Reply to Bazaz and Denning

To the Editor—We read with interest the letter by Bazaz and Denning reporting on a patient with nonoperable hepatocellular carcinoma who developed subacute invasive aspergillosis (IA) following treatment with the multikinase inhibitor sorafenib [1]. As correctly stated by the authors, in our recent review on invasive fungal infections (IFIs) associated with small molecule kinase inhibitors (SMKIs) targeting immune signaling pathways, we reported that there was “no evidence of opportunistic infections” related to sorafenib based on information obtained from the US Food and Drug Administration official website [2]. Following the case of IA reported by Bazaz and Denning, we extensively reviewed the literature and identified 3 additional published cases of sorafenib-associated IFIs, including 2 cases of IA [3–5] (Table 1). Of note, only 2 of 4 patients received immunosuppressive treatment with corticosteroids or chemotherapy within the month prior to the IFI diagnosis, suggesting that sorafenib alone was responsible for the heightened susceptibility in half of the reported cases thus far. In addition to IFIs, sorafenib has also been associated with the development of mucocutaneous fungal infections caused by Candida and other yeasts, underscoring the potential sorafenib-induced impairment of interleukin 17–dependent barrier immunity [6, 7].

Table 1.

Reported Cases of Invasive Fungal Infections Complicating Sorafenib Therapy

Pathogen	Time of IFI Diagnosis After SRF Initiation	Site of Infection	Type and Status of Underlying Cancer	Agea at IFI Diagnosis (y) /Sex	GC Use at IFI Diagnosisb	Comorbidities	Outcome	Reference
Aspergillus fumigatus	6 weeks	Lung	Hepatocellular carcinoma	64/M	No	DM, asthma	Alive	Bazaz et al [1]
Aspergillus spp.	N/A	Lung	Relapsed thyroid cancer	N/A	Yes	N/A	Alive	Kloos et al [3]
Aspergillus spp.	5 months	Lung	Metastatic salivary gland carcinoma	N/A	No	N/A	Alive	Locati et al [4]
Talaromyces marneffei	8 months	Disseminated	Relapsed AML	67/M	Noc	N/A	Alive	Chan et al [5]

Abbreviations: AML, acute myelogenous leukemia; DM, diabetes mellitus; GC, glucocorticoids; IFI, invasive fungal infection; N/A, not available; SRF, sorafenib.

^aIn years.

^bNo patient received concomitant immunosuppressive medications other than GC.

^cPatient received treatment with mitoxantrone, etoposide, daunarubicin, clofarabine, azacitidine, decitabine, and cytarabine 1 month before the infection.

In our recent review [2], we had (1) predicted that IFIs associated with SMKIs targeting antifungal immune signaling pathways will likely emerge and (2) emphasized the need for better epidemiological surveillance and increased awareness in order to capture cases of IFIs associated with these compounds. Notably, a major target of sorafenib is rapidly accelerated fibrosarcoma (RAF)/MAPK/ERK kinase/extracellular signal regulated (ERK) signaling, which regulates important antifungal effector pathways in phagocytes against fungal pathogens, including Aspergillus [8, 9]. Furthermore, sorafenib induces apoptosis and affects the antigen-presenting capacity of dendritic cells by inhibiting nuclear factor kappa-light-chain-enhancer of activated B cells signaling and other mitogen-activated protein kinase pathways besides ERK, thus resulting in impaired T-cell responses [10]. Finally, sorefanib inhibits RAF-dependent activation of Janus Kinase (JAK)/Signal Transducer and Activator of Transcription Proteins (STAT) signaling in a broad range of innate immune cells [11], with potential impact on a critical arm of innate antifungal immunity [12]. Arguably, additional complex immune defects related to iatrogenic immunosuppression, the underlying malignancy, comorbidities, and the intensity of exposure to environmental fungi could play an important role in development of IFIs in sorafenib-treated patients.

The letter by Bazaz and Denning further reinforces the message of our review regarding the importance of increased awareness for IFIs in patients treated with selective compounds targeting immune-signaling pathways. Having a high index of suspicion for IFIs in patients receiving therapy with SMKIs who develop compatible clinical syndromes such as pneumonia, policy changes toward mandatory reporting of IFIs as a separate class of opportunistic infections, and development of improved epidemiological tools for tracking of SMKI-associated IFIs are required and should result in improved patient outcomes.

Notes

Financial support. This work was supported in part by the Division of Intramural Research of the National Institute of Allergy and Infectious Diseases, National Institutes of Health (to M. S. L.), the Greek State Scholarship Foundation (to G. C.), and the Texas 4000 Distinguished Professorship Endowment for Cancer Research (to D. P. K.).

Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.