VCR/AraC chemotherapy and ND‐CNS‐LCH

To the Editor: We read with great interest the recent article by Allen et al. [1] on the use of vincristine (VCR) and cytosine arabinoside (AraC) combination for neurodegenerative central nervous system Langerhans cell histiocytosis (ND-CNS-LCH). The authors chose to employ this treatment regimen for two reasons: first, AraC can cross the blood–brain barrier, although no significant pharmacokinetic studies were done at the dose used; second, this combination was originally described by Egeler et al. [2] to be effective for patients with LCH at onset or relapse of disease. Starting in 1996, we have been testing whether induction therapies that consist of VCR/AraC/prednisolone (PSL), called the JLSG-96 and JLSG-02 protocols, are effective for newly diagnosed patients with LCH in Japan [3,4]. By the end of 2009, more than a total of 340 multifocal LCH cases have been treated with these two protocols. Prior to 1996 there was no clinical trial. Even after 1996 the patients not participating on the study were treated with individual non-VCR/AraC regimens. We compared the cases of ND-CNS as defined by the Vienna group [5,6], in the VCR/AraCtreated group and the group who received other treatments for newly diagnosed LCH. Of the 16 cases in total 13 cases developed NDCNS after systemic treatment for LCH; 8 had MRI abnormalities only and 5 had neurological symptoms. One case already had NDCNS at the time LCH was diagnosed and the remaining two cases already had ataxia before LCH was diagnosed (Table I). Of the 13 cases who developed ND-CNS after treatment, 5 had been treated with JLSG-96/02 protocols. The remaining eight had received other regimens (mostly a combination of vinblastine and PSL), of which four were the cases treated before 1996. The NDCNS incidence for the JLSG-96/02 group was 1.5% but it could not be calculated for the other group because the total number of patients with LCH treated with other regimens was unknown. The incidence of ND-CNS LCH in the JLSG-96/02 protocol looks low compared with other international treatment protocols [7], but we must wait for longer and more comparable follow-up. When we used the EDSS [8] to score the neurological symptoms as minimal (<2.5), moderate (2.5–5), or severe (>5.0), we found that, with the follow-up of a median 6.2 (range; 0.5–18) years, 9 of the 16 patients have moderate to severe ND-CNS disease. One case with ND-CNS at onset has been stable with JLSG-02 treatment as there was no progression of neurological symptoms. The remaining two cases who had presented with ataxia before the diagnosis of LCH and received JLSG-02 protocol, have the worst prognosis as their neurological symptoms are now severe. We are also testing whether high-dose intravenous immunoglobulin (IVIG) regimen can prevent further progression of neurological symptoms particularly in cases with minimal to moderate EDSS scores [9]. It remains unknown whether the initial systemic chemotherapy for multifocal LCH patients can limit the later occurrence of NDCNS. However, our data suggest that ND-CNS can also develop in LCH patients who were initially treated with the VCR/AraC combination. Thus, while this drug combination can be effective on active non-CNS LCH lesions, it is at present unclear whether it also acts on neurodegenerative lesions with the same mechanism.