# Presentation: 161381

## Iron Overload: Complications and Need for Therapy

**John B. Porter, MD****Professor of Hematology****University College, London, UK**

## Iron Distribution & Turnover In Humans

**Iron Distribution & Turnover In Humans**

-  Erythron
-       2g

**  ****Macrophages**
**        ****0.6g**
** **

**Transferrin**
**      ****3mg**

**Adapted with permission from Porter JB; *****Hematol/Oncol Clinics***** 2005; 19, 1-6. **
**Andrews NC. *****N Engl J Med*****. 1999; 341:1986****-****1995.**

**Parenchyma****0.3g**
**Liver****1g**

## Iron Loading From Blood Transfusions

**1 unit of blood contains approximately ****200 mg of iron****a**
**Normally, total body iron is approximately****3 to 4 g**
**Chronic transfusion-dependent patients have an iron excess of 0.3 to 0.7 mg/kg/day, equivalent to 4 to 10 g of iron per year****b**
**Iron accumulates with repeated blood transfusion **

**a**** Porter JB. *****Br J Haematol.***** 2001;115:239****-****252.**
**b**** Andrews NC. *****N Engl J Med*****. 1999;341:1986-1995.**

## Transfusional Iron Overload

- Hepatocytes

**Transfusional Iron Overload**

- Red

** **

** **

-     Erythron

**    ****Macrophages**

- Gut

**Transferrin**

**Adapted with permission from Porter JB; *****Hematol/Oncol Clinics***** 2005 19,1-6**

## Organ Systems Affected byIron Overload

**Organ Systems Affected by****Iron Overload**

**Pituitary gland**
**Heart**
**Liver**
**Pancreas**
**Gonadal**

**Iron overload results in n****on****–****transferrin****-b****ound****iron in the plasma**
**Increased iron uptake into selective organs**
**Generation of free hydroxyl radicals**

**Tissue damage**

## Complications of Iron Overload

**Cardiomyopathy and cardiac failure**
**Hepatic cirrhosis**
**Diabetes mellitus**
**Impaired growth**
**Hypogonadism and infertility**

**Andrews NC. *****N Engl J Med*****. 1999;341:1986****–****1995**

## Diseases Associated WithTransfusional Iron Overload

**β-thalassemia**
**Other chronic anemias**
**Fanconi anemia (hypoplastic anemia)**
**Diamond-Blackfan anemia (red cell aplasia)**
**Congenital dyserythropoietic anemias**
**Sickle cell anemia**
**Aplastic anemia**
**Myelodysplastic syndromes (MDS)**

**Andrews NC. *****N Engl J Med*****. 1999;341:1986****-****1995.**

## Initiation of Therapy for Iron OverloadCurrent Practice

**With repeated blood transfusions, iron rapidly accumulates in the body**
**Chelation treatment is generally initiated after 10 to 20  transfusions or when serum ferritin > 1000 μg/L**
**Alternatively, if iron loading is unclear, LIC may be measured**

**LIC = Liver iron concentration.**
**Porter JB. *****Br J Haematol.***** 2001;115:239****-****252.**

## Liver Iron Concentration Accurately Reflects Total Body Iron Stores

**Reprinted with permission from Angelucci E, et al. *****N Engl J Med. *****2000;343:327-331.**

**Liver iron concentration (LIC), mg/g dry weight**

**Total body iron stores, mg/kg**

**0**

**5**

**10**

**15**

**20**

**25**

**300**

**250**

**200**

**150**

**100**

**50**

**0**

***r***** = 0.98**

**Stores calculated by quantitative phlebotomy**
** **
**LIC measured from biopsy samples ≥ 1 mg dry weight in 25 patients**

**Body iron (mg/kg) = 10.6 x LIC  (mg/g dry wt)**

## Liver Iron and Risk of Complications From Iron Overload

**HH heterozygotes**

**50**

**40**

**30**

**20**

**10**

**0**

**50**

**   ****100**

**   ****150**

**   ****200**

**   ****250**

**Age, years**

**Hepatic iron, μmol/g wet weight**

**50**

**40**

**30**

**20**

**10**

**0**

**Hepatic iron, mg/g dry weight**

**Threshold for cardiac disease and early death**

**Increased risk of complications**

**Normal**

**    ****Olivieri & Brittenham, 1997 *****Blood.***** 89; 739-761.**

** ****Thalassemia major**

**Liver Iron and Risk of Complications From Iron Overload**

**0**

## Plasma Ferritin as a Monitor of Iron Loading

**Relatively non-invasive**
**Inexpensive**
**Obtained as****routine laboratory assay**
**Values confounded by**
**Inflammation**
**Liver function**

**0**

**4000**

**8000**

**12000**

**24,000**

**12,000**

**8000**

**4000**

**0**

**Hepatic iron, ****μ****g Fe/g liver ***

**Plasma ferritin, ****μ****g/L**

**Brittenham et al. *****Am J Hematol*****. 1993;42:81.**

**Sickle cell anemia (n = 37)**

**Thalassemia major (n = 74)**

## Liver Iron Concentration and Serum Ferritin

**Change in serum ferritin over time reflects change in LIC**
**Sequential evaluation of ferritin levels provides a good index of chelation history****a**
**Maintenance of serum ferritin < 2500 μg/L significantly correlates with cardiac****disease-free survival****b,c,d,e**

**a**** Gabutti V and Piga A. *****Acta Haematol*****. 1996;95:26-36.**
**b**** Olivieri NF, et al. *****N Engl J Med*****. 1994;331:574-578. **
**c ****Telfer PT, et al. *****Br J Haematol*****. 2000;110:971-977.**
**d**** ****Davis BA, et al. *****Blood*****. 2004;104:263-269.**
**e**** Borgna-Pignatti C, et al. *****Haematologica*****.***** *****2004;89:1187-1193.**

## Cardiac Disease and % of Time WithSerum Ferritin > 2500 μg/L

**Olivieri, et al. *****N Engl J Med.***** 1994;331:574.**

**Assessments > 2500 μg/L**

**1.00**

**0.75**

**0.50**

**0.25**

**0**

**0**

**2**

**4**

**6**

**8**

**10**

**12**

**14**

**16**

**Years of chelation therapy**

**Proportion without****cardiac disease**

**< 33%**

**33% - 67%**

**> 67%**

## Ideal Properties of an Iron Chelator

**Control of body iron**
**Prevention of iron mediated organ toxicity**
**Simplicity and ease of administration**
**Once daily oral administration**
**Suitable for monotherapy**
**Acceptable toxicity profile**
**Iron free drug - dose relationship **
**Iron complex - stable no redistribution of iron**
**Simplicity and ease of monitoring**

## Current Therapy for Iron Overload

**Deferoxamine (Desferal****®****) is the only drug available in US to treat iron overload**
**Because of short half-life (20 minutes), must be given by continuous infusion**
**8 to 12 hours/day, 5 to 7 days/week**
**Compliance is poor because of****side effects and quality-of-life issues**
**Oral therapy is highly desirable**

**Porter JB and Huehns CR. *****Baillieres Clin Haematol*****. 1989;2:459-474.**

## Compliance With Deferoxamine Infusions Is Related to Survival in Thalassemia

**Kaplan-Meier analysis of survival in 257 consecutive thalassemic patients**
**according to the mean compliance with subcutaneous DFO therapy****   **

**Age, years**

**Survival, %**

**0**

**10**

**20**

**30**

**40**

**50**

**60**

**70**

**80**

**90**

**100**

**0**

**2**

**4**

**6**

**8**

**10**

**12**

**14**

**16**

**18**

**20**

**22**

**24**

**26**

**28**

**30**

**32**

**34**

**36**

**38**

**40**

**0 - 75**

**75 - 150**

**150 - 225**

**225 - 300**

**300 - 365**

**Gabutti V and Piga A. *****Acta Haematol*****. 1995;95:26-36.**

**Deferoxamine****infusions/year**

## Summary of Medical Need

**Transfusional therapy results in iron overload****	**
**Currently, the only approved therapy for iron overload in US is deferoxamine, which requires subcutaneous infusion for 8 to 12 hours, 5 to 7 times per week**
**Compliance is an issue**
**Many patients are not adequately treated**

**Treadwell MJ, et al. *****Pediatr Blood Cancer*****. 2005;44:500-507.**
**Porter JB and Huehns CR. *****Baillieres Clin Haematol*****. 1989;2:459-474.**

## Summary of Medical Need

**Inadequately treated iron overload leads to****organ toxicity**
**Related to lack of control of reactive iron, and deposition of iron in key tissues**
**Developmental and endocrine dysfunction**
**Cardiac dysfunction results in early death**

**Beutler E, et al. *****Hematology (Am Soc Hematol Educ Program)*****. 2004:40-61.**