Pulmonary Vasculopathy Under Second-line Therapy of Chronic Myeloid Leukemia

Pulmonary Vascular Changes in Patients With Chronic Myeloid Leukemia With Second-line Therapy Dasatinib vs. Nilotinib

Chronic myelogenous leukemia (CML) is a chronic myeloproliferative disorder characterized by a translocation between chromosome 9 and 22, leading to a pathogenic tyrosine kinase signal transduction protein. CML can be treated with tyrosine kinase inhibitors (TKIs), which inhibit BCR/ABL kinase, such as imatinib. In about 20% of CML patients who are treated by imatinib, a complete cytogenetic response cannot be achieved. The other two novel TKIs (dasatinib and nilotinib), achieve higher rates of complete cytogenetic response and they are proposed as second-line therapy for imatinib-resistant patients or for those who do not tolerate imatinib. Dasatinib inhibits BCR/ABL kinase in about >300 times in vitro in more than imatinib and also inhibits several other kinases, including the Src family. Src tyrosine kinase is crucial for potassium channel function in human pulmonary arteries. Imatinib and nilotinib do not inhibit the Src.

Incident cases of precapillary PH have been reported in patients who have CML treated with the dasatinib. Improvements were usually observed after withdrawal of dasatinib.

This study is designed to identify incident cases of dasatinib-associated PH and describe pulmonary vascular changes induced by dasatinib. As comparison population will be patients who receive another second-line TKI (nilotinib).

Doppler echocardiography at rest will be performed in each patient. Patients without exercise capacity limitation an exercise test (Doppler echocardiography with spiroergometry) will be performed. Patients who show elevated SPAP at rest or during exercise (in this study SPAP ≥ 40 mmHg) or with reduced exercise capacity (peak VO2 < 75%) a right heart catheterization (RHC) will be suggested. Additionally for the evaluation of exercise capacity a 6 MWD will be performed. This work- up of patients allows clinical and hemodynamic evaluation.

Inclusion Criteria:

• patients with chronic myeloid leukemia under second-line therapy with dasatinib or nilotinib
• written informed consent

Exclusion Criteria:

• Manifest pulmonary hypertension
• significant pulmonary disease
• Left-sided heart failure or diastolic compliance dysfunction +
• Hemodynamic relevant valvular disease
• Systemic arterial hypertension (at rest systolic >150 mmHg, diastolic > 90 mmHg, during exercise > 220 mmHg)
• Severe anemia
• Uncontrolled supraventricular and ventricular arrhythmias
• Myocardial infarction (within the last 12 months)
• Pulmonary embolism (within the last 12 months)
• Recent therapy changes (within the last 12 months)
• Recent major surgeries (within the last 12 months)
• For exercise tests: musculoskeletal diseases which may unable the exercise tests.