Inclusion Criteria:

• - Stratum I.

• - Patients must be less than 18 years of age at the time of diagnosis.

• - Patients must have histological verification of the diagnosis of Langerhans cell histiocytosis according to the criteria described in Section 6.1.

• - Signed informed consent form.

• - Stratum II.

• - Patients of Stratum I who have: - Progressive disease (AD worse) in non-risk organs after 6 weeks (Initial Course.

• - AD intermediate or worse in non-risk organs or AD better in risk organs after 12 weeks (Initial Course 2) - Disease progression (AD worse) in non-risk organs at any time during continuation treatment.

• - Active disease at the end of Stratum I treatment.

• - Disease reactivation in non-risk organs at any time after completion of Stratum I treatment.

• - Stratum III.

• - Patients from Stratum I who fulfill the following criteria: - AD worse in risk organs after week 6 (after Initial Course 1), or AD worse or AD intermediate in risk organs after week 12 (after Initial Course 2).

• - Presence of unequivocally severe organ dysfunction at the above mentioned evaluation points (hematological dysfunction, liver dysfunction, or both of them) as.

• - Hb <70 g/L (<7.0 g/dl) and/or transfusion dependency.

• - PLT <20 x109/L (20,000/μL) and/or transfusion dependency (both criteria have to be fulfilled) AND/OR.

• - Liver dysfunction (or digestive involvement with protein loss) - Total protein <55 g/L or substitution dependency.

• - Albumin <25 g/L or substitution dependency (at least one of the two criteria to be fulfilled) - Stratum IV.

• - Patients from Stratum I or Stratum III who fulfill the following criteria: - AD worse in risk organs after week 6 (after Initial Course 1), or AD worse or AD intermediate in risk organs after week 12 (after Initial Course 2) of Stratum I OR.

• - AD worse after the 2nd and 3rd 2-CdA/Ara-C course, and those AD worse or AD intermediate after the 4th 2-CdA/Ara-C course of Stratum III AND.

• - Presence of unequivocally severe organ dysfunction at the above mentioned evaluation points (hematological dysfunction, liver dysfunction, or both of them) as defined in Table XI (see Section 10.3.

1).

• - Informed consent: All patients or their legal guardians (if the patient is <18 years of age) must sign an Ethics or institutional Review Board approved consent form indicating their awareness of the investigational nature and the risks of this study.

When appropriate, younger patients will be included in all discussions in order to obtain assent.

• - Adequate organ function: Patients should have adequate hepatic, renal, cardiac and pulmonary function to undergo reduced intensity HCT based upon local institutional guidelines, or at a minimum meet requirements noted in eligibility checklist Appendix A-VIII_1.

However, significant hepatic and pulmonary dysfunction, if secondary to underlying LCH disease activity, will not exclude patients from protocol enrollment and should be discussed with the National PI Coordinator and the Coordinating Principal Investigator.

• - Stratum V.

• - All patients with verified diagnosis of LCH and MRI findings consistent with ND-CNSLCH irrespective of previous treatments (also those not registered to other Strata ofLCH-IV).

• - Patients with isolated tumorous CNS-LCH (including isolated DI with mass lesion in the hypothalamus-pituitary axis).

In patients with already established diagnosis of LCH and radiologic finding of CNS lesions compatible with LCH, a biopsy of the lesion is not obligatory. In all other cases a biopsy of the lesion is needed for inclusion into the study.

• - Stratum VI.

-- Patients with newly diagnosed SS-LCH and localization other than "multifocal bone",isolated tumorous CNS lesion, or isolated "CNS-risk" lesion.

• - Stratum VII -- All patients registered in LCH IV (regardless of treatment) as long as consent for longterm follow-up has not been withheld.

Exclusion Criteria:

• - Stratum I.

• - Pregnancy (patients of child-bearing age must be appropriately tested before chemotherapy) - LCH-related permanent consequences (e.g. vertebra plana, sclerosing cholangitis, lung fibrosis, etc.) in the absence of active disease.

• - Prior systemic therapy.

• - Stratum II.

• - Patients with progressive disease in risk organs.

• - Permanent consequences (e.g. sclerosing cholangitis, lung fibrosis, etc.) without evidence of active LCH in the same organ or in any other locations.

• - No written consent of the patient or his/her parents or legal guardian.

• - Stratum III.

• - The presence of any of the following criteria will exclude the patient from the study: - Isolated sclerosing cholangitis without evidence of active hepatic LCH as the only evidence of risk organ involvement.

• - Inadequate renal function as defined by serum creatinine > 3x normal for age.

• - Stratum IV.

• - Pulmonary failure (requiring mechanical ventilation) not due to active LCH.

• - Isolated liver sclerosis or pulmonary fibrosis, without active LCH.

• - Uncontrolled active life-threatening infection.

• - Decreased renal function with a GFR of less than 50ml/1.73m2/min.

• - Pregnancy or active breast feeding.

• - Failure to provide signed informed consent.

• - Stratum VI.

- Patients with SS-LCH who have an isolated tumorous CNS lesion (they are eligible for Stratum V), - Patients with isolated "CNS-risk" or multifocal bone lesions (they are eligible for Stratum I, Group 2)

The international efforts of the past 20 years have shown that combination therapy with vinblastine and prednisone is an effective therapy for Multi-system (MS)-LCH. The previous prospective trial LCH-III confirmed this regimen as a standard regimen for MS-LCH in patients with and without risk organ involvement. It also showed that prolonged treatment in the latter group (treatment duration of 12 vs.#46; 6 months) is superior in preventing disease reactivations. The results of this trial are encouraging and serve as a basis for the LCH-IV study design.Due to the complexity of the disease presentations and outcomes, the LCH-IV study seeks to tailor treatment based on features at presentation and on response to treatment, leading to seven strata:

• - Stratum I: First-line treatment for MS-LCH patients (Group 1) and patients with Single system (SS)-LCH with multifocal bone or "Central Nervous System (CNS)-risk" lesions (Group 2) - Stratum II: Second-line treatment for non-risk patients (patients without risk organ involvement who fail first-line therapy or have a reactivation after completion of first-line therapy) - Stratum III: Salvage treatment for risk LCH (patients with dysfunction of risk organs who fail first-line therapy) - Stratum IV: Stem cell transplantation for risk LCH (patients with dysfunction of risk organs who fail first-line therapy) - Stratum V: Monitoring and treatment of isolated tumorous and neurodegenerative CNS-LCH.

- Stratum VI: Natural history and management of "other" SS-LCH (patients who do not need systemic therapy at the time of diagnosis) - Stratum VII: Long-term Follow up (all patients irrespective of previous therapy will be followed for reactivation or permanent consequences once complete disease resolution has been achieved and the respective protocol treatment completed)

Arms

Experimental: Stratum I

Stratum I The combination of Prednisone and vinblastine is the standard first-line combination for patients needing systemic therapy (Stratum I). Patients with MS-LCH and involvement of risk organs, who do not respond to 6-12 weeks of standard therapy, will be immediately switched to alternative treatment approaches (Stratum III or Stratum IV). Further therapy prolongation (12 vs. 24 months) and intensification (± mercaptopurine) will further reduce the reactivation rate and the permanent consequences.

Experimental: Stratum II

A uniform "intensive" 24-week course consisting of prednisolone, vincristine and cytosine-arabinoside will be introduced in Stratum II for eligible patients. It will be followed by a continuation therapy to total treatment duration of 24 months. Participants who after SL-IT (week 24) have a response (NAD or AD better) are eligible for randomization between the continuation arms "INDOMETHACIN" and "6-MP/MTX" (mercaptopurine and Methotrexate).

Experimental: Stratum III

Salvage treatment for risk LCH To assess the efficacy of the combination 2-CdA/Ara-C (Cytosine Arabinoside and 2-chlorodeoxyadenosine) in MS-LCH (patients with risk organ involvement, who fail to respond to front-line (Stratum I) therapy. The initial therapy consists of 2 courses of 2-CdA/Ara-C. Continuation of outlined treatment to be assessed at assigned intervals in each stratum.

Experimental: Stratum IV

To determine the overall and disease free survival at 1 and 3 years after reduced intensity conditioning hematopoietic stem cell transplantation (RIC-HSCT). Salvage treatment option for MS-LCH patients with risk organ involvement, who fail to respond to front-line therapy (Stratum I) OR to the salvage 2- CdA/Ara-C regimen (Stratum III).

Experimental: Stratum V

Stratum V Monitoring and Treatment of isolated tumorous and neurodegenerative CNS-LCH - Special regimens will be offered to patients with isolated tumorous CNS-LCH (repeated 2-CdA courses) and to patients with clinically manifested ND-CNS-LCH (+/- extracranial LCH manifestations). For the last group monotherapy with Ara-C courses or (Intravenous immunoglobulin)IVIG will be offered depending on physician's choice.

Experimental: Stratum VI

Natural history and management of "other" SS-LCH not eligible for stratum I group 2. Treatment Options- Management (mostly "wait & see" and topical treatment) is left to the discretion of the treating physician. All treatments and disease responses must be reported in the database. In the case of uncertainties please contact your National Coordinator. Patients being followed on Stratum VI who have progression of disease to MSLCH, multifocal bone disease or CNS-risk bone lesions should be enrolled on Stratum I therapy. Patients being followed on Stratum VI who develop isolated tumorous or neurodegenerative CNS-LCH should be enrolled on Stratum V.

Interventions

Drug: - Prednisone

Stratum I

Drug: - Vinblastine

Stratum I

Drug: - mercaptopurine

Stratum I

Drug: - INDOMETHACIN

Indomethacin fixed dose given daily orally in two divided doses with gastric protection for total treatment duration of 24 months.

Drug: - Methotrexate

fixed dose weekly orally for total treatment duration of 24 months.

Drug: - Cytosine Arabinoside

Drug: - 2-chlorodeoxyadenosine

Procedure: - hematopoietic stem cell transplantation (RIC-HSCT)

Biological: - Intravenous immunoglobulin