title: Efficacy of the oral mTORC1 inhibitor everolimus in relapsed or refractory indolent lymphoma.
abstract: Relapsed indolent lymphoma often becomes refractory to standard chemoimmunotherapy and requires new therapeutic strategies. Targeting the PI3K/mTOR pathway in several types of lymphoma has shown preclinical and clinical efficacy providing the rationale to test this strategy in the treatment of relapsed/refractory indolent lymphomas. We investigated in a phase II open label clinical trial the efficacy and safety of single agent everolimus, an inhibitor of mTORC1, in patients with relapsed/refractory indolent lymphomas. Eligible patients received oral everolimus 10 mg daily on a 28 day-cycle schedule. The primary endpoint was to evaluate the overall response rate (ORR) and safety of single-agent everolimus in this patient population. Fifty-five patients with indolent lymphoma were accrued. The median age was 67 years (range: 33-85) with a median of five prior therapies (range: 1-10). The ORR was 35% (19/55; 95% CI: 24-48%), with complete response unconfirmed in 4% (2/55), and partial response in 31% (17/55). The ORR was 61% (14/23) in the patients with FL. The median time to response was 2.3 months (range: 1.4-14.1), median duration of response of 11.5 months (95%-CI: 5.7-30.4), and a median progression-free survival of 7.2 months (95%-CI: 5.5-12.5). The most common toxicity was hematologic with grades 3-4 anemia, neutropenia, and thrombocytopenia documented in 15% (8/55), 22% (12/55), and 33% (18/55), respectively. There were no cases of febrile neutropenia, and eight patients discontinued therapy because of adverse events. Everolimus monotherapy is a valid therapeutic option in the relapsed and/or refractory indolent non-Hodgkin lymphoma patients and is well tolerated.
authors.affiliation: Division of Hematology, Department of Medicine, Mayo Clinic Rochester, Rochester, Minnesota.
authors.forename: N Nora
authors.initials: NN
authors.lastname: Bennani
authors.affiliation: Division of Biomedical Statistics and Bioinformatics, Department of Health Sciences Research, Mayo Clinic Rochester, Rochester, Minnesota.
authors.forename: Betsy R
authors.initials: BR
authors.lastname: LaPlant
authors.affiliation: Division of Hematology, Department of Medicine, Mayo Clinic Rochester, Rochester, Minnesota.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Ansell
authors.affiliation: Division of Hematology, Department of Medicine, Mayo Clinic Rochester, Rochester, Minnesota.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Habermann
authors.affiliation: Division of Hematology, Department of Medicine, Mayo Clinic Rochester, Rochester, Minnesota.
authors.forename: David J
authors.initials: DJ
authors.lastname: Inwards
authors.affiliation: Division of Hematology, Department of Medicine, Mayo Clinic Rochester, Rochester, Minnesota.
authors.forename: Ivana N
authors.initials: IN
authors.lastname: Micallef
authors.affiliation: Division of Hematology, Department of Medicine, Mayo Clinic Rochester, Rochester, Minnesota.
authors.forename: Patrick B
authors.initials: PB
authors.lastname: Johnston
authors.affiliation: Division of Hematology, Department of Medicine, Mayo Clinic Rochester, Rochester, Minnesota.
authors.forename: Luis F
authors.initials: LF
authors.lastname: Porrata
authors.affiliation: Division of Hematology, Department of Medicine, Mayo Clinic Rochester, Rochester, Minnesota.
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Colgan
authors.affiliation: Division of Hematology, Department of Medicine, Mayo Clinic Rochester, Rochester, Minnesota.
authors.forename: Svetomir N
authors.initials: SN
authors.lastname: Markovic
authors.affiliation: Division of Hematology, Department of Medicine, Mayo Clinic Rochester, Rochester, Minnesota.
authors.forename: Grzegorz S
authors.initials: GS
authors.lastname: Nowakowski
authors.affiliation: Division of Hematopathology, Department of Laboratory Medicine and Pathology, Mayo Clinic Rochester, Rochester, Minnesota.
authors.forename: William R
authors.initials: WR
authors.lastname: Macon
authors.affiliation: Division of Hematology, Department of Medicine, Mayo Clinic Scottsdale, Scottsdale, Arizona.
authors.forename: Craig B
authors.initials: CB
authors.lastname: Reeder
authors.affiliation: Division of Hematology, Department of Medicine, Mayo Clinic Scottsdale, Scottsdale, Arizona.
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Mikhael
authors.affiliation: Division of Hematology, Department of Medicine, Mayo Clinic Scottsdale, Scottsdale, Arizona.
authors.forename: Donald W
authors.initials: DW
authors.lastname: Northfelt
authors.affiliation: Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Irene M
authors.initials: IM
authors.lastname: Ghobrial
authors.affiliation: Division of Hematology, Department of Medicine, Mayo Clinic Rochester, Rochester, Minnesota.
authors.forename: Thomas E
authors.identifier: http://orcid.org/0000-0002-4215-6500
authors.initials: TE
authors.lastname: Witzig
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000740:Anemia / Q000139:chemically induced; D018572:Disease-Free Survival; D000068338:Everolimus / Q000008:administration & dosage* / Q000009:adverse effects; D005260:Female; D006801:Humans; D008228:Lymphoma, Non-Hodgkin / Q000150:complications / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D008875:Middle Aged; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors; D009503:Neutropenia / Q000139:chemically induced; D012074:Remission Induction; D016879:Salvage Therapy / Q000009:adverse effects / Q000379:methods*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D013921:Thrombocytopenia / Q000139:chemically induced; D016896:Treatment Outcome
chemical_list: D046912:Multiprotein Complexes; D000068338:Everolimus; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases