title: A phase 1 dose escalation study of bortezomib combined with rituximab, cyclophosphamide, doxorubicin, modified vincristine, and prednisone for untreated follicular lymphoma and other low-grade B-cell lymphomas.
abstract: BACKGROUND
  Bortezomib has demonstrated efficacy in patients with relapsed B-cell non-Hodgkin lymphoma (NHL) both alone and in combination with other agents; however, limited data exist regarding its toxicity in combination with common frontline therapies for indolent NHL. A phase 1 study of bortezomib combined with rituximab, cyclophosphamide, doxorubicin, modified vincristine, and prednisone (R-CHOP) was conducted in patients with untreated follicular lymphoma (FL) and other indolent NHLs.
  
  
  METHODS
  Nineteen patients, including 10 patients with FL, were enrolled. The median patient age was 59 years (range, 29-71 years). Seven patients had a FL International Prognostic Index score ≥3. R-CHOP with the vincristine dose capped at 1.5 mg was administered on a 21-day cycle for 6 to 8 cycles, and 1 of 3 dose levels of bortezomib (1.0 mg/m(2) [n = 1], 1.3 mg/m(2) [n = 6], or 1.6 mg/m(2) [n = 12]) was administered on days 1 and 8 of each cycle using a Bayesian algorithm for dose escalation.
  
  
  RESULTS
  The maximum tolerated dose (MTD) of bortezomib with modified R-CHOP was reached at 1.6 mg/m(2). Dose-limiting toxicity was observed in 5 patients (1 patient at a bortezomib dose of 1.0 mg/m(2), 1 patient at a bortezomib dose of 1.3 mg/m(2), and 3 patients at a bortezomib dose of 1.6 mg/m(2)). Neuropathy occurred in 16 patients (84%), including 2 patients (11%) who experienced grade 3 sensory neuropathy. Grade 4 hematologic toxicity occurred in 4 patients. Of 19 evaluable patients, 100% responded, and the complete response rate was 68%. At a median follow-up of 32 months, the 3-year progression-free survival rate was 89.5%.
  
  
  CONCLUSIONS
  Bortezomib combined with modified R-CHOP produced high response rates without substantial increases in toxicity. A phase 2 study of R-CHOP and bortezomib given at this established MTD is currently ongoing.
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University-School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Rajni
authors.initials: R
authors.lastname: Sinha
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Kaufman
authors.forename: Hanna Jean
authors.initials: HJ
authors.lastname: Khoury
authors.forename: Nassoma
authors.initials: N
authors.lastname: King
authors.forename: Pareen J
authors.initials: PJ
authors.lastname: Shenoy
authors.forename: Carol
authors.initials: C
authors.lastname: Lewis
authors.forename: Kevin
authors.initials: K
authors.lastname: Bumpers
authors.forename: Amanda
authors.initials: A
authors.lastname: Hutchison-Rzepka
authors.forename: Mourad
authors.initials: M
authors.lastname: Tighiouart
authors.forename: Leonard T
authors.initials: LT
authors.lastname: Heffner
authors.forename: Mary Jo
authors.initials: MJ
authors.lastname: Lechowicz
authors.forename: Sagar
authors.initials: S
authors.lastname: Lonial
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Flowers
mesh_terms: D000328:Adult; D000368:Aged; D058846:Antibodies, Monoclonal, Murine-Derived / Q000008:administration & dosage*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001897:Boronic Acids / Q000008:administration & dosage*; D000069286:Bortezomib; D003520:Cyclophosphamide / Q000009:adverse effects / Q000627:therapeutic use; D018572:Disease-Free Survival; D004317:Doxorubicin / Q000009:adverse effects / Q000627:therapeutic use; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D016393:Lymphoma, B-Cell / Q000188:drug therapy*; D008224:Lymphoma, Follicular / Q000188:drug therapy*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009431:Neural Conduction / Q000187:drug effects; D011241:Prednisone / Q000009:adverse effects / Q000627:therapeutic use; D011719:Pyrazines / Q000008:administration & dosage*; D000069283:Rituximab; D014750:Vincristine / Q000009:adverse effects / Q000627:therapeutic use
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D001897:Boronic Acids; D011719:Pyrazines; D000069283:Rituximab; D014750:Vincristine; D000069286:Bortezomib; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone