Long-Term Results of Combined Modularized, Immune-Modulatory, Angiostatic, and Antiinflammatory Therapy in Systemically Pre-Treated Multi-Systems Langerhans Cell Histiocytosis

Abstract

Up to now, systemically pretreated multi-systems Langerhans cell histiocytosis has been an incurable disease, and therapeutic options for patients have been limited. Acknowledging the fact that the continuous production of pro-inflammatory cytokines contributes to the resistance to commonly used agents, we hypothesized that a multi-targeted approach consisting of continuously administered anti-angiogenic, anti-inflammatory, immune-modulatory, and anti-tumor components may overcome such resistance mechanisms. To clinically test this hypothesis, we initiated a phase II trial with a combination of pioglitazone 60 mg daily, trofosfamide 50 mg thrice daily, and etoricoxib 60 mg daily (rofecoxib 25 mg). In the absence of toxicity > grade 2, patients were eligible to continue the treatment regimen until tumor progression or complete tumor remission. Key inclusion criteria were progressive or relapsing MS-LCH after at least two previous lines of systemic therapy. We here report on the long-term results of three consecutive patients treated at one center. Between November 2003 and December 2011, three patients with progressive multi-systems Langerhans cell histiocytosis (MS-LCH) were included into our phase II trial. Each patient was male and had been heavily pretreated. The median number of previous treatment lines was 3.3 (range 3–5). The median age was 34 years (range 22–50 years). Remarkably, none of the patients experienced dose-limiting toxicity (defined as any toxicity with NCI-CTCAE grade ≥ 3 during the first treatment cycle). Therefore, all patients continued treatment. Serious adverse reactions observed during the follow-up period were infections (n = 2, grade 2 NCI-CTCAE toxicity). Response assessment showed two patients with continuous complete remission (CR) and two patients with histologically confirmed CR in the respective lesions. One of the patients had progressive disease after long-term CR and responded again to study medication. Our prospective phase II trial showed that the combination of low-dose chemotherapy, COX-2 inhibitor, and pioglitazone administered as a long-term treatment on a daily basis has not only a very favorable toxicity profile but also represents a feasible treatment regimen applicable in an outpatient setting. Because of the high tolerance of this therapy and the encouraging long-term response data, this study protocol should be evaluated in a multi-center trial.