title: Lenalidomide-induced upregulation of CD80 on tumor cells correlates with T-cell activation, the rapid onset of a cytokine release syndrome and leukemic cell clearance in chronic lymphocytic leukemia.
abstract: BACKGROUND
  In chronic lymphocytic leukemia lenalidomide causes striking immune activation, possibly leading to clearance of tumor cells. We conducted this study to investigate the mechanism of action of lenalidomide and the basis for its unique toxicities in chronic lymphocytic leukemia.
  
  
  METHODS
  Patients with relapsed chronic lymphocytic leukemia were treated with lenalidomide 20 mg (n=10) or 10 mg (n=8) daily for 3 weeks on a 6-week cycle. Correlative studies assessed expression of co-stimulatory molecules on tumor cells, T-cell activation, cytokine levels, and changes in lymphocyte subsets.
  
  
  RESULTS
  Lenalidomide upregulated the co-stimulatory molecule CD80 on chronic lymphocytic leukemia and mantle cell lymphoma cells but not on normal peripheral blood B cells in vitro. T-cell activation was apparent in chronic lymphocytic leukemia, weak in mantle cell lymphoma, but absent in normal peripheral blood mononuclear cells and correlated with the upregulation of CD80 on B cells. Strong CD80 upregulation and T-cell activation predicted more severe side effects, manifesting in 83% of patients as a cytokine release syndrome within 8-72 h after the first dose of lenalidomide. Serum levels of various cytokines, including tumor necrosis factor-alpha, increased during treatment. CD80 upregulation on tumor cells correlated with rapid clearance of leukemic cells from the peripheral blood. In contrast, neither the severity of the cytokine release syndrome nor the degree of T-cell activation in vitro correlated with clinical response.
  
  
  CONCLUSIONS
  Upregulation of CD80 on tumor cells and T-cell activation correlate with unique toxicities of lenalidomide in chronic lymphocytic leukemia. However, T-cell activation appears to be dispensable for the drug's anti-tumor effects. This provides a rationale for combinations of lenalidomide with fludarabine or alemtuzumab.
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute/NIH, 10 Center Drive, Bethesda, MD 20892-1202, USA.
authors.forename: Georg
authors.initials: G
authors.lastname: Aue
authors.forename: Ndegwa
authors.initials: N
authors.lastname: Njuguna
authors.forename: Xin
authors.initials: X
authors.lastname: Tian
authors.forename: Susan
authors.initials: S
authors.lastname: Soto
authors.forename: Thomas
authors.initials: T
authors.lastname: Hughes
authors.forename: Berengere
authors.initials: B
authors.lastname: Vire
authors.forename: Keyvan
authors.initials: K
authors.lastname: Keyvanfar
authors.forename: Federica
authors.initials: F
authors.lastname: Gibellini
authors.forename: Janet
authors.initials: J
authors.lastname: Valdez
authors.forename: Carol
authors.initials: C
authors.lastname: Boss
authors.forename: Leigh
authors.initials: L
authors.lastname: Samsel
authors.forename: J Philip
authors.initials: JP
authors.lastname: McCoy
authors.forename: Wyndham H
authors.initials: WH
authors.lastname: Wilson
authors.forename: Stefania
authors.initials: S
authors.lastname: Pittaluga
authors.forename: Adrian
authors.initials: A
authors.lastname: Wiestner
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D018122:B7-1 Antigen / Q000096:biosynthesis*; D016207:Cytokines / Q000378:metabolism*; D005260:Female; D006801:Humans; D000077269:Lenalidomide; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000187:drug effects*; D008297:Male; D008875:Middle Aged; D013577:Syndrome; D013792:Thalidomide / Q000008:administration & dosage / Q000031:analogs & derivatives*; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D000970:Antineoplastic Agents; D018122:B7-1 Antigen; D016207:Cytokines; D013792:Thalidomide; D000077269:Lenalidomide