Efficacy and Toxicity Profile of Clofarabine in Patients with Recurrent/Refractory Langerhans Cell Histiocytosis and Other Histiocytic Disorders

Introduction: Langerhans Cell Histiocytosis (LCH) is an inflammatory myeloid neoplastic disorder. Patients with recurrent or refractory LCH are at increased risk of mortality and long-term morbidity. The standard of care for high-risk LCH patients who are refractory to vinblastine/prednisone or who relapse is very high dose While mostly cytarabine/cladribine. While effective, this strategy also has very high treatment-related mortality. Clofarabine is a nucleoside analog with efficacy in other myeloid malignancies. Case reports have suggest that is has activity in LCH and other histiocytic disorders at moderate doses. The purpose of this study was to report the efficacy and toxicity profile of a restrospective cohort of patients with histiocytic disorders treated with clofarabine.

Methods: Medical records were retrospectively reviewed for 26 pediatric patients with histiocytic disorders who were treated with clofarabine. Twenty-one of these patients had LCH and had failed at least one prior systemic therapy, while the remaining 5 patients had other histiocytic disorders (JXG, Rosai-Dorfman disease or mixed histiocytic disease). Patients were treated for a minimum of 6 months of with clofarabine (25 mg/m2/day x 5 days every 28 days), were reassessed for response at the end of therapy and monitored for relapse or progression post-treatment.

Results: All patients in this series started treatment under the age of 18 years old (median=1.5 years; range: 0.3-16.3). Patients with LCH had received a median of 3 prior treatments (range:1-5). A majority of the patients (n = 17, 65%) were received all clofarabine infusions in an outpatient clinic. The most common adverse event was fever requiring hospital admission (n = 18; 69%), followed by Grade 3 neutropenia (n = 12; 46%), and intractable nausea/vomiting (n = 7; 27%). Additional adverse events included Grade 3 anemia, Grade 2 dehydration, Grade 3 cytopenias, and Grade 3 infection. Overall survival was 100%. LCH patients who completd 6-months of clofarabine had an 85% overall response (33% complete response, 52% partial response); 10% progressed on therapy and 5% had stable disease. Relapse occurred in 5 (28%) patients with LCH after completion of treatment (median time to relapse=22 months; range: 1-42). The odds of relapse was approximately 4-times greater in LCH patients with CNS involvement (n=16) compared to those without (n=4), and also in those with high risk disease (n=5) relative to standard risk (n=10). One of the patients who experienced disease recurrence received an additional 12 cycles of clofarabine and is currently doing well with no active disease.

Conclusions: Clofarabine may be an effective and relatively safe salvage therapy for LCH and other histiocytic disorders. Future prospective trials for patients with refractory histiocytic disorders will directly compare efficacy and toxicity relative to other current salvage strategies with cytotoxic nucleoside analogs or targeted inhibitors.