Safety and efficacy of subcutaneous bolus injection of deferoxamine in adult patients with iron overload: an update

Multiply transfused patients, such as those with hematologic malignancies undergoing chemotherapy or those with thalassemia major, develop iron overload which in time becomes responsible for organ damage and dysfunction. Iron chelation therapy is therefore necessary to prevent or decrease the iron burden.^1,2  Subcutaneous continuous infusion of deferoxamine mesylate (DFO) through a battery-operated portable pump is the most effective and safest method of preventing or treating iron overload, but it is very demanding since it requires the patients' compliance for 8 to 12 hours daily. For this reason, alternative iron chelating approaches have been developed in the last few years.³  Borgna-Pignatti and Cohen⁴  first demonstrated in 1995 in thalassemic patients that the 48-hour DFO-induced urinary iron excretion after twice-daily subcutaneous bolus injections of deferoxamine is similar to that after continuous infusion. Subsequently, other studies confirmed these findings in thalassemic and nonthalassemic iron-overloaded patients.^5-8  More recently, we documented the long-term safety and efficacy of this method in 26 iron-overloaded adult patients.⁹  Since then, we have received many letters from colleagues who wanted to start such a method of administration or who asked us for an update of our patients. The great interest around twice-daily subcutaneous bolus injections of DFO, still existing 3 years after the publication of our study, despite the fact that this method has not been licensed by the pharmaceutical company producing DFO (Novartis Pharma, Origgio, Italy), gives us the opportunity to review our series and make some considerations.

During the follow-up period (April 1999 to September 2003), 7 of the 15 regularly transfused patients (patient nos. 3, 5, 9, 10, 15, 19, and 22) of the first group died due to disease progression, whereas 3 of the remaining 8 patients (patient nos. 1, 12, and 14) complained of the large volume of the single bolus injection (10 mL), which caused a postinjection, painful swelling that lasted several hours (12 to 24 hours), and these patients chose to continue chelation therapy with the standard subcutaneous continuous infusion of DFO. The data from the 5 patients who remained in the study, together with data from 7 additional cases, are shown in Table 1. We did not record any adverse events in the 7 new cases, after a median follow-up of 28 months. As regards the second group of 11 transfusion-independent patients, 3 patients (patient nos. 16, 23, and 27) died due to progression/relapse of disease and 2 patients (patient nos. 18 and 26), who are still alive, came out of the protocol because they restarted chemotherapy due to relapse of the hematologic malignancy. In the remaining 6 patients (patient nos. 11, 13, 20, 21, 24, and 25), the twice-daily subcutaneous bolus injections of DFO normalized ferritin levels. In these patients, who did not require transfusions during the follow-up after chemotherapy, DFO bolus injections were stopped once normal ferritin levels had been reached. The ferritin levels were then monitored every 3 months. Patient number 20 (with spherocytosis and hereditary hemochromatosis) started a maintenance phlebotomy program with bolus injection of DFO due to an increase of serum ferritin levels (780 μg/L).

Although the newly reported cases further testify to the efficacy of this method, there are some concerns regarding the long-term tolerance of DFO bolus injections. In fact, examining the follow-up of the previously published cases, we found that 3 of the 8 patients who remained in the study did not tolerate the volume of the bolus injections, preferring the subcutaneous continuous infusion. The pharmaceutical company producing DFO recommends a 10% final concentration of the drug, because higher concentrations have been shown to be associated with a higher incidence of local reactions at the injection site.¹⁰ 

Long-term follow-up trials on larger populations of patients are needed in order to clarify the real incidence of adverse reactions in patients using twice-daily subcutaneous bolus injections of deferoxamine.