Anti‐inflammatory and angiostatic therapy in chemorefractory multisystem Langerhans’ cell histiocytosis of adults

Langerhans’ cells show an impressive interaction with the adjacent mircroenvironment (Geissmann et al, 2001), associated with a strong lesional overexpression of prostaglandins and cyclo-oxygenase-2 (COX-2) (Brown, 2000). In addition to COX-2, a further target in the treatment of Langerhans’ cell histiocytosis (LCH) could be delineated by the action of peroxisome proliferator-activated receptor c (PPARc) ligands on dendritic cells (DCs): PPARc ligands may promote apoptosis in DCs (Nencioni et al, 2002). An additional therapeutic option in LCH could be angiostatic therapy as significantly increased serum levels of vascular endothelial growth factor (VEGF) were reported in paediatric patients with multisystem (MS)-LCH (Pavlakovic et al, 2001). In the current phase II study for chemorefractory LCH, we combined anti-inflammatory therapy with pioglitazone 45 mg, once daily p.o. , and rofecoxib 25 mg, once daily p.o. , day 1+, together with angiostatically scheduled (metronomic) chemotherapy with trofosfamide 50 mg, three times daily p.o. starting on day 15+, then continuously administered throughout the study along with pioglitazone and rofecoxib (Reichle et al, 2004). The patients gave written informed consent. This study was approved by the local ethics committee. A 31-year-old white man (patient A) had a 5-year history of a progressive feeling of thirst, a coxitis 3 years ago, recurrent otitis media, and progressive respiratory distress. The second patient, a 22-year-old white man (patient B), had a 1-year history of progressive back pain and drenching night sweats. Both were smokers. Upon admission, both patients presented with seborrhoeic dermatitis, tachypnoea, os ilem, honeycomb lung with multiple small infiltrations, multifocal liver lesions and hepatosplenomegaly. Patient A was also overweight (112 kg, 176 cm) and had painful swelling, a scaly scalp, punched-out osteolytic lesions in the skull, os femura, infiltrations in the anterior and posterior pituitary, thickening in the pituitary stalk, multifocal dural lesions and lesions in the medulla oblongata. Patient B additionally presented with secondary hypogonadism and os spine, but no cerebral involvement. Skin (patient A) and liver (patient B) biopsy confirmed the diagnosis of LCH with positive staining of LCH cells for S-100 and CD1a. Two courses (patient A) and one course (patient B) of vinblastine and prednisolone, according to the LCH-III study of the ‘Histiocyte Society’ (Minkov et al, 2000), failed to stop progression of the MS-LCH, as did the second-line protocol according to arm B of LCH-III (which included additional methotrexate) in patient A. During further disease progression, patient A suffered a pulmonary embolism (hyperhomocysteinaemia) and a purulent cholecystitis (cholecystectomy) on the basis of a sclerosing cholangitis. Patient B showed improved lung function and his skin lesions resolved, whereas liver and bone lesions remained unchanged during maintenance therapy (mercaptopurine) (Gadner et al, 2001). A continuous resolution of the skin (patient A), liver (patients A and B), lung (patients A and B) and brain lesions (patient A) and the persistence of osteolytic lesions (patients A and B) were observed over a period of 21 and 8 months on study respectively. Tumour regression was confirmed by biopsy of a residual liver lesion after 6 months on treatment (patient A). Functional pituitary deficiencies improved (patient A) during resolution of the LCH-associated brain lesions. The study medication was well tolerated. In patient A, trofosfamide dose was reduced to 50 mg, twice daily p.o. after 1 year although there was no haematological toxicity observed and rofecoxib was reduced to 12Æ5 mg/d [oedema, World Health Organization (WHO) Grade 1]. No other toxic side effects were observed according to the WHO criteria. This report is the first to show strong overexpression of PPARc on Langerhans’ cells (patients A and B) (Fig 1) and the clinical activity of PPARc ligands and COX-2 inhibitors combined with metronomic chemotherapy. The successful clinical courses in two patients with chemorefractory MS-LCH should stimulate the study of anti-inflammatory and angiostatic therapy in LCH.