The DEFEAT Mucor study was the first randomized trial conducted of any treatment strategy for mucormycosis, or indeed for any non-Aspergillus mould infection. Although SAEs and AEs were similar in frequency and severity in patients treated with deferasirox and placebo, by 90 days of follow-up the mortality rate was higher in patients treated with deferasirox than in those treated with placebo. The primary driver of excess mortality appeared to be clinical failure due to progression of infection and progression of underlying disease, rather than any specific toxicity. No subset was identified that had superior outcomes with deferasirox therapy versus placebo, including patients who completed all 14 days of study therapy or those without malignancy or neutropenia.
There are several possible explanations for the discrepancy between the promising efficacy of deferasirox seen in earlier studies and the current results. First, despite its fungicidal effects on Mucorales in vitro
and substantial efficacy in mice, deferasirox may have no impact on clinical disease or may even worsen the clinical course of mucormycosis in humans. There are no published reports of deferasirox antagonism with other antifungal agents and the drug does not promote fungal growth in vitro
or in mice.1
Hence, mechanisms by which the drug could worsen clinical infection are not clear. Second, efficacy of deferasirox was most apparent in mice with DKA, which have increased free iron levels, and efficacy was substantially less apparent in neutropenic mice.1
Similarly, in the open-label description of favourable clinical outcomes of adjunctive deferasirox therapy (including initial therapy), most patients were diabetic and/or receiving corticosteroids, and no patients were neutropenic.19
Very few patients in the current study had diabetes as their only risk factor for mucormycosis and it is possible that the results of the current study reflect diminished deferasirox efficacy in specific host populations (e.g. neutropenia, haematological malignancy etc.). As well, data were not available regarding the time from onset of symptoms to the initiation of antifungal therapy, which is now known to be a major predictor of survival from mucormycosis.21
Probably due to the small number of enrolled patients spread across five sites with highly heterogeneous patient populations, there were imbalances at the time of randomization in the underlying disease and risk factors in the deferasirox and placebo arms. Most of the patients enrolled at cancer centres were randomized to receive deferasirox therapy. As a result, more patients in the deferasirox arm had malignancy, including haematological malignancy and/or myelodysplastic syndrome and neutropenia. Furthermore, the majority of patients with pulmonary infection were randomized to the deferasirox arm. It is well established that clinical outcomes are worse and mortality higher in patients with pulmonary mucormycosis versus rhino-orbital infection, in patients with malignancy versus diabetes as the predominant risk factor for mucormycosis and in patients with prolonged bone marrow suppression.21–25
Thus, imbalances in unmeasured confounders as well as recognized imbalances in underlying diseases and site of infection make it challenging to interpret different survival and treatment success rates in the deferasirox versus placebo arm. The small number of patients enrolled precludes a multifactorial analysis to isolate the contribution of treatment versus baseline factors to outcomes. Nevertheless, future studies of mucormycosis should carefully stratify patients by underlying disease (diabetic and solid organ transplantation versus haematological malignancy, neutropenia and haematopoietic stem cell transplantation) and study site.
Peak and trough deferasirox serum levels were similar to previously published results from patients treated for transfusion-related iron overload, in whom mean peak and trough serum levels were 38 and 17 mg/L, respectively.26
Serum levels were in excess of the deferasirox MICs for the small number of fungal isolates available for testing. Small sample sizes preclude definitive conclusions regarding any pharmacokinetic/pharmacodynamic relationship with clinical outcome.
The DEFEAT Mucor study enrolled slowly, despite broad enrolment criteria. On average, 0.9 patients per month were enrolled, with enrolment open in at least five sites at any one time, resulting in a conservative estimate of an average enrolment rate of 0.15 patients per site per month. The slow enrolment rate underscores the need for any future study of mucormycosis to enrol in a large number of study sites to achieve large sample sizes in reasonable periods of time, including the possible use of sites in Europe, where the disease is rising in incidence,27
and in India, where some hospitals see ≥50 patients with mucormycosis per year.28,29
Concordant with studies in mice,30
recent retrospective studies have demonstrated a superior survival rate in patients with mucormycosis treated with LAmB versus amphotericin B deoxycholate.23,24,31,32
Survival in patients treated with LAmB has ranged from 40% to 70% in these studies, with the primary drivers of survival relating to underlying predisposing risk factors (mortality worse with haematopoietic malignancies and prolonged neutropenia). These retrospective comparisons appear validated by the surprisingly high treatment success and survival rates in patients treated with LAmB (i.e. the placebo arm) in the current study. These results are critical for planning future pivotal studies of novel treatment strategies for mucormycosis and support published expert opinion that LAmB is preferred to amphotericin B deoxycholate for the treatment of mucormycosis.22
In summary, given the excess mortality of patients treated with adjunctive deferasirox therapy, deferasirox cannot be recommended as part of an initial combination regimen for the treatment of mucormycosis. Although no obvious toxicities were identified, the limited sample size precludes definitive establishment of the safety of deferasirox therapy for mucormycosis. Imbalances in underlying diseases at the time of randomization may have accounted for treatment efficacy differences between the study arms. Only a large, Phase III trial, potentially enrolling only diabetic or corticosteroid-treated patients, and excluding cancer/neutropenia patients, could further elucidate the safety and efficacy of initial, adjunctive deferasirox for the treatment of mucormycosis. Furthermore, these data do not address the potential for deferasirox to be used as part of a combination salvage therapy regimen, as early pre-emptive therapy in patients with less advanced disease identified by novel biomarkers (e.g. PCR) or as prophylaxis in high-risk patients. However, until additional studies are conducted, caution should be used when administering deferasirox for patients with mucormycosis, even in a salvage setting.