title: A multicenter phase II study of single-agent enzastaurin in previously treated Waldenstrom macroglobulinemia.
abstract: OBJECTIVE
  Enzastaurin is a serine/threonine kinase inhibitor that showed antiangiogenic, antiproliferative, and proapoptotic properties in vitro and antitumor activity in vivo in a xenograft Waldenström macroglobulinemia (WM) model. These findings provided the rationale for a multicenter phase II trial of oral enzastaurin in previously treated patients with WM.
  
  
  METHODS
  Patients who were treated with 1 to 5 prior regimens and who had a baseline immunoglobulin M level 2 times or more the upper limit of normal received oral enzastaurin 250 mg twice daily (500 mg total) after a single loading dose (day 1, cycle 1) of 375 mg 3 times daily (1,125 mg total) for 8 cycles of 28 days each or until progressive disease. Six patients who progressed during treatment with enzastaurin had dexamethasone added per protocol.
  
  
  RESULTS
  From July 2008 to December 2010, 42 patients were enrolled. The objective response rate (RR) was 38.1% (2 partial and 14 minor responses). One patient had grade 3 leukopenia and one patient died during the study from septic shock; both events were considered drug related. A statistically significant association between RR and interleukin 15 (IL-15) was observed, suggesting that higher concentration levels of IL-15 may be associated with better response.
  
  
  CONCLUSIONS
  Enzastaurin was active and well tolerated in previously treated patients with WM. Because of the small sample size of this uncontrolled study, further assessment of the relationship between IL-15 and response to enzastaurin in patients with WM is required. These results warrant further investigation of enzastaurin for the treatment of WM.
authors.affiliation: Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA. irene_ghobrial@dfci.harvard.edu
authors.forename: Irene M
authors.initials: IM
authors.lastname: Ghobrial
authors.forename: Philippe
authors.initials: P
authors.lastname: Moreau
authors.forename: Brianna
authors.initials: B
authors.lastname: Harris
authors.forename: Tiffany
authors.initials: T
authors.lastname: Poon
authors.forename: Eric
authors.initials: E
authors.lastname: Jourdan
authors.forename: Hervé
authors.initials: H
authors.lastname: Maisonneuve
authors.forename: Karim A
authors.initials: KA
authors.lastname: Benhadji
authors.forename: Anwar M
authors.initials: AM
authors.lastname: Hossain
authors.forename: Tuan S
authors.initials: TS
authors.lastname: Nguyen
authors.forename: James E
authors.initials: JE
authors.lastname: Wooldridge
authors.forename: Veronique
authors.initials: V
authors.lastname: Leblond
mesh_terms: D000284:Administration, Oral; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007075:Immunoglobulin M / Q000097:blood; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D057170:Translational Research, Biomedical; D016896:Treatment Outcome; D008258:Waldenstrom Macroglobulinemia / Q000188:drug therapy*
chemical_list: D000970:Antineoplastic Agents; D007075:Immunoglobulin M; D007211:Indoles; C504878:enzastaurin