The LCH Study Center
- Prof. Dr. Wolfgang Holter, Medical Director St. Anna Children's Hospital, Director Children's Cancer Research Institute
- Prof. Dr. Milen Minkov, Study Chair LCH IV, Team Leader LCH Study Center
- Elfriede Thiem, Msc, Study Assistant
- Ulrike Pötschger, Msc, Statistician
- Evgenia Glogova, Msc, Statistician
- Prim. Dr. Karoly Lakatos, Radiologist
- DDr. Caroline Hutter, Molecular Biologist, Pediatrician, Oncology Dep. St. Anna Children's Hospital
Prof. Dr. Wolfgang Holter, Dr. Bernhard Fahrner, DDr. Caroline Hutter, Prof. Dr. Milen Minkov
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, the hematopoietic system, or central nervous system (CNS). Accordingly, the range of clinical symptoms is wide. There are two widely recognized disease extent categories: single-system LCH (SS-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. MS-LCH patients without involvement of “risk organs” have an excellent survival probability (>95%) when treated with a standard regimen consisting of vinblastine and steroids. In contrast, involvement of risk organs carries the risk of unfavourable outcome, particularly when combined with non-response to initial treatment.
Patients with reactivations or chronic disease may experience severe permanent consequences (hormone deficiencies, a neurodegenerative syndrome, lung fibrosis, etc.) reducing the patient’s quality of life.
The Study Center
In its role as international study reference center and sponsor the LCH-study team is collaborating with the international study committee responsible for the design and conduct of the study and the dissemination of the final results. In addition to scientific and medical expertise, specialized knowledge in the methodological, administrative, technical, and regulatory background of clinical trials is required.
Major tasks need to be performed at any stage of a clinical trial:
- Prior to the initiation of a study
consensus on aims, end-points and study design; protocol-writing; design of the case report forms; approval from regulatory authorities and ethic committees, contracts with participating national groups and study sites
- During an on-going study
data collection and data quality control, pharmacovigilance, design and implementation of amendments, reporting of interim results, advising clinicians on critical diagnostic or therapeutic questions, organization of national and international meetings
- After closure study
data analysis, coordinating drafting and submission of the manuscript with the final results.
As the current LCH IV study has been started on the background of a web based database, all issues concerning this database have to be monitored and possible adjustments have to be made.
Management tasks include supervision of personal agendas, financial management, organization of national and international working group meetings as well as communication with patients and parents initiatives.
Another very important function of our center is to advise clinicians on critical diagnostic or therapeutic questions. We receive about 250-300 inquiries per year concerning difficult LCH scenarios. About 50% of these require a review of radiological images to adequately assess the individual cases.
In case of diagnostic or therapeutic questions the treating physicians are advised to ask their national or local co-ordinator first. In difficult clinical scenarios the local co-ordinator may decide to contact the study center for further advice. In order to ensure proper diagnostic workup, we encourage clinicians to contact their local co-ordinator prior to a planned biopsy if LCH is suspected in a patient.
Children`s Cancer Research Institute
LCH Study Center
Phone: +43 1 40470 4760
Fax: +43 40470 7430
Clinical studies are a prerequisite for advancing our understanding and treatment of a disease. Due to the rarity of LCH, international collaboration is of paramount importance. Since 1983 the St. Anna Children’s Cancer Research Institute has been the study reference center for the International LCH-I, LCH-II, and LCH-III clinical trials and more than 2000 LCH patients have been registered to one of those studies. Thanks to these collaborative, international studies of the past 20 years, treatment strategies for LCH have been developed and refined.
Clinical research used to focus on the treatment of multisystem LCH, due to the inferior outcome in this patient group. The international efforts of the past 15 years could prove that a combination therapy with vinblastine and prednisone is an effective therapy for multisystem LCH that is superior to monotherapy. It was demonstrated that the response to initial therapy is an important prognostic factor and that mortality is limited to “risk” patients with involvement of critical organs, such as liver, spleen, hematopoietic system or lungs. The last trial (LCH III), which started in 2001 and closed for accrual in October 2007, could show that chemotherapy with vinblastine and prednisone is an efficient standard therapy for patients with and without risk organ involvement and that prolonged treatment in low risk patients is superior in preventing disease reactivations.
Based on the encouraging results of LCH-III, LCH-IV has been designed and launched in December 2012. This study is recruiting patients in numerous countries worldwide. Prerequisite for participation in the study (among other criteria) treatment in one of the collaborating trial sites is an informed consent of patients and parents to participate in the study. The LCH-IV study seeks to tailor treatment based on features at presentation and on response to treatment, leading to different strata. Some of the primary objectives of the new study are to decrease mortality in MS-LCH, to reduce reactivation rates and permanent consequences and to investigate the value of a uniform second-line therapy.
LCH is characterized by the accumulation of eponymous CD1a+, Langerin+ dendritic cells (LCH-cells). These dendritic cells are surrounded by other cells of the immune system such as lymphocytes and eosinophils. The etiology of LCH is not known, and it is even unclear whether it is an inflammatory disorder or neoplastic disease. One major goal of our research is to characterize the LCH cells in order to better understand the pathogenesis of this disease and to provide the basis for new treatment strategies. Together with collaborators from the Medical University of Vienna we have shown that LCH cells exhibit a unique transcriptional profile that is distinct from myeloid and plasmacytoid dendritic cells, as well as Langerhans cells. In order to further understand unique features of LCH cells, we are now focusing on a number of genes we have identified to be selectively expressed in LCH cells. Among those is the Notch ligand Jagged2. Jagged2 belongs to the ligands of the Delta/Jagged family, which can activate the Notch signaling pathway by binding to Notch receptors. This pathway is a highly conserved signaling system that influences normal development and is deregulated in various human diseases. One aim of our current research is to dissect signaling pathways induced by Notch activation in LCH cells and to investigate their potential impact on LCH development.
In a translational project we are currently analyzing genetic alterations in biopsies and the peripheral blood of patients with LCH. Using next-generation sequencing, we aim to characterize genetic modifications in LCH. Furthermore, we have established a protocol to track the level of defined mutations in the peripheral blood of patients with LCH, which could in the future help to monitor disease extent and response to therapy. We invite patients and their doctors to support this initiative by providing blood or tissue samples obtained during routine diagnostic procedures. Further information can be obtained by contacting the LCH Study Center.
Litature - Further Readings
The histiocytoses: the fall of the Tower of Babel.
Arceci RJ. Eur J Cancer. 1999 May;35(5):747-67.
Therapy prolongation improves outcome in multisystem Langerhans cell histiocytosis.
Gadner H, Minkov M, Grois N, Pötschger U, Thiem E, Aricò M, Astigarraga I, Braier J, Donadieu J, Henter JI, Janka-Schaub G, McClain KL, Weitzman S, Windebank K, Ladisch S; Histiocyte Society. Blood. 2013 Jun 20;121(25):5006-14.
Improved outcome in multisystem Langerhans cell histiocytosis is associated with therapy intensification.
Helmut Gadner, Nicole Grois, Ulrike Pötschger, Milen Minkov, Maurizio Arico`, Jorge Braier, Valerie Broadbent, Jean Donadieu, Jan-Inge Henter, Robert McCarter, and Stephan Ladisch, for the Histiocyte Society. Blood. 2008 Mar 1;111(5):2556-62.
Multisystem Langerhans cell histiocytosis in children: current treatment and future directions.
Minkov M. Paediatr Drugs. 2011 Apr 1;13(2):75-86.
Langerhans cell histiocytosis: pragmatic empirism on the road to rational cure.
Minkov M. Expert Opin Pharmacother. 2012 Aug;13(12):1671-3.
Improved outcome of treatment-resistant high-risk Langerhans cell histiocytosis after allogeneic stem cell transplantation with reduced-intensity conditioning
M Steiner, S Matthes-Martin, A Attarbaschi, M Minkov, N Grois, E Unger, W Holter, J Vormoor, A Wawer, M Ouachee, W Woessmann and H Gadner. Bone Marrow Transplant. 2005 Aug;36(3):215-25.
Pulmonary involvement in pediatric-onset multisystem Langerhans cell histiocytosis: effect on course and outcome.
Ronceray L, Pötschger U, Janka G, Gadner H, Minkov M; German Society for Pediatric Hematology and Oncology, Langerhans Cell Histiocytosis Study Group. J Pediatr. 2012 Jul;161(1):129-33.e1-3.
Risk factors for diabetes insipidus in langerhans cell histiocytosis.
Grois N, Pötschger U, Prosch H, Minkov M, Arico M, Braier J, Henter JI, Janka-Schaub G, Ladisch S, Ritter J, Steiner M, Unger E, Gadner H; DALHX- and LCH I and II Study Committee. Pediatr Blood Cancer. 2006 Feb;46(2):228-33.
Long-term outcome of hypothalamic pituitary tumors in Langerhans cell histiocytosis.
Fahrner B, Prosch H, Minkov M, Krischmann M, Gadner H, Prayer D, Grois N. Pediatr Blood Cancer. 2012 Apr;58(4):606-10.
Central Nervous System Disease in Langerhans Cell Histiocytosis
Nicole Grois, MD, PhD, Bernhard Fahrner, MD, Robert J. Arceci, MD, PhD, Jan-Inge Henter, MD, PhD, Kenneth McClain, MD, PhD, Hans Lassmann, MD, PhD, Vasanta Nanduri, MD, MRCP, FRCPCH, Helmut Prosch, MD, and Daniela Prayer, MD, PhD or the Histiocyte Society CNS LCH Study Group. J Pediatr. 2010 Jun;156(6):873-81, 881.
Bone marrow assessment in Langerhans cell histiocytosis.
Minkov M, Pötschger U, Grois N, Gadner H, Dworzak MN. Pediatr Blood Cancer. 2007 Oct 15;49(5):694-8.
Neuropathology of CNS disease in Langerhans cell histiocytosis
Nicole Grois, Daniela Prayer, Helmut Prosch, Hans Lassmann and the CNS LCH Co-operative Group. Brain. 2005 Apr;128(Pt 4):829-38.
Notch is active in Langerhans cell histiocytosis and confers pathognomonic features on dendritic cells
Caroline Hutter, Max Kauer, Ingrid Simonitsch-Klupp, Gunhild Jug, Raphaela Schwentner, Judith Leitner, Peter Bock, Peter Steinberger, Wolfgang Bauer, Nadia Carlesso, Milen Minkov, Helmut Gadner, Georg Stingl, Heinrich Kovar, and Ernst Kriehuber. Blood. 2012 Dec 20;120(26):5199-208.
BRAF, a piece of the LCH puzzle
Kim E. Nichols and Robert J. Arceci. Blood. 2010 Sep 16;116(11):1825-7.
Recurrent BRAF mutations in Langerhans cell histiocytosis.
Badalian-Very G, Vergilio JA, Degar BA, MacConaill LE, Brandner B, Calicchio ML, Kuo FC, Ligon AH, Stevenson KE, Kehoe SM, Garraway LA, Hahn WC, Meyerson M, Fleming MD, Rollins BJ. Blood. 2010 Sep 16;116(11):1919-23.