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Pulmonary Vasculopathy Under Second-line Therapy of Chronic Myeloid Leukemia

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ClinicalTrials.gov Identifier: NCT01805843
Recruitment Status : Completed
First Posted : March 6, 2013
Last Update Posted : September 9, 2015
Sponsor:
Information provided by (Responsible Party):
Medical University of Graz

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).


Condition or disease Intervention/treatment
Chronic Myeloid Leukemia 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.

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Study Type : Observational
Actual Enrollment : 16 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Pulmonary Vascular Changes in Patients With Chronic Myeloid Leukemia With Second-line Therapy Dasatinib vs. Nilotinib
Study Start Date : July 2012
Actual Primary Completion Date : June 2015
Actual Study Completion Date : June 2015


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




Primary Outcome Measures :
  1. systolic pulmonary arterial pressure during exercise (50W) [ Time Frame: at baseline ]
    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.


Secondary Outcome Measures :
  1. peak VO2 [ Time Frame: At baseline ]

    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.


  2. change of pulmonary arterial pressure [ Time Frame: between baseline and after 6 months ]
    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.

  3. Pulmonary vascular resistance [ Time Frame: at baseline ]
    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.


Biospecimen Retention:   Samples With DNA
Samples with DNA will be retained for later examinations at the Biobank, in case that the patient agrees (extra patient information). The blood samples are taken only during routine tests.


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Ages Eligible for Study:   18 Years to 95 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Probability Sample
Study Population
patients with chronic myeloid leukemia under second-line therapy with dasatinib or nilotinib,
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01805843


Locations
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Austria
Medical University of Graz, Division of Pulmonology
Graz, Austria, 8036
Sponsors and Collaborators
Medical University of Graz
Investigators
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Principal Investigator: Horst Olschewski, MD Medical University of Graz

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Responsible Party: Medical University of Graz
ClinicalTrials.gov Identifier: NCT01805843     History of Changes
Other Study ID Numbers: 24-311 ex 10/11
First Posted: March 6, 2013    Key Record Dates
Last Update Posted: September 9, 2015
Last Verified: September 2015

Keywords provided by Medical University of Graz:
Pulmonary hypertension
chronic myeloid leukemia
dasatinib
nilotinib

Additional relevant MeSH terms:
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Leukemia
Leukemia, Myeloid
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Neoplasms by Histologic Type
Neoplasms
Myeloproliferative Disorders
Bone Marrow Diseases
Hematologic Diseases
Dasatinib
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action