title: A phase I/II study of rituximab and etanercept in patients with chronic lymphocytic leukemia and small lymphocytic lymphoma.
abstract: Rituximab has modest activity in relapsed chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma but is associated with tumor necrosis factor-alpha (TNF-alpha) release that can cause CLL proliferation and inhibit apoptosis. We examined whether disruption of TNF-alpha by etanercept improves response to rituximab in CLL. Eligible patients had previously treated CLL with performance status 0-3. Patients received etanercept 25 mg subcutaneously twice weekly (weeks 1-5) and rituximab 375 mg/m(2) intravenously thrice weekly (weeks 2-5) using a phase I/II design. Primary end points were response and toxicity. The 36 enrolled patients had a median of two prior treatments; 50% were fludarabine refractory and 22% had del(17p13.1). Of the 34 response-evaluable patients, 10 (29%) responded, including 9 partial responses and 1 complete remission. Response was not affected by prior rituximab or fludarabine-refractory status, but no patients with del(17p13.1) responded. Median progression-free survival for responders was 9.0 months (range 1-43). Ten patients have had treatment-free intervals exceeding 12 months, including four who have remained untreated for 32, 43, 46 and 56 months. Adverse events were mild, including mild infusion reactions, transient cytopenias and grade 3 infections in 14% of the patients. The combination of etanercept and thrice weekly rituximab produces durable remissions in non-del(17p13.1) CLL patients and is well tolerated.
authors.affiliation: Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Woyach
authors.forename: T S
authors.initials: TS
authors.lastname: Lin
authors.forename: M S
authors.initials: MS
authors.lastname: Lucas
authors.forename: N
authors.initials: N
authors.lastname: Heerema
authors.forename: M E
authors.initials: ME
authors.lastname: Moran
authors.forename: C
authors.initials: C
authors.lastname: Cheney
authors.forename: D M
authors.initials: DM
authors.lastname: Lucas
authors.forename: L
authors.initials: L
authors.lastname: Wei
authors.forename: M A
authors.initials: MA
authors.lastname: Caligiuri
authors.forename: J C
authors.initials: JC
authors.lastname: Byrd
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D058846:Antibodies, Monoclonal, Murine-Derived; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm; D000068800:Etanercept; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000008:administration & dosage; D055104:Infusions, Subcutaneous; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009367:Neoplasm Staging; D011379:Prognosis; D018124:Receptors, Tumor Necrosis Factor / Q000008:administration & dosage; D012074:Remission Induction; D000069283:Rituximab; D016879:Salvage Therapy; D015996:Survival Rate; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism; D014740:Vidarabine / Q000008:administration & dosage / Q000031:analogs & derivatives
chemical_list: D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D007074:Immunoglobulin G; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D000069283:Rituximab; D014740:Vidarabine; D000068800:Etanercept; C024352:fludarabine