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. 5 In non-small cell lung
cancer (NSCLC), EML4-ALK fusion was detected in 20076and has been considered as a target of tyrosine kinase inhibitors. In
addition, KIF5B-ALK fusion is also identified in NSCLC in
2009.7 Recently, some cases of KIF5B-ALK fusion have
been reported in histiocytosis, including JXG.8-12Several teenage patients and adults with KIF5B-ALK fusion were treated
with ALK inhibitor.10-12 Chang et
al11 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.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.15,16 In
addition, alectinib had superior CNS activity and significantly
delayed the progression of CNS metastases as compared with crizotinib in
patients with advanced ALK-positive NSCLC.17Among
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.18,19 Since the comprehensive genomic analysis
by whole-exome and transcriptome haematological malignancies, actionable
targets could also be identified in histiocytic
neoplasms,3,4 including JXG and LCH which tend to
arise in neonates.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.