Hydroxyurea for the Treatment of Relapsed/Refractory Langerhans Cell Histiocytosis
Authors: Grimes Amanda Bell , Zinn Daniel , Eckstein Olive S. , Allen Carl , McClain Kenneth 
Published: October 2019

Abstract
Purpose: Langerhans cell histiocytosis (LCH) is a potentially fatal disease, clinically ranging from single bone or skin lesions to diffuse multi-system involvement. Given incomplete understanding of LCH pathogenesis, optimal therapies remain uncertain. An emerging model suggests that pathologic CD207+ Langerhans cells arise from myeloid dendritic precursor cells, driven by activating mutations in the MAPK pathway. Therefore, we hypothesize that therapies directed against immature myeloid cells may be effective in treatment of LCH. Hydroxyurea is a myelotoxic therapy with proven efficacy in other myleoproliferative neoplasms, such as CML. This study reports a single-center experience with hydroxyurea therapy in a cohort of LCH patients.
Methods: The charts of patients treated at Texas Children's Hospital from December 2009 to present were reviewed in accordance with IRB-approved protocols at Baylor College of Medicine. Patients were selected for hydroxyurea therapy based on specific clinical characteristics, including low-risk single-system disease on presentation, recurrent/refractory disease following standard of care front-line therapy, and intolerance of other therapies. Treatment response was reported using the criteria established in the Histiocyte Society Evaluation and Treatment Guidelines.
Results: Fourteen patients, ranging from 1 month to 66 years old, previously receiving 1-5 alternate regimens, have received hydroxyurea therapy. To date, patients have been on therapy for an average of 10.4 months, with dose ranging from 750 mg to 3000 mg daily (titrating for an ANC of 1500). Data shows that 57% of patients had improvement in symptoms/regression of disease, and we will continue to follow responses in the entire cohort of patients. One patient had anemia requiring dose reduction, but therapy was otherwise well tolerated.
Conclusion: Hydroxyurea demonstrated activity against LCH with minimal toxicity in patients with relapsed or refractory LCH following initial systemic chemotherapy. Disease control improved in the majority of patients on hydroxyurea monotherapy. A role for hydroxyurea in therapy of LCH patients is warranted. Chronic use of hydroxyurea is well tolerated, making it an ideal agent to investigate for the role of maintenance therapy. Furthermore, use of hydroxyurea in combination with other therapies is well established in other diseases, and should be investigated in patients with LCH.Table 1.Number of Patients14Number of Regimens prior to HydroxyureaMale4Mean2.8Female10Range1 to 5Pretreatment RegimenAge at DiagnosisMethotrexate, 6MP, Prednisone9Mean31 y 8 moCytarabine7Range1 mo - 66 yVinblastine, Prednisone, MTX, 6MP4Cladribine3Time from Diagnosis to Start of HydroxyureaEtoposide2Mean8 y 8 moPrednisone2Range4 mo - 26 yAKT inhibitor1Campath1Duration of HydroxyureaClofarabine1Mean7.4 moNarrow Spec UV1Range1 mo - 17 moRadiation Therapy1Response to TherapyComplete Resolution0Intermediate/Stable2Better/Regression8Worse1Intermediate/Mixed0Unknown3

Disclosures
Off Label Use: Hydroxyurea -- used for myeloproliferative neoplasms, but not traditionally for Langerhans Cell Histiocytosis. Allen:Roche: Consultancy, Other: unpaid; NovImmune: Consultancy, Other: unpaid.