title: Outcome of elderly patients with diffuse large B-cell lymphoma treated with R-CHOP: results from the UK NCRI R-CHOP14v21 trial with combined analysis of molecular characteristics with the DSHNHL RICOVER-60 trial.
abstract: BACKGROUND
  There is an on-going debate whether 2- or 3-weekly administration of R-CHOP is the preferred first-line treatment for elderly patients with diffuse large B-cell lymphoma (DLBCL). The UK NCRI R-CHOP14v21 randomized phase 3 trial did not demonstrate a difference in outcomes between R-CHOP-14 and R-CHOP-21 in newly diagnosed DLBCL patients aged 19-88 years, but data on elderly patients have not been reported in detail so far. Here, we provide a subgroup analysis of patients ≥60 years treated on the R-CHOP14v21 trial with extended follow-up.
  
  
  METHODS
  Six hundred and four R-CHOP14v21 patients ≥60 years were included in this subgroup analysis, with a median follow-up of 77.7 months. To assess the impact of MYC rearrangements (MYC-R) and double-hit-lymphoma (DHL) on outcome in elderly patients, we performed a joint analysis of cases with available molecular data from the R-CHOP14v21 (N = 217) and RICOVER-60 (N = 204) trials.
  
  
  RESULTS
  Elderly DLBCL patients received high dose intensities with median total doses of ≥98% for all agents. Toxicities were similar in both arms with the exception of more grade ≥3 neutropenia (P < 0.0001) and fewer grade ≥3 thrombocytopenia (P = 0.05) in R-CHOP-21 versus R-CHOP-14. The elderly patient population had a favorable 5-year overall survival (OS) of 69% (95% CI: 65-73). We did not identify any subgroup of patients that showed differential response to either regimen. In multivariable analysis including individual factors of the IPI, gender, bulk, B2M and albumin levels, only age and B2M were of independent prognostic significance for OS. Molecular analyses demonstrated a significant impact of MYC-R (HR = 1.96; 95% CI: 1.22-3.16; P = 0.01) and DHL (HR = 2.21; 95% CI: 1.18-4.11; P = 0.01) on OS in the combined trial cohorts, independent of other prognostic factors.
  
  
  CONCLUSIONS
  Our data support equivalence of both R-CHOP application forms in elderly DLBCL patients. Elderly MYC-R and DHL patients have inferior prognosis and should be considered for alternative treatment approaches.
  
  
  BACKGROUND
  ISCRTN 16017947 (R-CHOP14v21); NCT00052936 (RICOVER-60).
authors.affiliation: Department of Medicine, The Royal Marsden NHS Foundation Trust, London and Surrey.
authors.forename: A
authors.initials: A
authors.lastname: Kühnl
authors.affiliation: Department of Medicine, The Royal Marsden NHS Foundation Trust, London and Surrey.
authors.forename: D
authors.initials: D
authors.lastname: Cunningham
authors.affiliation: Cancer Research UK and UCL Cancer Trials Centre, UCL Cancer Institute, London, UK.
authors.forename: N
authors.initials: N
authors.lastname: Counsell
authors.affiliation: Department of Medicine, The Royal Marsden NHS Foundation Trust, London and Surrey.|Olivia-Newton John Cancer Research & Wellness Centre, Melbourne, Australia.
authors.forename: E A
authors.initials: EA
authors.lastname: Hawkes
authors.affiliation: Department of Oncology, Cambridge University Hospitals NHS Foundation Trust, Cambridge.
authors.forename: W
authors.initials: W
authors.lastname: Qian
authors.affiliation: Cancer Research UK and UCL Cancer Trials Centre, UCL Cancer Institute, London, UK.
authors.forename: P
authors.initials: P
authors.lastname: Smith
authors.affiliation: Cancer Research UK and UCL Cancer Trials Centre, UCL Cancer Institute, London, UK.
authors.forename: N
authors.initials: N
authors.lastname: Chadwick
authors.affiliation: Cancer Research UK and UCL Cancer Trials Centre, UCL Cancer Institute, London, UK.
authors.forename: A
authors.initials: A
authors.lastname: Lawrie
authors.affiliation: Cancer Research UK and UCL Cancer Trials Centre, UCL Cancer Institute, London, UK.
authors.forename: P
authors.initials: P
authors.lastname: Mouncey
authors.affiliation: HMDS, St James's Institute of Oncology, Leeds.
authors.forename: A
authors.initials: A
authors.lastname: Jack
authors.affiliation: East Kent Hospitals, Canterbury.
authors.forename: C
authors.initials: C
authors.lastname: Pocock
authors.affiliation: Department of Hematology, University College London, London.|Mount Vernon Cancer Centre, Northwood.
authors.forename: K M
authors.initials: KM
authors.lastname: Ardeshna
authors.affiliation: Department of Medical Oncology, University of Manchester and the Christie NHS Foundation Trust, Manchester.
authors.forename: J
authors.initials: J
authors.lastname: Radford
authors.affiliation: Department of Hematology, Nottingham City Hospital, Nottingham.
authors.forename: A
authors.initials: A
authors.lastname: McMillan
authors.affiliation: Western General Hospital, Edinburgh.
authors.forename: J
authors.initials: J
authors.lastname: Davies
authors.affiliation: Department of Hematology, Torbay Hospital, Torquay.
authors.forename: D
authors.initials: D
authors.lastname: Turner
authors.affiliation: Royal Cornwall Hospital, Truro.
authors.forename: A
authors.initials: A
authors.lastname: Kruger
authors.affiliation: Cancer Research UK Center, University of Southampton, Southampton, UK.
authors.forename: P W
authors.initials: PW
authors.lastname: Johnson
authors.affiliation: Cancer Research UK and UCL Cancer Trials Centre, UCL Cancer Institute, London, UK.
authors.forename: J
authors.initials: J
authors.lastname: Gambell
authors.affiliation: Institute of Pathology, Würzburg University, Würzburg.
authors.forename: A
authors.initials: A
authors.lastname: Rosenwald
authors.affiliation: Department of Clinical Pathology, Robert-Bosch-Krankenhaus, Stuttgart.
authors.forename: G
authors.initials: G
authors.lastname: Ott
authors.affiliation: Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart and University of Tübingen, Stuttgart.
authors.forename: H
authors.initials: H
authors.lastname: Horn
authors.affiliation: Institute for Medical Informatics, Statistics, and Epidemiology, University of Leipzig, Leipzig.
authors.forename: M
authors.initials: M
authors.lastname: Ziepert
authors.affiliation: Department of Medicine, Saarland University Medical School, Homburg/Saar, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Pfreundschuh
authors.affiliation: Department of Hematology, University College London, London.
authors.forename: D
authors.initials: D
authors.lastname: Linch
mesh_terms: D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D058846:Antibodies, Monoclonal, Murine-Derived / Q000008:administration & dosage / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D014408:Biomarkers, Tumor / Q000235:genetics*; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000009:adverse effects; D004317:Doxorubicin / Q000008:administration & dosage / Q000009:adverse effects; D004334:Drug Administration Schedule; D005260:Female; D015321:Gene Rearrangement; D006801:Humans; D053208:Kaplan-Meier Estimate; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D018579:Patient Selection; D057285:Precision Medicine; D011241:Prednisone / Q000008:administration & dosage / Q000009:adverse effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics*; D051560:Proto-Oncogene Proteins c-bcl-6 / Q000235:genetics*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D012307:Risk Factors; D000069283:Rituximab; D013997:Time Factors; D016896:Treatment Outcome; D006113:United Kingdom; D014750:Vincristine / Q000008:administration & dosage / Q000009:adverse effects
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; C000595707:BCL2 protein, human; C084103:BCL6 protein, human; D014408:Biomarkers, Tumor; C489427:MYC protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D051560:Proto-Oncogene Proteins c-bcl-6; D016271:Proto-Oncogene Proteins c-myc; C571759:R-CHOP protocol; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone
keywords: MYC; R-CHOP; diffuse large B-cell lymphoma; double-hit lymphoma; elderly