title: Everolimus in combination with rituximab induces complete responses in heavily pretreated diffuse large B-cell lymphoma.
abstract: Diffuse large B-cell lymphoma is an aggressive non-Hodgkin's lymphoma without a standard therapy for patients who relapse after or are not eligible for salvage autologous stem cell transplantation. In vitro analysis of lymphoma cell lines has shown that everolimus can inhibit cell cycle progression in vitro and inhibitors of the mammalian target of rapamycin have already demonstrated single-agent activity in relapsed non-Hodgkin's lymphomas including diffuse large B-cell lymphoma, validating mammalian target of rapamycin as a viable therapeutic target. We performed an open label phase II study of everolimus, an inhibitor of mammalian target of rapamycin, in combination with rituximab to examine efficacy and tolerability in patients with relapsed/refractory diffuse large B-cell lymphoma. Eligible patients were treated with everolimus 10 mg by mouth once daily on days 1-28 of a 28-day cycle with rituximab administered weekly during cycle one and then on day one of subsequent cycles. Patients were treated for a total of 12 cycles or until disease progression. The primary end-point was objective response rate, with secondary end-points being toxicity, progression-free survival, duration of response, and overall survival. Twenty-six patients (24 evaluable) were enrolled and had an overall response rate of 38% [90% CI (21%-56%)] with three complete responses and six partial responses among these 24 patients. The median duration of response among responders was 8.1 months. At a median follow-up of 12 months, the overall survival rate was 37% [90% CI (20%-54%)]. The most common grade 3 to 4 toxicities were neutropenia, anemia, and thrombocytopenia. In conclusion, everolimus in combination with rituximab is well tolerated and demonstrates activity in relapsed diffuse large B-cell lymphoma. Further studies of this combination are warranted.
authors.affiliation: Massachusetts General Hospital Cancer Center, Boston, MA, USA. jabarnes@partners.org
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Barnes
authors.forename: Eric
authors.initials: E
authors.lastname: Jacobsen
authors.forename: Yang
authors.initials: Y
authors.lastname: Feng
authors.forename: Arnold
authors.initials: A
authors.lastname: Freedman
authors.forename: Ephraim P
authors.initials: EP
authors.lastname: Hochberg
authors.forename: Ann S
authors.initials: AS
authors.lastname: LaCasce
authors.forename: Philippe
authors.initials: P
authors.lastname: Armand
authors.forename: Robin
authors.initials: R
authors.lastname: Joyce
authors.forename: Aliyah R
authors.initials: AR
authors.lastname: Sohani
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Rodig
authors.forename: Donna
authors.initials: D
authors.lastname: Neuberg
authors.forename: David C
authors.initials: DC
authors.lastname: Fisher
authors.forename: Jeremy S
authors.initials: JS
authors.lastname: Abramson
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000740:Anemia / Q000139:chemically induced; D058846:Antibodies, Monoclonal, Murine-Derived / Q000008:administration & dosage / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D000068338:Everolimus; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D009503:Neutropenia / Q000139:chemically induced; D012074:Remission Induction; D000069283:Rituximab; D020123:Sirolimus / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D016896:Treatment Outcome
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D000069283:Rituximab; D000068338:Everolimus; D020123:Sirolimus