Clinical Trial: Treatment of Iron Overload With Deferasirox (Exjade) in Hereditary Hemochromatosis and Myelodysplastic Syndrome

Study Status: Terminated
Recruit Status: Terminated
Study Type: Interventional

Official Title: Deferasirox Versus Venesection in Patients With Hemochromatosis and for Treatment of Transfusional Siderosis in Myelodysplastic Syndrome: Diagnostics and New Biomarkers.

Brief Summary:

Hypothesis: Deferasirox can be used as a therapeutic agent to deplete the liver, heart and bone marrow of excess iron in patients with iron overload caused by myelodysplastic syndrome (MDS) and hemochromatosis (HC.

Assess the effect of new serum biomarkers (NTBI and hepcidin) and MRI as indicators of iron overload and their usefulness to monitor iron depletion treatment.

Study the effect of iron overload and iron depletion on intracellular signal transduction, trace metals concentrations in serum and urine and markers of oxidative stress in blood cells and urine.


Detailed Summary:

The two most important causes of iron overload disease in humans are the iron-loading disorder hereditary hemochromatosis (HC), and transfusional siderosis in patients with chronic hematological diseases like myelodysplastic syndrome (MDS), thalassemia, and leukemia.

Hemochromatosis. In HC the molecular regulation of iron uptake across the intestinal mucosa is disturbed, leading to hyperabsorption and accumulation of iron in parenchymal tissues such as the liver, pancreas, endocrine organs and heart. Hepcidin, a small peptide hormone synthesized in the liver, apparently functions as the master regulator of systemic iron homeostasis by its ability to control the efflux of iron from the enterocytes and macrophages into blood plasma. This happens by diminishing the iron transfer capacity through the basolateral, transmembrane protein, ferroportin. Expression of hepcidin is carefully adjusted by the iron status of the hepatocytes through a multimolecular signal transducing pathway which acts as a positive feedback mechanism with increased hepcidin synthesis in iron overload (and inflammation). Mutation of one of the signal molecules, leads to inadequate hepcidin synthesis. The most common are the classic C282Y and H63D point mutations of the hemochromatosis protein HFE, which disturbs its interaction with the transferrin receptor 1, the first step in the hepcidin signal cascade. Homozygosity for C282Y is the strongest risk factor for serious iron overload and disease which develops after a long-lasting, asymptomatic period. In Norway the prevalence of C283Y homozygosity is approximately 0.75 in both genders. The preclinical, biochemical phenotype of HC is disclosed by blood tests with elevated transferrin saturation as a marker of hyperabsorption of iron, and increasing ferritin concentration as a surrogate marker of a growing iron overload. As an alternative to liver biopsy,
Sponsor: Haukeland University Hospital

Current Primary Outcome: Changes from baseline in liver iron concentration (LIC) and heart iron concentration (HIC) determined by Magnetic Resonance Imaging (MRI), and in bone marrow iron content determined by microscopy after treatment with deferasirox. [ Time Frame: 0, 6 and 12 months ]

Original Primary Outcome: Same as current

Current Secondary Outcome:

  • Change of hepcidin concentration in serum [ Time Frame: 0, 6 and 12 months ]
  • Change of non-transferrin bound iron (NTBI) concentration in serum [ Time Frame: 0, 6 and 12 months ]
  • Change of multiple trace metals in serum [ Time Frame: 0, 6 and 12 months ]
  • Change of intracellular signal molecules, mTOR, NFkB and stress sensor p53 in blood cells [ Time Frame: 0, 6 and 12 months ]
  • Change of 8-oxodG in urine [ Time Frame: 0, 6 and 12 months ]
    Marker of oxidative DNA damage
  • Change of Cu,Zn-SOD activity in erythrocyte hemolysate [ Time Frame: 0, 6 and 12 months ]
    Cu,Zn-Super Oxid Dismutase (SOD)is an antioxidant enzyme
  • Clinical chemistry: Na, K, Ca, Creatinine, creatinine kinase, CRP, alanine aminotransferase (ALAT), aspartate aminotransferase (ASAT), alkaline phosphatase (ALP), gamma-glutamyl transferase (GT), lactate dehydrogenase (LD), albumin, bilirubin. [ Time Frame: 0, 2,4,6,8 weeks, 3,4,5,6,7,8,9,10,11,12 months, 5 weeks posttreatment ]
    Serum analysis
  • Urine routine test strip for detection of blood, protein, and nitrite [ Time Frame: 0,2,4,6,8 weeks and 3,4,5,6,7,8,9,10,11,12 months ]
    Morning spot urine sample.
  • Ferritin concentration in serum [ Time Frame: 0,2,4,6,8 weeks, 3,4,5,6,7,8,9,10,11,12 months, 5 weeks post treatment ]
  • Transferrin saturation in serum [ Time Frame: 0,2,4,6,8 weeks, 3,4,5,6,7,8,9,10,11,12 months, 5 weeks post treatment ]
  • HbA1c [ Time Frame: 0, 2,6,12 months ]
  • INR ( International normalized ratio) [ Time Frame: 0,2,6,12 months ]
  • Analysis of hemoglobin, reticulocytes, hematocrit, MCV, leukocyte count (total and differential), and platelets [ Time Frame: 0, 2,4,6,8 weeks, 3,4,5,6,7,8,9,10,11,12 months, 5 weeks posttreatment ]
  • Urine trace metals [ Time Frame: 0, 6 and 12 months ]
  • Bone marrow sample [ Time Frame: 0, 6 and 12 months ]


Original Secondary Outcome: Same as current

Information By: Haukeland University Hospital

Dates:
Date Received: July 1, 2013
Date Started: May 2013
Date Completion:
Last Updated: January 20, 2017
Last Verified: January 2017