Clinical trial NCT01805843: Pulmonary Vasculopathy Under Second-line Therapy of Chronic Myeloid Leukemia
Official title: Pulmonary Vascular Changes in Patients With Chronic Myeloid Leukemia With Second-line Therapy Dasatinib vs. Nilotinib
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Chronic Myeloid Leukemia
Keywords: Pulmonary hypertension
chronic myeloid leukemia
dasatinib
nilotinib
Lead sponsor: Medical University of Graz
Sponsor class: OTHER
First posted: 2013-03-06
Enrollment: 16
Sex: ALL
Minimum age (years): 18
Maximum age (years): 95
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: patients with chronic myeloid leukemia under second-line therapy with dasatinib or nilotinib,

Brief summary: 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).

Detailed description: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: systolic pulmonary arterial pressure during exercise (50W)
timeFrame: at baseline
Secondary outcomes:
measure: peak VO2
timeFrame: At baseline
measure: change of pulmonary arterial pressure
timeFrame: between baseline and after 6 months
measure: Pulmonary vascular resistance
timeFrame: at baseline
Other outcomes:
Locations:
city: Graz
country: Austria
facility: Medical University of Graz, Division of Pulmonology
Study officials:
affiliation: Medical University of Graz
name: Horst Olschewski, MD
role: PRINCIPAL_INVESTIGATOR
References: