title: Sequential treatment with rituximab followed by CHOP chemotherapy in adult B-cell post-transplant lymphoproliferative disorder (PTLD): the prospective international multicentre phase 2 PTLD-1 trial.
abstract: BACKGROUND
  Post-transplantation lymphoproliferative disorder (PTLD) develops in 1-10% of transplant recipients and can be Epstein-Barr virus (EBV) associated. To improve long-term efficacy after rituximab monotherapy and to avoid the toxic effects of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) chemotherapy seen in first-line treatment, we initiated a phase 2 trial to test whether the subsequent use of rituximab and CHOP would improve the outcome of patients with PTLD.
  
  
  METHODS
  In this international multicentre open-label phase 2 trial, treatment-naive adult solid-organ transplant recipients diagnosed with CD20-positive PTLD who had failed to respond to upfront immunosuppression reduction received four courses of rituximab (375 mg/m(2) intravenously) once a week followed by 4 weeks without treatment and four cycles of CHOP every 3 weeks. In case of disease progression during rituximab monotherapy, CHOP was started immediately. Supportive therapy with granulocyte-colony stimulating factor after chemotherapy was mandatory and antibiotic prophylaxis was recommended. The primary endpoint was treatment efficacy measured as response rates in all patients who completed treatment with rituximab and CHOP, per protocol, and response duration, in all patients who completed all planned therapy and responded. Secondary endpoints were frequency of infections, treatment-related mortality, and overall survival. This study is registered at ClinicalTrials.gov, number NCT01458548.
  
  
  RESULTS
  74 patients were enrolled between Dec 12, 2002 and May 5, 2008, of whom 70 patients were eligible to receive treatment. PTLD was of late type in 53 (76%) of 70 patients, monomorphic in 67 (96%) of 70, and histologically EBV associated in 29 (44%) of 66 cases. Four of 70 patients did not receive CHOP. 53 of 59 patients had a complete or partial response (90%, 95% CI 79-96), of which 40 (68%, 55-78) were complete responses. At data cutoff (June 1, 2011) median response duration in the 53 patients who had responded to treatment had not yet been reached (>79·1 months). The main adverse events were grade 3-4 leucopenia in 42 of 62 patients (68%, 55-78) and infections of grade 3-4 in 26 of 64 patients (41%, 29-53). Seven of 66 patients (11%, 5-21) had CHOP-associated treatment-related mortality. Median overall survival was 6·6 years (95% CI 2·8-10·4; n=70).
  
  
  CONCLUSIONS
  Our results support the use of sequential immunochemotherapy with rituximab and CHOP in PTLD.
  
  
  BACKGROUND
  F Hoffmann-La Roche, Amgen Germany, Chugaï France.
authors.affiliation: Department of Haematology and Oncology, Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Berlin, Germany. ralf.trappe@uksh.de
authors.forename: Ralf
authors.initials: R
authors.lastname: Trappe
authors.forename: Stephan
authors.initials: S
authors.lastname: Oertel
authors.forename: Veronique
authors.initials: V
authors.lastname: Leblond
authors.forename: Peter
authors.initials: P
authors.lastname: Mollee
authors.forename: Monica
authors.initials: M
authors.lastname: Sender
authors.forename: Petra
authors.initials: P
authors.lastname: Reinke
authors.forename: Ruth
authors.initials: R
authors.lastname: Neuhaus
authors.forename: Hans
authors.initials: H
authors.lastname: Lehmkuhl
authors.forename: Heinz August
authors.initials: HA
authors.lastname: Horst
authors.forename: Gilles
authors.initials: G
authors.lastname: Salles
authors.forename: Franck
authors.initials: F
authors.lastname: Morschhauser
authors.forename: Arnaud
authors.initials: A
authors.lastname: Jaccard
authors.forename: Thierry
authors.initials: T
authors.lastname: Lamy
authors.forename: Malte
authors.initials: M
authors.lastname: Leithäuser
authors.forename: Heiner
authors.initials: H
authors.lastname: Zimmermann
authors.forename: Ioannis
authors.initials: I
authors.lastname: Anagnostopoulos
authors.forename: Martine
authors.initials: M
authors.lastname: Raphael
authors.forename: Hanno
authors.initials: H
authors.lastname: Riess
authors.forename: Sylvain
authors.initials: S
authors.lastname: Choquet
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D058846:Antibodies, Monoclonal, Murine-Derived / Q000008:administration & dosage / Q000627:therapeutic use*; D018951:Antigens, CD20 / Q000276:immunology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000627:therapeutic use; D004317:Doxorubicin / Q000008:administration & dosage / Q000627:therapeutic use; D020031:Epstein-Barr Virus Infections / Q000175:diagnosis / Q000628:therapy; D005260:Female; D005602:France; D005858:Germany; D004854:Herpesvirus 4, Human / Q000472:pathogenicity; D006801:Humans; D008232:Lymphoproliferative Disorders / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D008297:Male; D008875:Middle Aged; D016377:Organ Transplantation / Q000009:adverse effects* / Q000473:pathology; D011239:Prednisolone / Q000008:administration & dosage / Q000627:therapeutic use; D011446:Prospective Studies; D000069283:Rituximab; D014750:Vincristine / Q000008:administration & dosage / Q000627:therapeutic use
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011239:Prednisolone