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.