High-risk LCH in infants is serially transplantable in a xenograft model but responds durably to targeted therapy

Abstract

Langerhans cell histiocytosis (LCH) is a rare hematologic neoplasm characterized by a clonal proliferation of Langerhans-like cells. Genomic profiling has identified recurrent somatic activating mutations in the mitogen-activated protein kinase pathway, which are targetable by small-molecule inhibitors. However, key questions such as the curative potential of targeted therapy and the cell of origin remain unanswered. In this study, we describe clinical outcomes of a series of pediatric patients with multisystem BRAF V600E–mutant LCH, as well as the results of accompanying murine xenograft experiments. Four infants with LCH (range, 7-11 months at diagnosis) and secondary hemophagocytic lymphohistiocytosis were referred to our institution and subsequently treated with the BRAF V600E–specific inhibitor dabrafenib. All patients achieved complete clinical responses by 8 weeks of therapy, with remissions lasting a median of 36 months (range, 27-42 months). One infant successfully discontinued therapy long-term upon achieving a molecular response by real-time quantitative polymerase chain reaction (RT-qPCR). We further characterized the disease-propagating cell population in a subset of these patients by transplanting whole bone marrow into immunodeficient mice. Xenografted animals exhibited decreased survival with hematologic abnormalities, splenomegaly, and histiocytic infiltrates in the bone marrow resembling human disease. This process could also be secondarily transplanted, resulting in a comparable disease latency with similar histologic findings. These data further support the presence of a disease-initiating cell in the bone marrow compartment. We demonstrate that despite aggressive disease behavior in a xenograft model, these patients can achieve sustained clinical remissions with targeted monotherapy, with a select subset achieving molecular responses by RT-qPCR.

High prevalence of BRAFV600E in patients with cholestasis, sclerosing cholangitis or liver fibrosis secondary to Langerhans cell histiocytosis

“…[23][24][25] In this sense, Lee and coworkers observed that patients with MS-LCH who were considered to achieve molecular response after dabrafenib treatment, presented BRAF V600E+ cells in the bone marrow, indicating that clonal mutation-bearing cells persisted even though pathological or histological signs were absent, and developing over time an LCH reactivation. 26,27 Our results suggest that active disease process in the liver may persist alongside irreversible damage, that is usually assumed to represent pure sequelae, an interpretation that should be reconsidered in the light of our results. [28][29][30] Furthermore, patients should also be prospectively monitored, looking for potential subclinical disease such as circulating and/or tissular BRAF V600E positive cells, 28,31 inflammatory cytokines, 32,33 neurocognitive and haematological studies, among others.…”

“…Then, despite CD1a negative staining, the presence of BRAF V600E+ cells may indicate by itself that LCH cells remain within the affected tissue 23–25 . In this sense, Lee and coworkers observed that patients with MS‐LCH who were considered to achieve molecular response after dabrafenib treatment, presented BRAF V600E+ cells in the bone marrow, indicating that clonal mutation‐bearing cells persisted even though pathological or histological signs were absent, and developing over time an LCH reactivation 26,27 …”

Liver transplantation in a child with liver cirrhosis caused by langerhans cell histiocytosis: a case report

“…The mutation may also contribute to the pathogenesis of LCH through activation of the MAPKinase RAS-RAF-MEK-ERK cell signaling pathway, and has been identified in more than half of the childhood LCH[ 3 , 19 , 20 ]. Therefore, MAPK pathway inhibitors (including dabrafenib and vemurafenib) have been applied as targeted therapy in LCH patients recently [ 21 – 24 ]. Similar with the patients who were treated with chemotherapy, the recurrence can also occur in LCH patients treated with targeted therapy, and the rate was reported to be as high as 84% after 12 months of the discontinuation in refractory or relapse LCH[ 21 ].…”

“…Similar with the patients who were treated with chemotherapy, the recurrence can also occur in LCH patients treated with targeted therapy, and the rate was reported to be as high as 84% after 12 months of the discontinuation in refractory or relapse LCH[ 21 ]. However, targeted therapy can achieve a response rate about 86% in LCH patients during its application with more tolerable adverse effects, especially in patients who have had little or no response to previous treatments and suffering refractory or relapse LCH [ 21 – 24 ]. Thus, targeted therapy (dabrafenib) was used in this patient after careful evaluation.…”

Clinical features and treatment outcomes of pediatric Langerhans cell histiocytosis with macrophage activation syndrome-hemophagocytic lymphohistiocytosis

“…Secondary HLH associated with defined rheumatologic conditions is called MAS-HLH [ 17 ]. Several studies found that a few LCH patients had a presentation of MAS-HLH, and most of them had poor prognosis and a high risk of death [ 18 – 22 ]. LCH with MAS-HLH has been described in a few cases reports due to the rarity and high heterogeneity of LCH.…”