Clinical and prognostic characteristics of 95 cases of Langerhans cell histiocytosis in children: a single-institute experience from 2013 to 2020

Abstract

Background: This study aimed to understand the clinical characteristics and outcomes of children with Langerhans cell histiocytosis (LCH) in China.

Methods: We conducted a retrospective study of 95 paediatric patients with LCH in West China Second University Hospital of Sichuan University between July 2013 and August 2020.

Results: The onset age of multisystem LCH (MS-LCH) patients with risk organ (RO) involvement was younger than that of MS-LCH without RO involvement (p = .002) and single system LCH (p < .001) patients; bone was the most frequently involved organ, followed by the skin. Of all, the BRAF-V600E mutation was detected in 48 out of 84 patients who underwent gene analysis. Additionally, in our study, BRAF p.N486_T491 > K, BRAF p.L485_P490delinsF, BRAF p.R506_K507insLLR, ARAF p.Q349_F351delinsL and MAP2K1 p.Q58_E62del were known mutations in the mitogen-activated protein kinase (MAPK) pathway. The BRAF-V600E genotype in the tissue and plasma prior to therapy were detected in 16 patients, and the concordance was only 37.5% (6/16). According to the modified LCH-III-based-protocol, JLSG-02 protocol chemotherapy, and vemurafenib, the estimated five-year overall survival, event-free survival (EFS) and cumulative reactivation rates of 95 patients were 98.8%, 74.6% and 24.5%, respectively. The EFS rate in good responders was better than that in poor responders at 12-week (HR = 0.022, 95%CI 0.002-0.231, p = .002), and EFS was not affected by age, RO involvement or BRAF-V600E mutation. Regarding sequelae, nine patients had central diabetes insipidus and two had growth retardation.

Conclusions: In this study, LCH was a highly heterogeneous disease characterized molecularly by MAPK-pathway activating mutations. Vincristine, prednisone and cytarabine-based chemotherapy combined with vemurafenib improved the prognosis of childhood LCH. In future, prospective clinical trials and novel therapeutic strategies should be developed to improve outcomes in paediatric patients with LCH.KEY MESSAGEChildren with Langerhans cell histiocytosis in China present highly heterogeneous clinical characteristics, with up to 60% of cases harbouring mutations in MAPK pathway.Treatment response at 12-week is associated with EFS in our study.Vincristine, prednisone and cytarabine-based chemotherapy combined with vemurafenib improved the prognosis of Chinese childhood LCH, but the reactivation rate is still high.

Keywords: Langerhans cell histiocytosis; children; clinical characteristics; prognosis; therapy.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Figure 1.

Treatment protocol of modified LCH-III-based chemotherapy. PDN: prednisolone; VCR: vincristine; 6-MP: 6-mercaptopurine; NAD: non-active disease; AD: active disease; intermed.: intermediate.

Figure 2.

Treatment plans of JLSG-02 protocol chemotherapy. Ara-C: cytarabine; VCR: vincristine; PSL: prednisolone; MTX methotrexate; 6-MP: 6-mercaptopurine; ADR: adriamycin; CPM: cyclophosphamide; CSA: cyclosporine A; GR: good response; PR: partial response; NR: non-response; PD: progressive disease.

Figure 3.

The result of ccf BRAF-V600E mutation load in five patients before therapy and after treatment. The treatment contained chemotherapy or/and vemurafenib. The quantitative detection of the ccf BRAF-V600E mutation was analysed by droplet-digital PCR assay. ccf: circulating cell-free.

Figure 4.

Kaplan–Meier’s curves for overall survival of the cohort (A), event-free survival of the cohort (B), cumulative reactivation of the cohort (C), patients according to different response to treatment at 6 weeks (D), patients according to different response to treatment at 12 week (E), patients according toBRAF-V600E (F), patients according to clinical classification (G) and patients according to age (H). NAD: non-active disease; AD: active disease; inter: intermediate.