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\begin{document}

\title{Successful Isavuconazole Salvage Therapy for Cerebral Mucormycosis in A
child With Relapsed Leukemia, A light in The Dark Tunnel}



\author[1]{Karl  Balsara }%
\author[2]{Muayad Alali}%
\author[3]{Alka Khaitan}%
\author[1]{Drew  Streicher }%
\author[2]{Hailey  Budnick}%
\author[1]{Rachael  Schulte}%
\affil[1]{Indiana University Purdue University Indianapolis}%
\affil[2]{Indiana University Purdue University at Indianapolis}%
\affil[3]{Riley Hospital for Children}%


\vspace{-1em}



  
  \date{May 28, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Mucormycosis is an angioinvasive lethal fungal infection in pediatric
cancer patients. We present 10-year-old female with relapsed B-cell
acute lymphoblastic leukemia undergoing chemotherapy was diagnosed with
isolated cerebral mucormycosis (ICM). Despite surgical debridement and
liposomal amphotericin B, repeat imaging showed concern for disease
progression. Chemotherapy was discontinued and the patient was
discharged on salvage therapy oral isavuconazole (ISAV). Over two months
later, the patient was unexpectedly clinically stable, and imaging
showed near resolution. After confirming continuous disease remission,
the patient was restarted on modified chemotherapy. Serial MRI's during
continued chemotherapy showed stable MRI findings. This case illustrates
a rare presentation of successful salvage monotherapy ISAV for this
deadly infection with complete remission for relapsed leukemia.%
\end{abstract}%



\sloppy


Successful Isavuconazole Salvage Therapy for Cerebral Mucormycosis in A
child With Relapsed Leukemia: A light in The Dark Tunnel

Muayad Alali \textsuperscript{1}, Karl Balsara\textsuperscript{2}, Alka
Khaitan\textsuperscript{1}, Drew A Streicher\textsuperscript{3}, Hailey
C Budnick\textsuperscript{2}, Rachael R Schulte\textsuperscript{4}

\begin{enumerate}
\tightlist
\item
  Indiana University School of Medicine, Indianapolis, Indiana, USA,
  Department of Pediatrics, Ryan White Center for Pediatric, Infectious
  Diseases and Global Health
\item
  Indiana University School of Medicine, Indianapolis, Indiana, USA,
  Section of Pediatric Neurosurgery, Department of Neurosurgery, Goodman
  Campbell Brain and Spine, Riley Hospital for Children, Indiana
  University School of Medicine
\item
  Indiana University School of Medicine, Indianapolis, Indiana, USA,
  Department of Radiology, Indiana University School of Medicine,
  Indianapolis
\item
  Indiana University School of Medicine, Indianapolis, IN, USA,
  Department of Pediatrics, Section of Hematology/Oncology, Department
  of Pediatrics
\end{enumerate}

Correspondence to Muayad Alali, MD, Department of Pediatrics, Ryan White
Center for Pediatric Infectious Diseases and Global Health, Indiana
University School of Medicine, 705 Riley Hospital Drive, RI-5862,
Indianapolis, Indiana 46202, Ph: 872-305-7714 | FAX: 317.948.0860,
Email: muayad.alali20@gmail.com

Text word count 1600

Abstract word count: 115

Brief running title: CNS Mucormycosis in pediatric cancer

Key words: Cerebral Mucormycosis, Isavuconazole, pediatric cancer

Tables: 0

Figures: 2

abbreviations\selectlanguage{english}
\begin{longtable}[]{@{}ll@{}}
\toprule
ICM & Isolated cerebral mucormycosis\tabularnewline
ISAV & Isavuconazole\tabularnewline
B-ALL & B-cell acute lymphoblastic leukemia\tabularnewline
COG & Children's Oncology Group\tabularnewline
\bottomrule
\end{longtable}

\textbf{Abstract}

Mucormycosis is an angioinvasive lethal fungal infection in pediatric
cancer patients. We present 10-year-old female with relapsed B-cell
acute lymphoblastic leukemia undergoing chemotherapy was diagnosed with
isolated cerebral mucormycosis (ICM). Despite surgical debridement and
liposomal amphotericin B, repeat imaging showed concern for disease
progression. Chemotherapy was discontinued and the patient was
discharged on salvage therapy oral isavuconazole (ISAV). Over two months
later, the patient was unexpectedly clinically stable, and imaging
showed near resolution. After confirming continuous disease remission,
the patient was restarted on modified chemotherapy. Serial MRI's during
continued chemotherapy showed stable MRI findings. This case illustrates
a rare presentation of successful salvage monotherapy ISAV for this
deadly infection with complete remission for relapsed leukemia.

\textbf{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)-\selectlanguage{greek}β-\selectlanguage{english}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.

\textbf{Discussion}

Invasive CNS mucormycosis (CNS-M) is a rare but often deadly invasive
fungal infection in the pediatric population (4)(5). The acute and
rapidly progressive evolution generally causes unfavorable outcomes with
very high mortality rates of up to 65\% despite appropriate treatment
(5).

CNS-M can manifest in three distinct clinical forms: as rhinocerebral
mucormycosis (RCM), disseminated mucormycosis with CNS involvement, or
as ICM(6). The latter is the least frequent form, accounting for only
8\% of CNS-M cases (7, 8)

Isolated cerebral mucormycosis has been described in the literature as
having an exceedingly poor prognosis(7, 9-11)\{Kerezoudis, 2019
\#143;Kerezoudis, 2019 \#143\}. The pooled mortality rate in a
meta-analysis by the Mayo clinic was noted at 65\%in adults(12),
Rhizopus has been shown to be the most common isolated organism
(59\%)(13). Cases of isolated cerebral mucormycosis usually involve the
basal ganglia or thalamus(7). Lesions are usually deep-seated with
common basal ganglia involvement which is thought to be due to seeding
from the middle cerebral artery, especially in intravenous drug
users(6). However, interestingly, it has been shown that in
immunocompromised patients, cortical lesions are more common like our
case(6, 14)

Our case outlines the major obstacles in diagnosis of ICM as the
clinical symptoms were initially fairly subtle, conventional stains and
cultures were negative, and obtaining a CNS biopsy specimen is not
always feasible in vulnerable populations such as pediatric cancer
patients (9). There are currently no clinically available circulating
biomarkers of mucormycosis (9). Serum tests such as the 1,3-\selectlanguage{greek}β-\selectlanguage{english}D-glucan
assay and the~aspergillus~galactomannan assay are typically negative in
invasive mucormycosis (10). Therefore, definitive diagnosis requires
microbiological analysis of tissue obtained by biopsy or surgical
debridement (11), high degree of clinical suspicion and prompt
intervention (9, 12). The inclusion of PCR based testing for infectious
organisms was critical in this cryptogenic presentation as the first
finding to indicate the correct diagnosis(11, 15).

There are limited prospective clinical data on optimal therapies for
CNS-M in children(10, 12, 16). A combined medical and surgical approach
has repeatedly been shown to lead to the best outcomes(17), though
aggressive surgical debridement is not always feasible depending on
location of the infection, such as the CNS, where severe sequelae may
result from attempting to surgically remove all fungal disease(12, 18).
It has been widely accepted that early and aggressive surgical
debridement in rhinosinus mucormycosis is essential to survival but this
has not been established for isolated cerebral mucormycosis(13). Some
studies have shown decreased mortality with stereotactic
aspiration/debridement, but others have shown no differences in
outcome(14). In our case, an aggressive debridement of all
radiologically involved tissue would have conferred a neurological
deficit that was not acceptable to the patient or family. The positive
outcome in this case from a more limited debridement in combination with
a salvage medical regimen supports a measured approach(15, 18).

Until recently, amphotericin B and the triazole antifungals
(Posaconazole and ISAV) were the only systemic antifungals available
with good activity against Mucorales species (18, 19). Posaconazole has
been used in invasive mucormycosis in adults and adolescents as salvage
therapy; however, CNS penetration has been reported to be poor (20), and
Posaconazole monotherapy in CNS-M has not been adequately studied(20).
Furthermore, there are concerns about the oral bioavailability of
Posaconazole oral suspension in younger children who can't swallow the
extended-release tablet(21).

ISAV, a second-generation triazole, was approved for the treatment of
invasive aspergillosis (IA) or invasive mucormycosis(22). There is
limited information on the CNS penetration of ISAV, however, a few
studies demonstrated efficacy with ISAV treatment for CNS infections
caused by a wide range of different fungi(9, 23). More recently, ISAV
was assessed prospectively in a single-arm study of patients with
mucormycosis and other rare fungal infections (the VITAL trial) (16,
24). In this study, ISAV showed promising results against mucormycosis
with efficacy and outcomes similar to amphotericin B, these results turn
light in horizon for ISAV not only as salvage but also as first-line
agent of mucormycosis treatment(22). VITAL trial didn't look
specifically effectiveness of ISAV in CNS-M, but 29\% of cases had CNS
involvement. Meanwhile, the pediatric dosing regimen of this drug has
not been established. Desai et al. extrapolated an adult population
pharmacokinetic model to determine the appropriate dose of ISAV for
children(16). Accordingly, our patient received 10mg/kg of the prodrug
isavuconazonium sulfate (equivalent to 5.4mg/kg of isavuconazole) every
8 hours for the first 2 days and once daily thereafter. Duration of
therapy is always a question. Although our patient achieved radiographic
resolution(10), we would continue ISAV suppressive treatment until the
patient completes chemotherapy, is no longer in an immunosuppressive
state and has reconstitution of the immune system.

In summary, our case is noteworthy in highlighting several challenges
encountered in the diagnostics and management of ICM with eventually
successful salvage treatment with monotherapy ISAV with complete
clinical and radiologic responses. We hope that our case adds to the
growing evidence supporting of ISAV as well-tolerated, safe, and
efficacious therapy in ICM and promising therapy for salvage treatment
and could be hope in horizon in children with ICM. The availability of
an IV and oral of ISAV makes an attractive oral step-down therapy for
with invasive or disseminated mucormycosis. Prospective clinical trials
are needed to evaluate the established pediatric dose, safety, and
efficacy of ISAV in children and its role as first-line treatment for
ICM.

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