Olivier Hermine1, Eva Hoster2, Jan Walewski3, André Bosly4, Stephan Stilgenbauer5, Catherine Thieblemont6, Michal Szymczyk3, Reda Bouabdallah7, Michael Kneba8, Michael Hallek9, Gilles Salles10, Pierre Feugier11, Vincent Ribrag12, Josef Birkmann13, Roswitha Forstpointner14, Corinne Haioun15, Mathias Hänel16, René Olivier Casasnovas17, Jürgen Finke18, Norma Peter19, Kamal Bouabdallah20, Catherine Sebban21, Thomas Fischer22, Ulrich Dührsen23, Bernd Metzner24, Georg Maschmeyer25, Lothar Kanz26, Christian Schmidt14, Richard Delarue27, Nicole Brousse28, Wolfram Klapper29, Elizabeth Macintyre30, Marie-Hélène Delfau-Larue31, Christiane Pott8, Wolfgang Hiddemann14, Michael Unterhalt14, Martin Dreyling32. 1. 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. 2. 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. 3. Department of Lymphoid Malignancies, The Maria Skłodowska-Curie Memorial Cancer Centre and Institute of Oncology, Warsaw, Poland. 4. Louvain Catholic University, Namur University Hospital, Namur, Belgium. 5. Department of Internal Medicine, University of Ulm, Ulm, Germany. 6. APHP-Saint-Louis Hospital, Hemato-oncology Department, Paris, France. 7. Department of Hematology, Institut Paoli-Calmettes, Marseille, France. 8. Second Medical Department, University Hospital Schleswig-Holstein, Kiel, Germany. 9. Department I of Internal Medicine, University of Cologne, Cologne, Germany. 10. Hospices Civils de Lyon, Université Claude Bernard, Centre Hospitalier Lyon-Sud, Pierre Bénite, France. 11. Nancy University Hospital, Department of Hematology, Nancy, France. 12. Institut Gustave Roussy, Villejuif, France. 13. Department of Oncology, Paracelsus Medical University, Nuremberg, Germany. 14. Department of Internal Medicine III, Ludwig-Maximilians-University Hospital Munich, Munich, Germany. 15. Lymphoid Malignancies Unit, Hospital Henri Mondor, Créteil, France. 16. Department of Internal Medicine III, Klinikum Chemnitz, Germany. 17. Hematologie Clinique, CHU Dijon, Dijon, France. 18. Department of Hematology and Oncology, University Hospital Freiburg, Freiburg, Germany. 19. Second Medical Department, Carl-Thiem-Klinikum Cottbus, Cottbus, Germany. 20. Department of Hematology and Cell Therapy, University Hospital of Bordeaux, Pessac, France. 21. Department of Haematology, Centre Léon Bérard, Lyon, France. 22. Department of Hematology and Oncology, University Hospital Magdeburg, Magdeburg, Germany. 23. Department of Hematology, University Hospital Essen, Essen, Germany. 24. Department of Hematology and Oncology, University Hospital Oldenburg, Oldenburg, Germany. 25. Department of Hematology, Oncology and Palliative Medicine, Ernst-von-Bergmann-Hospital, Potsdam, Germany. 26. Department of Medicine II, University of Tübingen, Tübingen, Germany. 27. Department of Hematology, Hôpital Necker, Assistance Publique Hôpitaux de Paris, University Paris Descartes, Paris, France. 28. Department of Pathology, Hôpital Necker, Assistance Publique Hôpitaux de Paris, University Paris Descartes, Paris, France. 29. Department of Pathology, Hematopathology Section, and Lymph Node Registry, University of Kiel, Kiel, Germany. 30. Department of Biological Hematology, Hôpital Necker, Assistance Publique Hôpitaux de Paris, University Paris Descartes, Paris, France. 31. Department of Biological Hematology and Immunology, Henri-Mondor Hospital, Assistance Publique-Hôpitaux de Paris, INSERM U955, UPEC University, Creteil, France. 32. Department of Internal Medicine III, Ludwig-Maximilians-University Hospital Munich, Munich, Germany. Electronic address: Martin.Dreyling@med.uni-muenchen.de.
Abstract
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. FINDINGS: 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 thecytarabine 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. INTERPRETATION: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. FUNDING: European Commission, Lymphoma Research Foundation, and Roche.
RCT Entities:
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. FINDINGS: 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. INTERPRETATION: 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. FUNDING: European Commission, Lymphoma Research Foundation, and Roche.
Authors: Jeff D Wang; Samuel G Katz; Elizabeth A Morgan; David T Yang; Xueliang Pan; Mina L Xu Journal: Hum Pathol Date: 2019-08-16 Impact factor: 3.466
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