title: NCRI phase II study of CHOP in combination with ofatumumab in induction and maintenance in newly diagnosed Richter syndrome.
abstract: Richter syndrome (RS) is associated with chemotherapy resistance and a poor historical median overall survival (OS) of 8-10 months. We conducted a phase II trial of standard CHOP-21 (cyclophosphamide, doxorubicin, vincristine, prednisolone every 21 d) with ofatumumab induction (Cycle 1: 300 mg day 1, 1000 mg day 8, 1000 mg day 15; Cycles 2-6: 1000 mg day 1) (CHOP-O) followed by 12 months ofatumumab maintenance (1000 mg given 8-weekly for up to six cycles). Forty-three patients were recruited of whom 37 were evaluable. Seventy-three per cent were aged >60 years. Over half of the patients received a fludarabine and cyclophosphamide-based regimen as prior CLL treatment. The overall response rate was 46% (complete response 27%, partial response 19%) at six cycles. The median progression-free survival was 6·2 months (95% confidence interval [CI] 4·9-14·0 months) and median OS was 11·4 months (95% CI 6·4-25·6 months). Treatment-naïve and TP53-intact patients had improved outcomes. Fifteen episodes of neutropenic fever and 46 non-neutropenic infections were observed. There were no treatment-related deaths. Seven patients received platinum-containing salvage at progression, with only one patient obtaining an adequate response to proceed to allogeneic transplantation. CHOP-O with ofatumumab maintenance provides minimal benefit beyond CHOP plus rutuximab. Standard immunochemotherapy for RS remains wholly inadequate for unselected RS. Multinational trials incorporating novel agents are urgently needed.
authors.affiliation: Department of Haematology, Oxford University Hospitals NHS Foundation Trust, Churchill Hospital, Oxford, UK.
authors.forename: Toby A
authors.initials: TA
authors.lastname: Eyre
authors.affiliation: Department of Haematology, Oxford University Hospitals NHS Foundation Trust, Churchill Hospital, Oxford, UK.|NIHR BRC Oxford Molecular Diagnostic Centre, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford, UK.
authors.forename: Ruth
authors.initials: R
authors.lastname: Clifford
authors.affiliation: Department of Haematology, The Christie Hospital NHS Trust, Wimslow Road, Manchester, UK.
authors.forename: Adrian
authors.initials: A
authors.lastname: Bloor
authors.affiliation: OCTO - Oncology Clinical Trials Office, Department of Oncology, University of Oxford, Oxford, UK.
authors.forename: Lucy
authors.initials: L
authors.lastname: Boyle
authors.affiliation: Centre for Statistics in Medicine, Nuffield Department of Orthopaedics, Rheumatology & Musculoskeletal Sciences, University of Oxford, Oxford, UK.
authors.forename: Corran
authors.initials: C
authors.lastname: Roberts
authors.affiliation: NIHR BRC Oxford Molecular Diagnostic Centre, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford, UK.
authors.forename: Maite
authors.initials: M
authors.lastname: Cabes
authors.affiliation: Department of Haematology, Oxford University Hospitals NHS Foundation Trust, Churchill Hospital, Oxford, UK.
authors.forename: Graham P
authors.initials: GP
authors.lastname: Collins
authors.affiliation: Department of Haematology, Kings College Hospital, London, UK.
authors.forename: Stephen
authors.initials: S
authors.lastname: Devereux
authors.affiliation: Department of Haematology, Addenbrooke's Hospital NHS Trust, Cambridge, UK.
authors.forename: George
authors.initials: G
authors.lastname: Follows
authors.affiliation: Department of Haematology, Nottingham University Hospitals NHS Trust, Nottingham, UK.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Fox
authors.affiliation: Institute of Cancer, Barts & the London School of Medicine & Dentistry, London, UK.
authors.forename: John
authors.initials: J
authors.lastname: Gribben
authors.affiliation: St James's Institute of Oncology; Dena Cohen, University of Leeds, Leeds, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Hillmen
authors.affiliation: Department of Haematology, Oxford University Hospitals NHS Foundation Trust, Churchill Hospital, Oxford, UK.
authors.forename: Chris S
authors.initials: CS
authors.lastname: Hatton
authors.affiliation: Department of Haematology, Oxford University Hospitals NHS Foundation Trust, Churchill Hospital, Oxford, UK.
authors.forename: Tim J
authors.initials: TJ
authors.lastname: Littlewood
authors.affiliation: Department of Haematology, Royal Bournemouth Hospital, Bournemouth, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: McCarthy
authors.affiliation: Department of Haematology, Queen Elizabeth Hospital, Birmingham, UK.
authors.forename: Jim
authors.initials: J
authors.lastname: Murray
authors.affiliation: Royal Liverpool and Broadgreen University Hospitals NHS Trust, Liverpool, Merseyside, UK.|Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Pettitt
authors.affiliation: Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Soilleux
authors.affiliation: NIHR BRC Oxford Molecular Diagnostic Centre, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford, UK.|Department of Cellular Pathology, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford, UK.
authors.forename: Basile
authors.initials: B
authors.lastname: Stamatopoulos
authors.affiliation: Centre for Statistics in Medicine, Nuffield Department of Orthopaedics, Rheumatology & Musculoskeletal Sciences, University of Oxford, Oxford, UK.
authors.forename: Sharon B
authors.initials: SB
authors.lastname: Love
authors.affiliation: Laboratory of Clinical Cell Therapy, Jules Bordet Institute, Université Libre de Bruxelles (ULB), Brussels, Belgium.
authors.forename: Andrew
authors.initials: A
authors.lastname: Wotherspoon
authors.affiliation: Department of Haematology, Oxford University Hospitals NHS Foundation Trust, Churchill Hospital, Oxford, UK. anna.schuh@oncology.ox.ac.uk.|NIHR BRC Oxford Molecular Diagnostic Centre, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford, UK. anna.schuh@oncology.ox.ac.uk.|Department of Histopathology, The Royal Marsden Hospital, London, UK. anna.schuh@oncology.ox.ac.uk.|Department of Oncology, University of Oxford, Oxford, UK. anna.schuh@oncology.ox.ac.uk.
authors.forename: Anna
authors.initials: A
authors.lastname: Schuh
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D015415:Biomarkers; D003520:Cyclophosphamide / Q000009:adverse effects / Q000627:therapeutic use; D018450:Disease Progression; D004317:Doxorubicin / Q000009:adverse effects / Q000627:therapeutic use; D005260:Female; D006801:Humans; D060828:Induction Chemotherapy; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000150:complications*; D008223:Lymphoma / Q000175:diagnosis / Q000188:drug therapy* / Q000209:etiology*; D060046:Maintenance Chemotherapy; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D000072078:Positron Emission Tomography Computed Tomography; D011241:Prednisone / Q000009:adverse effects / Q000627:therapeutic use; D016019:Survival Analysis; D013577:Syndrome; D016896:Treatment Outcome; D014750:Vincristine / Q000009:adverse effects / Q000627:therapeutic use
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D015415:Biomarkers; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; C527517:ofatumumab; D011241:Prednisone
keywords: CHOP; Chronic lymphocytic leukaemia; Ofatumumab; Richter syndrome; TP53