title: In vitro and in vivo growth-inhibitory effects of cladribine on neoplastic mast cells exhibiting the imatinib-resistant KIT mutation D816V.
abstract: OBJECTIVE
  In most patients with systemic mastocytosis (SM), including aggressive SM (ASM) and mast cell (MC) leukemia (MCL), neoplastic cells express the oncogenic KIT mutation D816V, which confers resistance to imatinib. Cladribine (2CdA) is a nucleoside analog that has been introduced as a promising agent for treatment of advanced SM.
  
  
  METHODS
  We examined the in vitro effects of 2CdA on growth of neoplastic MC, and the in vivo effects of 2CdA (0.13 mg/kg/day intravenously, days 1-5; three to eight cycles) in seven patients with advanced SM.
  
  
  RESULTS
  Cladribine was found to inhibit growth of primary MC and the MC line HMC-1 in a dose-dependent manner, with lower IC(50) values recorded in HMC-1.2 cells harboring KIT D816V (IC(50): 10 ng/mL) compared to HMC-1.1 cells lacking KIT D816V (IC(50): 300 ng/mL). In two patients with progressive smoldering SM, 2CdA produced a long-lasting response with a sustained decrease in serum tryptase levels, whereas in patients with progressive ASM or MCL, 2CdA showed little if any effects. The drug was well-tolerated in most cases. However, one patient developed a massive generalized purulent long-lasting skin rash. The antiproliferative effects of 2CdA on MC were found to be associated with morphologic signs of apoptosis and caspase cleavage. Cladribine did not counteract the kinase activity of KIT D816V or KIT-downstream signaling molecules.
  
  
  CONCLUSIONS
  Cladribine may be a promising agent for treatment of progressive smoldering KIT D816V(+) SM. In rapidly progressing ASM or MCL, additional or alternative drugs are required to induce long-lasting antineoplastic effects.
authors.affiliation: Department of Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Böhm
authors.forename: Karoline
authors.initials: K
authors.lastname: Sonneck
authors.forename: Karoline V
authors.initials: KV
authors.lastname: Gleixner
authors.forename: Karina
authors.initials: K
authors.lastname: Schuch
authors.forename: Winfried F
authors.initials: WF
authors.lastname: Pickl
authors.forename: Katharina
authors.initials: K
authors.lastname: Blatt
authors.forename: Barbara
authors.initials: B
authors.lastname: Peter
authors.forename: Harald
authors.initials: H
authors.lastname: Herrmann
authors.forename: Gerit-Holger
authors.initials: GH
authors.lastname: Schernthaner
authors.forename: Hubert
authors.initials: H
authors.lastname: Pehamberger
authors.forename: Werner
authors.initials: W
authors.lastname: Rabitsch
authors.forename: Wolfgang R
authors.initials: WR
authors.lastname: Sperr
authors.forename: Peter
authors.initials: P
authors.lastname: Valent
mesh_terms: D000328:Adult; D000368:Aged; D019943:Amino Acid Substitution; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001549:Benzamides; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D017338:Cladribine / Q000008:administration & dosage*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D006801:Humans; D000068877:Imatinib Mesylate; D008297:Male; D008407:Mast Cells / Q000201:enzymology* / Q000473:pathology; D034721:Mastocytosis, Systemic / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D008875:Middle Aged; D020125:Mutation, Missense; D010879:Piperazines / Q000494:pharmacology*; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology*; D053802:Tryptases / Q000097:blood
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D017338:Cladribine; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit; D053802:Tryptases; D020169:Caspases