Clofarabine for relapsed/refractory Langerhans cell (LC) and non-LC histiocytosis

Langerhans cell histiocytosis (LCH) and non-LC histiocytosis are rare neoplastic diseases with variable behavior. Although chemotherapy is effective in many patients, disease recurrence is common, and some patients respond poorly to treatment and/or experience long-term morbidity and mortality. Clofarabine (Clolar), a deoxyadenosine analog, has shown encouraging activity in histiocytic disorders. Here, we report the first prospective, multicenter, phase II study (NCT02425904) evaluating the efficacy and toxicity of clofarabine in recurrent/refractory (R/R) LCH (Stratum 1) and non-LC histiocytosis (Stratum 2). All participants received clofarabine on days 1-5 of each 28-day cycle. Response was assessed after 2 cycles; participants without evidence of disease progression received 4 additional cycles. Twenty-five participants enrolled: 20 in Stratum 1, five in Stratum 2 (including one patient later deemed inevaluable). In Stratum 1, 17/20 participants (85%; 95% CI: [62%, 97%]) were responders, and three had stable disease after cycle 2. Nineteen Stratum 1 participants completed 6 cycles; one withdrew after cycle 3. No Stratum 1 participants progressed during treatment and three had residual or recurrent disease after cycle 6, resulting in 2-year PFS ± SE and OS of 89±7% and 100%, respectively (n=20; median follow-up: 40.9; range: 2.7-49.4). In Stratum 2, 3/4 participants (75%; 95% CI: [19%, 99%]) had partial response. Overall, 80% (20/25) of participants had one or more grade ≥3 toxicities attributed to protocol therapy. In conclusion, clofarabine is active and tolerable in children with R/R LCH and warrants further study in patients with non-LC histiocytosis. Further study of clofarabine in these populations is warranted.