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LCH is a rare disease of the myeloid cells 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: 1) single-system LCH (involvement of a single organ or system), and 2) multisystem LCH (involvement of two 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 unfavorable 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).


  • 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 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.


St. Anna Kinderkrebsforschung, Children's Cancer Research Institute, Vienna, Austria

St. Jude Children's Research Hospital, Memphis, TN USA

Milen Minkov, MD, PhD, Chair
St. Anna Kinderkrebsforschung, Children's Cancer Research Institute, Vienna, Austria

Carlos Rodriguez-Galindo, MD, Co-Chair
​St. Jude Children's Research Hospital, Memphis, TN USA

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