Clinical Profile and BRAF Status of 30 Japanese Patients with Adult Langerhans Cell Histiocytosis

Background: Langerhans cell histiocytosis (LCH) is a rare inflammatory myeloid neoplasm characterized by aberrant expansion of CD1a+CD207+ Langerhans-like cells with a variable infiltration of immune cells. Although the precise pathophysiology is to be elucidated, a frequent occurrence of oncogenic BRAF-V600E mutation in high-risk patients (Badalian-Very, et al. Blood. 2010) has made it one of the candidates of major driver mutations in LCH as well as in hairy cell leukemia. Its onset in adulthood is rather infrequent as compared with that in childhood, and the clinical profile and treatment outcome of adult LCH is poorly documented. Here, we report the clinical features and BRAF status of Japanese patients with adult LCH in a single institution.

Methods: Between 2005 and 2016, 30 adult LCH patients with histopathological diagnosis and/or characteristic radiological findings were referred to our hospital for evaluation and treatment. In almost all cases, we re-evaluated the involved organs and determined the clinical subtypes. For detection of BRAF-V600E, cell-free DNA (cfDNA) was prepared from plasma of patients and was subjected to genotyping of BRAF mutations by allele-specific Q-PCR, which was specifically designed for detection of BRAF-V600E with a 3'-phosphate-modified oligonucleotide blocker as previously described (Kobayashi M and Tojo A. Blood. 2014). Mutant BRAF load was estimated from the standard curve in each assay and was expressed as the percentage of mutant alleles to total number of alleles. Considering the safety and efficacy at outpatient clinic without hospitalization, we adopted 9 cycles of JLSG Special C regimen as a first-line therapy for the patients who require treatment. The protocol is consisted of 6mg vinblastine (VBL) on Day1, 60mg oral prednisolone (PSL) on Day1-5, and 20mg/m² methotrexate (MTX) on Day15 with 1.5mg/kg daily 6-mercaptopurine (6MP) (Morimoto A, et al. Int J Hematol. 2013).

Results: Patients' median age at diagnosis was 43 (range 24-66) and 50% was female. Fourteen patients (47%) had a single organ disease (single-system; Ss) and others had multi-organ disease (multi-system; Ms). Bone (50%) and skin (29%) were main lesions in Ss patients, who were younger (median 39) than Ms patients (median 44). Nine patients (30%) developed diabetes insipidus caused by pituitary lesions. Pulmonary involvement was found in 6 patients (20%), and all except one were heavy smokers at the onset or relapse of LCH in these patients. Among Ms patients, there were 8 high-risk patients with lung, liver, spleen or bone marrow involvement. We performed ASQ-PCR analysis of BRAF mutation in 20 patients (12 Ms patients and 8 Ss patients), and only 4 Ms patients were positive for V600E mutant. Twenty-three patients received Special C regimen and 4 refractory patients were followed by 2-chlorodeoxyadenosine (2-CdA) as a salvage therapy. After Special C regimen with or without a salvage therapy, five patients had relapsed. Three of them received once more Special C regimen and two among them showed improvement. During their clinical courses, only two Ms patients, who were positive for BRAF-V600E and received 2-CdA, died of LCH progression and a cerebrovascular event, respectively.

Conclusion: Since adult LCH is quite rare and most likely ignored by physicians, the diagnosis and the clinical intervention is generally delayed. Nonetheless, most of patients benefited from the low-intensity chemotherapy and their prognosis is rather favorable. Recent findings of MAPK and PI3K pathway mutation in LCH will facilitate the understanding of its pathogenesis and development of its novel molecular therapy.