Here, we report the case of a 59-year-old man with acute myeloid leukemia (AML) arising in August 2017 from a 5q- myelodysplastic syndrome treated with lenalidomide. A Mito-FLAG induction scheme (G-CSF from day -1, fludarabine 60 mg/die days 1-5, cytarabine 2 g over 3 h every 12 h days 1-5, mitoxantrone 12 mg/die day 1, 3 and 5) followed by two cycles of consolidation chemotherapy were administrated (Mito-FLAG again and one cycle with high-doses-cytarabine); meanwhile a donor search was started. In March 2018, after a TBF reduced-intensity conditioning regimen (thiotepa 390 mg day -6, busulfan 240 mg/die days -5 and -4; fludarabine 80 mg day -3) the patient underwent allogeneic HSCT from a matched unrelated donor. Micafungin was used for fungal prophylaxis. Rabbit-derived anti-thymocyte globulins infusion (2.5 mg/Kg days -3, -2, -1), cyclosporine A (3 mg/Kg, continuous infusion from day -1) and methotrexate (30 mg day +1 then 20 mg days +3 and +6) were administered for GvHD prophylaxis. Since the diagnosis of AML to HSCT a total of 47 units of red blood cells were transfused, deferasirox (an iron-chelating agent) was started two months before HSCT producing a ferritinemia reduction from 2713 to 1489 ng/ml few days before the beginning of conditioning regimen; deferasirox administration was stopped during the transplant procedure.
Day +1 from HSCT, the patient complained, on the right side of the face, a sharp pain mimicking trigeminal neuralgia and responsive to high doses of morphine. CT scan of brain and sinuses showed a picture of pansinusitis. At day +2, after a sudden onset of fever, empirical antibacterial therapy (piperacillin/tazobactam plus amikacin) and antifungal therapy with liposomal amphotericin B (L-Amb) were started. Diplopia occurred in day +6, a palsy of VI right cranial nerve was detected plus a sensitive deficit of V cranial nerve of the same side. Magnetic resonance imaging (MRI) of brain and sinuses plus MR angiography with contrast dye showed the presence of a mycetoma in the right sphenoidal sinus associated with thrombophlebitis of the cavernous sinus, thrombosis of the superior ophthalmic vein and possible involvement of temporal meninges in contiguity with the bone cavity.
Blood indirect biomarkers for the detection of a fungal infection (1,3-beta-D-glucan and galactomannan) were negatives over the entire period. Antifungal therapy was reinforced, a combination of L-AmB at the dosage of 7.5 mg/Kg/die plus iv isavuconazole (ISC) 200 mg (375 mg of isavuconazonium sulfate equivalent to 200 mg of ISC) every 8 hours for six doses followed by 200 mg/die was started. Day +11, the patient, still in aplasia (WBC 10/mm3, Hb 7.0 g/dl, platelets 10000/mm3), underwent a procedure of endoscopic sinus surgery (ESS) after transfusions of blood components with no complications. The cultural and histological examination does not reveal presence of hyphae; Rhizomucor was identified by amplification and sequencing of two Internal Transcribed Spacer regions (ITS1 and ITS2) in rRNA gene. The Sanger sequencing was performed after amplification using ITS1-Forward and ITS4-reverse primers.
The patient achieved myeloid engraftment at day +16 and became afebrile. The trigeminal neuralgia regressed although the VI right cranial nerve palsy persistence, antibiotics were stopped and the combined antifungal therapy was continued. A new MRI, at day +41, revealed the presence of a brain mycotic abscess with associated vasogenic cerebral edema of the right temporal lobe (Figure 1). Although the involvement of the cavernous sinus was detected, an excisional neurosurgery intervention of the cerebral abscess was not undertaken considering the procedural high-risk balanced to the benefits of an incomplete drainage. The patient was discharged, ISC was switched to oral formulation, and L-AmB was administered in an outpatient setting for 74 days in total. Cyclosporine administration was stopped one month after transplantation for fear to promote Rhizomucor growth and further dissemination. The general condition of the patient worsened; he lost 30 Kg of weight in total, parenteral nutrition was started. We were forced to introduce steroid therapy (prednisone 1 mg/Kg/die) for severe gastrointestinal, cutaneous and ocular GvHD. Because the response of cutaneous GvHD to steroids was not adequate, extracorporeal photoapheresis was started with benefit. Megestrol acetate, an orexigenic, was dispensed to treat cachexia. ISC dosage was increased to 300 mg/die in consideration of ISC plasma concentrations (Figure 2); deferasirox was reintroduced in therapy.
At six months from HSCT, a new MRI of the brain showed the reduction of the para-cavernous abscess with partial reabsorption of the purulent quote and temporal lobe edema (Figure 1). Complete thrombosis of the right internal carotid artery was detected but patient remained completely asymptomatic for it. We decided to continue antifungal therapy with ISC at 300 mg/die then we reduced the dosage to 200 mg/die based on therapeutic drug monitoring (TDM).
Patient's mood improved and body weight with it, he started to have a complete meal and to walk again with crutches. Palsy of VI right cranial nerve regressed almost completely; prednisone was reduced and maintain to a dose of 10 mg/die for hepatic and intestinal GvHD. Revaluation of bone marrow at one year from HSCT confirmed full donor chimerism. Brain MRI revealed further reduction of the endocranial mycotic abscess (8 x 3 mm), no purulent quote was present. In accordance with clinical improvement we considered it a full response, and we decided to stop isavuconazole after 354 days of treatment.