@article{5d59457459374d84979078d8fd1f0748,
title = "Phase 1 study of lenalidomide plus dose-adjusted EPOCH-R in patients with aggressive B-cell lymphomas with deregulated MYC and BCL2",
abstract = "Background: Dual translocation of MYC and BCL2 or the dual overexpression of these proteins in patients with aggressive B-cell lymphomas (termed double-hit lymphoma [DHL] and double-expressor lymphoma [DEL], respectively) have poor outcomes after chemoimmunotherapy with the combination of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Retrospective reports have suggested improved outcomes with dose-intensified regimens. In the current study, the authors conducted a phase 1 study to evaluate the feasibility, toxicity, and preliminary efficacy of adding lenalidomide to dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin with rituximab (DA-EPOCH-R) in patients with DHL and DEL. Methods: The primary objective of the current study was to determine the maximum tolerated dose of lenalidomide in combination with DA-EPOCH-R. A standard 3+3 design was used with lenalidomide administered on days 1 to 14 of each 21-day cycle (dose levels of 10 mg, 15 mg, and 20 mg). Patients attaining a complete response after 6 cycles of induction therapy proceeded to maintenance lenalidomide (10 mg daily for 14 days every 21 days) for 12 additional cycles. Results: A total of 15 patients were enrolled, 10 of whom had DEL and 5 of whom had DHL. Two patients experienced dose-limiting toxicities at a lenalidomide dose of 20 mg, consisting of grade 4 sepsis. The maximum tolerated dose of lenalidomide was determined to be 15 mg. The most common nonhematologic grade ≥3 adverse events included thromboembolism (4 patients; 27%) and hypokalemia (2 patients; 13%) (toxicities were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0]). The preliminary efficacy of the regimen was encouraging, especially in the DEL cohort, in which all 10 patients achieved durable and complete metabolic responses with a median follow-up of 24 months. Conclusions: The combination of lenalidomide with DA-EPOCH-R appears to be safe and feasible in patients with DHL and DEL. These encouraging results have prompted an ongoing phase 2 multicenter study.",
keywords = "aggressive lymphoma, chemotherapy, double-expressor lymphoma, double-hit lymphoma, lenalidomide, phase I",
author = "Godfrey, {James K.} and Chadi Nabhan and Theodore Karrison and Kline, {Justin P.} and Cohen, {Kenneth S.} and Bishop, {Michael R.} and Stadler, {Walter M.} and Reem Karmali and Parameswaran Venugopal and Rapoport, {Aaron P.} and Smith, {Sonali M.}",
note = "Funding Information: Justin P. Kline has received research support and consulting fees from Merck, research support from iTeos, and consulting fees from Kite Pharma and Seattle Genetics for work performed outside of the current study. Kenneth S. Cohen has no conflict of interest disclosures. Michael R. Bishop received nonfinancial support from ArticulateScience LLC; is employed by and has acted as a paid member of the Advisory Board for United Healthcare; has acted as a paid member of the Advisory Board for Seattle Genetics, Juno Therapeutics, Novartis, and Pharmacyclics; has acted as a member of the Speakers{\textquoteright} Bureau and Advisory Board for Celgene; has acted as a member of the Scientific Advisory Board for CRISPR Therapeutics; and has acted as a member of the Advisory Board, as a paid consultant, and as a member of the Speakers{\textquoteright} Bureau for Kite Pharma for work performed outside of the current study. Walter M. Stadler was supported by a grant from the National Cancer Institute for work performed as part of the current study and has acted as a paid consultant and member of the Data Safety Monitoring Board for and received support to his institution for trials from AstraZeneca and Bayer; has acted as a consultant for and received support from a contract to his institution for trials from Bristol-Myers Squibb; has acted as a paid consultant for Caremark/CVS and Clovis; has acted as a paid consultant and member of the Data Safety Monitoring Board for Eisai; has acted as a consultant for and received support from a contract to his institution for trials from Genentech; has acted as a paid consultant for Pfizer; has acted as a paid consultant and member of the Data Safety Monitoring Board for Sotio; and has received support from a contract to his institution for trials from AbbVie, Astellas, Boehringer-Ingelheim, Calithera, Clovis, Exelixis, Johnson & Johnson, Merck, Novartis, Pfizer, Seattle Genetics, Tesaro, and X4 Pharmaceuticals for work performed outside of the current study. Reem Karmali received a grant from Celgene for work performed as part of the current study and has acted as a member of the Speakers{\textquoteright} Bureau for AstraZeneca and as a paid member of the Advisory Board for Gilead/Kite Pharma for work performed outside of the current study. Sonali M. Smith received institutional funding for conduct of the trial from Celgene for work performed as part of the current study; has acted as a paid consultant for Seattle Genetics, Bayer, Gilead/Kite Pharma, AstraZeneca, AbbVie, Bristol-Myers Squibb, Juno, and TGTX; and has acted as a paid consultant and received institutional fees for trials from Portola, Pharmacyclics/ Janssen, and Celgene for work performed outside of the current study. Funding Information: Justin P. Kline has received research support and consulting fees from Merck, research support from iTeos, and consulting fees from Kite Pharma and Seattle Genetics for work performed outside of the current study. Kenneth S. Cohen has no conflict of interest disclosures. Michael R. Bishop received nonfinancial support from ArticulateScience LLC; is employed by and has acted as a paid member of the Advisory Board for United Healthcare; has acted as a paid member of the Advisory Board for Seattle Genetics, Juno Therapeutics, Novartis, and Pharmacyclics; has acted as a member of the Speakers? Bureau and Advisory Board for Celgene; has acted as a member of the Scientific Advisory Board for CRISPR Therapeutics; and has acted as a member of the Advisory Board, as a paid consultant, and as a member of the Speakers? Bureau for Kite Pharma for work performed outside of the current study. Walter M. Stadler was supported by a grant from the National Cancer Institute for work performed as part of the current study and has acted as a paid consultant and member of the Data Safety Monitoring Board for and received support to his institution for trials from AstraZeneca and Bayer; has acted as a consultant for and received support from a contract to his institution for trials from Bristol-Myers Squibb; has acted as a paid consultant for Caremark/CVS and Clovis; has acted as a paid consultant and member of the Data Safety Monitoring Board for Eisai; has acted as a consultant for and received support from a contract to his institution for trials from Genentech; has acted as a paid consultant for Pfizer; has acted as a paid consultant and member of the Data Safety Monitoring Board for Sotio; and has received support from a contract to his institution for trials from AbbVie, Astellas, Boehringer-Ingelheim, Calithera, Clovis, Exelixis, Johnson & Johnson, Merck, Novartis, Pfizer, Seattle Genetics, Tesaro, and X4 Pharmaceuticals for work performed outside of the current study. Reem Karmali received a grant from Celgene for work performed as part of the current study and has acted as a member of the Speakers? Bureau for AstraZeneca and as a paid member of the Advisory Board for Gilead/Kite Pharma for work performed outside of the current study. Sonali M. Smith received institutional funding for conduct of the trial from Celgene for work performed as part of the current study; has acted as a paid consultant for Seattle Genetics, Bayer, Gilead/Kite Pharma, AstraZeneca, AbbVie, Bristol-Myers Squibb, Juno, and TGTX; and has acted as a paid consultant and received institutional fees for trials from Portola, Pharmacyclics/Janssen, and Celgene for work performed outside of the current study. Supported by Celgene. Publisher Copyright: {\textcopyright} 2019 American Cancer Society",
year = "2019",
month = jun,
day = "1",
doi = "10.1002/cncr.31877",
language = "English (US)",
volume = "125",
pages = "1830--1836",
journal = "cancer",
issn = "0008-543X",
publisher = "John Wiley and Sons Inc.",
number = "11",
}
