Evaluating Anti-TNF-Alpha Therapy in Patients with Relapsed and Refractory Langerhans Cell Histiocytosis

Purpose: Tumor necrosis factor alpha (TNF-alpha) is produced in Langerhans cell histiocytosis (LCH) lesions and is elevated in active high-risk vs low-risk LCH vs control patient blood, where TNF-alpha has been reported at 12 pg/ml in juvenile rheumatoid arthritis (JRA). Anti-TNF therapeutic etanercept is used in TNF-mediated diseases, such as JRA, and was successfully used in one case of LCH. We therefore conducted phase II study for etanercept therapeutic efficacy for refractory or relapsed LCH patients. Methods: Luminex platform was used to assess patient blood TNF-alpha level. This phase II study was approved by the Baylor College of Medicine IRB with research support from Amgen/Immunex. Eligibility included LCH patients with progressive disease post-initial treatment and ≥1 salvage therapy. Etanercept was injected 0.4mg/kg subcutaneously twice/week for 12 weeks. Therapeutic response were evaluated at 4 and 8 weeks. Results: TNF-alpha is elevated in blood LCH high-risk (average 45pg/ml) vs low-risk (average 13pg/ml) vs control (average 13pg/ml). Five LCH patients (1.6-42 years) with multi-system involvement, 2 with high-risk disease were enrolled. A median of 5 doses of etanercept were administered (range 1-14). One high-risk patient died 18 days after the first dose from disease progression. At week 4 evaluation, one patient had stable disease and 3 progressed and all subjects progressed by week 8. Ultimately 0/5 patients had disease improvement with etanercept. Conclusion: Etanercept therapy, at JRA-effective dose, in this trial did not improve LCH disease. It is possible that this may not be an effective strategy. Alternatively, it is also possible that drug dose or distribution was suboptimal. While anti-TNF therapies, including etanercept, are effective for treatment of RA, etanercept is not effective for granulomatous diseases such as Crohn's, sarcoidosis or Wegner's disease. Additional studies exploring potential efficacy of higher dose or alternative forms of TNF-alpha inhibition in LCH may be warranted.