Clinical Outcomes and Molecular Responses in Children with Langerhans Cell Histiocytosis Treated with MAPK Pathway Inhibitors
Authors: Eckstein Olive S. , Zinn Daniel , Fein Levy Carolyn , Henry Michael M. , Campbell Patrick , Jordan Michael B. , Kumar Ashish R , Rodriguez-Galindo Carlos , Hijiya Nobuko , Abla Oussama , McClain Kenneth L. , Allen Carl E. 
Published: October 2019

Abstract
Background: Langerhans Cell Histiocytosis (LCH) is an inflammatory myeloid neoplasia. Activating somatic mutations in MAPK pathway genes have been identified in almost all cases of LCH with BRAF-V600E as the most common somatic mutation, occurring in approximately 60% of lesions. Enforced expression of BRAF-V600E in myeloid precursors recapitulates an LCH-like phenotype in mice, supporting a central pathogenic role for MAPK activation in LCH. Given the near universal occurrence and central pathogenic role of activating MAPK pathway gene mutations in LCH, targeted inhibition of the MAPK pathway is a rationale therapeutic strategy to explore in patients with relapsed disease.
Design/Methods: Medical records from 20 pediatric patients with LCH (systemic and/or LCH-associated neurodegeneration) from 12 institutions were systematically reviewed; 2 patients had disease which was mixed LCH with juvenile xanthogranuloma (JXG) and 2 patients had secondary hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS). All patients had failed at least one prior systemic therapy and had a proven MAPK pathway somatic mutation. Response assessment was based on applicable criteria for each individual including PET (metabolic) criteria, bone marrow evaluation, brain MRI, clinical history and physical exam.
Results: All patients in this series were less than 21 years old (median age at start of therapy 6.9 years; range: 0.4-20.7 years) with median disease duration of 4 years prior to start of MAPK inhibitor (range 0.07-18.4 years). Twelve patients had LCH-ND diagnosed clinically and/or by radiographic imaging, while the remaining 8 patients had systemic disease with no LCH-ND (7 with high risk organ involvement).
In terms of best response, 3 patients (15%) achieved a complete response (CR) and eleven patients (55%) achieved a partial response (PR), while 3 patients (15%) only achieved stable disease (SD), and 1 patient (5%) died early on in therapy due to progressive disease (PD) complicated by secondary HLH/MAS. Of the 12 patients who had LCH-ND, none achieved a CR, but 10 (83%) had a best response of PR by either clinical or radiographic assessment. Median progression free survival (PFS) was 11.8 months (range 2-36 months), while median time to disease progression or recurrence was 4.6 months (range 1-46 months). Four of the 20 patients (20%) had a Grade 3 or 4 toxicity; 2 of these patients required dose modification in order to successfully resume therapy.
Seven patients had measurable peripheral blood mononuclear cells (PBMC) or bone marrow cells with detectable BRAF-V600E mutation just prior to start of MAPK inhibitor with subsequent assessments obtained during therapy.
Conclusions: MAPK pathway inhibitors may be a relatively safe salvage therapy for refractory systemic LCH and LCH-ND but the efficacy and durability of responses with this strategy remains to be delineated. Children with relapsed/refractory high-risk LCH who were at the highest risk of death from disease generally benefited from this strategy. Patients with longstanding neurodegenerative disease seem to have the least benefit from MAPK inhibitors. However, patients with relatively early onset neurodegenerative disease, especially without clinical manifestations, seem to have the greatest benefit. While the presence of persistent BRAF-V600E+ circulating cells appears to be associated with risk of relapse and type of LCH organ involvement, quantifiable changes in these levels did not consistently correlate with clinical disease activity or response (in contrast to those treated with chemotherapy). We hypothesize that inhibition of the MAPK pathway may confer clinical benefit by blocking differentiation and proliferation of lesions, but may not have cytotoxic effect on precursor cells. This is supported by the observation that MAPK regulates lesion progression by inhibiting CCR7 expression, thereby blocking emigration of LCH cells from the lesion. Persistence of BRAF-V600E+ mononuclear cells in blood and bone marrow even in patients with impressive clinical responses may underlie the high rates of eventual progression/relapse with this type of treatment. Future prospective trials of MAPK pathway inhibitors for patients with refractory LCH possibly in combination with chemotherapy will be needed in order to directly compare their efficacy and toxicity relative to other current salvage strategies.

Disclosures
No relevant conflicts of interest to declare.