Invasive mucormycosis during treatment for acute lymphoblastic leukaemia—successful management of two life-threatening diseases
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A 5-year-old patient treated for acute lymphoblastic leukaemia (ALL) developed proven pulmonary invasive fungal disease (IFD) due to Actinomucor elegans. While completing ALL treatment according to AIEOP ALL protocol 2009 for further 15 months, antifungal treatment with liposomal amphotericin B and intermittent additional posaconazole was continued until immune reconstitution 7 months after the end of ALL treatment. Repeated imaging guided treatment decisions. Twenty-six and 19 months after the end of ALL treatment and antifungal treatment, respectively, the patient is still in the first complete remission and shows no signs of active invasive fungal disease (IFD).
KeywordsALL Mucormycosis IFD Antimycotic treatment Chemotherapy
Associazione Italiana Ematologia Oncologia Pediatrica
Acute lymphoblastic leukaemia
Central nervous system
European Conference on Infections in Leukaemia
European Organisation for Research and Treatment of Cancer
Invasive fungal disease
Invasive mould infection
Magnetic resonance imaging
Polymerase chain reaction
Positron emission tomography
Invasive mould diseases remain an important cause of death in immunocompromised patients [1, 2]. While invasive diseases with Aspergillus sp. have mortality rates of 20–50%, mortality rates in mucormycosis range from 50 to 100% [3, 4, 5]. Differentiation between mucormycoses and other mould infections remains challenging, since these pathogens are difficult to culture and show similar radiological and clinical features leading from 4% to up to 90% of suspected mucormycosis cases not being confirmed until post-mortem examination [1, 4, 5]. Moreover, mucormycetes lack susceptibility to many antifungal agents and need higher dosages of amphotericin B [6, 7]. A mainstay of the successful management is the reversal of the underlying condition . On the other hand, treatment of (haematologic) malignancies often leads to enhanced susceptibility for mucormycosis necessitating sophisticated management of these infections with concurrent further sufficient treatment of the malignant disease.
We describe the successful management of mucormycosis during ALL treatment.
We report the successful management of a 5-year-old patient treated for ALL, complicated by an opportunistic infection with Actinomucor elegans representing the first paediatric patient with this pathogen.
Actinomucor elegans belongs to the genus Actinomucor in the order Mucorales. So far, only 5 cases of infection with Actinomucor elegans in humans have been described in adults [2, 10, 11]. Two patients (1 immunocompetent, 1 recipient of an allogeneic stem cell transplantation for lymphoma) were described with sinusitis and were cured with debridement, irrigation and antifungal treatment [2, 12]. Two patients were described with soft tissue infections. One of them with underlying refractory aplastic anaemia died despite debridement and antifungal treatment . In the other patient, treatment and outcome were not reported . Another patient developed disseminated disease after extensive wounds and died despite extensive debridement and antifungal treatment .
While mucormycosis in patients with diabetes mainly causes rhinocerebral and sino-orbital infections, patients with malignancy typically develop pulmonary infections. The extensive angioinvasive properties result in vessel thrombosis, tissue necrosis and haematogenous dissemination. Furthermore, ischaemic necrosis prevents leukocyte and drug penetration .
In our case, host factors and imaging (representing possible IFD [8, 15]) led to the initiation of antifungal treatment. The growth of Aspergillus fumigatus from BAL fluid retrospectively most likely represents airway colonisation, reflecting the low specificity of cultivation of moulds from BAL fluid . The detection of hyphae from otherwise sterile material and molecular analyses led to the diagnosis of proven mucormycosis .
Currently no indirect methods are available facilitating the diagnosis , since cell walls of Mucorales spp. are lacking (1–3)-beta-d-glucan and galactomannan, which therefore cannot be used to diagnose invasive mucormycosis [1, 4, 17].
Initial empiric antifungal therapy comprising caspofungin, conventional doses of liposomal amphotericin B and voriconazole did not prevent deterioration. After proof of mucormycosis, therapy was switched to a combination of high-dose liposomal amphotericin B and posaconazole; despite lacking clear evidence, we decided for combination therapy due to the extent of the pulmonary lesions and the poor prognosis of invasive mucormycoses. Due to the widespread diffuse character of the infiltrates, we abandoned thoracotomy and surgical debridement. Mucorales spp. are considered to be resistant against echinocandins as well as against most azoles like voriconazole, fluconazole and itraconazole [7, 18] and require higher doses of amphotericin B usually administered in the liposomal formulation (AmBisome®) [6, 19]. Early treatment with high doses of amphotericin B is important since a delay results in a twofold increase in mortality leading to an overall mortality of up to 100% for patients with disseminated disease . The optimal dosage has still not been determined. Many clinicians use the maximum tolerable dosages, condoning nephrotoxicity, while efficacy results from a phase II clinical trial of high-dose therapy with 10 mg/kg/day i.v. are still pending (http://clinicaltrials.gov/show/NCT00467883) . Furthermore, posaconazole monotherapy is not recommended due to several reports on breakthrough mucormycoses under posaconazole prophylaxis .
In addition to antifungal treatment, the elimination of risk factors such as immunosuppressive therapies is essential for successful management of mucormycosis [4, 21]. As in our patient, a common risk factor is the treatment of haematologic and other malignancies, which on the other hand is vital to be cured. Therefore, it was crucial to continue treatment of ALL as soon as possible, despite invasive pulmonary mucormycosis. After initiation of adequate therapy for mucormycosis, we also reinitiated antileukaemic treatment with an interval treatment aligned to the ALL maintenance therapy and switched to the reinduction according to protocol 7 weeks later. The duration of treatment for mucormycosis remains unclear. ECIL recommends duration on an individual basis, but should continue for at least 6–8 weeks . We gradually reduced dosages and prolonged intervals of AmBisome® infusions during ALL maintenance therapy to minimise side effects and to enable ambulatory parenteral therapy during several months of treatment. Intermittent AmBisome® administration is considered to be an effective alternative to the standard regimen in preventing and possibly treating invasive fungal diseases, since it appears to accumulate in tissue [23, 24]. We used this approach for a long time therapy of 1.5 years. However, after 1 year of antifungal treatment and 10 months of ALL maintenance therapy, again progression of the infiltrates was seen, which underlines the importance of radiologic monitoring and constant adequate treatment until immune reconstitution clearly has been achieved. We reintensified and successfully continued antifungal treatment with intermittent AmBisome® until numerical immune reconstitution had been indicated by flow cytometry 7 months after the end of ALL treatment. We monitored our patient via intermittent thoracic MRI in addition to CT scans to reduce radiation. To discriminate active infection from tissue scarring, we also used FDG-PET imaging, which has been described to have valuable sensitivity in detecting fungal lesions . To gain immune reconstitution, one might be misled to extensively shorten maintenance therapy. However, we shortened ALL therapy by only 2 months, since it had been clearly shown that shortening therapy for ALL from 18 to 12 months leads to significantly worse outcome .
In conclusion, proof of mucormycetes from otherwise sterile material is essential for adequate diagnostics and therapy. Continued treatment of ALL is as important as concurrent adequate (long-term) antifungal treatment, alongside radiologic and immunologic monitoring which are essential in managing these both potentially fatal diseases.
Open access funding provided by Medical University of Graz.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
The authors have full control of all primary data and allow the journal to review this data if requested.
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