Pulmonary Hypertension (PHT) and Pleural Effusion During Dasatinib Therapy For CML Frequently Lead To Drug Withdrawal

Abstract

Aim/Background Imatinib, a tyrosine-kinase inhibitor (TKI), first line therapy for chronic myeloid leukemia in chronic phase (CML-CP) for over a decade, has an established side-effect profile. Clinical trials with 2nd generation (2G) TKIs have significantly deeper and faster cytogenetic and major molecular responses (MMR), though impact on long-term toxicity and survival remains to be determined. Dasatinib (DAS), an oral 2G TKI 350x more potent than imatinib in vitro, is generally well tolerated, with <15% patients in clinical trials requiring change in therapy due to adverse events (AE). However, potentially life-threatening PHT or pleural effusions can occur in up to 10% and 25% respectively. Little is known about this important toxicity, in terms of risk factors and natural history (including reversibility post drug cessation or dose modifications). We present our local experience with DAS, with a focus on pulmonary toxicity. Methods Retrospective review of all patients treated with DAS at PMCC (Melbourne, Australia) April 2003-July 2013. Patient data including demographics, disease characteristics, co-morbidities, pathology, radiology, TKI regimens, clinical course and AE were extracted from institution electronic records. Results Cohort included 37 patients: 33 CML-CP, 1 CML in accelerated phase, 1 post allograft relapsed Ph+ Acute Lymphoblastic Leukemia, 2 Ph+ Acute Myeloid Leukemia. 13/37 (35%) developed clinically significant pulmonary toxicity, including 9 (24%) patients with transthoracic echocardiography (TTE) evidence of elevated resting right ventricular pulmonary venous pressures (RVSP) whilst on DAS: 5 (14%) confirmed PHT (RVSP>36 mmHg), 3 (8%) RVSP in upper limit of normal (RVSP 30-36mmHg) and 1 with RVSP>30 post DAS cessation (RVSP not available during therapy). 7 (19%) were symptomatic of PHT, 4 (11%) required medical management. 12/37 (32%) had radiological evidence of pleural effusion: 10 (27%) symptomatic, 5 (14%) bilateral, 5 (14%) right sided, 2 (5%) left sided. 7 (19%) patients with PHT had associated pleural effusion (5/5 with RVSP >36, 2 RVSP>30), however 5 (14%) developed symptomatic pleural effusions without evidence of PHT. 6 (16%) patients required surgical intervention (5 drainage, 1 pleurodesis). 2 (5%) had persistent symptoms despite DAS cessation. RVSP normalised in 3 patients post DAS cessation (median time 24 months, range 1-26) but did not in 1 patient (follow up: 38 months). Serial TTEs were not performed in 5 patients. Risk factors (e.g. cardiovascular, pulmonary, other medications, vasculitides, disease status) were not more prominent in the PHT group, though a statistically significant difference in age between the two groups was noted. Of the entire cohort, 23/37 (62%) have ceased DAS for the following reasons: 8 (22%) disease progression, 5 (14%) PHT, 1 (3%) pleural effusion (without associated PHT), 4 (11%) other DAS-related toxicity, 2 (5%) sustained MMR, 1 (3%) sepsis, 1 (3%) pregnancy, 1 (3%) acute coronary syndrome. Conclusion The current model of TKIs use in CML requires life-long therapy, which demands durable tolerability and safety. We found clinically relevant pulmonary complications of DAS therapy to be more frequent than previously reported, perhaps due to non-specific symptoms and low levels of awareness. We now recommend obtaining baseline chest X-ray and TTE prior to DAS therapy. Any new pulmonary signs or symptoms warrant early investigation, including repeat TTE for assessment of pulmonary arterial pressures. Moreover, the patient’s capacity to tolerate PHT or pleural effusions, although difficult to predict, should be considered in choice of TKI agent. Disclosures: No relevant conflicts of interest to declare.

Tyrosine Kinase Inhibitors for the Treatment of Chronic-Phase Chronic Myeloid Leukemia: Long-Term Patient Care and Management

“…Pulmonary arterial hypertension (PAH) is a rare but serious dasatinib toxicity with the potential of occurring at any time after treatment is initiated (Montani et al, 2012;NCCN, 2014;Tatarczuch, Seymour, Creati, Januszewicz, & Burbury, 2013). The 2014 NCCN guidelines recommend evaluating patients for underlying cardiopulmonary disease (as no specific methodology is given, evaluation must be done per provider discretion) prior to and during dasatinib therapy and discontinuing dasatinib permanently in any patient with PAH (NCCN, 2014).…”