Langerhans cell histiocytosis (LCH) is a rare clonal myeloid neoplastic disease characterized by the typical Langerhans-type cells that express CD1a, S100, and CD207 (1). LCH can occur as multisystemic (2) or localized disease (3). About 50% of LCH harbor the BRAF V600E mutation, leading to constitutive ligand-independent activation of the mitogen-activated protein kinase (MAPK) signaling pathway, which promotes cell proliferation and survival (4). LCH is associated with other hematological malignancies in 10% of all cases (5), which may present synchronously or later during the course of disease; a common clonal origin has been suggested (4).

The identification of somatic BRAF V600E mutation in patients with Erdheim–Chester disease (ECD) provided the rationale for BRAF inhibition in the treatment of histiocytosis with altered MAPK pathway (6). In a single-center study, 85% of patients with LCH showed an activating mutation within the MAPK pathway (7). Most often, the activating BRAF V600E mutation and more rarely mutations in the tyrosine kinases NRAS and KRAS have been reported (1, 4). Allogeneic hematopoietic stem cell transplantation is potentially curative in myeloid neoplastic disorders such as LCH. Yet, only few patients and mostly children have received HSCT so far (8, 9).

A 61-year-old European male patient presented with persistent cough, thoracic pain, intermittent dyspnea, and progressive weakness of 3 months’ duration. He was an active and heavy smoker (100 pack-years). Relevant previous medical records included anti-dsDNA-antibody-positive systemic lupus erythematosus (SLE) with skin and joint involvement, mild cytopenia, and complement consumption, well controlled under hydroxychloroquine.

At presentation, neutropenia (0.897 × 10S9/l), monocytosis (0.639 × 10S9/l), thrombocytopenia (80 × 10S9/l), and C-reactive protein (CRP) elevation (93.4 mg/L) were noted. Thoracic CT scan demonstrated disseminated micronodules and few cysts, combined with centrilobular pulmonary emphysema. Lung function was impaired.

Histology of transbronchial cryobiopsy was consistent with LCH ( Figures 1A–C ). Sanger sequencing revealed a BRAF V600E mutation. Next-generation sequencing (NGS) confirmed the BRAF mutation and showed additional mutations in IDH2, ASXL1, SRSF2, and NF1 ( Table 1 ).

Finally, PET/CT scan demonstrated increased accumulation of 18F-fluorodeoxyglucose (¹⁸F-FDG) in the spleen, the lungs (diffuse), and bone marrow, and in multiple, enlarged cervical, mediastinal, and abdominopelvic lymph nodes ( Figure 1D ). Therefore, an integrative clinical, radiological, and histologic diagnosis of multisystemic LCH was established.

In the light of cytopenia, further diagnostics including NGS of peripheral blood cells were performed, revealing mutations in IDH2, ASXL1, SRSF2, and NF1 highly predictive for myeloid neoplasm (10, 11). BRAF, however, was not mutated ( Table 1 ). Morphological assessment of the bone marrow (cytology and histology) a few days later did not show dysplastic changes or excess of blasts and conventional karyotyping was normal, so an integrative diagnosis of CCUS was made. At the time of NGS, no bone marrow DNA was available; thus the analysis was performed from peripheral blood. Since several mutations were observed, and the allelic burden of mutations in the bone marrow and peripheral blood of MDS patients is similar (12), NGS was not repeated from bone marrow DNA. The initial therapy included smoking cessation and oral steroids. Three months later, disease progression of LCH was detected, with worsening pulmonary symptoms and deterioration of oxygenation. Due to the known BRAF V600E mutation in the transbronchial cryobiopsy and after a detailed explanation in mutual agreement with the patient, a treatment with the BRAF inhibitor vemurafenib was established.

Four weeks after, pulmonary function tests revealed a significant improvement of diffusion capacity with corresponding decrease in dyspnea and improvement of general condition. Accordingly, chest CT scan showed reduced micronodular changes. Due to commonly occurring phototoxic side effects, vemurafenib was replaced by dabrafenib 2 months after.

One month later, the patient presented to the emergency department with fever, generalized weakness, and cough. Peripheral blood showed marked neutrophilia (59.23 × 10S9/L), monocytosis (20.8 × 10S9/L), and blasts (12.5%). Thrombocytes were within normal range, and hemoglobin slightly decreased (126 g/L). In the bone marrow, infiltration of monoblasts was up to 75%, consistent with the diagnosis of AML. NGS of bone marrow revealed an additional NPM1 mutation and a second NF1 mutation ( Table 1 ).

Dabrafenib treatment was immediately stopped due to the evolution of the CCUS to AML. A cytoreductive therapy with hydroxyurea was initiated. One month later, peripheral blood values were normal, yet the bone marrow still showed an infiltration of monoblasts up to 70%. After two cycles of induction therapy with azacytidine, HSCT from the patient’s HLA-identical sister was subsequently performed.

At the last control, 24 months after transplantation, the patient was in complete molecular remission of his AML. PET/CT also demonstrated a near complete morphological and metabolic remission of the LCH (isolated, residual hypermetabolic cervical lymph node) ( Figure 1E ). His forced vital capacity improved by 700 ml, and arterial oxygen pressure was normal. He suffered an overall moderate graft-versus-host disease but was in a good clinical state.

The detection of IDH2, ASXL1, SRSF2, and NF1 mutations in both CCUS and LCH clones strongly suggests that both clones originate from a common clonal precursor cell ( Table 1 ). The LCH clone additionally acquired BRAF V600E, while the CCUS clone did not. Regarding the amount of mutations and the high VAF (20%–30%), it is surprising that the diagnosis of a myeloid neoplasm could not be established initially. It was, however, clear that the mutational profile of this CCUS clone was associated with very high risk of progression (10).

In BRAF wild-type cells with CRAF-BRAF heterodimers, BRAF inhibition (e.g., dabrafenib) can cause paradoxical transactivation of the drug-free promoter leading to extracellular signal-regulated kinase (ERK) activation (13–15). This mechanism is thought to explain why BRAF inhibitors are associated with the occurrence of, e.g., squamous-cell skin carcinomas (16). In our patient, there was an additional mechanism that gave the CCUS clone a proliferation advantage over the other BRAF wild-type cells in the bone marrow: At the time of progression to AML, there were two different NF1 mutations with VAF of almost 50%, and both mutations are loss of function ( Table 1 ). We assume that these two mutations are placed on the different alleles of NF1 leading to a compound heterozygote state. One major role of NF1 is to negatively regulate RAS proteins through GTPase activity. Thus, biallelic loss of function of NF1 leads to a complete loss of RAS suppression resulting in increased proliferation.

Both BRAF inhibition triggered paradoxical ERK activation, and synergistic NF1-induced RAS activation promoted the progression of the CCUS to leukemia. One similar case report portrayed the rapid progression of chronic myelomonocytic leukemia associated with a RAS mutation under vemurafenib therapy for malignant melanoma. However, in that case, monocytosis was reversible after stopping BRAF inhibition, as the clonal selection was largely dependent on additional paradoxical ERK activation (17).

This is to our knowledge the first case of an AML occurring during BRAF inhibition. Because of the possibility of potential paradoxical activation of the MAPK pathway in LCH patients with concomitant clonal hematopoiesis without BRAF VE600 mutation, a thorough evaluation including molecular diagnostics in cases of blood counts abnormalities before BRAF inhibition is warranted. In such cases, inhibition of the MAPK pathway further downstream (e.g., MEK inhibitors) may prevent such an unwanted activation (18).

The successful course of both diseases in our patient after HSCT suggests that a complete renewal of the immune system in patients with severe LCH, with or without concomitant hematological neoplasm, by allogeneic stem cell transplantation may also be a valid treatment option for adult patients.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

All patients submitted for allogeneic hematopoietic stem cell transplantation complete extensive general consent forms, attached to their medical records, to the use of their data for scientific purposes. Therefore, permission by the local ethics committee was not required. Nevertheless, the patient was informed in detail about this process and his anonymity is guaranteed.

KH analyzed data, helped in drafting the manuscript, and did the interpretation of clinical pulmonary disease related data as pulmonologist. ECQ analyzed data and drafted manuscript and figures. MT gave input in final data analyses and helped drafting the manuscript. SSP performed and interpreted histological diagnostic procedures and gave input in manuscript preparation. GS analyzed longitudinal PET and CT scans and contributed to the drafting of the manuscript. W-CC gave input in initial data analyses and helped drafting the manuscript. PL performed and analyzed molecular genetic tests and helped drafting the manuscript. TN gave input in final data analysis and manuscript preparation. GTS analyzed data and co-drafted the manuscript and the figures. TD initiated and supervised the project, analyzed data, and co-drafted the manuscript.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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