Abstract
Background:
Langerhans cell histiocytosis (LCH) is a disorder characterized by lesions that include CD207+ dendritic cells along with an inflammatory infiltrate, ranging from a single lesion to potentially fatal multi-system disease. Empirically derived chemotherapy with vinblastine and prednisone still represents the standard of care, curing fewer than 50% of patients. As a result of the discovery of activating mutations in the MAPK-pathway, BRAF inhibitors seem to be a novel therapeutic option. In LCH patients who were refractory to (or not eligible for) conventional chemotherapy we administered a multi-targeted therapeutic approach targeting the deregulation of homeostatic pathways in LCH, e.g. notch, thereby simultaneously modulating tumor-associated inflammation, angiogenesis and immune response. The present retrospective analysis reports a single-center experience with a biomodulatory therapy in a cohort of patients with refractory LCH.
Methods:
At the University Hospital Regensburg seven patients with multi-system LCH (2 female/5 male, including two pediatric patients), ranging from 11 months to 77 years old, were selected for compassionate use treatment with a biomodulatory therapy schedule (Br J Haematol. 2005;128:730-2). Six patients have been refractory to up to three different standard regimens. One patient was not eligible for conventional therapy due to severe comorbidities. The biomodulatory metronomic therapy consisted of low dose trofosfamide, pioglitazone, a PPAR alpha/gamma agonist, etoricoxib, a COX-2 inhibitor and low-dose dexamethasone. Each drug was administered daily until disease progression or in case of complete remission for additional 6 months. Treatment response was reported using the criteria established in the Histiocyte Society Evaluation and Treatment Guidelines.
Results:
All of the patients in our cohort showed response to treatment as determined clinically, by CT/MRI scans and re-biopsies. Two of them developed a complete remission, three regression of disease and two stable disease. To date, none of the patients developed progressive disease (representing a progression-free-survival of 10 to 55 months until now). In one patient a dose reduction had to be made due to leukopenia. No other significant adverse events have been observed.
Conclusion:
Biomodulatory metronomic therapy demonstrated high activity against multi-system LCH with minimal toxicity even in refractory patients following multiple systemic chemotherapies. Long-lasting disease control was achieved in all of the treated patients. Confirmation of efficacy should be evaluated in a prospective trial.
No relevant conflicts of interest to declare.
