kinases (SFK) recently approved by the US Food and Drug Administration for treatment of CML patients after imatinib failure.5,6 Dasatinib has a 2-log increased kinase inhibitory potency relative to imatinib and is active against most imatinib-resistant bcr-abl mutants, except T315I.6,7 In a phase I study, therapy with dasatinib in patients with imatinib-resistant CP CML induced complete hematologic response (CHR) in 92% and major cytogenetic response in 60%.6 The most common adverse effects were GI, peripheral edema, and myelosuppression.6,8,9 Pleural effusion was reported in 14% to 30% of patients, particularly among those treated in accelerated phase (AP) or blast phase (BP), with grade 3 to 4 effusion occurring in 19% of patients in CP and 28% in myeloid BP.8,9 Thus far, a systematic investigation of the predictive factors, management, and outcome of pleural effusion associated with dasatinib therapy is not available. To this end, we evaluated 138 consecutive patients with CML treated with dasatinib.
Study Group We analyzed all patients with CML treated with dasatinib at our institution from November 2003 to January 2006 in one phase I (n = 50) and four phase II (n = 88) studies. Patients were required to have experienced treatment failure with imatinib therapy because of hematologic/cytogenetic resistance or intolerance.6 Other entry criteria were as previously reported.6,8-10 Studies were approved by the institutional review board and conducted in accordance with the Declaration of Helsinki. All patients provided written informed consent before study entry.
Study Design
CBCs and serum chemistry evaluations were performed weekly for 12 weeks, then every other week for 3 months, then every 6 weeks. All patients underwent an ECG and chest x-ray (CXR) before starting dasatinib. A repeat CXR, with or without chest computed tomography (CT) scan, was obtained in the presence of dyspnea, chest pain, or respiratory symptoms. Patients with pleural effusion grade 2 or worse were evaluated by a pneumologist.
Evaluation of Pleural Effusion Pleural fluid samples were categorized as transudates or exudates according to the Light criteria.12 Specific diagnoses included (1) malignancy: documentation of malignant cells by cytology or flow cytometry; (2) chylous effusion: turbid effusion with triglycerides more than 110 mg/dL; (3) parapneumonic effusion: fever, new pulmonary infiltrate, ipsilateral effusion, and pleural fluid analysis with polymorphonuclear predominant exudate and an infectious agent isolated from respiratory tract specimens.
Statistical Analysis
A total of 138 patients (69 female) treated with dasatinib were included. Median age was 57 years (range, 15 to 81 years). Among 50 patients treated in the phase I study, 23 (46%) were in CP, seven (14%) in AP, and 20 (40%) in BP at the time dasatinib was initiated. Eighty-eight patients, 43 (49%) in CP, 25 (28%) in AP, and 20 (23%) in BP, received dasatinib in phase II studies. Fifteen patients (11%) started dasatinib at a dose less than 100 mg, 22 (16%) at 100 mg, 92 (67%) at 140 mg, and 9 (6%) at more than 140 mg daily. The median time receiving dasatinib therapy was 42 weeks (range, 4 to 120 weeks): 69 weeks (range, 18 to 120 weeks) for patients in the phase I and 34 weeks (range, 4 to 61 weeks) for those in phase II studies.
Characteristics of Pleural Effusion
Fluid analysis in nine of the 10 cases that required thoracentesis or pericardiocentesis revealed seven exudates (78%) and two transudates (22%; Table 3). Cytologic analysis revealed marked lymphocyte predominance (median, 90%; range, 69% to 100%). Neither malignant cells nor bacterial growth were demonstrated in any of them. One patient developed recurrent chylous effusions that required 12 thoracenteses. A thorough radiologic work-up failed to demonstrate any anatomic damage to the thoracic duct.
Eighteen patients had an echocardiogram at the onset of pleural effusion. All had a left ventricular ejection fraction (LVEF) within normal limits (range, 55% to 65%) before dasatinib therapy, except one patient with history of coronary artery disease (CAD) who had a baseline LVEF of 40% and decreased to 26% during the first episode of pleural effusion. When compared with baseline values (median, 29 mmHg; range, 21 to 44 mmHg), an increase in right ventricular systolic pressure (RVSP), a noninvasive surrogate marker of pulmonary artery pressure, was observed at the onset of pleural effusion (median, 42 mmHg; range, 25 to 75 mmHg; P = .0014). The LVEF remained unchanged in all patients at the time of pleural effusion. The patient in whom the LVEF dropped to 26% had an LVEF of 30% after resolution of the acute event. Discontinuation of dasatinib in 10 patients (83%) resulted in resolution of pleural effusion and a significant decrease in RVSP (median 30 mmHg; range, 22 to 40 mmHg; P = .01). The level of pro-brain (B-type) natriuretic peptide (BNP) was measured in the sera of 14 of 23 patients who developed grade 3 or worse pleural effusion. BNP levels are considered an accurate discriminator in identifying CHF as the cause of dyspnea, with a diagnostic accuracy of 83.4% at a cutoff of 100 pg/mL.13 The median level was 355 pg/mL (range, 26 to 2,800 pg/mL), and 11 patients (79%) had levels greater than 100 pg/mL at the time of pleural effusion. Pretreatment values were not available in any patient.
Relationship to CML Phase, Dasatinib Dose, and Schedule
Nine (24%) of 37 patients who received an initial daily dose of 100 mg or less developed pleural effusion (n = 3 grade 1, n = 1 grade 2, and n = 5 grade 3), compared with 39 (39%) of 101 who started dasatinib at 140 mg or more (n = 12 grade 1, n = 9 grade 2, n = 18 grade 3; P = .29; Table 4). Because the dasatinib dose could be modified according to response and/or toxicity, we analyzed the impact of dasatinib dose at the onset of pleural effusion. At this point, 39 (81%) of the 48 patients with pleural effusion were receiving a daily dasatinib dose of at least 140 mg (31 at 70 mg twice daily, four at 140 mg daily, and four at > 140 mg daily). In contrast, only nine patients (19%) receiving a daily dasatinib dose of 100 mg or less developed effusions (P < .0001). The median time from dasatinib start to pleural effusion onset was 73 weeks (range, 2 to 107 weeks) among patients receiving less than 140 mg and 4 weeks (range, 1 to 54 weeks) among those receiving at least 140 mg. Among the 23 patients with grade 3 or higher pleural effusion, 18 (78%) had received an initial daily dasatinib dose of at least 140 mg. Seventeen (94%) of these 18 patients received dasatinib 70 mg bid and only one received 140 mg daily. By univariate analysis, variables associated with risk of development of pleural effusion included age, hemoglobin, CML duration, prior history of cardiac disease, hypertension, CML phase, and dosing schedule (Table 5). In a multivariate analysis, prior cardiac history, hypertension, and a twice-daily dasatinib schedule were associated with increased risk of pleural effusion (Table 6). Notably, CML phase (CP v AP/BP) was associated with probability of development of pleural effusion by univariate analysis (P = .04), but not by multivariate analysis.
Management of Effusion Pleural effusion led to transient dasatinib interruptions in 40 patients (83%) (level 1 in six, level 2 in 18, level 3 in 13, level 4 in two, and level 5 in one; grade 3 to 4 in 20 [50%]) for a median of 27 days (range, 4 to 113 days). Dasatinib dose was reduced in 34 patients with pleural effusion (71%; five with level 1, 13 with level 2, 13 with level 3, two with level 4, and one with level 5; grade 3 to 4 in 17 [50%]). Fourteen patients (29%) required treatment interruptions on more than one occasion because of recurrent effusion. Dasatinib was interrupted for a median of 27 days (range, 4 to 113 days), although 11 patients who withheld dasatinib therapy had developed simultaneously grade 3 to 4 neutropenia (n = 6), thrombocytopenia (n = 2), lower GI bleed (n = 2), or elevated transaminases (n = 1) that contributed to dasatinib discontinuation beyond the resolution of pleural effusion in some patients. All 28 episodes of radiologic level 1 to 2 pleural effusion resolved on dasatinib discontinuation (n = 8), loop diuretics (n = 4), or both (n = 16). Seven of 10 patients in whom dasatinib was withheld received short courses of prednisone (40 mg daily for 4 days), resulting in disappearance of radiologic findings of pleural effusion in less than 72 hours. Among the 19 patients with larger effusions (level  3), three continued on dasatinib because of advanced disease and 16 interrupted dasatinib. All received diuretics (11 of them on a continuous basis while receiving dasatinib) and seven also received a short course of prednisone. The median time off-dasatinib among the seven patients who received steroids was 23 days, compared to 25 days for the 13 whose treatment was managed without steroids (P = .21). However, in some patients with recurrent effusions treated with and without steroids on different occasions, steroids provided a more rapid symptomatic relief than that provided by dasatinib discontinuation alone. Nine (19%) of the 48 patients (n = 4 CP, n = 1 AP, n = 4 BP) who developed pleural effusions (n = 2 level 2, n = 4 level 3, n = 2 level 4, and n = 1 level 5) required at least one therapeutic thoracentesis (median, 3 thoracenteses; range, 1 to 12 thoracenteses) because of dyspnea grade 3 or higher (Table 3). The median withdrawn fluid volume per thoracentesis was 1.5 L (range, 0.5 to 2 L). Two (4%) patients, who developed grade 3 pleural effusions, eventually had a Denver peritoneovenous shunt placed into the pleural space because of recurrent effusion. One patient with grade 4 pericardial effusion and level 2 pleural effusion required a pericardial window.
Drug-induced pleural effusion is an uncommon occurrence that has been linked to a relatively limited number of drugs.14 Fluid retention resulting in anasarca, pleural or pericardial effusion, or ascites has been reported rarely with imatinib (1% in CP and 3% in BP).15 We report pleural effusion in 35% of patients with CML treated with dasatinib (grade 3 to 4 in 17%). We identified hypertension, prior cardiac history, and administration of dasatinib on a twice-daily schedule as risk factors for development of pleural effusion. The mechanism by which dasatinib induces pleural effusion is likely related to off-target kinase inhibition. Besides Abl, dasatinib inhibits potently platelet-derived growth factor receptor beta (PDGFRß; half maximal inhibitory concentration [IC50], 28 nmol/L),5,16 a receptor that is expressed in pericytes17 and is involved in the regulation of angiogenesis.18 PDGFRß-deficient mouse embryos lack microvascular pericytes and develop defective blood vessels and edema.19 Blockade of PDGFRß with CDP860, a humanized, pegylated diFab' in patients with advanced ovarian and colorectal carcinoma, resulted in early interruption of the study after three of eight treated patients developed significant ascites and/or pleural effusion, likely resulting from a marked reduction in interstitial fluid pressure.20 The weaker effect of imatinib on PDGFRß might explain the low incidence of this event with this agent.21-23 Another possible explanation is that tyrosine kinases responsible for capillary integrity may be overexpressed in the pulmonary vasculature and/or pleural epithelium. Src regulates focal adhesions and adherens junctions, two subcellular cell-matrix attachment structures key in regulating cell adhesion24,25 that might play a role in the stability of the pleural epithelium and pleural space homeostasis. More important, the vascular permeability activity mediated by vascular endothelial growth factor is directly dependent on the Src-related kinases Yes and Src, which are widely expressed in lung tissue,26,27 and are inhibited by dasatinib (IC50, approximately 0.50).5,16,28 However, other dual Src and abl inhibitors such as bosutinib (SKI-606) have not been associated with pleural effusion.29 Interestingly, bosutinib is a very weak inhibitor of PDGFR.30 Finally, the temporal relation between pleural effusion and significant increments in RVSP and BNP without changes in ejection fraction suggests the possibility of dasatinib-induced pulmonary hypertension and subsequent subclinical heart failure in a subset of patients. This is further supported by a marked decrease of RVSP on dasatinib discontinuation. Additional studies are required to further define the cause of these adverse events in dasatinib-treated patients. By multivariate analysis, prior cardiac history, hypertension, and twice-a-day administration of dasatinib were associated with an increased risk of pleural effusion. The importance of the latter factor is supported by recently published studies comparing daily versus twice-daily dasatinib schedules. In CP, patients treated with 100 mg once daily had lower incidence of pleural effusion compared with those treated with 50 mg bid, 140 mg once daily, or 70 mg bid. In AP and BP, 140 mg once daily also resulted in fewer effusions and less GI hemorrhage. Importantly, the efficacy was similar with all dose schedules.31,32 Although not statistically significant by multivariate analysis, advanced-phase CML was a risk factor by univariate analysis and it is recommended to be vigilant with patients treated with dasatinib in AP or BP, particularly at doses at or greater than140 mg daily. Patients should be monitored for development of early manifestations of fluid retention (ie, peripheral edema, dry cough, dyspnea). Once established, the management of pleural effusion must be predicated on its severity. Grade 1 (asymptomatic) effusions, which are detected by routine CXR or whenever a CXR is done for unrelated reasons, may require only close monitoring. In patients with grade 2 to 3 pleural effusion, dasatinib therapy must be discontinued; a short trial of diuretics and possibly oral steroids may be considered. However, the actual contribution of these agents to the resolution of effusions (v dasatinib interruption alone with dose adjustment on restart) needs to be defined in controlled trials. In patients with recurrent large effusions, thoracentesis may be necessary. Repeat thoracentesis, placement of an indwelling thoracostomy catheter, a temporary pleuroperitoneal shunt (ie, Denver shunt), or chemical pleurodesis are rarely necessary. After the effusion has resolved, dasatinib can be resumed at a reduced dose. With adequate management, most patients continue therapy and have the opportunity to achieve the antileukemic effect reported with dasatinib. In summary, pleural effusion is a complication of dasatinib therapy in CML. This occurrence is usually mild or moderate and more frequent among patients in advanced CML phases and in those treated at daily doses of 140 mg or higher, particularly when administered on a twice-daily schedule. With adequate management, most patients can continue therapy with dasatinib. Further studies are needed to elucidate the pathophysiology of this complication.
Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: None Stock Ownership: None Honoraria: None Research Funding: Hagop Kantarjian, Bristol-Myers Squibb; Jorge Cortes, Bristol-Myers Squibb Expert Testimony: None Other Remuneration: None
Conception and design: Alfonso Quintás-Cardama, Hagop Kantarjian, John Bruzzi, Reginald Munden, Jorge Cortes Provision of study materials or patients: Susan O'Brien Collection and assembly of data: Alfonso Quintás-Cardama, Jorge Cortes Data analysis and interpretation: Alfonso Quintás-Cardama, John Bruzzi, Reginald Munden, Jorge Cortes Manuscript writing: Alfonso Quintás-Cardama, Jorge Cortes Final approval of manuscript: Alfonso Quintás-Cardama, Hagop Kantarjian, Susan O'Brien, Gautam Borthakur, Jorge Cortes
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Lombardo LJ, Lee FY, Chen P, et al: Discovery of N-(2-chloro-6-methyl- phenyl)-2-(6-(4-(2-hydroxyethyl)- piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide (BMS-354825), a dual Src/Abl kinase inhibitor with potent antitumor activity in preclinical assays. J Med Chem 47:6658-6661, 2004[CrossRef][Medline] 6. Talpaz M, Shah NP, Kantarjian H, et al: Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N Engl J Med 354:2531-2541, 2006 7. Shah NP, Tran C, Lee FY, et al: Overriding imatinib resistance with a novel ABL kinase inhibitor. Science 305:399-401, 2004 8. Cortes J, Rousselot P, Kim DW, et al: Dasatinib induces complete hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in blast crisis. Blood 109:3207-3213, 2006[CrossRef][Medline] 9. 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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 test and the Mann-Whitney U test were used to identify prognostic factors, which were subsequently included as variables in a multivariate regression model for development of pleural effusion. Multivariate analysis used the Cox proportional hazard model. 
