Treatment of a Patient with Refractory Non-Langerhans-Cell-Histiocytosis with the Tyrosine Kinase Inhibitor Sorafenib: Clinical and Genetic Implications
Authors: Viardot Andreas , Stegelmann Frank , Zenz Thorsten , Möller Peter , Döhner Konstanze 
Published: October 2019

Abstract
Abstract 4715
Non-Langerhans-cell-histiocytosis (Non-LCH) represents a rare disorder with a broad spectrum of clinical features and various outcome.
We here report on a 61 years old man with Non-LCH with severe skin and bone marrow involvement. At the time of diagnosis in 2006, the patient presented with up to four centimeter large cutaneous papules involving face, stem, hands and feet. Since two years, the patient also developed an increasing tricytopenia due to an extensive bone marrow infiltration of histiocytes (80%). Since diagnosis, the patient received a large number of various therapies including daily glucocorticoids at different dosages (continuously since diagnosis), low-dose methotrexate (10-40mg s.c. per week; from may to september 2007), experimental treatment with lenalidomide (5-10mg per day; from february to june 2008), continous oral trofosfamide (100mg per day; from july to august 2008), cladribine monotherapy (2,1mg/m2 d1-5; 4 cycles; from December 2008 to march 2009) and the combination of cladribine (2.1mg/m2 d1-5) and cytarabine (40 mg s.c. d1-7; 3 cycles; from january to march 2010). The patient did not respond to any of these therapies. Due to the persistent distinctive clinical symptoms (massive skin involvement, tricytopenia), we started in July 2010 an experimental therapy with sorafenib at a dosage of 200mg per day for four days, followed by 400mg per day for another four days, and subsequently increased the dosage to 800mg daily. After four weeks, the marked skin papules flattened to skin level at all preferential sites. Small skin ulcers at the cheeks healed up. In parallel, there was a significant improvement of hematopoiesis since start of therapy with haemoglobin levels raising from 8,6g/dl to 12,2g/dl and normalization of leukocyte count (from 3.1/nl to 5.2/nl). Bone marrow rebiopsy is intended after three month of therapy, data on the actual grade of infiltration will be presented at the meeting. Based on the impressive clinical improvement under sorafenib, we analyzed selected target genes of the multityrosine kinase inhibitor: mutation screening was performed on the FLT3 (internal tandem duplication, point mutations of the tyrosine kinase domain) and KIT genes (exon 8 and exon 17) as well as for the recently described BRAF V600E mutation found in a significant number of patients with LCH (G. Badalian-Very et al., Blood prepublished online June 2, 2010; DOI 10.1182/blood-2010-04-279083). However, in none of these genes, mutations were found and further molecular analysis of the patient's bone marrow is currently under investigation.
To our knowledge, this is the first report on the efficacy of sorafenib in a case of histiocytosis. However, the underlying genetic mechanisms of Non-LCH still have to be elucidated.

Disclosures:
Off Label Use: Sorafenib is approved for unresectable hepatocellular carcinoma and advanced renal cancer. We present an off-label use of sorafenib in a case of a severe orphan disease refractory to all standard therapies. Zenz:Roche: Honoraria; Boehringer: Honoraria; GSK: Honoraria; Celgene: Honoraria.