Addition of high-dose cytarabine to immunochemotherapy before autologous stem-cell transplantation in patients aged 65 years or younger with mantle cell lymphoma (MCL Younger): a randomised, open-label, phase 3 trial of the European Mantle Cell Lymphoma Network.
BACKGROUND
Mantle cell lymphoma is characterised by a poor long-term prognosis. The European Mantle Cell Lymphoma Network aimed to investigate whether the introduction of high-dose cytarabine to immunochemotherapy before autologous stem-cell transplantation (ASCT) improves outcome.


METHODS
This randomised, open-label, parallel-group, phase 3 trial was done in 128 haemato-oncological hospital departments or private practices in Germany, France, Belgium, and Poland. Patients aged 65 years or younger with untreated stage II-IV mantle cell lymphoma were centrally randomised (1:1), with computer-assisted random block selection, to receive either six courses of R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) followed by myeloablative radiochemotherapy and ASCT (control group), or six courses of alternating R-CHOP or R-DHAP (rituximab plus dexamethasone, high-dose cytarabine, and cisplatin) followed by a high-dose cytarabine-containing conditioning regimen and ASCT (cytarabine group). Patients were stratified by study group and international prognostic index. The primary outcome was time to treatment failure from randomisation to stable disease after at least four induction cycles, progression, or death from any cause. Patients with stage II-IV mantle cell lymphoma were included in the primary analysis if treatment was started according to randomisation. For safety analyses, patients were assessed according to the treatment actually started. This study is registered with ClinicalTrials.gov, number NCT00209222.


RESULTS
Of 497 patients (median age 55 years [IQR 49-60]) randomised from July 20, 2004, to March 18, 2010, 234 of 249 in the control group and 232 of 248 in the cytarabine group were included in the primary analysis. After a median follow-up of 6.1 years (95% CI 5.4-6.4), time to treatment failure was significantly longer in the cytarabine group (median 9.1 years [95% CI 6.3-not reached], 5 year rate 65% [95% CI 57-71]) than in the control group (3.9 years [3.2-4.4], 40% [33-46]; hazard ratio 0.56; p=0.038). During induction immunochemotherapy, patients who received high-dose cytarabine had increased grade 3 or 4 haematological toxicity (haemoglobin 71 [29%] of 241m vs 19 [8%] of 227 controls; platelets 176 [73%] of 240 vs 21 [9%] of 225), grade 3 or 4 febrile neutropenia (39 [17%] of 230 vs 19 [8%] of 224), and grade 1 or 2 renal toxicity (creatinine 102 [43%] of 236 vs 22 [10%] of 224). The number of ASCT-related deaths was similar (eight [3.4%]) in both groups.


CONCLUSIONS
Immunochemotherapy containing high-dose cytarabine followed by ASCT should be considered standard of care in patients aged 65 years or younger with mantle cell lymphoma.


BACKGROUND
European Commission, Lymphoma Research Foundation, and Roche.
Department of Hematology, Hôpital Necker, Assistance Publique Hôpitaux de Paris, University Paris Descartes, Paris, France; INSERM U1163 and CNRS 8254, Imagine Institute, Université Sorbonne Paris Cité, Paris, France.
Olivier
O
Hermine
Department of Internal Medicine III, Ludwig-Maximilians-University Hospital Munich, Munich, Germany; Institute of Medical Informatics, Biometry, and Epidemiology, Ludwig-Maximilians-University of Munich, Munich, Germany.
Eva
E
Hoster
Department of Lymphoid Malignancies, The Maria Skłodowska-Curie Memorial Cancer Centre and Institute of Oncology, Warsaw, Poland.
Jan
J
Walewski
Louvain Catholic University, Namur University Hospital, Namur, Belgium.
André
A
Bosly
Department of Internal Medicine, University of Ulm, Ulm, Germany.
Stephan
S
Stilgenbauer
APHP-Saint-Louis Hospital, Hemato-oncology Department, Paris, France.
Catherine
C
Thieblemont
Department of Lymphoid Malignancies, The Maria Skłodowska-Curie Memorial Cancer Centre and Institute of Oncology, Warsaw, Poland.
Michal
M
Szymczyk
Department of Hematology, Institut Paoli-Calmettes, Marseille, France.
Reda
R
Bouabdallah
Second Medical Department, University Hospital Schleswig-Holstein, Kiel, Germany.
Michael
M
Kneba
Department I of Internal Medicine, University of Cologne, Cologne, Germany.
Michael
M
Hallek
Hospices Civils de Lyon, Université Claude Bernard, Centre Hospitalier Lyon-Sud, Pierre Bénite, France.
Gilles
G
Salles
Nancy University Hospital, Department of Hematology, Nancy, France.
Pierre
P
Feugier
Institut Gustave Roussy, Villejuif, France.
Vincent
V
Ribrag
Department of Oncology, Paracelsus Medical University, Nuremberg, Germany.
Josef
J
Birkmann
Department of Internal Medicine III, Ludwig-Maximilians-University Hospital Munich, Munich, Germany.
Roswitha
R
Forstpointner
Lymphoid Malignancies Unit, Hospital Henri Mondor, Créteil, France.
Corinne
C
Haioun
Department of Internal Medicine III, Klinikum Chemnitz, Germany.
Mathias
M
Hänel
Hematologie Clinique, CHU Dijon, Dijon, France.
René Olivier
RO
Casasnovas
Department of Hematology and Oncology, University Hospital Freiburg, Freiburg, Germany.
Jürgen
J
Finke
Second Medical Department, Carl-Thiem-Klinikum Cottbus, Cottbus, Germany.
Norma
N
Peter
Department of Hematology and Cell Therapy, University Hospital of Bordeaux, Pessac, France.
Kamal
K
Bouabdallah
Department of Haematology, Centre Léon Bérard, Lyon, France.
Catherine
C
Sebban
Department of Hematology and Oncology, University Hospital Magdeburg, Magdeburg, Germany.
Thomas
T
Fischer
Department of Hematology, University Hospital Essen, Essen, Germany.
Ulrich
U
Dührsen
Department of Hematology and Oncology, University Hospital Oldenburg, Oldenburg, Germany.
Bernd
B
Metzner
Department of Hematology, Oncology and Palliative Medicine, Ernst-von-Bergmann-Hospital, Potsdam, Germany.
Georg
G
Maschmeyer
Department of Medicine II, University of Tübingen, Tübingen, Germany.
Lothar
L
Kanz
Department of Internal Medicine III, Ludwig-Maximilians-University Hospital Munich, Munich, Germany.
Christian
C
Schmidt
Department of Hematology, Hôpital Necker, Assistance Publique Hôpitaux de Paris, University Paris Descartes, Paris, France.
Richard
R
Delarue
Department of Pathology, Hôpital Necker, Assistance Publique Hôpitaux de Paris, University Paris Descartes, Paris, France.
Nicole
N
Brousse
Department of Pathology, Hematopathology Section, and Lymph Node Registry, University of Kiel, Kiel, Germany.
Wolfram
W
Klapper
Department of Biological Hematology, Hôpital Necker, Assistance Publique Hôpitaux de Paris, University Paris Descartes, Paris, France.
Elizabeth
E
Macintyre
Department of Biological Hematology and Immunology, Henri-Mondor Hospital, Assistance Publique-Hôpitaux de Paris, INSERM U955, UPEC University, Creteil, France.
Marie-Hélène
MH
Delfau-Larue
Second Medical Department, University Hospital Schleswig-Holstein, Kiel, Germany.
Christiane
C
Pott
Department of Internal Medicine III, Ludwig-Maximilians-University Hospital Munich, Munich, Germany.
Wolfgang
W
Hiddemann
Department of Internal Medicine III, Ludwig-Maximilians-University Hospital Munich, Munich, Germany.
Michael
M
Unterhalt
Department of Internal Medicine III, Ludwig-Maximilians-University Hospital Munich, Munich, Germany. Electronic address: Martin.Dreyling@med.uni-muenchen.de.
Martin
M
Dreyling
D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D003131:Combined Modality Therapy; D003520:Cyclophosphamide / Q000627:therapeutic use; D003561:Cytarabine / Q000008:administration & dosage* / Q000009:adverse effects; D004317:Doxorubicin / Q000627:therapeutic use; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000009:adverse effects; D007167:Immunotherapy; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D011241:Prednisone / Q000627:therapeutic use; D019172:Transplantation Conditioning; D017211:Treatment Failure; D014750:Vincristine / Q000627:therapeutic use
D007166:Immunosuppressive Agents; D003561:Cytarabine; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone