Clofarabine salvage therapy in refractory multifocal histiocytic disorders, including Langerhans cell histiocytosis, juvenile xanthogranuloma and Rosai-Dorfman disease

Abstract

Background: Existing therapies for recurrent or refractory histiocytoses, including Langerhans cell histiocytosis (LCH), juvenile xanthogranuloma (JXG), and Rosai-Dorfman disease (RDD), have limited effectiveness. We report our experience with using clofarabine as therapy in children with recurrent or refractory histiocytic disorders, including LCH (11 patients), systemic JXG (4 patients), and RDD (3 patients).

Methods: Patients treated with clofarabine for LCH, JXG, or RDD by Texas Children's Hospital physicians or collaborators between May 2011 and January 2013 were reviewed for response and toxicity.

Results: Patients were treated with a median of three chemotherapeutic regimens prior to clofarabine. Clofarabine was typically administered at 25 mg/m(2) /day for 5 days. Cycles were administered every 28 days for a median of six cycles (range: 2-8 cycles). Seventeen of 18 patients are alive. All surviving patients showed demonstrable improvement after two to four cycles of therapy, with 11 (61%) complete responses, 4 (22%) partial responses, and 2 patients still receiving therapy. Five patients experienced disease recurrence, but three of these subsequently achieved complete remission. All patients with JXG and RDD had complete or partial response at conclusion of therapy. Side effects included neutropenia in all patients. Recurring but sporadic toxicities included prolonged neutropenia, severe vomiting, and bacterial infections.

Conclusion: Clofarabine has activity against LCH, JXG, and RDD in heavily pretreated patients, but prospective multi-center trials are warranted to determine long-term efficacy, optimal dosing, and late toxicity of clofarabine in this population.

Keywords: Langerhans cell histiocytosis; Rosai-Dorfman disease; clofarabine; histiocytosis; juvenile xanthogranuloma.

Figure 1

Kaplan-Meier curves of estimated progression-free survival (PFS, in blue) and overall survival (OS, in red) of patients treated with clofarabine, from time of clofarabine initiation, in A) all histiocytic disorders and B) LCH. Patients were censored at progression/death or time of last follow up.

Figure 2

Brain MRI axial T1 post-contrast images of patients with JXG. A,B: 2-month-old patient (#12) with central nervous system JXG. A) prior to clofarabine. B) post two cycles of clofarabine. Minimal residual tumor was present. C–E: 1-year-old patient (#13) treated with clofarabine for multisystem JXG, including CNS involvement. C) pretreatment image. D) persistent disease after therapy with vinblastine/prednisone and cladribine. E) near resolution of disease after 6 cycles of clofarabine.

Figure 3

MRI T2 orbital images of 18-year-old patient (#16) with orbital Rosai-Dorfman disease. A) orbital disease with proptosis evident despite multiple treatment courses. Normal orbital musculature not visualized. B) Complete resolution of orbital disease and proptosis, with restoration of normal orbital muscular architecture.