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\begin{document}

\title{Observation of notable therapeutic response in a patient with systemic
juvenile xanthogranuloma with KIF5B-ALK fusion}



\author[1]{Minako Sugiyama}%
\author[1]{Shinsuke Hirabayashi}%
\author[2]{Yukitomo Ishi}%
\author[1]{Junko Kikuchi}%
\author[3]{Ayako Ishikura}%
\author[2]{Hiroaki Motegi}%
\author[1]{Yuki Ueda}%
\author[1]{Saori Sawai}%
\author[1]{Kazuya Hara}%
\author[1]{Yukayo Terashita}%
\author[1]{Yuko Cho}%
\author[1]{Emi Takakuwa}%
\author[1]{Shohei Honda}%
\author[2]{Shigeru Yamaguchi}%
\author[1]{Ichiro Kinoshita}%
\author[1]{Atsushi Manabe}%
\affil[1]{Hokkaido University Hospital}%
\affil[2]{Faculty of Medicine, Hokkaido University}%
\affil[3]{Hakodate Central General Hospital}%


\vspace{-1em}



  
  \date{May 17, 2024}


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\selectlanguage{english}
\begin{abstract}
We report the case of a 1-year-old male patient with systemic juvenile
xanthogranuloma in whom central nervous system lesions caused
developmental retardation, spasticity and clonus of the lower
extremities. He needed tube feeding and experienced severe bronchitis
and generalised convulsive seizure. KIF5B-ALK fusion was identified in
the cutaneous lesion, and he was administered alectinib, an ALK
inhibitor. Two months after the initiation of alectinib administration,
the central nervous system lesions achieved partial regression. The
spasticity and clonus were also relieved. A high index of cognition is
needed for ALK fusion in infants with histiocytosis.%
\end{abstract}%



\sloppy


\textbf{Introduction}

Juvenile xanthogranuloma (JXG) is classified as a histiocytosis that is
generally diagnosed on the basis of the presence of cutaneous nodules in
infancy. It has been considered benign and could undergo spontaneous
regression without therapy.\textsuperscript{1} However, some patients
with systemic JXG, particularly patients with central nervous system
(CNS) involvement, might have severe neurological
sequelae.\textsuperscript{2}\begin{CJK}{UTF8}{gbsn}　\end{CJK}\selectlanguage{english}Conventional chemotherapy based on
Langerhans cell histiocytosis (LCH) have been applied for these severe
cases,\textsuperscript{2} but the response rate remains unclear. In
addition, adverse events and late complications induced by anticancer
drugs should be avoided in paediatric patients as much as possible,
especially in neonates. Recently, BRAF V600E mutation and recurrent
kinase fusions, including BRAF, NTRK and anaplastic lymphoma kinase
(ALK), including KIF5B-ALK fusion, have been identified in histiocytic
neoplasms.\textsuperscript{3,4}. We present the case of a patient with
systemic JXG with KIF5B-ALK fusion detected by next-generation
sequencing (NGS) panel -based comprehensive genome profiling (CGP) for
solid tumours, in whom CNS lesions had caused neurological disorders.
There has been no report about ALK inhibitor for an infant case of
histiocytosis.

\textbf{CASE PRESENTATION}

The patient was a 1-year-old male infant born to non-consanguineous
Japanese parents. He presented with multiple subcutaneous tumours of up
to 6.0 cm in diameter when he was 2 weeks old (Fig. 1A). No neurological
abnormality was found except the lack of movement in his right arm. His
laboratory test findings were within normal limits. An enhanced computed
tomography (CT) scan demonstrated subpleural nodular shadows in both
lung fields (Fig. 1B), and multiple low-density areas in the liver (Fig.
1C) and in the right kidney (Figure. 1D). Brain and whole spine magnetic
resonance imaging (MRI) revealed enlargement of the left side of the
medulla, the tumour of cerebellum, and an intra-axial massive tumour
with contrast enhancement in the cervico-thoracic spinal cord. Biopsy of
a cutaneous lesion was performed, and spindle cells with circular
unequal nucleus and light cytoplasm were proliferating between the
dermal collagen fibres (Fig. 2A-C). Immunohistochemical staining showed
that the cells were positive for CD68, CD4, factor XIIIa and CD163 but
negative for CD1a, CD34, CD21, CD35, and s-100 protein. In addition, ALK
D5F3 and ALK1 were positive (Fig. 2D-F). Taken together, the diagnosis
of JXG was made.

The patient did not receive any anti-tumoural treatment at first, and
his developmental retardation became increasingly accentuated in his
first year of life. He could not turn over and he uttered only a few
lallings. He showed abnormal posturing with arched his back induced by
emotional changes or subtle stimulation. Severe foot clonus was also
evoked easily by only touching his lower extremities. In addition, the
spasticity and muscle weakness of the lower extremities progressed. The
patient needed tube feeding owing to dysphagia, and he experienced
severe bronchitis 5 times and a generalised convulsive seizure. At 12
months of age, CT revealed a new lesion in an ischial bone in addition
to the lesions in the liver, kidney and lungs. The lesions in the right
lung became enlarged. MRI revealed that the CNS lesions had also become
progressed (Fig.1 E, F). The NGS-based CGP test,
FoundationOne\textsuperscript{?} CDx was peformed on the specimens
obtained from the cutaneous lesion. KIF5B-ALK fusion was identified as
an activating mutation. Administration of an ALK-inhibitor for the
patient was discussed in the molecular tumour board called `expert
panel', and approved by the institutional clinical review board for
off-label use. After obtaining informed consent from parents, the
patient was given alectinib at 16 months of age. Two months after the
initiation of alectinib administration, the subcutaneous lesions
decreased in size. MRI revealed that the lesions of the medulla and
cerebellum achieved complete regression (Fig. 1G). The lesion in the
cervico-thoracic spinal cord also regressed (Fig. 1 H). The patient's
condition improved, and he started ingestion of food orally and could
say a few sentences. The spasticity and clonus of the extremities were
relieved. For the 3 months treatment periods, adverse events were only
observed the localized eczema and fever evaluated as grade 1 according
to the Common Terminology Criteria for Adverse Events version 5.0.

\textbf{Discussion}

ALK is a tyrosine kinase gene located on chromosome 2p23, and its
rearrangement is identified for the first time in non-Hodgkin's lymphoma
in 1994 by Morris et al. \textsuperscript{5} In non-small cell lung
cancer (NSCLC), EML4-ALK fusion was detected in
2007\textsuperscript{6}and has been considered as a target of tyrosine
kinase inhibitors. In addition, KIF5B-ALK fusion is also identified in
NSCLC in 2009.\textsuperscript{7} Recently, some cases of KIF5B-ALK
fusion have been reported in histiocytosis, including
JXG.\textsuperscript{8-12}Several teenage patients and adults with
KIF5B-ALK fusion were treated with ALK inhibitor.\textsuperscript{10-12}
Chang et al\textsuperscript{11} presented the case of a 15-year-old male
patient with histiocytosis affected cavernous sinus. He received
crizotinib therapy, and the lesion resolved 3 months later. However, no
case has been reported in infants with histiocytic neoplasm treated with
ALK inhibitors.

Several ALK inhibitors, including crizotinib, alectinib, and ceritinib,
have been approved mainly for NSCLC in Japan. Crizotinib has been
administered for paediatric patients with anaplastic large cell lymphoma
(ALCL) and solid tumours, including neuroblastoma, and its tolerability
and safety have been established.\textsuperscript{13,14} Alectinib was
indicated to show a favourable clinical activity and was well tolerated
by paediatric patients with ALK-positive ALCL that progressed under
conventional chemotherapy.\textsuperscript{15,16} In addition,\textbf{~}
alectinib had superior CNS activity and significantly delayed the
progression of CNS metastases as compared with crizotinib in patients
with advanced ALK-positive NSCLC.\textsuperscript{17}Among these ALK
inhibitors, we selected alectinib for the present case because the CNS
lesions were most critical lesions in this patient.

Actionable targets, including ALK fusion, are screened on the NGS-based
CGP tests covered by the national health insurance~system for refractory
and recurrent solid tumours in Japan. Actionable targets have also been
revealed in paediatric patients. Although most of the drugs
corresponding to the target genes are off-labelled in paediatric
patients, it is estimated that the effect of the molecular target agents
is superior, and adverse events and late complications are not more
severe than those in patients treated with conventional anticancer
drugs.\textsuperscript{18,19} Since the comprehensive genomic analysis
by whole-exome and transcriptome haematological malignancies, actionable
targets could also be identified in histiocytic
neoplasms,\textsuperscript{3,4} including JXG and LCH which tend to
arise in neonates.\textsuperscript{1,2,20} The administration of these
molecular target agents may be preferable for those patients with
actionable targets to conventional chemotherapy. It is possible that
histiocytosis will be classified according to its activating mutations
in the near future, which directly link to targeted therapy.

The present patient with systemic JXG who had KIF5B-ALK fusion achieved
clinical improvement with alectinib therapy. A high index of cognition
should be appreciated for such an actionable target in histiocytic
neoplasms.

\textbf{CONFLICT OF INTEREST STATEMENT}

The authors declare no conflicts of interest.

\textbf{AcknowleDgements}

We thank all participating doctors whose comments and suggestions were
of inestimable value for the case and clinical practices. Especially,
the members of the molecular tumour board called `expert panel'
contributed the administration of alectinib for the present case.

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\textbf{Legends}

\textbf{Figure 1.} (A) A retroauricular subcutaneous nodule. (B)
Enhanced computed tomograohy image showing peri-pleural nodular shadows
mainly in the right lung field. (C) Multiple low-density areas in the
liver. (D) Multiple low-density areas of approximately 1.0 cm in
diameter in the right kidney. (E) Enhanced magnetic resonance images of
the lesions of the medulla and cerebellar hemisphere and (F) the massive
tumour in the spinal cord from the level of the atlas to the upper
thoracic spine before the initiation of alectinib therapy. (G) Complete
regression of the lesions of the medulla and cerebellum 2 months after
the initiation of alectinib therapy. (H) The lesions of the spinal cord
also regressed.

\textbf{Figure 2.} (A) Histological examination (HE; haematoxylin-eosin)
result of the biopsy specimen from the cutaneous lesion. (B) The spindle
cells with circular unequal nucleus and light cytoplasm. (C) Increased
tumor cells between the dermal collagen fibres. (D) The spindle cells
showing positivity for ALK1 antibody and (E, F) positivity for ALK D5F3
by immunohistological tests.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/JXG-FIGURE1/JXG-FIGURE1}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/JXG-FIGURE-2/JXG-FIGURE-2}

\end{center}
\end{figure}

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