Transfusional Iron Overload: An Underappreciated Danger in AML Patients?

Abstract 4133

The survival rate for childhood cancer has improved steadily over the last 3 decades creating an increasing population of survivors. Though this is one of the great successes in medicine, there is a growing awareness that survivors are at increased risk for late therapy related adverse effects including cardiovascular toxicity. The Childhood Cancer Survivor Study showed that the standardized mortality ratio for cardiac causes was > 8 times higher than expected and cumulative probability of cardiac death increased 15-25 years after cancer diagnosis.[i]

The cardiotoxic effects of anthracyclines are well documented in the literature. They are an essential component of treatment for AML. However, their use is limited by dose-related cardiomyopathy. An important factor in anthracycline toxicity is iron's role in promoting the formation of toxic oxygen species. Cardiac tissue is recognized to be especially vulnerable to free radical damage. Anthracyclines cause altered expression of iron-regulated genes and change intracellular iron trafficking. It is known that, dexrazoxane-an iron chelator, is an effective cardioprotective agent against doxorubicin effects in animal models. The American Society of Clinical Oncology recommends its use in metastatic breast cancer patients receiving a doxorubicin dose of >300 mg/m².[ii] Dexrazoxane was found to prevent or reduce cardiac injury associated with doxorubicin use in childhood ALL without compromising the anti-leukemic effect.[iii]

We hypothesize that cardiomyocytes damaged by anthracyclines are more susceptible to iron accumulation, potentiating anthracycline toxicity in patients with a heavy transfusion burden.

Consecutive adolescent patients with AML admitted to our institution were reviewed. These patients received a cumulative anthracycline dose of 200 to 300 mg/m². Iron loading was estimated from the number of red cell units given. The iron content of a single red cell unit is approximately 200 mg. 10 AML patients received 24-59 units of blood (median 35) over a median of 222 days. This equates to 65-235 mg of iron/kg (median of 129 mg/kg).

Iron loading was identified in AML patients due to transfusion. The iron load is less than seen in children with thalassemia but in AML patients, who are known to have increased adverse cardiac events, it is possible that anthracycline induced cardiomyopathy could have been exacerbated by transfused iron. To prove the hypothesis the next step is to investigate T2* MRI detectable myocardial iron deposition and cardiac dysfunction and markers of myocardial injury in AML patients. These observations may provide evidence for using iron chelation therapy in the treatment of AML.

[i] Lipshultz S, Alvarez JA, Scully RE. Anthracycline associated cardiotoxicity in survivors of childhood cancer. Heart 2008; 94: 525-533

[ii] Carver JR, Shapiro CL, Ng A, et al. ASCO Cancer Survivorship Expert Panel. American Society of Clinical Oncology clinical evidence review on the ongoing care of adult cance survivors: cardiac and pulmonary late effects. J Clin Oncol 2007; 25: 3991-4008

[iii] Lipshultz SE, Rifai N, Dalton VM, et al. The effect of dexrazoxane on myocardial injury in doxorubicin-treated children with acute lymphoblastic leukemia. N Engl J Med 2004; 351: 145-53