Induction Chemotherapy (R-CHOP Vs. R-FC) Followed by Interferon Maintenance Versus Rituximab Maintenance in MCL

The aim of this study is to answer the following independent questions in the treatment of mantle cell lymphomas: * Can rituximab-fludarabine, cyclophosphamide (R-FC) improve the reduction of lymphoma mass compared to rituximab-cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP) and so become a new standard for initial cytoreductive therapy? * Can maintenance with rituximab substitute the interferon maintenance and even improve the progression free survival in patients after successful initial cytoreductive therapy?

Sex

All

Minimum age

60 Years

Inclusion Criteria:

* Histologically proven mantle cell lymphoma according to the World Health Organization (WHO) classification, preferably confirmed by central pathology review before entering the study
* Clinical stage II, III or IV
* Previously untreated patients
* Above the age of 65 years and older or patients at the age between 60 and 65, if not eligible for high dose chemotherapy
* WHO performance grade 0, 1 or 2
* Informed consent according to International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use/European Union Good Clinical Practice (ICH/EU GCP) and national/local regulations
* Measurable disease. If, for example only bone marrow (BM) infiltration, patients can only undergo a second randomization if a CR is obtained.

Exclusion Criteria:

* WHO performance of 3 or more
* Known anti-murine antibody (HAMA) reactivity or known hypersensitivity to murine antibodies
* Leukocytes \<2.0x 10\^9/l or thrombocytes \<100x 10\^9/l, unless clearly related to mantle cell lymphoma (MCL) bone marrow infiltration
* Patients previously treated for lymphoma
* Patients without measurable lesions; if, for example only bone marrow infiltration, patients may be included, but can only undergo a second randomization in case of a CR
* Patients with stage I disease
* Patients with central nervous system involvement
* Patients with a history of autoimmune hemolytic anaemia or autoimmune thrombocytopenia
* Patients with serious cardiac disease (uncontrolled arrhythmias, unstable angina, severe congestive heart failure)
* Patients with serious pulmonary, neurological, endocrinological or other disorder interfering with full dosing of CHOP or FC chemotherapy
* Liver enzymes \>3x normal or bilirubin \>2.5x normal (not due to lymphoma)
* Creatinine \>2x normal value, corrected for age and weight (not due to lymphoma)
* Patients with unresolved hepatitis B or C infection or known HIV positive infection
* Uncontrolled infection
* Patients with a serious depression that needed therapy within the last 5 years
* Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule
* Concomitant or previous malignancies other than basal cell or squamous cell skin cancer, in situ cervical cancer and other cancer for which the patient has been disease-free for at least 5 years

• RESULTKluin-Nelemans HC, Hoster E, Hermine O, Walewski J, Trneny M, Geisler CH, Stilgenbauer S, Thieblemont C, Vehling-Kaiser U, Doorduijn JK, Coiffier B, Forstpointner R, Tilly H, Kanz L, Feugier P, Szymczyk M, Hallek M, Kremers S, Lepeu G, Sanhes L, Zijlstra JM, Bouabdallah R, Lugtenburg PJ, Macro M, Pfreundschuh M, Prochazka V, Di Raimondo F, Ribrag V, Uppenkamp M, Andre M, Klapper W, Hiddemann W, Unterhalt M, Dreyling MH. Treatment of older patients with mantle-cell lymphoma. N Engl J Med. 2012 Aug 9;367(6):520-31. doi: 10.1056/NEJMoa1200920. PMID 22873532
• DERIVEDHoster E, Delfau-Larue MH, Macintyre E, Jiang L, Stilgenbauer S, Vehling-Kaiser U, Salles G, Thieblemont C, Tilly H, Wirths S, Feugier P, Hubel K, Schmidt C, Ribrag V, Kluin-Nelemans JC, Dreyling M, Pott C; European MCL MRD Working Group and the European MCL Network. Predictive Value of Minimal Residual Disease for Efficacy of Rituximab Maintenance in Mantle Cell Lymphoma: Results From the European Mantle Cell Lymphoma Elderly Trial. J Clin Oncol. 2024 Feb 10;42(5):538-549. doi: 10.1200/JCO.23.00899. Epub 2023 Nov 22. PMID 37992261
• DERIVEDKluin-Nelemans HC, Hoster E, Hermine O, Walewski J, Geisler CH, Trneny M, Stilgenbauer S, Kaiser F, Doorduijn JK, Salles G, Szymczyk M, Tilly H, Kanz L, Schmidt C, Feugier P, Thieblemont C, Zijlstra JM, Ribrag V, Klapper W, Pott C, Unterhalt M, Dreyling MH. Treatment of Older Patients With Mantle Cell Lymphoma (MCL): Long-Term Follow-Up of the Randomized European MCL Elderly Trial. J Clin Oncol. 2020 Jan 20;38(3):248-256. doi: 10.1200/JCO.19.01294. Epub 2019 Dec 5. PMID 31804876
• DERIVEDHoster E, Klapper W, Hermine O, Kluin-Nelemans HC, Walewski J, van Hoof A, Trneny M, Geisler CH, Di Raimondo F, Szymczyk M, Stilgenbauer S, Thieblemont C, Hallek M, Forstpointner R, Pott C, Ribrag V, Doorduijn J, Hiddemann W, Dreyling MH, Unterhalt M. Confirmation of the mantle-cell lymphoma International Prognostic Index in randomized trials of the European Mantle-Cell Lymphoma Network. J Clin Oncol. 2014 May 1;32(13):1338-46. doi: 10.1200/JCO.2013.52.2466. Epub 2014 Mar 31. PMID 24687837
• DERIVEDPott C, Hoster E, Delfau-Larue MH, Beldjord K, Bottcher S, Asnafi V, Plonquet A, Siebert R, Callet-Bauchu E, Andersen N, van Dongen JJ, Klapper W, Berger F, Ribrag V, van Hoof AL, Trneny M, Walewski J, Dreger P, Unterhalt M, Hiddemann W, Kneba M, Kluin-Nelemans HC, Hermine O, Macintyre E, Dreyling M. Molecular remission is an independent predictor of clinical outcome in patients with mantle cell lymphoma after combined immunochemotherapy: a European MCL intergroup study. Blood. 2010 Apr 22;115(16):3215-23. doi: 10.1182/blood-2009-06-230250. Epub 2009 Dec 23.