title: Clinical end points for drug treatment trials in BCR-ABL1-negative classic myeloproliferative neoplasms: consensus statements from European LeukemiaNET (ELN) and Internation Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT).
abstract: The discovery of somatic mutations, primarily JAK2V617F and CALR, in classic BCR-ABL1-negative myeloproliferative neoplasms (MPNs) has generated interest in the development of molecularly targeted therapies, whose accurate assessment requires a standardized framework. A working group, comprised of members from European LeukemiaNet (ELN) and International Working Group for MPN Research and Treatment (IWG-MRT), prepared consensus-based recommendations regarding trial design, patient selection and definition of relevant end points. Accordingly, a response able to capture the long-term effect of the drug should be selected as the end point of phase II trials aimed at developing new drugs for MPNs. A time-to-event, such as overall survival, or progression-free survival or both, as co-primary end points, should measure efficacy in phase III studies. New drugs should be tested for preventing disease progression in myelofibrosis patients with early disease in randomized studies, and a time to event, such as progression-free or event-free survival should be the primary end point. Phase III trials aimed at preventing vascular events in polycythemia vera and essential thrombocythemia should be based on a selection of the target population based on new prognostic factors, including JAK2 mutation. In conclusion, we recommended a format for clinical trials in MPNs that facilitates communication between academic investigators, regulatory agencies and drug companies.
authors.affiliation: Center for the Study of Myelofibrosis, Biotechnology Research Area, IRCCS Policlinico S. Matteo Foundation, Pavia, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Barosi
authors.affiliation: Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: A
authors.initials: A
authors.lastname: Tefferi
authors.affiliation: Department of Haematology, Hospital del Mar-IMIM, Barcelona, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Besses
authors.affiliation: Department of Haematology, Uppsala University Hospital, Uppsala, Sweden.
authors.forename: G
authors.initials: G
authors.lastname: Birgegard
authors.affiliation: Hospital Clínic, IDIBAPS, University of Barcelona, Barcelona, Spain.
authors.forename: F
authors.initials: F
authors.lastname: Cervantes
authors.affiliation: Division of Hematology, Papa Giovanni XXIII Hospital, Bergamo, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Finazzi
authors.affiliation: Department of Hematology, Medical University of Vienna, Vienna, Austria.
authors.forename: H
authors.initials: H
authors.lastname: Gisslinger
authors.affiliation: Academic Department of Hematology and Oncology, Johannes Wesling Teaching Hospital, Minden, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Griesshammer
authors.affiliation: Department of Haematology, Guy's and St Thomas' NHS Foundation Trust, London, UK.
authors.forename: C
authors.initials: C
authors.lastname: Harrison
authors.affiliation: III Medizinische Universitätsklinik, Medizinische Fakultät Mannheim der Universität Heidelberg, Mannheim, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Hehlmann
authors.affiliation: 1] Inserm UMR 892, Institut de Recherche en Santé, Université de Nantes, Nantes, France [2] Chair of MPN&MPNr-EuroNet, Institut de Recherche en Santé, Université de Nantes, Nantes, France.
authors.forename: S
authors.initials: S
authors.lastname: Hermouet
authors.affiliation: Centre d'Investigations Cliniques-CIC 9504, Assistance Publique -Hôpitaux de Paris, Hôpital Saint-Louis; Université Paris 7, Paris, France.
authors.forename: J-J
authors.initials: JJ
authors.lastname: Kiladjian
authors.affiliation: Department of Stem Cell Transplantation, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Kröger
authors.affiliation: Division of Hematology and Oncology, Mayo Clinic, Scottsdale, AZ, USA.
authors.forename: R
authors.initials: R
authors.lastname: Mesa
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University, Belfast, UK.
authors.forename: M F
authors.initials: MF
authors.lastname: Mc Mullin
authors.affiliation: Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: A
authors.initials: A
authors.lastname: Pardanani
authors.affiliation: Division of Hematology, Ospedale di Circolo di Varese, Varese, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Passamonti
authors.affiliation: Department of Medicine Stockholm South Hospital, Karolinska Institute, Stockholm, Sweden.
authors.forename: J
authors.initials: J
authors.lastname: Samuelsson
authors.affiliation: Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
authors.forename: A M
authors.initials: AM
authors.lastname: Vannucchi
authors.affiliation: III Medizinische Universitätsklinik, Medizinische Fakultät Mannheim der Universität Heidelberg, Mannheim, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Reiter
authors.affiliation: Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York, NY, USA.
authors.forename: R T
authors.initials: RT
authors.lastname: Silver
authors.affiliation: Department of Leukemia, University of Texas, M.D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: S
authors.initials: S
authors.lastname: Verstovsek
authors.affiliation: Consorzio Mario Negri Sud, Santa Maria Imbaro, Chieti, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Tognoni
authors.affiliation: Division of Hematology, Papa Giovanni XXIII Hospital, Bergamo, Italy.
authors.forename: T
authors.initials: T
authors.lastname: Barbui
mesh_terms: D023381:Endpoint Determination; D016044:Fusion Proteins, bcr-abl / Q000235:genetics*; D006801:Humans; D009196:Myeloproliferative Disorders / Q000188:drug therapy* / Q000235:genetics; D011379:Prognosis
chemical_list: C581634:BCR-ABL1 fusion protein, human; D016044:Fusion Proteins, bcr-abl