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.