Non-Langerhans cell histiocytosis is a rare disorder lacking a standard treatment strategy. Due to the discovery of activating and targetable MAPK-ERK pathway mutations in the vast majority of patients with ECD, the therapeutic landscape of ECD has changed drastically over the last decade[4, 5]. BRAF inhibitors, such as vemurafenib or dabrafenib, are recommended as first-line therapy for patients with multisystem BRAF-V600-mutant ECD who have life-threatening cardiac or neurologic involvement; for patients without BRAF-V600 mutation, NGS is suggested to evaluate other MAPK-ERK pathway alterations that can be treated with a MEK inhibitor[14]. However, BRAF and MEK inhibitors are costly (far beyond what most patients in China can afford) and are not covered by health insurance in China.
Treatment is reserved for symptomatic disease or multisystemic involvement for patients with RDD. The conventional systemic therapies for RDD include steroids, chemotherapy, sirolimus, and immunomodulatory therapy, such as thalidomide and lenalidomide[15]; however, the efficacy of steroids or other systemic therapies for RDD is variable. MEK inhibitors such as cobimetinib used in patients with MAPK-ERK pathway alterations seem promising[6], but have limited experience. Data regarding the efficacy and safety of systemic treatments for other non-Langerhans cell histiocytic disorders, such as ICH and JXG, are especially lacking. Overall, the management of patients with non-Langerhans cell histiocytosis is challenging. Systemic nontargeted therapy for patients with non-Langerhans cell histiocytosis deserves exploration.
Our previous data suggested that CNS involvement was a poor prognostic factor for ECD patients with interferon-a-2a (IFN-a)[16]. Therefore, we attempted to explore treatments other than IFN-a for non-Langerhans cell histiocytosis, especially drugs that can penetrate the blood–brain barrier. Cytarabine easily penetrates the blood–brain barrier and has shown promising therapeutic prospects in non-Langerhans cell histiocytic disorders[8, 9].
The patients enrolled in the present study had multisystem involvement with or without previous therapy. Most relapsed patients in this study accepted standard first-line treatments, as reported in the literature[14, 15]. Although some patients in our study carried the BRAFV600E mutation, they could not afford BRAF inhibitors as first-line treatment. We found that cytarabine has favourable clinical efficacy in non-Langerhans cell histiocytosis patients with multisystem involvement regardless of its use as frontline therapy or subsequent-line treatment. The overall clinical response rate was 86.7%, with 1-year PFS and OS rates of 85.6% and 92.3%, respectively. Impressive responses were seen in patients with central nervous system involvement.
In terms of regimen toxicity, grade 4 neutropenia was noted in all patients, and grade 3-4 thrombocytopenia occurred in 53.3% of patients during treatment. Nevertheless, no treatment-related deaths occurred. It is critical to monitor routine blood tests regularly and use granulocyte colony-stimulating factor, granulocyte stimulating factor or transfuse platelets according to routine blood results.
This study’s limitations include the small number of patients, the retrospective nature of the analysis, and the lack of long-term follow-up for outcomes and toxicity. Nevertheless, large-scale cohort studies or prospective clinical trials are of great difficulty due to the rarity of the disease. We will extend the follow-up duration to monitor the long-term outcomes and toxicity.