Clinical Sience

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.



Basic Sience

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.