Vemurafenib Use in an Infant for High-Risk Langerhans Cell Histiocytosis

Langerhans cell histiocytosis (LCH) is a clonal disorder characterized by lesions containing pathological CD207⁺ dendritic cells. Refractory high-risk LCH is a life-threatening disease that affects mostly infants. Patients with a Disease Activity Score (DAS) higher than 6, in whom vinblastine sulfate–steroid treatment had failed, have a greater than 50% risk of death, which mostly concerns children younger than 2 years.¹ Because somatic BRAF V600E mutation plays an important role in LCH pathophysiology,² BRAF inhibitors could offer a new therapeutic approach³ but, to our knowledge, have never been proposed as a treatment in infants.

Our patient was an 8-month-old girl who was diagnosed as having BRAF V600E–mutated LCH with skin, bone, gut, node, and spleen involvement and hematological dysfunction (DAS, 5). After the failure of 2 vinblastine-steroid inductions followed by 1 course of cladribine, her DAS was 10. Off-label treatment with the BRAF inhibitor vemurafenib was started at an initial dose of 120 mg twice daily (33.8 mg/kg/d) for 60 days after written informed consent was obtained from the parents. The tablets were split, crushed, and suspended in water for oral administration. To assess the efficacy of treatment, the DAS was determined twice per week, and we also performed computed tomographic (CT) scans using RECIST (Response Evaluation Criteria in Solid Tumors) version 1.1 criteria.⁷

On day 3, the patient’s general health improved with apyrexia, oral feeding, decreased skin lesions, and tumoral syndrome. On day 7, the biological inflammatory syndrome disappeared, and hypoalbuminemia and anemia showed progressive improvement (Figure 1). On day 14, all signs of disease activity had disappeared (DAS, 0), and CT scan showed partial remission (Figure 2). Skin toxicity (cutaneous eruption, WHO [World Health Organization] grade 2) occurred on day 20, and vemurafenib dose was reduced to 60 mg once daily (8.5 mg/kg/d) without adverse events. A CT scan at day 60 showed complete remission, and vemurafenib therapy was discontinued. On day 90, skin relapse was diagnosed (DAS, 1). Vemurafenib was resumed at 120 mg once daily (13.3 mg/kg/d) for 2 months and was effective (DAS, 0) without adverse effects. Five months after the second discontinuation of vemurafenib therapy, the patient remains in complete remission without any sequelae. Because we used crushed, suspended tablets, we checked whether vemurafenib was detectable within plasma using liquid chromatography coupled with mass spectrometry.⁴ Between 2 and 8 hours after ingestion, we detected a mean concentration at 8.9 µg/mL (range, 8.2-10.3 µg/mL) at day 3 and 11.8 µg/mL (range, 9.8-13.1 µg/mL) at day 18, thus confirming absorption of at least part of the drug.

We report the first use of vemurafenib in an infant with LCH, to our knowledge. In the absence of pharmacological data in infants, the initial dose was empirically chosen, aiming for similarity to the body weight–related adult reference dose used in melanoma treatment. Despite the low plasma concentration, possibly explained by manipulation of the tablet or by different pharmacokinetics in children,⁵ a quick efficacy of treatment was observed. Efficacy was also observed with a once-daily administration during the second course of treatment for skin. However, a once-daily administration should lead to a higher variability of vemurafenib concentration in regard to elimination half-life time at 27.3 hours as estimated in our patient.

The present report is limited in that only 1 patient is described and the follow-up duration was 10 months. We did not observe major adverse effects such as squamous cell carcinoma⁶ or renal dysfunction, and our patient’s cutaneous eruption was managed with dose reduction. A close follow-up was maintained to detect possible long-term sequelae. Pharmaceutical data are needed to support and specify the modalities of the use of crushed tablets of vemurafenib in the absence of a specific oral solution for young children. Moreover, as an on-going study investigates the anti-BRAF drug dabrafenib in children (clinicaltrials.gov identifier: NCT01677741), a phase 1/2 study is likely mandatory for the clinical development of vemurafenib treatment for LCH, especially in infants, who are the most vulnerable to high-risk LCH.

Corresponding Author: Sébastien Héritier, MD, French Reference Center for Langerhans Cell Histiocytosis, Trousseau Hospital, 26 Avenue du Dr Netter, 75012 Paris, France (sebastien.heritier@trs.aphp.fr).

Published Online: April 30, 2015. doi:10.1001/jamaoncol.2015.0736.

Author Contributions: Drs Héritier and Donadieu had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Héritier, Jehanne, Leverger, Emile, Donadieu.

Acquisition, analysis, or interpretation of data: Héritier, Emile, Alvarez, Haroche, Donadieu.

Drafting of the manuscript: Héritier, Emile, Donadieu.

Critical revision of the manuscript for important intellectual content: Jehanne, Leverger, Emile, Alvarez, Haroche, Donadieu.

Obtained funding: Donadieu.

Administrative, technical, or material support: Héritier, Emile, Alvarez, Haroche, Donadieu.

Study supervision: Héritier, Jehanne, Leverger, Haroche.

Conflict of Interest Disclosure: Dr Emile received honoraria from Roche for counseling on detection of BRAF mutations and treatment of patients with melanoma with BRAF inhibitors. Dr Haroche received honoraria from GlaxoSmithKline and Roche for counseling patients with histiocytosis on targeted treatments. No other disclosures are reported.

Funding/Support: This study was supported by a grant from the Société Française des Cancers de l’Enfant (SFCE) and the French Histiocytosis Association.

Role of the Funder/Sponsor: The funding sources had no role in the design and conduct of the study; the collection, management, analysis, and interpretation of the data; the preparation, review, or approval of the manuscript; or the decision to submit the manuscript for publication.

Additional Contributions: We thank Audrey Derouet, MD, Sophie Osdoit-Médart, MD, and Yves Reguerre, MD, from Felix Guyon Hospital, Saint-Denis Réunion, and Amaury Leruste, MD, Deborah Meyran, MD, Marion Estelle, BScN, and the team nurse from Trousseau Hospital, Paris, who contributed to the diagnosis and care of the patient. We also thank Sabah Boudjemaa, MD, and François Chalard, MD, from Trousseau Hospital, Paris, for pathological diagnosis and iconographic evaluation. Financial compensation was not provided for their contributions.