Clinical trial NCT02809274: Incidence of Iron Deficiency in Polycythemia Vera (PV) and Association With Disease Features
Official title: Incidence of Iron Deficiency in Polycythemia Vera (PV) and Association With Disease Features
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Polycythemia Vera
Keywords: iron deficiency
polycythemia vera
Lead sponsor: Rambam Health Care Campus
Sponsor class: OTHER
Collaborators: name: Meir Medical Center
First posted: 2016-06-22
Enrollment: 200
Sex: ALL
Minimum age (years): 18
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: An adult population (patients \>18 years old) of men and women who have been diagnosed with clinically overt PV will be enrolled. Sites will include both community and academic centers across Isreal.

Brief summary: Iron deficiency is a known feature of PV, occurs because of accelerated erythropoiesis, gastrointestinal blood loss and phlebotomy. Incidence and effect of iron deficiency in these patients is not well characterized. The study will assess the incidence of iron deficiency at diagnosis and during the course of PV, assess effect of iron deficiency on patient symptoms and its correlation with disease features.

This is a multicenter, non-interventional, non-randomized, prospective, observational study in an adult population (patients \>18 years old) of patients who have been diagnosed with PV and are being followed in either community or academic medical centers in Israel.

Detailed description: Background:

Within intestinal epithelial cells, some of the imported iron is incorporated into ferritin and other storage forms. A fraction of the iron taken up from the intestinal lumen passes through the cell, and is exported across the basolateral membrane to enter the body. Ferroportin, a metal ion transporter, serves as the basolateral iron exporter. Hepcidin regulates basolateral iron export by binding to ferroportin to trigger its internalization and lysosomal degradation. Each day, normal adults need 25 mg of iron to support hemoglobin production in maturing erythrocytes. This amount is much greater than the iron absorbed daily through the intestine. Obviously, iron needed for erythropoiesis must be acquired from supplies already existing in the body. The primary source of plasma iron is the reticuloendothelial macrophage system, which recovers iron from senescent and damaged erythrocytes. Other significant site of iron exchange is the liver.

Dietary iron absorption is enhanced in response to insufficient iron stores, increased erythropoietic demand or hypoxia. It is diminished in response to iron surfeit and inflammation. Based on these observations, four different "regulators" have been defined functionally: 1) The stores regulator modulates absorption several fold, increasing it in iron deficiency and decreasing it in iron overload. 2) The erythroid regulator is more potent-it can increase iron absorption 6- to 10-fold when erythropoiesis becomes iron -restricted, result either from iron deficiency or from accelerated production of erythroid precursors. 3) The hypoxia regulator mediates an increase in iron absorption in response to hypoxia, to allow for production of hemoproteins that bind and carry oxygen. 4) An inflammatory regulator also exists, which acts to decrease iron absorption in response to inflammation. All of these regulators act through a common, humoral effector that coordinates intestinal iron absorption and macrophage iron recycling. Hepcidin plays a major role in iron metabolism. It is produced in the liver, cleaved from a larger precursor molecule and secreted into the plasma. Circulating hepcidin attaches to ferroportin expressed on enterocytes and macrophages, causing ferroportin to be internalized into the cell and degraded in lysosomes. Hepcidin is induced in response to iron overload and inflammation. It is turned off in response to iron deficiency , ineffective erythropoiesis and hypoxia.

Polycythemia vera (PV) is one of the myeloproliferative neoplasms (MPNs) and is characterized by marrow hyperplasia with an increased number of erythrocytes, leukocytes and platelets in peripheral blood. Several studies have shown that iron deficiency is common in PV patients and can significantly influence the quality of their life. These complications are a result of expansive erythropoiesis, in addition to phlebotomy and/or gastrointestinal bleedings. The role of JAK2V617F in pathogenesis of iron deficiency in PV is also very intriguing. Kinase JAK2 is involved in signal transduction via the erythropoietin receptor. EPO is one of the hepcidin synthesis regulators. Some of the data has confirmed that JAK2 mutation may be involved in the regulation of the iron status in myeloproliferative disorders.

There are several reports in the literature on thrombotic complications in iron-deficient adults. Secondary thrombocytosis has been implicated in many cases.

In addition to the increased thrombotic risk associated with high platelet count, the decrease in antioxidant defense in iron deficiency may cause increased oxidant stress, which in turn may result in a tendency toward platelet aggregation. The abnormal platelet count and function observed in iron deficiency anemia could act synergistically to promote thrombus formation. Iron deficiency may contribute to a hypercoagulable state by affecting blood flow patterns within the vessels because of reduced deformability and increased viscosity of microcytic red blood cell.

Purpose:

Incidence and effect of iron deficiency in patients with PV is not well characterized. The study will assess the incidence of iron deficiency at diagnosis and during the course of PV, assess effect of iron deficiency on patient symptoms and its correlation with disease features.

Eligibility criteria: Inclusion Criteria:

* Age ≥18 years
* Diagnosis of Polycythemia Vera (PV)
* Willing and able to provide written informed consent
* Willing and able to complete patient assessment questionnaires either alone or with minimal assistance from a caregiver and/or trained site personnel
* Under the supervision of a physician for the current care of PV including but not limited to watchful waiting, acetylsalicylic acid (ASA) 81mg or greater, antithrombotic therapy, Phlebotomy (PHL), Hydroxyurea (HU), interferon (recombinant or pegylated), busulfan, anagrelide

Exclusion Criteria:

* Diagnosis of myelofibrosis (MF) \[including primary MF, post-PV MF, or post-essential thrombocythemia MF (post-ET MF)\]
* Diagnosis of secondary Acute Myeloid Leukemia (AML)
* Diagnosis of Myelodysplastic Syndrome (MDS)
* Splenectomy

Primary outcomes:
measure: Incidence of iron deficiency in patients with PV
timeFrame: 2 years
Secondary outcomes:
measure: Association between iron deficiency and other clinical features
timeFrame: 2 years
measure: Influence of therapy (phlebotomies, hydroxyurea, other therapies) on iron parameters
timeFrame: 2 years
measure: Influence of iron parameters on Patient-reported symptoms
timeFrame: 2 years
measure: Influence of iron deficiency on arterial and venous thrombosis rate
timeFrame: 2 years
Other outcomes:
Locations:
city: Afula
country: Israel
facility: Emek Medical center
city: Beer Sheva
country: Israel
facility: Soroka medical center
city: Hadera
country: Israel
facility: Hillel Yaffe Medical Center
city: Haifa
country: Israel
facility: Bnei Zion medical center
city: Haifa
country: Israel
facility: Rambam Medical center
city: Kfar Saba
country: Israel
facility: Meir Medical center
city: Ramat Gan
country: Israel
facility: Sheba medical center
city: Rehovot
country: Israel
facility: Kaplan medical center
city: Tel Aviv
country: Israel
facility: Maccabi
city: Tel Aviv
country: Israel
facility: Tel Aviv Sourasky
city: Zefat
country: Israel
facility: Ziv Medical center
city: Zerifin
country: Israel
facility: Assaf Harofeh Medical Center
Study officials:
affiliation: Rambam Health Care Campus
name: Noa Lavi, Dr
role: PRINCIPAL_INVESTIGATOR
References:
citation: Pearson TC, Grimes AJ, Slater NG, Wetherley-Mein G. Viscosity and iron deficiency in treated polycythaemia. Br J Haematol. 1981 Sep;49(1):123-7. doi: 10.1111/j.1365-2141.1981.tb07205.x.
citation: Hutton RD. The effect of iron deficiency on whole blood viscosity in polycythaemic patients. Br J Haematol. 1979 Oct;43(2):191-9. doi: 10.1111/j.1365-2141.1979.tb03741.x.
citation: Kwapisz J, Zekanowska E, Jasiniewska J. Decreased serum prohepcidin concentration in patients with polycythemia vera. J Zhejiang Univ Sci B. 2009 Nov;10(11):791-5. doi: 10.1631/jzus.B0920217.
citation: Rector WG Jr, Fortuin NJ, Conley CL. Non-hematologic effects of chronic iron deficiency. A study of patients with polycythemia vera treated solely with venesections. Medicine (Baltimore). 1982 Nov;61(6):382-9. doi: 10.1097/00005792-198211000-00004. No abstract available.
citation: Franchini M, Targher G, Montagnana M, Lippi G. Iron and thrombosis. Ann Hematol. 2008 Mar;87(3):167-73. doi: 10.1007/s00277-007-0416-1. Epub 2007 Dec 8.
citation: Birgegard G, Carlsson M, Sandhagen B, Mannting F. Does iron deficiency in treated polycythemia vera affect whole blood viscosity? Acta Med Scand. 1984;216(2):165-9. doi: 10.1111/j.0954-6820.1984.tb03788.x.