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).

Study Overview

• Status: Completed
• Conditions: Chronic Myeloid Leukemia
• Intervention / Treatment: Other: Echo, exercise echo, and if indicated, right heart catheter

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.

• Study Type: Observational
• Enrollment (Actual): 16

Contacts and Locations

Study Locations

• Austria
  • Graz, Austria, 8036
    • Medical University of Graz, Division of Pulmonology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 95 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

patients with chronic myeloid leukemia under second-line therapy with dasatinib or nilotinib,

Description

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 Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
chronic meloid leukemia; echo, exercise echo, and if indicated, right heart catheter	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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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
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

Collaborators and Investigators

• Sponsor: Medical University of Graz

Study record dates

Study Major Dates

• Study Start: July 1, 2012
• Primary Completion (Actual): June 1, 2015
• Study Completion (Actual): June 1, 2015

Study Registration Dates

• First Submitted: October 10, 2012
• First Submitted That Met QC Criteria: March 5, 2013
• First Posted (Estimate): March 6, 2013

Study Record Updates

• Last Update Posted (Estimate): September 9, 2015
• Last Update Submitted That Met QC Criteria: September 7, 2015
• Last Verified: September 1, 2015

More Information

Terms related to this study

• Keywords: Pulmonary hypertension; chronic myeloid leukemia; dasatinib; nilotinib
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Bone Marrow Diseases; Hematologic Diseases; Myeloproliferative Disorders; Leukemia; Leukemia, Myeloid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive
• Other Study ID Numbers: 24-311 ex 10/11