@article{b1a058417bff4d0c90b6f6498b96951b,
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.",
author = "Larsen, {Jeremy T.} and Shanafelt, {Tait D.} and Leis, {Jose F.} and Betsy LaPlant and Tim Call and Adam Pettinger and Curtis Hanson and Charles Erlichman and Habermann, {Thomas Matthew} and Craig Reeder and Daniel Nikcevich and Deborah Bowen and Michael Conte and Justin Boysen and Charla Secreto and Connie Lesnick and Renee Tschumper and Diane Jelinek and Kay, {Neil E.} and Wei Ding",
note = "Funding Information: The work was supported by funding from NCI grant K23CA160345 (WD), NCI grant CA95241 (NEK) and Alliance for Clinical Trials in Oncology (CA0252224 and CA33601). TDS has received research support from Celgene, Hospira, Cephalon, Genentech, Glaxo-Smith-kline and Polyphenon E International. CE was on the advisory board of Merck over 1 year ago. NEK has received research support from Celgene and Gilead. WD received research support from Merck. All other authors declare no competing financial interests. All authors read and approved the final version of the manuscript. Extracted data: Jeremy T. Larsen Performed statistical analysis: Jeremy T. Larsen, Betsy LaPlant, Adam Pettinger, Connie Lesnick, Diane Jelinek, Wei Ding Interpreted the results: Jeremy T. Larsen, Tait D. Shanafelt, Neil E. Kay, Betsy LaPlant, Adam Pettinger, Connie Lesnick, Diane Jelinek, Justin Boysen, Charla Secreto, Connie Lesnick, Renee Tschumper Wrote the article: Jeremy T. Larsen, Tait D. Shanafelt, Neil E. Kay, Wei Ding Designed research: Tait D. Shanafelt, Neil E. Kay, Betsy LaPlant, Adam Pettinger, Connie Lesnick, Diane Jelinek Analyzed the results: Tait D. Shanafelt, Neil E. Kay Recruited patient: Jose F. Leis, Tim Call, Curtis Hanson, Charles Erlichman, Thomas Matthew Habermann, Craig Reeder, Daniel Nikcevich, Deborah Bowen, Michael Conte Provided input: Jose F. Leis, Tim Call, Curtis Hanson, Charles Erlichman, Thomas Matthew Habermann, Craig Reeder, Daniel Nikcevich, Deborah Bowen, and Michael Conte Reviewed the manuscript: Jose F. Leis, Tim Call, Curtis Hanson, Charles Erlichman, Thomas Matthew Habermann, Craig Reeder, Daniel Nikcevich, Deborah Bowen, and Michael Conte Performed the experiments: Justin Boysen, Charla Secreto, Connie Lesnick, Renee Tschumper Designed the study: Wei Ding Contributed patients: Wei Ding Publisher Copyright: {\textcopyright} 2017 Wiley Periodicals, Inc.",
year = "2017",
month = aug,
doi = "10.1002/ajh.24762",
language = "English (US)",
volume = "92",
pages = "759--763",
journal = "American journal of hematology",
issn = "0361-8609",
publisher = "Wiley-Liss Inc.",
number = "8",
}