title: Nilotinib in patients with systemic mastocytosis: analysis of the phase 2, open-label, single-arm nilotinib registration study.
abstract: OBJECTIVE
  Activating KIT mutations are part of the pathogenesis of systemic mastocytosis (SM). Nilotinib is a tyrosine kinase inhibitor that potently inhibits activated forms of KIT. This phase 2, open-label, single-arm study (CAMN107A2101; www.clinicaltrials.gov NCT00109707) evaluated nilotinib in patients with SM.
  
  
  METHODS
  Patients with SM [aggressive SM (ASM), indolent SM, or other] received nilotinib 400 mg twice daily. C-findings were collected retrospectively to assess response using criteria proposed after trial initiation. Response was evaluated using improvements in laboratory findings (for all patients) and ASM response criteria (for the ASM subgroup).
  
  
  RESULTS
  In 61 patients enrolled, the median nilotinib exposure was 232 days (range 3-1274 days) with a median follow-up of 34.7 months. In patients with ASM (n = 37), the overall response rate was 21.6 %. In the eight responders, all of whom had a KIT D816V mutation at any time, mast cell infiltration and tryptase level decreased by 70 % and 29.8 %, respectively; absolute neutrophil count increased by 94.7 %. Laboratory parameters also improved in the non-ASM subgroups. Overall survival at 24 months was 81.2 % (95 % CI 70.6-91.8 %) with median survival not yet reached. New or worsening grade 3/4 hematologic adverse events (AEs) included thrombocytopenia (10.3 %), anemia (10.0 %), and neutropenia (6.9 %). The most common grade 3/4 nonhematologic drug-related AEs were diarrhea (6.6 %) and headache (4.9 %). Eleven patients (9 with ASM, 2 with MCL) died, 10 due to progressive disease; 7 deaths occurred ≥28 days after treatment discontinuation.
  
  
  CONCLUSIONS
  Nilotinib 400 mg twice daily was effective in some patients with SM, including patients with mutated KIT D816V.
authors.affiliation: Abteilung für Hämatologie und Internistische Onkologie, Universitätsklinikum Jena, Erlanger Allee 101, 07740, Jena, Germany. andreas.hochhaus@med.uni-jena.de.
authors.forename: Andreas
authors.initials: A
authors.lastname: Hochhaus
authors.affiliation: University of Bologna, Bologna, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Baccarani
authors.affiliation: Northwestern Medicine Developmental Therapeutics Institute, Chicago, IL, USA.
authors.forename: Francis J
authors.initials: FJ
authors.lastname: Giles
authors.affiliation: Charité - University of Medicine Berlin, Berlin, Germany.
authors.forename: Philipp D
authors.initials: PD
authors.lastname: le Coutre
authors.affiliation: Medizinische Universitätsklinik, Medizinische Fakultät Mannheim der Universität Heidelberg, Mannheim, Germany.
authors.forename: Martin C
authors.initials: MC
authors.lastname: Müller
authors.affiliation: Medizinische Universitätsklinik, Medizinische Fakultät Mannheim der Universität Heidelberg, Mannheim, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Reiter
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
authors.forename: Helene
authors.initials: H
authors.lastname: Santanastasio
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
authors.forename: Mimi
authors.initials: M
authors.lastname: Leung
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Novick
authors.affiliation: The University of Texas, MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Hagop M
authors.initials: HM
authors.lastname: Kantarjian
mesh_terms: D000328:Adult; D000368:Aged; D005260:Female; D006801:Humans; D007958:Leukocyte Count; D008297:Male; D034721:Mastocytosis, Systemic / Q000188:drug therapy* / Q000401:mortality; D008875:Middle Aged; D009196:Myeloproliferative Disorders / Q000188:drug therapy* / Q000401:mortality; D009504:Neutrophils / Q000276:immunology; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D019009:Proto-Oncogene Proteins c-kit / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000009:adverse effects / Q000627:therapeutic use*; D012189:Retrospective Studies; D016896:Treatment Outcome
chemical_list: D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011505:Protein-Tyrosine Kinases; D019009:Proto-Oncogene Proteins c-kit; C498826:nilotinib
keywords: Aggressive systemic mastocytosis; Indolent systemic mastocytosis; KIT D816V; Nilotinib; Systemic mastocytosis; Tyrosine kinase inhibitor