title: Front-line, dose-escalated immunochemotherapy is associated with a significant progression-free survival advantage in patients with double-hit lymphomas: a systematic review and meta-analysis.
abstract: 'Double-hit lymphomas' (DHL), defined by concurrent MYC and BCL2 (or, alternatively, BCL6) rearrangements, have a very poor outcome compared to standard-risk, diffuse large B-cell lymphomas (DLBCL). Consequently, dose-intensive (DI) therapies and/or consolidation with high-dose therapy and transplant have been explored in DHL, although benefit has been debated. This meta-analysis compared survival outcomes in DHL patients receiving dose-escalated regimens [DI: R-Hyper-CVAD (rituximab, cyclophosphamide, vincristine, doxorubicin, dexamethasone) or R-CODOX-M/IVAC (rituximab, cyclophosphamide, doxorubicin, vincristine, methotrexate/ifosfamide, etoposide, high dose cytarabine); or intermediate-dose: R-EPOCH (rituximab, etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone)] versus standard-dose regimens (R-CHOP; rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) in the first-line setting. Data were synthesized to estimate hazard ratios of dose-escalated treatments versus R-CHOP using a Weibull proportional hazards model within a Bayesian meta-analysis framework. Eleven studies examining 394 patients were included. Patients were treated with either front-line R-CHOP (n = 180), R-EPOCH (n = 91), or R-Hyper-CVAD/rituximab, methotrexate, cytarabine (R-M/C), R-CODOX-M/R-IVAC (DI) (n = 123). Our meta-analysis revealed that median progression-free survival (n = 350) for the R-CHOP, R-EPOCH and DI groups was 12·1, 22·2, and 18·9 months, respectively. First-line treatment with R-EPOCH significantly reduced the risk of a progression compared with R-CHOP (relative risk reduction of 34%; P = 0·032); however, overall survival (n = 374) was not significantly different across treatment approaches. A subset of patients might benefit from intensive induction with/without transplant. Further investigation into the role of transplant and novel therapy combinations is necessary.
authors.affiliation: Department of Pharmacy and Clinical Services, John Theurer Cancer Center at Hackensack University Medical Center, Hackensack, NJ, USA.|Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, USA.
authors.forename: Christina
authors.initials: C
authors.lastname: Howlett
authors.affiliation: Pharmerit International, Bethesda, MD, USA.
authors.forename: Sonya J
authors.initials: SJ
authors.lastname: Snedecor
authors.affiliation: Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Landsburg
authors.affiliation: Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Jakub
authors.initials: J
authors.lastname: Svoboda
authors.affiliation: Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Elise A
authors.initials: EA
authors.lastname: Chong
authors.affiliation: Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Schuster
authors.affiliation: Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Sunita Dwivedy
authors.initials: SD
authors.lastname: Nasta
authors.affiliation: John Theurer Cancer Center at Hackensack University Medical Center, Hackensack, NJ, USA.
authors.forename: Tatyana
authors.initials: T
authors.lastname: Feldman
authors.affiliation: Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Allison
authors.initials: A
authors.lastname: Rago
authors.affiliation: Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Kristy M
authors.initials: KM
authors.lastname: Walsh
authors.affiliation: Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Weber
authors.affiliation: John Theurer Cancer Center at Hackensack University Medical Center, Hackensack, NJ, USA.
authors.forename: Andre
authors.initials: A
authors.lastname: Goy
authors.affiliation: Center for Chronic Lymphocytic Leukemia and Lymphoma Program, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Anthony
authors.initials: A
authors.lastname: Mato
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D004268:DNA-Binding Proteins / Q000235:genetics*; D018572:Disease-Free Survival; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy / Q000235:genetics / Q000401:mortality; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics*; D051560:Proto-Oncogene Proteins c-bcl-6; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D015996:Survival Rate
chemical_list: C000595707:BCL2 protein, human; C084103:BCL6 protein, human; D004268:DNA-Binding Proteins; C489427:MYC protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D051560:Proto-Oncogene Proteins c-bcl-6; D016271:Proto-Oncogene Proteins c-myc
keywords: dose-escalated; double-hit lymphomas; front-line; immunochemotherapy; progression-free survival