Advanced systemic mastocytosis: from molecular and genetic progress to clinical practice.
Systemic mastocytosis is a heterogeneous disease characterized by the accumulation of neoplastic mast cells in the bone marrow and other organ organs/tissues. Mutations in KIT, most frequently KIT D816V, are detected in over 80% of all systemic mastocytosis patients. While most systemic mastocytosis patients suffer from an indolent disease variant, some present with more aggressive variants, collectively called "advanced systemic mastocytosis", which include aggressive systemic mastocytosis, systemic mastocytosis with an associated hematologic, clonal non mast cell-lineage disease, and mast cell leukemia. Whereas patients with indolent systemic mastocytosis have a near normal life expectancy, patients with advanced systemic mastocytosis have a reduced life expectancy. Although cladribine and interferon-alpha are of benefit in a group of patients with advanced systemic mastocytosis, no curative therapy is available for these patients except possible allogeneic hematopoietic stem cell transplantation. Recent studies have also revealed additional somatic defects (apart from mutations in KIT) in a majority of patients with advanced systemic mastocytosis. These include TET2, SRSF2, ASXL1, RUNX1, JAK2, and/or RAS mutations, which may adversely impact prognosis and survival in particular systemic mastocytosis with an associated hematological neoplasm. In addition, several additional signaling molecules involved in the abnormal proliferation of mast cells in systemic mastocytosis have been identified. These advances have led to a better understanding of the biology of advanced systemic mastocytosis and to the development of new targeted treatment concepts. Herein, we review the biology and pathogenesis of advanced systemic mastocytosis, with a special focus on novel molecular findings as well as current and evolving therapeutic options.
Department of Medicine, Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, MN, USA custun@umn.edu.
Celalettin
C
Ustun
Molecular and Cellular Oncology, LBPA CNRS UMR8113, Ecole Normale Supérieure de Cachan, France Laboratory of Hematology, Pitié-Salpêtrière Hospital, Pierre et Marie Curie Paris VI University, France.
Michel
M
Arock
Department of Hematology, University Medical Center Groningen, University of Groningen, The Netherlands.
Hanneke C
HC
Kluin-Nelemans
Department of Hematology and Oncology, University Medical Centre Mannheim, Germany.
Andreas
A
Reiter
Department of Internal Medicine I, Division of Hematology & Hemostaseology, Medical University of Vienna, Austria Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Austria.
Wolfgang R
WR
Sperr
Hematopathology Division, University of New Mexico and TriCore Reference Laboratories, Albuquerque, NM, USA.
Tracy
T
George
Institute of Pathology, Ludwig-Maximilians-University, Munich, Germany.
Hans-Peter
HP
Horny
Department of Dermatology, University of Cologne, Germany; Department of Dermatology, University of Luebeck, Germany.
Karin
K
Hartmann
Institute of Pathology, Ludwig-Maximilians-University, Munich, Germany.
Karl
K
Sotlar
Department of Clinical Hematology, Caen University Hospital, France.
Gandhi
G
Damaj
Clinical Hematology Department, Faculty of Medicine and AP-HP Necker-Enfants Malades, Paris Descartes University, France Faculty of Medicine and AP-HP Necker-Enfants Malades, Mastocytosis Reference Center, Paris, France.
Olivier
O
Hermine
Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Srdan
S
Verstovsek
Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD, USA.
Dean D
DD
Metcalfe
Division of Hematology, Stanford Cancer Institute, CA, USA.
Jason
J
Gotlib
Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Cem
C
Akin
Department of Internal Medicine I, Division of Hematology & Hemostaseology, Medical University of Vienna, Austria Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Austria.
Peter
P
Valent
D019337:Hematologic Neoplasms; D006801:Humans; D008407:Mast Cells / Q000473:pathology; D034721:Mastocytosis, Systemic / Q000235:genetics / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D058990:Molecular Targeted Therapy / Q000379:methods*; D009154:Mutation