Dasatinib therapy can result in significant pulmonary toxicity
Authors: Maciek Tatarczuch, Kate Burbury, Louise Creati, Elchanan H. Januszewicz, John F. Seymour
Journal: American Journal of Hematology (2015)

To the Editor: We read with interest the article by Shah et al. and wish to share our experience with dasatinib (DAS)-induced pulmonary adverse events (PAE) which is concordant: pulmonary arterial hypertension (PAH) is an infrequent but reproducible complication of DAS with significant morbidity 1. It appears unrelated to dose or treatment duration, often presenting as dyspnoea concomitant with pleural effusion(s). We also found older age a significant predictor of PAE. In contrast to Shah's findings, the number of preceding therapies was not predictive and, more importantly, PAH was not always reversible. Specifically, a retrospective review of all patients treated with DAS at Peter MacCallum Cancer Centre (Melbourne, Australia), April 2005–July 2013, identified a cohort of 33 patients: 26 with chronic myeloid leukemia (CML) in chronic phase, 3 accelerated phase, 3 in blast crisis, and 1 Philadelphia chromosome positive ALL. Patient demographics, disease characteristics, comorbidities, pathology, radiology, tyrosine kinase inhibitor (TKI), clinical course, and adverse events were extracted from electronic medical records. The Mann Witney U-test was used to calculate P-values. PAE included PAH and/or radiological evidence of pleural effusion. PAH was defined as right ventricular systolic pressure (RVSP) >30 mmHg on transthoracic echocardiography (TTE) and subdivided into two groups: confirmed PAH (>36 mmHg), and elevated RVSP (30–36 mmHg). Patient characteristics of the non-PAE and PAE groups are summarized in Table 1. PAE cohort (n = 13, 39%) included 9 with elevated pulmonary pressures, 5 of whom had PAH with RSVP >36 mmHg. The most common symptoms were dyspnoea (85%), cough (54%), peripheral oedema (31%), and fatigue (23%). Within the PAH subgroup, all 5 had radiologically confirmed pleural effusions and required cardiovascular pharmacotherapy. 2/5 patients underwent therapeutic pleurocentesis. DAS was ceased in 4 and dose reduced in one. Symptoms resolved after DAS modification (2 ceased, 1 reduced) in 3 patients and follow-up echocardiogram demonstrated normalization of RVSP in 2. Two patients had persistent symptoms (one with elevated RVSPs) 43 and 9 months post drug cessation. In the elevated-RVSP subgroup, 2/4 patients had pleural effusions: 1 required pharmacotherapy and 1 pleurocentesis. DAS was ceased in 2 and dose-reduced for 1. Symptoms resolved in the 2 patients who ceased DAS (data N/A for the 2 patients who continued DAS). Normalization of RVSP occurred in one patient only. Four patients developed pleural effusion but did not undergo PAH assessment at time of symptoms. Three required DAS modification (2 cessation, 1 reduced); all 4 required interventions: 3 pleurocentesis, 1 pleurodesis; 2/4 additional pharmacotherapy. Elevated RVSP was identified in 1 patient post study period, while on DAS. There were 7 deaths in total, including 5 patients in the PAE group. DAS induced PAE was a contributing factor in 2 of these patients. Our study is a retrospective analysis and a small cohort. Nevertheless, we observed that PAE may be more frequent than previously recognized in clinical trials, and confer more significant morbidity. This important complication should be considered by clinicians prescribing second-generation TKIs as first-line therapy for CML. We agree with the authors' proposal for baseline screening with chest X-ray and TTE, especially in the elderly and/or those with pre-existing PAH risk factors. Early investigation of pulmonary symptoms, particularly dyspnoea or unexplained cough, is vital, and identification of a pleural effusion should prompt assessment for PAH. Maciek Tatarczuch,1* Kate Burbury,1 Louise Creati,2 Elchanan H. Januszewicz,1 John F. Seymour1 1Department of Haematology, Peter MacCallum Cancer Centre (PMCC), East Melbourne, Victoria, Australia, 2Department of Cardiology, St. Vincent's Hospital, Melbourne, Victoria, Australia