Introduction
A significant source of morbidity and mortality in haematological patients, particularly those undergoing hematopoietic stem cell transplantation (HSCT), is invasive fungal diseases (IFD). Due to non-specific symptoms and a small antifungal arsenal, diagnosis and treatment remain difficult despite the relatively high frequency. The USA Food and Drug Administration recently approved the use of ibrexafungerp, a first-in-class triterpenoid antifungal, to treat vaginal yeast infections. This medication works by inhibiting the glucan synthase enzyme in the fungal cell wall. Preclinical results demonstrate effectiveness against a variety of fungus species, including strains that are resistant to azoles and echinocandins. The role of ibrexafungerp in haematological patients who acquire fungal infections has not yet been characterised, despite preliminary results from ongoing phase 3 trials in IFD that are being conducted in this area being positive. For adult patients with haematological malignancies who have either had HSCT or received treatment with a novel targeted therapeutic drug, we examine the viability of oral ibrexafungerp-based antifungal therapy in this article. This article outlines four clinical situations where ibrexafungerp, either by itself or in combination with other antifungal medications, was effective in treating resistant fungal infections. We provide real-world examples of the possible clinical application of ibrexafungerp for patients with newly diagnosed haematological malignancies in an effort to spark further discussion.
Case 1
A 72-year-old unfit male was diagnosed with secondary acute myeloid leukemia (AML) and was unsuccessfully treated with low-dose cytarabine (LDAraC) in combination with glasdegib. However, during the treatment, asymptomatic funguria and elevated C-reactive protein (CRP) values were observed with a Pichia kudriavzevii (synonymously known as Candida krusei) identification in the patient’s urine culture.However, 3 weeks later, a recurrence of Candida krusei in the urine was detected despite the absence of common risk factors such as a bladder catheter. Due to poor general health, impaired kidney function, and the patient’s will to continue outpatient therapy, oral ibrexafungerp 750 mg QD was started as an alternative to azoles to avoid any potential interactions with venetoclax. The patient remains in CR receiving anti-leukemic maintenance therapy with no further fungi isolation from microbiological samples.
Case 2
High-risk myelodysplastic syndrome (HR-MDS) was diagnosed for a 70-year-old male patient. Despite antifungal prophylaxis with IV micafungin 150 mg QOD, the patient developed sepsis caused by Candida krusei on the 12th day of salvage therapy. Based on antifungal susceptibility testing using the concentration gradient Etest strip technique, IV liposomal amphotericin B 200 mg QD was added to IV micafungin 150 mg QD, and administered for 18 days. However, a fever up to 38 °C and an increase in CRP were observed during treatment; thus, monotherapy with oral ibrexafungerp 750 mg QD was initiated. The patient did not develop any further fungal infection, but unfortunately died of HR-MDS progression after several months.
Case 3
AML with a monoallelic mutation of CEPBA was diagnosed in a 60-year-old male who was successfully treated with 7 + 3 induction and allogeneic HSCT from a matched (HLA 10/10) unrelated donor. On day +73 post-HSCT, the patient complained about joint (right knee and right elbow) pain and swelling. Microbiological examination of the synovial fluid confirmed fungal arthritis caused by Candida krusei. After 16 days of dual antifungal therapy, the clinical effect was subtle: CRP remained high, as did the fever, and Candida krusei persisted in the synovial fluid culture. After 15 days of combination treatment, the liposomal amphotericin B was discontinued to minimize drug-related toxicity, and ibrexafungerp 750 mg QD was continued with no recurring fungal infections. The patient died due to refractory graft-versus-host disease after several months.
Case 4
A 65-year-old male was diagnosed with FLT3-mutated AML and underwent frontline 7 + 3 induction and salvage ACTIVE + gilteritinib therapy before proceeding to matched unrelated donor allogeneic HSCT. Four months post-HSCT, during the maintenance therapy with gilteritinib, the patient developed dyspnea, cough, and a fever with high CRP values. Despite the front-line therapy with micafungin 150 mg QD, second-line isavuconazole 200 mg QD, and third-line liposomal amphotericin B 150 mg QD in combination with inhaled voriconazole 40 mg TID, only minimal improvement was evident. Triple antifungal therapy resulted in the resolution of the fever and dyspnea, and improved the cough. A lack of radiological improvement and the elevation of CRP were attributable to the residual pulmonary granulomatous inflammation.
Discussion
Despite significantly lower rates of invasive candidiasis (IC), Candida species are becoming more and more resistant to azoles, as well as echinocandins. The latter two cases support the idea that the possible synergy between ibrexafungerp and polyenes could overcome the fungal resistance problem and improve outcomes of patients who develop IFD, including those with invasive aspergillosis. Currently, echinocandins are recommended for front-line therapy against IC in neutropenic patients due to their excellent activity against Candida spp. Despite moderate hepatotoxicity, echinocandins are otherwise well tolerated and can be safely employed in hematological patients. However, echinocandins can only be administered intravenously, creating challenges for treatment in the outpatient setting.
Although ibrexafungerp is a substrate of CYP3A4 and a potential inhibitor of CYP2C8, it overcomes major CYP-mediated drug interactions in vivo, resulting in the safer and easier coadministration of ibrexafungerp and other CYP3A4 substrates frequently used in HSCT, such as tacrolimus or cyclosporin A. We represent four clinical cases where ibrexafungerp, either as a monotherapy or in combination with liposomal amphotericin B, was effective for the treatment of fungal infections when alternative antifungal therapies had previously failed, or had to be avoided due to possible treatment-related toxicities or drug–drug interactions. For the first time, we suggest that ibrexafungerp may be considered as an add-on or monotherapy for the treatment of fungal infections in hematological patients, especially for those undergoing HSCT.
Source: Daraskevicius, J.; Petraitis, V.; Davainis, L.; Zucenka, A. The Feasibility of Ibrexafungerp for the Treatment of Fungal Infections in Patients with Hematological Malignancies. J. Fungi 2022, 8, 440. https://doi.org/10.3390/jof8050440.
