Case presentation
A 10-year-old female was diagnosed with late combined (bone marrow and central nervous system (CNS)) relapse of B-cell acute lymphoblastic leukemia (B-ALL) approximately 3.5 years after completing chemotherapy for standard risk B-ALL. She had a high burden of CNS disease at time of relapse diagnosis. She was started on therapy per the low-risk control arm of the Children’s Oncology Group (COG) study AALL1331 with regimen as previously published(1). She was started on prophylactic trimethoprim-sulfamethoxazole and fluconazole at time of relapse diagnosis. Her bone marrow and CNS were negative for leukemia at the end of Block 1 of therapy. She completed Block 2 chemotherapy and started Block 3 chemotherapy per protocol.
One week after receiving Day 8 high-dose cytarabine, she was admitted with febrile neutropenia. She was found to have Enterobacter cloacae bacteremia which was treated with a course of cefepime; fevers resolved, and blood cultures cleared quickly. Five days later, while still on cefepime, fevers recurred along with left-sided headache, photophobia, and emotional lability. On exam, she had a subtle superficial scalp lesion initially concerning for leukemia cutis. CT head showed a large left parieto-occipital lesion concerning for fungal infection. MRI brain/spine showed a 4.3 x 3.7 cm area of abnormality in the left parieto-occipital area, and no abnormal spine findings (Fig2/panel A). Fungal biomarkers (serum aspergillus galactomannan and (1,3)-β-D-glucan) were negative. Dual broad anti-fungal therapy was initiated including liposomal amphotericin B and voriconazole, and fluconazole was stopped.
Based on imaging demonstrating enhancing tissue in the scalp adjacent to the lesion, and given risk of brain biopsy, a CT-guided biopsy of the scalp lesion by interventional radiology was obtained but was non-conclusive. Ultimately, an open brain biopsy was performed with tissue samples sent for oncology and infectious disease diagnostics including bacterial, fungal, and AFB cultures and molecular PCR-based testing. PCR testing returned positive for Rhizomucor pucillus. Pathology showed a hypocellular sample with some neutrophils and lymphocytes, and flow cytometry was negative for relapsed leukemia. While the initial fungal cultures were reported as negative, further fungal immunostaining (H&E, GMS) of specimens showed findings consistent with mucormycosis (Figure1). Expanded work up including pan-CT imaging looking for disseminated disease showed no sinus or orbital disease. CT chest did not show specific signs of pulmonary mucormycosis such as the “reverse halo” sign; however, there was one small focal ground-glass nodule in the lung(2). The patient had no respiratory symptoms during hospitalization. Based on otherwise negative imaging, she was diagnosed with isolated cerebral mucormycosis (ICM). Liposomal amphotericin B was increased to high-dose therapy at 10 mg/kg/day, micafungin was added as synergistic therapy based on literature (2)(3) and voriconazole was stopped. Based on histopathological findings, she underwent emergent aggressive surgical debridement by neurosurgery comprising the enhancing and necrotic tissue in the superior parietal lobule and the adjacent gyri but sparing the occipital cortex and the peri-ventricular white matter to decrease the morbidity of the surgery and the risk of peri-ventricular spread. The immediate postoperative MRI reflected resection of the enhancing tissue but persistent FLAIR hyperintensity in the margins of the resection cavity (Figure 2/panel B). Repeat brain MRI brain 13 days later showed abnormalities consistent likely with progression of ICM including increase in enhancement around the resection cavity, leptomeningeal enhancement within the left posterior frontal and parietal sulci, and worsening mass effect with new 3 mm left-to-right midline shift (Figure 2/panel C). Given the progression and extension of the disease there was concern that further surgical debridement would have unacceptable morbidity and be possibly life-threatening. After multidisciplinary discussions with the patient’s family, her parents elected to discontinue chemotherapy and engage hospice services rather than pursue additional aggressive treatment. She was discharged on oral ISAV as compassionate salvage treatment.
Unexpectedly, over two months after hospital discharge on hospice care, the patient continued doing well without further deterioration on ISAV monotherapy. Brain MRI was repeated and showed near resolution of previously seen concerning areas of enhancement. Bone marrow and spinal fluid evaluations were negative for leukemia. After discussion with family, the patient was re-initiated on a modified chemotherapy regimen with the goal of maintaining leukemia remission while avoiding excessive myelosuppression which was felt to increase risk for recurrence of ICM if any microscopic fungal disease were still present. She was treated with 28 days of continuous blinatumomab per AALL1331 and MRI after this cycle showed only expected post-operative changes in the left parieto-occipital resection cavity with slight enhancement of this cavity (Fig2/panel D). She completed one additional cycle of blinatumomab per AALL1331 followed by 16 weeks of continuation therapy per a modified version of the St. Jude Total XVI protocol weeks(4) Intermittent imaging during therapy showed stable CNS findings and she remained clinically stable aside from episodes of dizziness and occasional headaches, managed by neurology. She remained in continuous remission and was started on Maintenance chemotherapy per AALL1331.