LCH-IV, International Collaborative Treatment Protocol for Children and Adolescents With Langerhans Cell Histiocytosis

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 cellhistiocytosis 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 12weeks (Initial Course 2)
• Disease progression (AD worse) in non-risk organs at any time during continuationtreatment
• Active disease at the end of Stratum I treatment
• Disease reactivation in non-risk organs at any time after completion of Stratum Itreatment
• 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 ADintermediate in risk organs after week 12 (after Initial Course 2).
• Presence of unequivocally severe organ dysfunction at the above mentionedevaluation 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 haveto 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 criteriato 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 ADintermediate in risk organs after week 12 (after Initial Course 2) of Stratum IOR
• AD worse after the 2nd and 3rd 2-CdA/Ara-C course, and those AD worse or ADintermediate after the 4th 2-CdA/Ara-C course of Stratum III AND
• Presence of unequivocally severe organ dysfunction at the above mentionedevaluation 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 <18years of age) must sign an Ethics or institutional Review Board approved consentform indicating their awareness of the investigational nature and the risks ofthis study. When appropriate, younger patients will be included in alldiscussions in order to obtain assent.
• Adequate organ function: Patients should have adequate hepatic, renal, cardiacand pulmonary function to undergo reduced intensity HCT based upon localinstitutional guidelines, or at a minimum meet requirements noted in eligibilitychecklist Appendix A-VIII_1. However, significant hepatic and pulmonarydysfunction, if secondary to underlying LCH disease activity, will not excludepatients from protocol enrollment and should be discussed with the National PICoordinator and the Coordinating Principal Investigator.
• Stratum V
• All patients with verified diagnosis of LCH and MRI findings consistent withND-CNSLCH irrespective of previous treatments (also those not registered to otherStrata ofLCH-IV).
• Patients with isolated tumorous CNS-LCH (including isolated DI with mass lesionin the hypothalamus-pituitary axis). In patients with already establisheddiagnosis of LCH and radiologic finding of CNS lesions compatible with LCH, abiopsy of the lesion is not obligatory. In all other cases a biopsy of the lesionis needed for inclusion into the study
• Stratum VI -- Patients with newly diagnosed SS-LCH and localization other than "multifocalbone",isolated tumorous CNS lesion, or isolated "CNS-risk" lesion.
• Stratum VII -- All patients registered in LCH IV (regardless of treatment) as long asconsent for longterm follow-up has not been withheld.

Exclusion Criteria:

• Stratum I
• Pregnancy (patients of child-bearing age must be appropriately tested beforechemotherapy)
• 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.) withoutevidence 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 thestudy:
• Isolated sclerosing cholangitis without evidence of active hepatic LCH as theonly 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 eligiblefor Stratum V),
• Patients with isolated "CNS-risk" or multifocal bone lesions (they are eligiblefor Stratum I, Group 2)