Rituximab after lymphoma-directed conditioning and allogeneic stem-cell transplantation for relapsed and refractory aggressive non-Hodgkin lymphoma (DSHNHL R3): an open-label, randomised, phase 2 trial.
BACKGROUND
Allogeneic stem-cell transplantation has had limited success for patients with refractory and relapsed aggressive B-cell or T-cell lymphoma. We investigated the effect of adding rituximab to standard prophylaxis for graft-versus-host disease after transplantation and estimated overall survival when using a lymphoma-directed myeloablative conditioning regimen.


METHODS
We did this randomised, open-label, phase 2 study at seven German transplantation centres. We enrolled patients with aggressive B-cell or T-cell lymphoma and primary refractory disease, early relapse (<12 months after first-line treatment), or relapse after autologous transplantation. Conditioning with fludarabine (125 mg/m(2)), busulfan (12 mg/kg oral or 9·6 mg/kg intravenous), and cyclophosphamide (120 mg/kg) was followed by allogeneic stem-cell transplantation. Patients were randomly assigned (1:1) to receive rituximab (375 mg/m(2) on days 21, 28, 35, 42, 175, 182, 189, and 196) or not. Allocation was done with a centralised computer-generated procedure; patients were stratified by histological subtype (B-cell vs T-cell lymphoma) and donor match (HLA-identical vs non-identical). Neither investigators nor patients were masked to allocation. The primary endpoints were the incidence of acute graft-versus-host disease grade 2-4 in each treatment group and overall survival at 1 year in both groups combined. All analyses were done for the intention-to-treat population. The study is registered with ClinicalTrials.gov, number NCT00785330.


RESULTS
Between June 16, 2004, and March 24, 2009, we screened 86 patients and enrolled 84; 42 were randomly assigned to each group. The cumulative incidence of grade 2-4 acute graft-versus-host disease was 46% (95% CI 32-62) in the rituximab group and 42% (95% CI 29-59) in the no rituximab group (hazard ratio [HR] 0·91, 95% CI 0·52-1·60; p=0·74). Overall survival at 1 year for the whole study population was 52% (95% CI 41-62). Grade 4 haematological toxic effects and grade 3 alopecia occurred in all patients. The most common non-haematological grade 5 toxic effects were pneumonia (nine in the no rituximab group vs ten in the rituximab group) and other infections (seven vs four).


CONCLUSIONS
The lymphoma-directed myeloablative conditioning regimen developed here is promising for patients with refractory and relapsed aggressive B-cell and T-cell lymphomas. However, the addition of rituximab did not affect the incidence of graft-versus-host disease or overall survival.


BACKGROUND
Hoffmann-La Roche, Amgen, Astellas Pharma.
Department of Hematology, Oncology and Stem Cell Transplantation, Asklepios Hospital St Georg, Hamburg, Germany.
Bertram
B
Glass
Department of Hematology & Oncology, University Medicine Goettingen, Goettingen, Germany.
Justin
J
Hasenkamp
Department of Hematology & Oncology, University Medicine Goettingen, Goettingen, Germany.
Gerald
G
Wulf
Department of Medicine V, University of Heidelberg, Heidelberg, Germany.
Peter
P
Dreger
Department of Internal Medicine I, Saarland University Medical School, Homburg/Saar, Germany.
Michael
M
Pfreundschuh
Medical Clinic II, Section for Stem Cell Transplantation and Immunotherapy, University Clinic Schleswig-Holstein, Kiel, Germany.
Martin
M
Gramatzki
Center for Bone Marrow Transplantation, University Clinic Muenster, Muenster, Germany.
Gerda
G
Silling
Clinic for Hematology, Oncology and Immunology, University Clinic Giessen and Marburg, Marburg, Germany.
Christian
C
Wilhelm
Department of Hematology, Oncology and Stem Cell Transplantation, Asklepios Hospital St Georg, Hamburg, Germany.
Matthias
M
Zeis
Institute of Application-oriented Research and Clinical Trials, University Medicine Goettingen, Goettingen, Germany.
Anke
A
Görlitz
Institute of Application-oriented Research and Clinical Trials, University Medicine Goettingen, Goettingen, Germany.
Sebastian
S
Pfeiffer
Institute of Medical Statistics, University Medicine Goettingen, Goettingen, Germany.
Reinhard
R
Hilgers
Department of Hematology & Oncology, University Medicine Goettingen, Goettingen, Germany.
Lorenz
L
Truemper
Department of Hematology, Oncology and Stem Cell Transplantation, Asklepios Hospital St Georg, Hamburg, Germany. Electronic address: n.schmitz@asklepios.com.
Norbert
N
Schmitz
D000328:Adult; D058846:Antibodies, Monoclonal, Murine-Derived / Q000009:adverse effects / Q000627:therapeutic use*; D003131:Combined Modality Therapy; D005260:Female; D006086:Graft vs Host Disease / Q000209:etiology; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects; D006801:Humans; D008228:Lymphoma, Non-Hodgkin / Q000401:mortality / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D012008:Recurrence; D000069283:Rituximab; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous
D058846:Antibodies, Monoclonal, Murine-Derived; D000069283:Rituximab