Reversible Secondary Myelofibrosis or Clonal Myeloproliferative Disorder

March 17, 2016 updated by: University of Utah
To determine the prevalence of myelofibrosis in patients with primary pulmonary hypertension, and to discover if the fibrosis in these patients is primary (AMM) or secondary.

Study Overview

Detailed Description

Pulmonary arterial hypertension: Pulmonary arterial hypertension (PAH) is a disease primarily affecting the small precapillary pulmonary vessels. It is characterized by sustained elevation of the pulmonary vascular resistance (PVR). Without therapy, right heart failure and death eventually occur. PAH occurs in an idiopathic form, primary pulmonary hypertension (PPH), and in association with other disorders such as connective tissue diseases or congenital heart disease (CHD). PAH remains a disease of unknown etiology. Until recently, prognosis for PAH was poor, with a median survival of less than 3 years.

Prostacyclin (PGI2) is the main product of arachidonic acid in all vascular endothelium. It is a potent vasodilator in all vascular beds. In addition, it is a potent endogenous inhibitor of platelet aggregation and smooth muscle growth. The prostacyclin receptor (IP) is located on a variety of cell types, enabling prostacyclin to exert a range of biologic actions by means of raising intracellular levels of cAMP through activation of adenylate cyclase. The stable, freeze-dried salt preparation of prostacyclin is known as epoprostenol and is available for IV administration under the brand name Flolan (Glaxo Wellcome, Research Triangle Park, N.C.). The first randomized clinical trial in PPH showed that epoprostenol improved quality of life, hemodynamics, exercise tolerance, and survival over a 12-week period. Epoprostenol has become the standard of care for patients with advanced PPH. Recently, chronic intravenous epoprostenol has been shown to be an effective therapy to improve long-term quality of life and survival in patients with PPH. Epoprostenol also improves hemodynamics, exercise capacity, and quality of life (but not survival) in PAH associated with CHD and connective tissue disease.

Side effects of epoprostenol infusion include rash, headache, jaw pain, leg pain, diarrhea, nausea, catheter infections, chest pain, anxiety dizziness, bradycardia, dyspnea, abdominal pain, musculoskeletal pain, tachycardia, flu-like symptoms, and anxiety/nervousness. Thrombocytopenia is commonly seen in patients with PPH treated with PG12. Occasionally, a decrease in other blood cell lines occurs leading to anemia or pancytopenia. Splenomegaly and hypersplenism are observed at times. While thrombocytopenia has been attributed to the antiplatelet effects of prostacyclin, the pathophysiology of pancytopenia is poorly understood. There are no studies that address thrombocytopenia and other hemopoietic abnormalities in people with pulmonary hypertension receiving epoprostenol. The possibility of myelofibrosis causing these hematologic abnormalities has not been investigated.

Primary myelofibrosis is a myeloproliferative disorder, characterized typically by pancytopenia, splenomegaly, a leukoerythroblastic blood smear, fibrosis on the bone marrow examination, and myeloid metaplasia. Like all myeloproliferative disorders, it is due to somatic mutation and clonal proliferation of hematopoietic progenitors. Fibrosis occurs secondary to cytokines secreted by malignant cells. These patients are symptomatic because of cytopenias. Bone marrow failure and transformation to acute myeloid leukemia is the major reason for mortality in these patients. Elevated blood levels of hematopoietic progenitors (identified by positivity for the CD34 antigen) are well documented and correlates with prognosis. Therefore two major identifying features of primary myelofibrosis as opposed to secondary fibrosis of the marrow are: 1) clonal hematopoiesis and 2) high CD 34 positive hematopoietic precursors.

We therefore hypothesize these two will be normal in patients with secondary myelofibrosis and help us distinguish the two entities.

Clonality Studies: Clonality is based on the principal of X-chromosome inactivation and thus, for clonality studies only females can be used as subjects. It is based on the principal that while female cells have two X-chromosomes, one is randomly inactivated during early embryonic development and thus female tissue is a mixture of cells expressing either paternal or maternal inherited x-chromosome genes. In the first step, DNA analysis will study 5 exonic polymorphisms for the X-chromosome genes which have previously been shown to be useful for these purposes. If any of the five loci is heterozygous then the subject is said to be informative for clonality. Studies which will proceed as follows: The fresh blood platelets and granulocytes will be isolated and the RNA isolated and used later for reverse transcription to cDNA which will then be analyzed for X-chromosome allelic usage ratio by single-stranded conformational polymorphisms (SSCP). If only one allele is expressed in platelets or granulocytes the patient is said to be clonal and favors a diagnosis of myeloproliferative disorder (such as AMM), while polyclonal blood (both X-chromosome alleles expressed in platelets and granulocytes) is compatible with secondary myelofibrosis.

A three-color direct immunofluorescent staining method will be used in the evaluation of CD34+ cells. In our preliminary experience we observed four Flolan treated patients with PPH who had splenomegaly, anemia and/or thrombocytopenia. All of these patients had severe marrow fibrosis. The purpose of this study is to determine whether the incidence of the bone marrow fibrosis in this patient population is primary or secondary, and whether a secondary effect is a fibrosis that would be expected to be transient and resolve after discontinuation of Flolan.

Participating subjects will Patients will undergo the following studies:

  1. History and Physical examination
  2. Peripheral blood smear
  3. Bone marrow examination to determine the presence and severity of fibrosis. The bone marrow specimen taken for diagnostic purposes will be examined by three independent hematologists/hematopathologists in a masked fashion for the presence of fibrosis using routine methods.
  4. Blood: 30 cc of blood will be collected for

    1. Clonality studies (female subjects only),
    2. CD34 quantitation.
    3. Further studies will be done to monitor the aberrant trafficking of hemopoietic stem cells, the adhesion molecules, and any disease related genes, such as JAK2V617F and cMPL, if indicated.
    4. The above studies will be repeated in patients undergoing lung transplants at 3 months, 6 months and 1 year after transplantation.

Study Type

Observational

Enrollment (Actual)

15

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

    • Utah
      • Salt Lake City, Utah, United States, 84132
        • University of Utah
      • Salt lake City, Utah, United States, 84148
        • VA Salt Lake City Health Care System

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Sampling Method

Non-Probability Sample

Study Population

Patients suffering from primary pulmonary hypertension or myelofibrosis (primary or secondary)

Description

Inclusion Criteria:

  1. > 18 years of age
  2. Signed Informed Consent
  3. Subjects diagnosed with Primary Pulmonary Hypertension or Myelofibrosis (primary or secondary)

Exclusion Criteria:

  1. Anyone not meeting the above inclusion criteria
  2. Pregnant women

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Observational Models: Cohort
  • Time Perspectives: Prospective

Cohorts and Interventions

Group / Cohort
PPH
Subjects diagnosed with primary pulmonary hypertension (PPH)
Myelofibrosis
Subjects diagnosed with Primary or Secondary Myelofibrosis

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Determine the prevalence of myelofibrosis in patients with primary pulmonary hypertension
Time Frame: After sample is obtained
After sample is obtained

Secondary Outcome Measures

Outcome Measure
Time Frame
Discover if the fibrosis in patients with primary pulmonary hypertension is primary (AMM) or secondary.
Time Frame: After sample is obtained
After sample is obtained
Clonality
Time Frame: After sample is obtained
After sample is obtained

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

June 1, 2006

Primary Completion (Actual)

February 1, 2009

Study Completion (Actual)

February 1, 2009

Study Registration Dates

First Submitted

July 23, 2008

First Submitted That Met QC Criteria

July 23, 2008

First Posted (Estimate)

July 25, 2008

Study Record Updates

Last Update Posted (Estimate)

March 21, 2016

Last Update Submitted That Met QC Criteria

March 17, 2016

Last Verified

March 1, 2016

More Information

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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