Retrospective Analysis of Clofarabine Salvage Therapy in Refractory Multifocal Langerhans Cell Histiocytosis (LCH)

Purpose: LCH is a neoplastic inflammatory disorder driven by recurrent somatic mutations in the MAPK pathway in myeloid precursors. Over 50% of patients with systemic LCH are not cured with front-line therapies and data to guide salvage options are limited. In this study, we describe 58 patients with relapsed/refractory LCH who were treated with clofarabine.

Methods: Data were extracted from clinical records of patients treated with clofarabine for LCH by Texas Children’s Hospital physicians or collaborators between May 2011 and 2023.

Results: Patients were treated with a median of two chemotherapeutic regimens prior to receiving clofarabine; median age was 3.49 (4 months to 61 years). The typical treatment course was 25mg/m2 daily for 5 consecutive days per month; 19%(11/58) received treatment for less than 6 months; 26%(15/58) for 6-9 months; and 55%(32/58) for 9-24 months. OS in this cohort was 100%(58/58) and PFS was 75% with median 2-year follow-up (range: 5 months to 11 years); The objective response rate (ORR) for all patients was 84% with 9%(5/58) maintaining stable disease and 7%(4/58) developing progressive disease during the study period. Patients treated for LCH-associated neurodegeneration had relatively worse outcomes (ORR: 63%) compared to patients with systemic disease without LCH-ND (ORR: 88%). Patients treated with clofarabine showed significant decreases in the amount of detectable BRAF^V600E alleles in their circulating peripheral blood mononuclear cells. Toxicities included cytopenia, vomiting, and bacterial infections, but the majority tolerated chemotherapy in the outpatient setting.

Conclusion: Clofarabine monotherapy has activity against LCH in heavily pretreated patients, the majority of whom achieved durable remission. Prospective multi-center trials are warranted to determine optimal dosing as well as long-term efficacy, late toxicities, relative cost and patient reported outcomes of clofarabine compared to alternative salvage therapy strategies (e.g. MAPK inhibitors) in patients with relapsed/refractory LCH.