Failure of salvage vemurafenib therapy for refractory multisystem Langerhans cell histiocytosis with BRAF-V600E mutation

Background Langerhans cell histiocytosis (LCH) has been dened as a disorder driven by misguided myeloid differentiation, with up to 50% of cases harboring the BRAF-V600E mutation. Salvage treatment with LCH refractory to vinblastine and steroid regimen is intractable. Vemurafenib is safe and effective in children with refractory BRAF-V600E-positive LCH, but the disease always reactivates with the withdrawal of vemurafenib. Case presentation:


Background
Langerhans cell histiocytosis (LCH) has been de ned as a disorder driven by misguided myeloid differentiation, with up to 50% of cases harboring the BRAF-V600E mutation. Salvage treatment with LCH refractory to vinblastine and steroid regimen is intractable. Vemurafenib is safe and effective in children with refractory BRAF-V600E-positive LCH, but the disease always reactivates with the withdrawal of vemurafenib.
Case presentation: Here, we report the rst case of BRAF-V600E positive LCH resistant to vemurafenib therapy but effectively salvaged by cytarabine-based chemotherapy.

Conclusions
Our case report shows that vemurafenib monotherapy might not be effective for every BRAF-V600Epositive refractory LCH, and cytarabine-based chemotherapy might still be a cost-effective therapeutic alternative. Keywords: Langerhans cell histiocytosis, BRAF-V600E mutation, Vemurafenib, Chemotherapy Full Text A 2-year-old boy was admitted to our hospital with mass in his hard palate for more than 8 months. On admission, he presented polydipsia, polyuria, rash and marked abdominal distention. He had underlying recurrent otitis media from the age of 6 months. On physical examination he showed irregular lump in hard palate (Fig. 1A), marked hepatomegaly (8cm and 10cm below the right costal margin and the xiphoid, respectively) and splenomegaly (6cm below the left costal margin) (Fig. 1A), yellowish secretions in bilateral auditory canal and rash losing freshness in the abdomen and inguinal regions. Complete blood counts were normal. Liver function test showed slightly elevated liver enzymes (ALT 97U/L, AST 108U/L) and signi cantly elevated γ-glutamyl transpeptidase (1228U/L). Soft tissue masses were documented in the left nasal cavity, maxillary sinus cavity and right external auditory canal by CT scanning. In addition, CT scanning found multifocal bone destructions in the bilateral maxillary sinus, local orbital surface, bilateral hard palate, superior alveolar bone and right mastoid bone. Therefore, the diagnosis of multisystem Langerhans cell histiocytosis (LCH) with involvement of risk organs was made.
Biopsy of hard palate demonstrated that the lesion cells were positively stained with CD207, CD1a and S-100. Mutation analysis revealed BRAF-V600E mutation.
Induction chemotherapy with prednisone and vincristine combination was instituted according to the LCH-III protocol [1]. However, therapy response was judged as active disease worse, with aggravation of severity of hepatosplenomegaly, at end of 6-week induction therapy (Fig. 1B). Hence, salvage vemurafenib monotherapy (20mg/kg/d, bid) was given to the patient. A month later, the patient achieved active disease better without side-effects (Fig. 1C). The circulating cell-free BRAF-V600E load decreased from 1.79% to 0.05%. Surprisingly, a new mass occurred in the oral cavity and the liver and spleen enlarged again by oral vemurafenib for two months (Fig. 1D). Unfortunately, determination of blood concentration of vemurafenib was not available. Finally, we adopted Japan Langerhans Cell Histiocytosis Study Group-02 (JLSG-02) -protocol chemotherapy [2] to control the active disease. The mass in the mouth disappeared completely and the liver and spleen become smaller after 6 weeks of chemotherapy (Fig. 1E). Besides, both secretions in auditory canal and rash dissolved, but he still need the same dose of desmopressin to control diabetes insipidus.
LCH has been de ned as a disorder driven by misguided myeloid differentiation, with up to 50% of cases harboring the BRAF-V600E mutation [3]. Vinblastine combined with prednisone have remarkably improved the overall survival of LCH. However, LCH refractory to the standard vinblastine and steroid regimen has a poor survival. Recently, a series of studies have indicated that vemurafenib (BRAF-V600E inhibitor) is safe and effective in children with refractory BRAF-V600E-positive LCH [4], but the optimal dose and duration of vemurafenib, monotherapy or combination chemotherapy, and long-term safety pro le remain to be established. To our best understanding, this patient is the rst reported case of BRAF-V600E positive LCH resistant to vemurafenib therapy but effectively salvaged by cytarabine-based chemotherapy. Our case report shows that vemurafenib monotherapy might not be effective for every BRAF-V600E-positive refractory LCH, and cytarabine-based chemotherapy might still be a cost-effective therapeutic alternative. Further studies are needed to identify the risk factors associated with resistance to vemurafenib, and to better formulate individualized therapy for refractory LCH in children.

Declarations
Declarations Ethics approval and consent to participate The study was approved by China Ethics Committee of Registering Clinical Trials (ChiECRCT20200147) and acquired the consent to participate of the patients' father.

Consent for publication
Consent was obtained from the patients' father for publication of this report and accompanying images.