title: Akt inhibitor MK-2206 in combination with bendamustine and rituximab in relapsed or refractory chronic lymphocytic leukemia: Results from the N1087 alliance study.
abstract: Akt is a downstream target of B cell receptor signaling and is a central regulator of CLL cell survival. We aim to investigate the safety and efficacy of the Akt inhibitor MK-2206 in combination with bendamustine and rituximab (BR) in relapsed and/or refractory CLL in a phase I/II study. A standard phase I design was used with cohorts of three plus three patients to determine the maximum tolerated dose (MTD) of MK-2206 in combination with BR in relapsed CLL. Single-agent MK-2206 (weekly dosed) was administered one-week in advance before BR on cycle 1 and subsequently was given with BR at the same time for cycle 2-6. Phase II employed the MTD of MK-2206 with BR to evaluate safety and efficacy of this study combination. Thirteen relapsed/refractory CLL were treated for maximal 6-cycle of therapy. The maximum tolerated dose of MK-2206 was 90 mg by mouth once weekly. The most common grade 3/4 adverse events were neutropenia (46%), febrile neutropenia (23%), rash (15%), diarrhea (15%), and thrombocytopenia (15%). Overall response rate was 92% with a median progression free survival and treatment free survival of 16 and 24 months, respectively. Five patients (38%) achieved complete remission or complete remission with incomplete count recovery, two of whom were MRD negative. The efficacy and tolerability of this combination indicates that Akt inhibition combined with chemoimmunotherapy is a promising novel treatment combination in CLL and deserves further prospective clinical trial.
authors.affiliation: Division of Hematology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Jeremy T
authors.initials: JT
authors.lastname: Larsen
authors.affiliation: Division of Hematology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Tait D
authors.initials: TD
authors.lastname: Shanafelt
authors.affiliation: Division of Hematology and Oncology, Mayo Clinic, Scottsdale, Arizona.
authors.forename: Jose F
authors.initials: JF
authors.lastname: Leis
authors.affiliation: Alliance Statistics, Rochester, Minnesota.
authors.forename: Betsy
authors.initials: B
authors.lastname: LaPlant
authors.affiliation: Division of Hematology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Tim
authors.initials: T
authors.lastname: Call
authors.affiliation: Alliance Statistics, Rochester, Minnesota.
authors.forename: Adam
authors.initials: A
authors.lastname: Pettinger
authors.affiliation: Division of Hematopathology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Curtis
authors.initials: C
authors.lastname: Hanson
authors.affiliation: Division of Medical Oncology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Charles
authors.initials: C
authors.lastname: Erlichman
authors.affiliation: Division of Hematology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Thomas Matthew
authors.initials: TM
authors.lastname: Habermann
authors.affiliation: Division of Hematology and Oncology, Mayo Clinic, Scottsdale, Arizona.
authors.forename: Craig
authors.initials: C
authors.lastname: Reeder
authors.affiliation: Essentia Health-Duluth, Minnesota.
authors.forename: Daniel
authors.initials: D
authors.lastname: Nikcevich
authors.affiliation: Division of Hematology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Deborah
authors.initials: D
authors.lastname: Bowen
authors.affiliation: Division of Hematology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Michael
authors.initials: M
authors.lastname: Conte
authors.affiliation: Division of Hematology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Justin
authors.initials: J
authors.lastname: Boysen
authors.affiliation: Division of Hematology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Charla
authors.initials: C
authors.lastname: Secreto
authors.affiliation: Division of Hematology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Connie
authors.initials: C
authors.lastname: Lesnick
authors.affiliation: Division of Immunology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Renee
authors.initials: R
authors.lastname: Tschumper
authors.affiliation: Division of Immunology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Diane
authors.initials: D
authors.lastname: Jelinek
authors.affiliation: Division of Hematology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Neil E
authors.initials: NE
authors.lastname: Kay
authors.affiliation: Division of Hematology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Wei
authors.identifier: http://orcid.org/0000-0001-9811-4601
authors.initials: W
authors.lastname: Ding
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D000069461:Bendamustine Hydrochloride / Q000008:administration & dosage; D019008:Drug Resistance, Neoplasm; D005260:Female; D005500:Follow-Up Studies; D006575:Heterocyclic Compounds, 3-Ring / Q000008:administration & dosage; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D012008:Recurrence; D019233:Retreatment; D000069283:Rituximab / Q000008:administration & dosage; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D006575:Heterocyclic Compounds, 3-Ring; C548887:MK 2206; D000069283:Rituximab; D000069461:Bendamustine Hydrochloride