title: Bortezomib therapy in patients with relapsed or refractory lymphoma: potential correlation of in vitro sensitivity and tumor necrosis factor alpha response with clinical activity.
abstract: OBJECTIVE
  To determine the efficacy of bortezomib in patients with lymphoid malignancy, correlating clinical response with effect on plasma cytokines and in vitro activity in primary cultures.
  
  
  METHODS
  Patients received bortezomib (1.3 mg/m2) on days 1, 4, 8, and 11 of a 3-week cycle. Plasma tumor necrosis factor alpha (TNF-alpha) and interleukin-6 were measured before each treatment, and bortezomib activity was examined in patient samples grown in primary culture.
  
  
  RESULTS
  Fifty-one patients received a total of 193 cycles of treatment. Twenty-four patients had mantle cell lymphoma (MCL), 13 had follicular lymphoma (FL), six had lymphoplasmacytic lymphoma, six had Hodgkin's disease (HD), and one each had diffuse large B-cell lymphoma and adult T-cell leukemia/lymphoma. Patients were heavily pretreated with a median of four previous therapies. Significant grade 3 to 4 toxicities were thrombocytopenia (n = 22), fatigue (n = 10), and peripheral neuropathy (n = 3). Seven patients with MCL responded to treatment (one complete response, six partial responses [PRs]; overall response rate, 29%). Two patients with FL achieved a late PR 3 months after discontinuing therapy. Two patients with Waldenström's macroglobulinemia and one patient with HD achieved a PR. MCL primary cultures demonstrated greater sensitivity to bortezomib than FL (median 50% effective concentration for viability, 209 nmol/L v 1,311 nmol/L, respectively; P = .07), which correlated with clinical response. A median reduction in plasma TNF-alpha of 98% was observed in six patients with MCL who responded to bortezomib compared with a reduction of 38% in six nonresponders (P = .07).
  
  
  CONCLUSIONS
  Bortezomib demonstrates encouraging efficacy in MCL in heavily pretreated individuals. Response was associated with a reduction in plasma TNF-alpha and in vitro sensitivity in a small number of patients.
authors.affiliation: Cancer Research UK Medical Oncology Unit, St Bartholomew's Hospital, W Smithfield, London, United Kingdom.
authors.forename: Sandra J
authors.initials: SJ
authors.lastname: Strauss
authors.forename: Lenushka
authors.initials: L
authors.lastname: Maharaj
authors.forename: Susan
authors.initials: S
authors.lastname: Hoare
authors.forename: Peter W
authors.initials: PW
authors.lastname: Johnson
authors.forename: John A
authors.initials: JA
authors.lastname: Radford
authors.forename: Sarah
authors.initials: S
authors.lastname: Vinnecombe
authors.forename: Lynda
authors.initials: L
authors.lastname: Millard
authors.forename: Ama
authors.initials: A
authors.lastname: Rohatiner
authors.forename: Anthony
authors.initials: A
authors.lastname: Boral
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Trehu
authors.forename: David
authors.initials: D
authors.lastname: Schenkein
authors.forename: Frances
authors.initials: F
authors.lastname: Balkwill
authors.forename: Simon P
authors.initials: SP
authors.lastname: Joel
authors.forename: T Andrew
authors.initials: TA
authors.lastname: Lister
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001897:Boronic Acids / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D000069286:Bortezomib; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000097:blood; D004317:Doxorubicin / Q000494:pharmacology; D005260:Female; D006801:Humans; D008223:Lymphoma / Q000188:drug therapy* / Q000276:immunology; D008297:Male; D008875:Middle Aged; D011719:Pyrazines / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D012008:Recurrence; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis*
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D016207:Cytokines; D011719:Pyrazines; D014409:Tumor Necrosis Factor-alpha; D000069286:Bortezomib; D004317:Doxorubicin