Assessment of Chelator side-effects and toxicity

The primary signs of chelator toxicity are hearing loss, temporary loss of sight, cataracts, renal dysfunction, growth failure, and symptoms related to iron deficiency. Side effects from deferoxamine toxicity include auditory and visual changes, and may occur when total body iron is low but high doses of deferoxamine are still being used. The table below indicates toxicity-monitoring parameters. The following should be routinely monitored.

Audiology

A baseline formal audiology exam should be given prior to starting a chelator. Any history of hearing difficulty or tinnitus should prompt a physical exam of the tympanic membranes and formal audiology testing.

Inquire about hearing problems at each monthly visit. A screening audiogram should be performed in clinic every six months. Refer patients for formal audiogram assessment every 12 months, or more often if a patient is unable to undergo a screening test in clinic.

If there is new onset of hearing loss or tinnitus, the chelator should be stopped and the audiogram repeated. The testing should be confirmed within a month. The chelator can be restarted if the hearing changes have improved. Reevaluation of iron status may be necessary.

Ophthalmology

Inquire about decreased visual acuity at each visit—especially changes in color perception. Changes in color vision are often the first symptoms of over-chelation.

An annual evaluation by an ophthalmologist should be performed to rule out cataracts, decreased acuity, night blindness, and decreased visual fields. Any vision change should be examined with causes unrelated to iron in mind, as well. A reevaluation of the chelation regimen should be done if any ophthalmologic abnormalities are found.

Nephrology

Creatinine and BUN with the serum chemistry, urine protein/creatinine, and microalbumin should be monitored monthly for patients on deferasirox and every three months for patients on deferoxamine.

Neutropenia

Neutropenia, or low neutrophil count, must be monitored weekly with a CBC for patients on deferiprone.

Growth

Evaluate patients for evidence of growth delay. Routinely record height and weight monthly and calculate annually growth velocity. Measure sitting height every six months to assess truncal shortening. Tibial and spinal radiographs should be evaluated for evidence of metaphyseal cartilaginous dysplasia in younger patients with evidence of growth delay.

Local and allergic reactions

Local reactions at the deferoxamine injection site that are urticarial in nature will usually respond to increased dilution of the deferoxamine by 25 to 30 percent. Hydrocortisone should be used only in severe cases and under the direction of the consulting hematologist. In some cases, treatment with antihistamines may be helpful.

Severe, life-threatening allergic reactions may occur. Patients who report systemic allergic symptoms should be observed and possibly challenged in clinic. Desensitization protocols have been used successfully on some patients. When desensitization has been accomplished, it is critical that the patient does not stop the medication, as it may necessitate reinstitution of the entire desensitization process. With the availability of alternative chelation drugs, changing chelators may be a better option than desensitization.

Over-chelation

Persistent low serum ferritin levels (below 500 ng/mL) in the face of regular chelation are not optimal due to the increased toxicity of deferoxamine, particularly in children, and presumably deferasirox, at low levels of total body iron. The chelation program should be modified and the LIC evaluated. In select high-risk patients, very low iron levels are maintained but consultation with experts in iron chelation is required due to toxicity. Low levels of zinc, copper, selenium, and ionized calcium can also be indicators of deferoxamine toxicity.

Table: Chelation Toxicity Monitoring