INTERNATIONAL COLLABORATIVE TREATMENT PROTOCOL FOR
CHILDREN AND ADOLESCENTS WITH LANGERHANS CELL HISTIOCYTOSIS

LCH is a rare disease of the immune system that may affect any age group. It
can affect many different organs, including the skeleton, skin, lymph nodes,
liver, lungs, spleen, hematopoiesis, or central nervous system (CNS).
Accordingly, the range of clinical symptoms is wide. There are two widely
recognized disease extent categories: single-system LCH (involvement of a
single organ or system) and multisystem LCH (involvement of 2
or more organ systems). Patients with SS-LCH of the skeleton, skin, or the
lymph nodes have an excellent prognosis and are felt to need a minimum or
sometimes even no treatment at all. The course of multisystem LCH (MS-LCH) is
unpredictable upon diagnosis, ranging from spontaneous resolution to fulminant
progression and fatal outcome. Involvement of crucial organs like the
hematopoietic system, liver, or spleen has been found to herald a poor
prognosis in different studies. Recent large clinical trials have shown that
the response to initial treatment is a
highly important prognostic factor. Patients with MS-LCH without involvement of
*risk organs* have very high (>95%) probability of survival when treated with a
standard regimen consisting of vinblastine and steroids. In contrast,
involvement of risk organs carries the risk of unfavourable outcome. Patients
with reactivations or chronic disease may experience severe permanent
consequences (PC) reducing the patient*s quality of life, in particular when
they affect the CNS or lungs and lead to hormone deficiencies, a
neurodegenerative syndrome, lung fibrosis, etc.
The international efforts of the past 20 years have shown that combination
therapy with vinblastine and prednisone is an effective therapy for 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. 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 SS-LCH with multifocal bone or *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)

This study has been transitioned to CTIS with ID 2024-512676-36-00 check the CTIS register for the current data.

* To decrease mortality in MS-LCH by an early switch of patients with risk
organ involvement, who do not respond to front-line therapy, to a more
intensive treatment (Stratum III or Stratum IV).
* To reduce reactivation rates and permanent consequences in MS-LCH (Group 1)
through prolongation (12 vs. 24 months) and intensification (+/- 6-MP) of
continuation treatment (2x2 factorial randomized trial)
* To reduce reactivation rates and permanent consequences in a subset of SS-LCH
(multifocal bone or isolated *CNS-Risk* lesions (Group 2) through prolongation
(6 vs. 12 months) of continuation therapy (randomized trial)
* To investigate the value of a uniform second-line therapy with PRED/ARA-C/VCR
followed by randomized continuation therapy (24 months of Indomethacin vs.
6-MP/MTX) in patients with non-risk organ LCH (both nonresponders to first-line
regimen and those who experience disease reactivation in non-risk organs after
its completion) with respect to achievement of complete disease resolution,
prevention of further reactivations and permanent consequences
* To evaluate the value of 2-CdA in patients with isolated tumorous CNS-LCH
* To evaluate whether systemic therapy with intravenous immunoglobulin (IVIG)
or low dose cytarabine can achieve improvement of the neuropsychological
symptoms in patients with clinically manifest neurodegenerative CNS-LCH.
* To describe the spectrum and incidence of permanent consequences in
systemically treated patients, identify possible risk factors, and assess the
role of systemic treatment in their prevention
* To prospectively study the natural course of SSLCH in patients who initially
are not candidates for systemic therapy, with respect to disease progression,
reactivations, need for medical interventions, as well as permanent
consequences, at any time after diagnosis.

Clinical treatment study with a randomisation for 2 strata

Children and adolescents with LCH need to be treated. Treatment is based on the
different strata as named in the background and in the protocol. The protocol
is the internationally accepted guideline for treatment of children with LCH.
For 2 strata a randomisation will be performed (after consent from patient and/
or parents). In MS-LCH (Group 1) through prolongation (12 vs. 24 months) and
intensification (+/- 6-MP) of continuation treatment (2x2 factorial randomized
trial). In a subset of SS-LCH (multifocal bone or isolated *CNS-Risk* lesions
(Group 2) through prolongation (6 vs. 12 months) of continuation therapy.

Children and adolescents with LCH need to be treated. Treatment is based on the
different strata as named in the background and in the protocol. The protocol
is the internationally accepted guideline for treatment of children with LCH.
Nevertheless safety guidelines are reported in the protocol. There will be no
extra interventions apart from the standard interventions as described in the
protocol.