Evaluation of Cladribine-Based Regimen in Pediatric and Adolescent Langerhans Cell Histiocytosis: A Randomized, Multicenter Clinical Trial

The primary objective of this study is to reduce **mortality** in patients with multi-system Langerhans Cell Histiocytosis (ms-LCH) by implementing an early switch to salvage treatment for those with risk organ involvement who do not respond to first-line therapy. Additionally, the study aims to investigate the effects of prolonging or intensifying continuation therapy to decrease reactivations and late sequelae in ms-LCH. For patients with single-system LCH (ss-LCH) with isolated "CNS-Risk" lesions or multifocal bone lesions, the study will explore the impact of extending continuation therapy from 6 to 12 months to reduce reactivation rates and late sequelae. Furthermore, the study seeks to achieve disease resolution and prevent reactivations and late sequelae in non-risk organ involvement patients through a second-line treatment regimen followed by continuation therapy.

Secondary objectives include:

• Prospective validation of a new scoring system for assessing disease activity and treatment response.
• Investigation of the cumulative incidence of radiographic and clinical neurodegeneration in patients with "CNS-Risk" bone lesions and endocrine deficits.
• Study of the natural history of LCH in patients not requiring upfront systemic therapy, as well as the long-term consequences and quality of life in all registered patients, regardless of systemic therapy status.

The clinical trial involves a total of **906 participants** diagnosed with **Langerhans Cell Histiocytosis**. The study population includes both male and female subjects under the age of 18, with no prior systemic therapy for the condition. Participants were selected based on histological verification of the diagnosis and the provision of signed informed consent, meeting the inclusion criteria for their respective stratum. The trial population is considered vulnerable due to the age range and the nature of the disease. Lifestyle considerations such as diet, physical activity, or habits are not specified in the available data. The study aims to address the reduction of mortality and reactivation rates, as well as the prevention of late sequelae in patients with multi-system and single-system LCH.

The clinical trial is designed to evaluate the efficacy of various treatment regimens in children and adolescents diagnosed with **Langerhans Cell Histiocytosis** (LCH). The trial employs a randomized, double-blind, controlled methodology to ensure the reliability and validity of the results. The primary objective is to reduce mortality in multi-system LCH by implementing an early switch to salvage treatment for patients with risk organ involvement who do not respond to first-line therapy. Additionally, the trial investigates the prolongation or intensification of continuation therapy to reduce reactivations and late sequelae in both multi-system and single-system LCH cases.

The trial is expected to run until December 2025, with participant recruitment having commenced in December 2012. Participants will be involved in the study for a maximum of 24 months, depending on their response to treatment and the specific stratum they are assigned to. The study includes several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor treatment response and side effects, and an end-of-study visit to assess overall outcomes and any long-term effects.

Inclusion criteria for the trial require histological verification of LCH, age under 18 years, no prior systemic therapy, and signed informed consent. Participants must meet the inclusion criteria for their respective stratum. The primary endpoints include reactivation-free survival, overall and disease-free survival, and the response of isolated tumorous CNS lesions to treatment. Secondary endpoints focus on the incidence of permanent consequences, treatment toxicity, and the cumulative incidence of reactivations in risk organs.

Participants may be withdrawn from the study early if they experience unacceptable toxicity, fail to comply with the study protocol, or if the investigator deems it in the participant's best interest. The trial's comprehensive design aims to provide valuable insights into the management of LCH, potentially improving outcomes for affected individuals.

The clinical trial involves the administration of several experimental medications, each with specific pharmaceutical forms, dosages, and routes of administration. **LITAK 2 mg/ml solution for injection**, containing the active substance **cladribine**, is administered via **intravenous infusion**. The maximum daily dose is 9 mg/m², with a total dose not exceeding 150 mg/m² over a treatment period of 24 weeks. This medication is produced by Lipomed GmbH and is classified as a cytostatic agent.

**Prednisolone 5mg Tablets** are administered orally, with a maximum daily dose of 40 mg/m² and a total dose of 8070 mg/m² over a 96-week period. The active substance is **prednisolone**, and the product is manufactured by Wockhardt UK Ltd. It is also categorized as a cytostatic agent.

**Fludarabine phosphate 25 mg/ml Concentrate for Solution for Injection or Infusion** is administered via **IV infusion**. The active substance, **fludarabine phosphate**, has a maximum daily dose of 30 mg/m² and a total dose of 150 mg/m² over a 5-day treatment period. Accord Healthcare Ireland Limited produces this cytostatic medication.

**Cytarabine 20 mg/ml Solution for Injection/Infusion** is administered through **intravenous administration**. The active substance, **cytarabine**, has a maximum daily dose of 100 mg/m² and a total dose of 9750 mg/m² over a 24-week period. This cytostatic agent is produced by Accord Healthcare Ireland Limited.

**Vinblastine Sulfate 1 mg/ml Solution for Injection or Infusion** is administered via **intravenous bolus use**. The active substance, **vinblastine sulfate**, has a maximum daily dose of 6 mg/m² and a total dose of 258 mg/m² over a 104-week period. Pfizer Healthcare Ireland manufactures this cytostatic medication.

**OCTAGAM 10 %, Lösung zur intravenösen Infusion** is administered via **infusion**. The active substance is **human normal immunoglobulin (IV)**, with a maximum daily dose of 500 mg/kg and a total dose of 6000 mg/kg over a 12-week period. This product is manufactured by Octapharma GmbH and is classified as a cytostatic agent.

**Mercaptopurine Silver Pharma 50 mg tablets** are administered orally, with a maximum daily dose of 50 mg/m² and a total dose of 33950 mg/m² over a 96-week period. The active substance is **mercaptopurine monohydrate**, and the product is produced by Silver Pharma S.L. It is categorized as a cytostatic agent.

**Melphalan 50 mg Powder and Solvent for Solution for Injection/Infusion** is administered via **intravenous infusion**. The active substance, **melphalan**, has a maximum daily dose of 140 mg/m² and a total dose of 140 mg/m² over a 1-day treatment period. Aspen Pharma Trading Limited manufactures this cytostatic medication.

**LEMTRADA 12 mg concentrate for solution for infusion** is administered via **intravenous infusion**. The active substance is **alemtuzumab**, with a maximum daily dose of 0.2 mg/kg and a total dose of 1 mg/kg over a 5-day period. This product is manufactured by Sanofi Belgium and is classified as an anti-inflammatory agent.

**INDOMETACIN CAPSULES BP 25mg** are administered orally, with a maximum daily dose of 2 mg/kg and a total dose of 1120 mg/kg over an 80-week period. The active substance is **indometacin ph. eur.**, and the product is produced by Actavis UK Limited. It is categorized as an anti-inflammatory agent.

**Methotrexate 10 mg Tablets** are administered orally, with a maximum daily dose of 20 mg/m² and a total dose of 1600 mg/m² over an 80-week period. The active substance is **methotrexate**, and the product is manufactured by Accord Healthcare Ireland Limited. It is classified as a cytostatic agent.

The efficacy of the clinical trial for Langerhans Cell Histiocytosis (LCH) will be assessed using several primary and secondary endpoints. The primary endpoints include **reactivation-free survival**, overall and disease-free survival, the course of neurodegenerative CNS-LCH, response of isolated tumorous CNS lesions to 2-CdA, and the rate and spectrum of permanent consequences. Secondary endpoints will focus on the incidence of permanent consequences, treatment toxicity, the proportion of patients alive and free of disease without permanent consequences, and the cumulative incidence of reactivations in risk organs.

Data collection and analysis will be conducted at specified intervals throughout the trial, with a focus on both short-term and long-term outcomes. The trial aims to reduce mortality in multi-system LCH by early intervention and to investigate the effects of prolongation or intensification of continuation therapy. The study will also explore the efficacy of second-line treatments in achieving disease resolution and preventing reactivations in patients without risk organ involvement. The trial is designed to provide comprehensive insights into the treatment efficacy for different LCH patient groups, with a planned completion date by the end of 2025.