Sickle Cell Information Center Guidelines

Edited by James Eckman, M.D. and Allan Platt, PA-C

Iron Overload and Chelation Therapy by Beatrice Gee, MD

Iron is an essential nutrient for all living organisms. People with sickle cell disease are unlikely to become iron deficient due to recycling of iron from red cells by the reticuloendothelial system. Chronically anemic individuals also have increased gastrointestinal iron absorption.

Iron overload occurs in people with sickle cell syndromes who have required numerous red cell transfusions. The body’s iron stores become saturated after receiving approximately 500 mg Fe/kg, or 20-30 transfusions. Progressive iron accumulation beyond this point will lead to organ toxicity, particularly to the heart, liver, endocrine organs. The toxicity of iron is believed to be due to free radical damage to tissues induced by iron that is circulating unbound to plasma proteins such as transferrin. The human body does not excrete a significant amount of iron. Phlebotomy, the treatment of choice for iron overload due to hereditary hemachromatosis, is not an option for chronically anemic individuals.

Patients with significant iron overload may develop signs of organ dysfunction. Cardiac effects are cardiomyopathy and conduction abnormalities. Hepatic effects include hepatomegaly, liver dysfunction, cirrhosis. All endocrine glands can be effected, but most commonly the pancreas (leading to diabetes mellitus), anterior pituitary (causing short stature and hypogonadism), parathyroid (causing hypocalcemia) and thyroid.

Clinical Findings

Present Illness.Increased jaundice, nausea, hepatomegally, abdominal swelling, easy bruising, prolonged bleeing, weight loss, polyuria, polydipsea, malaise, muscle cramps

Past Medical History. Past past surgery, number of blood transfusions, past travel, recent immunizations and medications, Orthopnea, pedal edema, PND, growth..

Physical Examination.

• Vital Signs..pulse, respiratory rate , blood pressure, height, weight
• General Inspection. Signs of recent weight loss, cirrhosis, short stature.
• Eye. Jaundice.
• Ear – hearing test
• Mouth/Throat. Palatine petechiae, tonsils, thrush.

• Cardiovascular. JVD, PMI, Murmers or gallups
• Lymph Nodes. Characterize size, location, consistency, inflammation, fixed or non-fixed, local verses generalized lymphadenopathy
• Abdominal. Liver/spleen size and tenderness, masses.
• Extremities. Joint pain, range of motion, synovial thickening, effusions, edema.

• Minimum Evaluation. CBC with differential, reticulocyte and platelet count, SMA 18, Serum ferritin, Serum iron (Fe) and total iron binding capacity (TIBC): Transferrin
• - Additional Testing.
• Consider a liver biopsy to quantitate iron burden or super-conducting quantum interference device (SCQUID).
• Testing rational

Serum ferritin is the most frequently used non-invasive measure of total body iron burden. Ferritin is an iron storage protein synthesized by the liver. Serum ferritin correlates well with body iron content between 1 - 3 gms, but less well in ranges beyond that. Ferritin may be further elevated by liver injury or inflammation. Individuals with sickle cell disease may have serum ferritin values much higher than expected, possibly due to chronic inflammation or related to African type hemachromatosis. Quantitation of hepatic iron concentration may be helpful for determining iron burden in such patients.

Serum iron (Fe) and total iron binding capacity (TIBC): Transferrin saturation will eventually reach 100% after about 2-3 years of monthly transfusions. After this time, Fe and TIBC measurements are no longer helpful in determining iron burden.

Hepatic iron concentration (HIC) is considered to be the most accurate measure of total body iron. It can be quantitated from liver biopsy tissue. Percutaneous liver biopsy should be performed by an experienced practitioner. Samples should not be handled with metal instruments and they should be transported in iron-free containers to a reference laboratory. Some authors suggest routine assessment of HIC by liver biopsy. Potential risks and benefits of liver biopsy should reviewed individually for each patient. HIC is correlates fairly well with the volume of red cells transfused. In people with hereditary hemachromatosis, the incidence of cardiac disease and early death is highest in those with HIC > 15 mg/gm dry weight.

HIC can be measured non-invasively by a super-conducting quantum interference device (SCQUID). This technique is available in only a few locations in the world (Columbia University, NY; Universitätskrankenhaus Eppendorf, Hamburg, Germany; Torino, Italy). Magnetic resonance imaging (MRI) methods may potentially be developed for quantitation of hepatic iron but are not currently available.

Deferoxamine mesylate (DesferrioxamineÔ , DesferalÔ , DF) is the only iron chelator approved for use in the United States. This medication is derived from a naturally occurring siderophore (iron-binding protein) produced by the fungus Streptomyces pilosus. Iron bound to DF is excreted in the urine and turns the urine pink. DF is not lipid soluble and has a short plasma half-life, so it is only effective for chronic chelation therapy when given as a continuous subcutaneous or intravenous infusion. DF has been in regular use for treatment of transfusional iron overload since the mid-1970s. It is most frequently given as a subcutaneous infusion over 8-12 hours at least 5 nights a week using a small pump. The effectiveness of DF chelation therapy may be limited in some patients due to discomfort, inconvenience, cost, and/or psychologic stress.

Initiation of deferoxamine therapy should be considered if any of the following occur

• After 20-25 transfusions
• Transferrin saturation (Fe/TIBC ratio) > 80%
• Ferritin is 2000 or higher
• Hepatic iron concentration > 3 mg/gm of dry weight

Prior to beginning DF therapy, baseline asssessment of hearing, vision, cardiac function (echocardiogram, EKG, Holter monitoring of rhythm), hepatic function, renal function, and growth and development are recommended.

Annual reassessment of above parameters, calcium metabolism, and endocrine function (including thyroid, parathyroid, and sex hormones, glucose tolerance) are suggested.

General Considerations. Hands should be washed with soap and water before mixing medication and beginning infusions. Aseptic technique should always be used. Needles and tubing should be disposed properly and never be reused. Medication and needles should be stored out of reach of children.

Dosage. Deferoxamine 25-50 mg/kg over 8-12 hours as a subcutaneous infusion at least 5 nights per week. 2.5-3.0 gm is probably the maximal tolerated amount for subcutaneous infusion.

Dilution. Each 500 mg of DF should be diluted in a minimum of 2 ml preservative free water. Some pharmacies can premix a week’s supply in a cartridge. DF should be stored at room temperature. Reconstituted DF should not be stored for more than one week.

Equipment. DF mixed sterilely in a bag or syringe, infusion pump set to run at proper rate, infusion set, butterfly needle (25 guage is recommended) or other injection needle, antiseptic swabs/wipes, tape, dressing, topical anesthetic cream if desired, needle disposal container.

Infusion sites. DF should be given in areas with the most subcutaneous fat, such as the abdomen, thighs, upper arms, or buttocks. Infusion sites should be rotated to a different place each day. To avoid bone infections, thin individuals should avoid inserting the needle near bony prominences. The infusion needle should be inserted at a 45^o angle. Subcutaneous nodules and reactions are more likely to occur if the angle of entry of the needle is too shallow.

Monitoring Adherence to Therapy. A daily calendar to record infusions is helpful for both the patient and physician to monitor adherence to therapy. Infusion sites should be examined. Skin sites may be hyperpigmented or show subcutaneous nodules, though some patients may have no skin reactions to DF. Honest self-reporting of DF usage by the patient and/or family member is encouraged. Empty DF vials can be collected and returned to the physician after usage for counting. For those patients using infusion pumps with computerized recording, a report can be generated and reviewed.

Overview. Overall, DF is a very safe and effective medication. Severe toxicity's most frequently occur when very high dosages are administered (>60 mg/kg/day). Chronic toxicity's that may be associated with long-term usage include hearing loss, renal calcium loss, and possibly osteopenia. Chronic toxicity's may be prevented by regular monitoring for side effects and reduction of the DF dose.

Local reactions. Pain, induration, and erythema are fairly common with subcutaneous infusions. Local anesthetic cream reduces local pain for some people. Some patients may develop subcutaneous nodules at the site of infusions. Addition of hydrocortisone 1 mg/ml may help relieve local reactions.

Allergic reactions. Urticarial reactions and angioedema occur very rarely, most often when a very high dose is given IV. Desensitization is sometimes possible.

Acute neurologic events. One patient has been reported who developed transient loss of consciousness, vision loss, headache and aphasia associated with a rapid intravenous infusion. These effects resolved after cessation of the infusion and after administration of intravenous fluids, suggesting that rapid intravenous DF infusion may cause abnormal vaso-regulation.

Interstitial pneumonitis. A pulmonary syndrome of tachypnea, hypoxia, and interstitital pulmonary changes on chest radiogram has been described with high dose intravenous DF (100 - 200 mg/kg/day). The histologic findings and peripheral blood eosinophilia in one case suggest a hypersensitivity reaction. Pulmonary reactions have not been described with the usual DF doses (25 - 50 mg/kg/day) or when it is administered by subcutaneous infusions.

Cardiac. In people with severe iron overload, worsening of cardiac function has been described when DF was given with high doses of vitamin C (>500 mg/day). This effect resolved when vitamin C was discontinued.

Hearing and Vision. High doses of DF can cause direct damage to the auditory apparatus and retina. People with low amounts of iron in their bodies or previous damage to these organs (such as diabetic retinopathy) are more prone to auditory and visual toxicities. Hearing abnormalities include tinnitus and high frequency sensorineural hearing loss. Symptoms of retinal toxicity include problems with night vision and blurred vision. Some improvement of hearing or vision can occur with cessation of DF and resumption at lower doses.

Infections. Some bacteria and fungi grow better in the presence of DF because it provides iron needed by thenorganisms. In particular, people using DF have a higher chance of developing intestinal infections or bacteremia from Yersinia enterocolitica. If bloody diarrhea, severe stomach pain, or fevers develop, DF should be stopped immediately, blood and stool cultures obtained, and antibiotic coverage begun. Fungal infections with Rhizopus species can occur in people with renal failure who are receiving DF for aluminum chelation.

Kidneys. DF can cause renal insufficiency with increased creatinine or tubular dysfunction with excessive excretion of calcium or other minerals.

Bones and Growth. Children who start DF treatments before 3 years old tend to be shorter than average and develop dysplastic bones. Some people also develop osteopenia and osteoporosis. There appears to be a relationship between a high level DF compliance and more severe osteopenia. The mechanism of osteopenia in DF therapy is unknown, but it may be related to urinary excretion of calcium and other minerals.

Possible Birth Defects. Pregnant animals given DF may have offspring with abnormal bones. Some women have taken Deferoxamine during pregnancy and their babies have been normal. DF use is not recommended while a woman is pregnant, though some authors suggest it may be safe.

Initiation of DF therapy. Most authors now recommend initiating DF therapy after a moderate amount of iron has accumulated, as opposed to beginning it with chronic transfusion therapy. Frequently used parameters for determining when to begin DF therapy include those listed earlier, and after age 3 years to reduce the incidence of bony changes.

DF dosing. "Standard" dosages of DF (25- 50 mg/kg/day) appear to be associated with a lower incidence of toxicities. Higher dosages of 100-200 mg/kg/day are used by some physicians to treat patients with extreme organ dysfunction from hemachromatosis. There are numerous case reports of side effects occurring with high doses or rapid infusion rates of DF. Encourage patient compliance to avoid the need for high doses in the future.

Avoid high doses of Vitamin C. Vitamin C (ascorbic acid) mobilizes iron from tissues. Doses > 500 mg/day have been associated with worsening of cardiac dysfunction in patients with severe iron overload. If vitamin C is prescribed, a maximum daily dose of 200 mg for an adult is suggested, to be given after the DF infusion is begun.

Dose adjustments of chronic DF therapy. The effectiveness of DF therapy can be monitored and doses adjusted to minimize toxicities. Measure ferritin at least every 6 months. Some authors suggest liver biopsy for HIC every 18 months.

Some centers use urinary iron excretion (UIE) to determine the adequacy of DF dosing. Ideally, a patient’s daily dose of DF will mobilize at least 1/25 of the iron acquired each month from transfusions. Accurate measurement of UIE is difficult usually due incomplete 24 hour urine collections. Some iron is also excreted in stool. Precise measurement of iron balance is limited to in-patient research settings.

Regular assessment of hearing, vision, linear growth, bone density, renal function and urinary calcium excretion may be helpful in early identification of DF side effects.

Consider reduction of DF dosage if:
Abnormalities are found on follow-up assessments or patient develops overt symptoms
Ferritin has fallen to less than 2000 ng/ml
Hepatic iron concentration (HIC) < 3.2 mg/gm dry weight of liver

Therapeutic index (TI) (Porter et al.): TI = mean daily DF dose (mg/kg)/mean serum ferritin (ng/ml)
A recommended range for the TI is less than 0.025, which would be achieved for a person treated with DF 50 mg/kg/day who had a serum ferritin greater than 2000 mg/L.

Avoid DF use during pregnancy if possible.

Intravenous (IV) administration. IV administration may be necessary for patients who cannot tolerate or adhere to subcutaneous infusions, or those who need higher dose, 24 hour continuous therapy. High dose therapy (> 60 mg/kg/day) may be associated with a higher incidence of toxicities (see above). Circulating DF levels are estimated to be 25% higher with IV therapy than subcutaneous infusions. A central venous catheter (e.g. Hickman, Broviac, or Port-a-cath) is usually needed. Complications such as infection or thrombosis may limit the lifespan of a catheter. Thrombosis may be more common in patients with sickle cell disease than the general population.

Bolus subcutaneous injections. A few series have shown that giving subcutaneous injections of DF twice daily may induce a similar degree of urinary iron excretion as the same total daily dose given as a continous infusion over 8-12 hours. In small series of patients, the reduction of non-transferrin bound iron (probably reflecting "free" iron with potential for oxidative damage) was similar for both continuous infusions and 2 bolus injections. Whether this method of administration can be effective for longterm chelation needs to be studied.

Oral chelators. 1,2-dimethyl-3-hydroxypyrid-4-one (Deferiprone, CP20, L1) is an oral iron chelator of the hydroxypyridinone family which has been studied since the mid-1980’s. It is currently being licensed in Europe and is available in India. A commonly used dose of L1 is 75 mg/kg/day divided into three doses. There is some controversy about whether or not L1 is as effective as DF. The most common side effects of L1 are neutropenia and arthropathy. One author suggests that L1 may be associated with a higher incidence of hepatic fibrosis in individuals with Hepatitis C and advanced iron overload. A number of other oral chelators have been developed and studied but are not used clinically due to excessive side effects or ineffectiveness.

Red cell exchange transfusion (Erythrocytapheresis). Chronic use of red cell exchange may be feasible for some patients to reduce the amount of iron associated with each transfusion. The procedure may be limited by lack of adequate venous access. Patients will be exposed to more donors per transfusion which may increase the risk of allo-antibody formation and/or viral infections.

Counsel parent and patient on chelation therapy when chronic transfusions are initiated.

 Instruct parent and family on administration of desferoximamine, use of pumps and equipment.

 Instruct on aseptic techniques, rotating sites, and encourage vigorous fluid intake.

 Explain common side effect like pain at site and dark coffee colored, or red urine.

 Coordinate care with home care nursing agencies regarding patient teaching, equipment, and medication orders.

 Instruct parents/patient that hearing, vision and cardiology procedures must be done prior to therapy and monitored closely.

 Observe administration sites for irritation and infection.

 Monitor patients closely under concomitant vitamin C therapy.

 Educate the patient/family to report visual or hearing changes

 Desferal must be administered at a steady rate - too rapid IV infusion could cause shock, hearing loss, visual loss, or other toxicities.

 Provide support to encourage compliance with treatment and reporting adverse occurrences.

Prior to the availability of DF therapy, chronically transfused thalassemia patients usually died from cardiac failure by their twenties. These individuals also developed hepatic cirrhosis, insulin dependent diabetes mellitus due to pancreatic insufficiency, growth and pubertal delays due to hypopituitarism, and possibly other hormone deficiencies. Since the advent of subcutaneous DF therapy using a portable pump, the longevity of chronically transfused individuals has improved considerably. Among patients with beta-thalassemia major who had at least 67% of ferritin levels £ 2500 ng/ml , there was a 91% chance of surviving for 15 years after initiation of DF therapy. Freedom from cardiac complications correlates well with the degree of patient compliance to DF therapy. However, growth and pubertal delays may not be completely preventable even in well-chelated patients who have been transfused since infancy.

Patients and participating family members should be instructed by an experienced healthcare provider. Patients and family members should have the opportunity to both observe and practice medication mixing, pump configuration, and infusion technique with their healthcare provider before beginning home infusions. Where available, home health nurses may be helpful for reinforcing proper technique and encouraging patients to administer medication regularly. Frequent reassessment and review of understanding of the rationale of chelation therapy, acceptance of the therapy, proper technique, adherence to therapy, and motivational support by medical personnel are important longterm aspects of chelation therapy. For young children, play therapy and motivational programs may be helpful in improving compliance and regularity of therapy. Peer support groups may be useful for older children, adults, and parents of children receiving DF therapy.

Links

Keisha's Coloring book about chelation therapy - Power Point Slide Show

How to do Desferal Therapy Power Point Slide Show

Grady STARS Clinic - A model for multidisciplinary care

Iron Overload and Chelation Therapy Information from The Children's Hospital at Oakland at http://www.thalassemia.com/transfusion/overload.shtml Chelation Therapy at http://www.thalassemia.com/transfusion/chelation.shtml

Iron Overload in Hematologic Disorders – Interactive CME Program from the  45th ASH Annual Meeting Corporate Friday Symposium. View interactive video presentations and one-on-one faculty interviews. Learn about exciting new developments in the treatment of iron overload and transfusion therapy in sickle cell disease. Professionals can obtain free CME credit  http://www.ironoverload-cme.com

Day S, Bullock R, Kelly K, Wang W. Guidelines for home infusion of Desferal. Cooley’s Anemia Foundation, Inc.

Kushner JP, Porter JP, Olivieri NF. Secondary iron overload. Hematology (Am Soc Hematol Educ Program) 2001 Jan;:47-61 http://www.asheducationbook.org/cgi/content/full/2001/1/47

Novartis Pharmaceuticals Corporation. Desferal vials. Physicians Desk Reference Electronic Library, 1999.

Olivieri NF, Berriman AM, Tyler BJ, et al. Reduction in tissue iron stores with a new regimen of continuous ambulatory intravenous deferoxamine. Am. J. Hematol. 1992; 41:61-63.

Olivieri NF, Nathan DG, MacMillan JH et al. Survival In Medically Treated Patients With Homozygous beta-Thalassemia. N. Engl. J. Med. 1994; 331(9): 574-578.

Olivieri NF, Brittenham GM. Iron-chelating therapy and the treatment of thalassemia. Blood 1997; 89(3): 739-61.

Olivieri NF, Brittenham GM, McLaren CE, et al. Long-term safety and effectiveness of iron-chelation therapy with deferiprone for thalassemia major. N. Engl. J. Med. 1998; 339(7):417-23.

Porter JB, Huehns ER. The toxic effects of desferrioxamine. Baillière’s Clinical Haematology 1989; 2(2):459-74.

Porter JB. A risk-benefit assessment of iron-chelation therapy. Drug Safety 1997; 17(6):407-21.

Harmatz P, Butensky E, et al. Severity of iron overload in patients with sickle cell disease receiving chronic red blood cell transfusion therapy. Blood 7/1/2000; 96: 76-79. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10891433&dopt=Abstract

Treadwell MJ, Weissman L Improving adherence with deferoxamine regimens for patients receiving chronic transfusion therapy.Semin Hematol 2001 Jan;38(1 Suppl 1):77-84

Treadwell MJ, Weissman L. Improving adherence with deferoxamine regimens for patients receiving chronic transfusion therapy. Semin Hematol. 2001 Jan;38(1 Suppl 1):77-84.

  Cohen AR, Martin MB. Iron chelation therapy in sickle cell disease. Semin Hematol. 2001 Jan;38(1 Suppl 1):69-72.

Porter JB. Deferoxamine pharmacokinetics. Semin Hematol. 2001 Jan;38(1 Suppl 1):63-8.

Olivieri NF. Progression of iron overload in sickle cell disease. Semin Hematol. 2001 Jan;38(1 Suppl 1):57-62.

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Last modified: June 11, 2004