Raphaela Schwentner1, Alexandra Kolenová2, Gunhild Jug1, Thomas Schnöller1, Martina Ahlmann3, Bernhard Meister4, Thomas Lehrnbecher5, Milen Minkov1, Caroline Hutter6. 1. Children's Cancer Research Institute, St. Anna Kinderkrebsforschung, Vienna, Austria. 2. Department of Pediatric Hematology and Oncology, Comenius University Medical School and University Children's Hospital, Bratislava, Slovak Republic. 3. Department of Pediatric Hematology and Oncology, University Children's Hospital Münster, Münster, Germany. 4. Department of Pediatrics I, Medical University of Innsbruck, Innsbruck, Austria. 5. Division of Pediatric Hematology and Oncology, Hospital for Children and Adolescents, Johann Wolfgang Goethe-University, Frankfurt, Germany. 6. Children's Cancer Research Institute, St. Anna Kinderkrebsforschung, Vienna, Austria. caroline.hutter@stanna.at.
Abstract
BACKGROUND: Langerhans cell histiocytosis (LCH) is a histiocytic disorder driven by a constitutive activation of the MAPK signaling pathway in myeloid cells. In 50-60% of cases, it is caused by the BRAFV600E mutation. There is evidence that levels of BRAFV600E in the peripheral blood of patients with LCH correlate with disease burden and could be used as marker for disease extent and response to therapy. However, there is currently no consensus on how testing for minimal disseminated disease should be performed. METHODS: Different approaches to determine the mutation load in patients with LCH were assessed and longitudinal evaluation of patient DNA during treatment with chemotherapy and/or the RAF inhibitor vemurafenib was performed. DNA was isolated from whole blood, different leukocyte subsets, and circulating cell-free DNA (ccf-DNA). RESULTS: We show that determining BRAF levels from whole blood is superior to using ccfDNA. Furthermore, it is important to identify the clinically relevant BRAF-mutated cellular subpopulations such as CD14+ monocytes or CD1c+ DCs, since other blood cells can also harbor the mutation and therefore confound whole blood or ccfDNA measurements. CONCLUSION: Our data support the view that single-agent treatment with an RAF inhibitor reduces disease activity but does not cure LCH.
BACKGROUND: Langerhans cell histiocytosis (LCH) is a histiocytic disorder driven by a constitutive activation of the MAPK signaling pathway in myeloid cells. In 50-60% of cases, it is caused by the BRAFV600E mutation. There is evidence that levels of BRAFV600E in the peripheral blood of patients with LCH correlate with disease burden and could be used as marker for disease extent and response to therapy. However, there is currently no consensus on how testing for minimal disseminated disease should be performed. METHODS: Different approaches to determine the mutation load in patients with LCH were assessed and longitudinal evaluation of patient DNA during treatment with chemotherapy and/or the RAF inhibitor vemurafenib was performed. DNA was isolated from whole blood, different leukocyte subsets, and circulating cell-free DNA (ccf-DNA). RESULTS: We show that determining BRAF levels from whole blood is superior to using ccfDNA. Furthermore, it is important to identify the clinically relevant BRAF-mutated cellular subpopulations such as CD14+ monocytes or CD1c+ DCs, since other blood cells can also harbor the mutation and therefore confound whole blood or ccfDNA measurements. CONCLUSION: Our data support the view that single-agent treatment with an RAF inhibitor reduces disease activity but does not cure LCH.
Authors: Florian Halbritter; Matthias Farlik; Raphaela Schwentner; Gunhild Jug; Nikolaus Fortelny; Thomas Schnöller; Hanja Pisa; Linda C Schuster; Andrea Reinprecht; Thomas Czech; Johannes Gojo; Wolfgang Holter; Milen Minkov; Wolfgang M Bauer; Ingrid Simonitsch-Klupp; Christoph Bock; Caroline Hutter Journal: Cancer Discov Date: 2019-07-25 Impact factor: 39.397
Authors: Jean Donadieu; Islam Amine Larabi; Mathilde Tardieu; Johannes Visser; Caroline Hutter; Elena Sieni; Nabil Kabbara; Mohamed Barkaoui; Jean Miron; François Chalard; Paul Milne; Julien Haroche; Fleur Cohen; Zofia Hélias-Rodzewicz; Nicolas Simon; Mathilde Jehanne; Alexandra Kolenova; Anne Pagnier; Nathalie Aladjidi; Pascale Schneider; Geneviève Plat; Anne Lutun; Anne Sonntagbauer; Thomas Lehrnbecher; Alina Ferster; Viktoria Efremova; Martina Ahlmann; Laurence Blanc; James Nicholson; Anne Lambilliote; Houda Boudiaf; Andrej Lissat; Karel Svojgr; Fanette Bernard; Sarah Elitzur; Michal Golan; Dmitriy Evseev; Michael Maschan; Ahmed Idbaih; Olga Slater; Milen Minkov; Valerie Taly; Matthew Collin; Jean-Claude Alvarez; Jean-François Emile; Sébastien Héritier Journal: J Clin Oncol Date: 2019-09-12 Impact factor: 44.544