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Antimicrobial Agents and Chemotherapy, July 2009, p. 3122-3125, Vol. 53, No. 7
0066-4804/09/$08.00+0     doi:10.1128/AAC.00361-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Safety and Outcomes of Open-Label Deferasirox Iron Chelation Therapy for Mucormycosis

Brad Spellberg,^1,2* David Andes,³ Mario Perez,⁴ Anne Anglim,⁵ Hector Bonilla,⁶ Glenn E. Mathisen,⁷ Thomas J. Walsh,⁸ and Ashraf S. Ibrahim^1,2

Division of Infectious Diseases, Los Angeles Biomedical Research Institute at Harbor-University of California at Los Angeles (UCLA) Medical Center, Torrance, California,¹ the David Geffen School of Medicine at UCLA, Los Angeles, California,² Departments of Medicine and Medical Microbiology and Immunology, University of Wisconsin School of Medicine, Madison, Wisconsin,³ Division of Infectious Diseases, University of Southern California (USC) School of Medicine Department of Medicine, Los Angeles, California,⁴ Long Beach Public Department of Health, Long Beach, California,⁵ Summa Health System, Akron, Ohio,⁶ Division of Infectious Diseases, Olive View-UCLA Medical Center, Sylmar, California,⁷ Immunocompromised Host Section, Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland⁸

Received 16 March 2009/ Returned for modification 21 April 2009/ Accepted 4 May 2009

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We sought to describe the safety profile of open-label, adjunctive deferasirox iron chelation therapy in eight patients with biopsy-proven mucormycosis. Deferasirox was administered for an average of 14 days (range, 7 to 21) at 5 to 20 mg/kg of body weight/day. The only adverse effects attributable to deferasirox were rashes in two patients. Deferasirox treatment was not associated with changes in renal or liver function, complete blood count, or transplant immunosuppressive levels. Thus, deferasirox appears safe as an adjunctive therapy for mucormycosis.

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Mucormycosis is a life-threatening infection caused by fungi of the subphylum Mucormycotina, order Mucorales (5, 10, 12). Iron availability is a critical factor in the growth of Mucorales (12). However, the potential therapeutic role of iron chelation therapy for mucormycosis was initially obscured by the paradoxically increased risk of developing mucormycosis during treatment with the iron chelator deferoxamine (2). This paradox was resolved when it was realized that deferoxamine actually enhances iron uptake by the fungi (2). Animal models have shown that other iron chelators do not act as iron siderophores for Mucorales (1, 7). Furthermore, deferasirox, an iron chelator recently approved by the U.S. Food and Drug Administration for the treatment of transfusion-related iron overload (3), had potent in vitro activity and in vivo efficacy in mice against clinical isolates of Mucorales (8).

To date, virtually all of the published clinical data on deferasirox therapy has been accumulated for uninfected patients with transfusion-related iron overload (13). Furthermore, safety concerns regarding potential use in infected patients have been underscored by sporadic postmarketing reports of acute renal failure, hepatic insufficiency, and agranulocytosis in iron-overloaded patients being treated with deferasirox (6). We therefore sought to define the safety of adjunctive deferasirox therapy for mucormycosis.

We reviewed data from eight patients with mucormycosis treated with open-label deferasirox (Table 1). All patients had biopsy-proven mucormycosis, in accordance with Mycosis Study Group-European Organization for the Research and Treatment of Cancer criteria (4). Seven of eight patients had diabetes mellitus, and five were taking corticosteroids at diagnosis. Five patients had received post-solid organ transplantation (two lung transplant patients, two kidney transplant patients, and one liver transplant patient). Active antifungal therapy was initiated a median of 9 days (range, 4 to 93) after symptom onset. Seven of eight patients underwent surgical debridement (all except patient 1) (Table 1), and the patients received their first surgical intervention at a median of 17 days (range, 5 to 86) after the start of symptoms.

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TABLE 1. Summary of cases

In all cases, deferasirox was used in combination with other antifungal therapy (Table 1). In three cases, deferasirox was added as salvage therapy after a failure of initial therapy, and in five cases, the deferasirox was added prior to disease progression on the initial treatment regimen. One patient was treated for 20 days with a dose of 5 mg/kg of body weight/day of deferasirox because he had coexisting hepatic disease; all other patients received 15 to 20 mg/kg/day for a median of 14 days (range, 7 to 21 days).

Five patients showed improvements in signs or symptoms attributable to mucormycosis by the end of deferasirox therapy; of the three patients who did not show improvement in signs or symptoms, two had persistent, irreversible blindness due to orbital exenteration which occurred prior to initiation of deferasirox therapy (Table 1). Five of the six patients with repeat imaging studies after the end of deferasirox therapy had improvement or resolution of lesions. These improvements were not related to surgical management, since the improved lesions were predominantly in the brain or cavernous sinus and hence were not debrided. Seven of the eight patients survived to hospital discharge, all of whom were alive and not in hospice care at 30 days postdischarge. Two of those patients remained on maintenance antifungal therapy as of the last follow-up, and five were considered cured (i.e., alive and well and off all antifungal therapy) at a median of 365 days (range, 60 to 730 days) of follow-up.

Median serum creatinine levels increased significantly between the time of mucormycosis diagnosis and the time of initiation of deferasirox therapy, consistent with polyene-mediated alterations in glomerular function (Table 2). However, neither serum creatinine nor blood urea nitrogen levels significantly changed during deferasirox therapy, including results for three patients with markedly elevated serum creatinines at the time deferasirox therapy began. Liver function tests, glucose, white blood cell count, absolute neutrophil count, hemoglobin, and platelet counts were not significantly altered during the course of therapy. In three patients, mean tacrolimus levels declined from 18 ng/ml at the time of diagnosis of mucormycosis to 9 ng/ml at the time of initiation of deferasirox therapy to 4 ng/ml at the end of deferasirox therapy.

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TABLE 2. Median (interquartile range) laboratory valuesa

Iron was measured for only two patients, one of whom developed massive hemolysis which artificially increased iron levels during deferasirox therapy. That hemolytic reaction occurred during a blood transfusion, and the patient was subsequently found to have a positive cross-match to the donor blood; hence the reaction was felt to be independent of the use of deferasirox. For five patients, ferritin levels were so variable that meaningful changes could not be defined.

Two patients developed rashes during deferasirox therapy, the first on day 7 of therapy and the second on day 11 of therapy. Both rashes were erythematous, generalized maculopapular eruptions which spared the mucosa and were considered mild to moderate in severity. Both rashes resolved off therapy. No other adverse events from deferasirox therapy were noted.

We are aware of at least three other cases of deferasirox therapy for mucormycosis which are not included in this series because data could not be abstracted. One of the cases was previously reported (11), and failure of deferasirox salvage therapy was described for a leukemic patient with widespread disseminated disease, including bowel involvement postcolectomy. Because deferasirox is available only in an enteral formulation, it is likely that malabsorption of the drug contributed to its failure in that case. One of the authors (T. J. Walsh) was involved with the care of the other two patients, both of whom received salvage deferasirox therapy after failing previous regimens and both of whom were subsequently cured of their infection.

A double-blinded, randomized, placebo-controlled phase II clinical trial of the safety and exploratory efficacy of adjunctive deferasirox therapy for patients with mucormycosis treated with liposomal amphotericin B (LAmB) is ongoing (the deferasirox-AmBisome therapy for mucormycosis [DEFEAT Mucor] study [NCT00419770]), and results are anticipated in late 2009. The purpose of the phase II study is to lay the groundwork for a future, definitive phase III efficacy study. The drug's promising safety profile in the current series supports the need for additional study of deferasirox efficacy for this disease.

 
This work was supported by Public Health Service grants K08 AI060641 and R01 AI072052 to B.S. and R01 AI063503 and R21 AI064716 to A.S.I. A.S.I. is also supported by a Burroughs Wellcome New Investigator Award in Molecular Pathogenic Mycology. B.S. is also supported by American Heart Association Beginning Grant-in-Aid 0665154Y.

B.S. has received research grant support from Astellas, Gilead, Novartis, Merck, and Pfizer, serves on the scientific advisory board of Merck, has consulted for Arpida, Basilea, Advanced Life Sciences, Novo Nordisk, and Theravance, and owns equity in NovaDigm Therapeutics, Inc. B.S. has previously received speaker's honoraria from Merck, Astellas, and Pfizer. A.S.I. has received research support from Astellas, Gilead, Enzon, Merck, Novartis, and Pfizer. All other authors have no disclosures.

 
* Corresponding author. Mailing address: 1124 West Carson St., RB2, Torrance, CA 90502. Phone: (310) 222-5381. Fax: (310) 782-2016. E-mail: bspellberg{at}labiomed.org

Published ahead of print on 11 May 2009.

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Antimicrobial Agents and Chemotherapy, July 2009, p. 3122-3125, Vol. 53, No. 7
0066-4804/09/$08.00+0     doi:10.1128/AAC.00361-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services E-mail this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Spellberg, B. Articles by Ibrahim, A. S. Search for Related Content PubMed PubMed Citation Articles by Spellberg, B. Articles by Ibrahim, A. S.