Pulmonary Vasculopathy Under Second-line Therapy of Chronic Myeloid Leukemia

Chronic Myeloid Leukemia Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01805843
• Other study ID #: 24-311 ex 10/11
• Status: Completed
• Phase: N/A
• First received: October 10, 2012
• Last updated: September 7, 2015
• Start date: July 2012
• Est. completion date: June 2015

Study information

• Verified date: September 2015
• Source: Medical University of Graz
• Contact: n/a
• Is FDA regulated: No
• Health authority: Austria: Federal Office for Safety in Health Care
• Study type: Observational

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 16
• Est. completion date: June 2015
• Est. primary completion date: June 2015
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 95 Years

Eligibility

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.

Study Design

Observational Model: Cohort, Time Perspective: Prospective

Related Conditions & MeSH terms

• Chronic Myeloid Leukemia
• Leukemia
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive
• Leukemia, Myeloid

Intervention

Other:
• Echo, exercise echo, and if indicated, right heart catheter
routine echocardiography and special measurements of the right heart are performed at rest and during exercise

Locations

Country	Name	City	State
Austria	Medical University of Graz, Division of Pulmonology	Graz

Sponsors (1)

Lead Sponsor	Collaborator
Medical University of Graz

Country where clinical trial is conducted

Austria, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	systolic pulmonary arterial pressure during exercise (50W)	In patients who undergo stressechocardiography: systolic pulmonary arterial pressure (SPAP) at 50W will be measured and the comparison between patients under dasatinib and nilotinib therapy will be performed.	at baseline	No
Secondary	peak VO2	Mean PAP at rest, mPAP at 50W, peak VO2, 6 minute walk distance (6MWD), N terminal pro brain natriuretic peptide (NT-proBNP) at "dasatinib" vs."nilotinib" patients.; Changes of SPAP at 50 W, pulmonary vascular resistance (PVR) at rest, changes of mPAP at rest and at 50W, peak VO2, 6 MWD, NT-pro BNP- in patients with dasatinib and nilotinib between the baseline and 6 months after.	At baseline	No
Secondary	change of pulmonary arterial pressure	Changes of SPAP at 50 W, pulmonary vascular resistance (PVR) at rest, changes of mPAP at rest and at 50W, peak VO2, 6 MWD, NT-pro BNP- in patients with dasatinib and nilotinib between the baseline and 6 months after.	between baseline and after 6 months	No
Secondary	Pulmonary vascular resistance	In patients who undergo a RHC: pulmonary vascular resistance (PVR) at rest will be measured and the comparison of patients with dasatinib and nilotinib therapy will be performed.	at baseline	No