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

• First randomisation: Reduction of lymphoma mass measured by the complete remission (CR) rate
• Second randomisation: progression-free survival after end of initial chemotherapy

• First randomisation: Reduction of lymphoma mass measured by the CR rate
• Second randomisation: progression-free survival after end of initial chemotherapy

• Survival after registration / first randomisation / second randomisation
• Survival after start / end of initial therapy
• Time to treatment failure after start of initial therapy
• Progression free survival after registration / first randomisation / second randomisation
• Side-effects of initial therapy
• Side-effects of maintenance therapy

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?

This study investigates two independent questions in the treatment of elderly patients with mantle cell lymphomas:

1. To test in elderly patients with advanced mantle cell lymphoma, whether rituximab plus a combination of fludarabine with cyclophosphamide (6 FC cycles) results in a higher reduction of lymphoma mass measured by the percentage of CR than rituximab combined with the standard chemotherapy scheme (8 CHOP cycles).
2. To compare maintenance therapy with rituximab with maintenance with interferon-alpha or pegylated interferon for progression free survival, after 2 different regimens of induction chemo-immunotherapy in elderly patients with mantle cell lymphoma.

This study will be performed as a prospective, randomized, open-label multicenter phase III trial. All patients will be randomized for an initial cytoreductive therapy with R-FC or R-CHOP.

The parameter for the comparison of R-FC and R-CHOP will be the percentage of complete remissions after initial cytoreductive therapy. According to the known results of R-FC and R-CHOP in lymphoma therapy, a relevant difference between R-CHOP and R-FC in the overall response rates is not expected. For both therapies an overall response rate of about 90% is expected. Since it is well known that the prognosis of patients who do not reach at least a PR in the initial therapy is very poor, it will be also necessary to control this parameter during the study. If an unexpected relevant difference in the overall response rates is observed during the study, the initial randomisation should be stopped and all patients should be assigned to the superior therapy. In this case the CR rates will not be important for the choice of the initial therapy. If no relevant differences in the overall response rates are observed, a one sided Fisher test will be performed at the end of the recruitment to test whether the rate of CR's after R-FC is significantly improved compared to R-CHOP.

The statistical parameters for controlling the overall response rates and for testing the CR rates are chosen in the following way: The working significance level for all statistical evaluations in this part of the study will be set to alpha=0.05. The expected CR rate after R-CHOP is according to the observations about 50%; a clinical relevant improvement by R-FC would be a CR rate of 65%. Such an improvement should be detected by the one sided Fisher test with a power of about 95%. According to these parameters about 246 observations for each treatment would be necessary. To control the overall response rates, a difference of 85% to 95% will be clinically so relevant that initial randomisation should be terminated with a probability of about 95%. Overall response rates will be controlled by a restricted sequential procedure.

Patients achieving at least a partial remission after R-FC or R-CHOP will be randomised for interferon maintenance versus rituximab maintenance in order to evaluate the impact of maintenance therapy in progression free survival.

The improvement expected by the new maintenance with rituximab for progression free survival can be expressed by reduction of relative risk (rr). Since a risk reduction to 60% was observed for indolent lymphomas by interferon maintenance, this seems to be a clinical relevant improvement for the new maintenance therapy. For a working significance level alpha=0.05 and a power of 95% the number of events (relapse or death) necessary for a two sided fixed sample trial is about 200. During this study the progression free survival in patients after successful initial therapy will be monitored by an equivalent restricted sequential procedure with a maximum number of 240 observation.

In order to evaluate the impact of initial therapy and maintenance therapy on overall survival in this patients, a total follow up of about 15 years for this study is expected.

• Drug: Rituximab
  antibody
• Drug: Cyclophosphamide
  chemotherapy
• Drug: Doxorubicin
  chemotherapy
• Drug: Vincristine
  chemotherapy
• Drug: Prednisone
  coricosteroide
• Drug: Fludarabine
  chemotherapy
• Drug: Interferon-alpha
  cytokine
• Drug: pegylated formula Interferon-alpha 2b
  cytokine
• Procedure: chemotherapy: R-CHOP
  immuno-chemotherapy
• Procedure: chemotherapy: R-FC
  immuno-chemotherapy
• Procedure: Interferon maintenance
  cytokine
• Procedure: Rituximab maintenance
  antibody

• Active Comparator: 1
  1. randomisation: R-CHOP
  2. randomisation: IFN maintenance
  Interventions:

  • Drug: Rituximab
  • Drug: Cyclophosphamide
  • Drug: Doxorubicin
  • Drug: Vincristine
  • Drug: Prednisone
  • Drug: Interferon-alpha
  • Drug: pegylated formula Interferon-alpha 2b
  • Procedure: chemotherapy: R-CHOP
  • Procedure: Interferon maintenance
• Experimental: 2
  1. randomisation: R-FC
  2. randomisation: Rituximab maintnenance
  Interventions:

  • Drug: Rituximab
  • Drug: Cyclophosphamide
  • Drug: Fludarabine
  • Procedure: chemotherapy: R-FC
  • Procedure: Rituximab maintenance

• Lenz G, Dreyling M, Schiegnitz E, Forstpointner R, Wandt H, Freund M, Hess G, Truemper L, Diehl V, Kropff M, Kneba M, Schmitz N, Metzner B, Pfirrmann M, Unterhalt M, Hiddemann W; German Low-Grade Lymphoma Study Group. Myeloablative radiochemotherapy followed by autologous stem cell transplantation in first remission prolongs progression-free survival in follicular lymphoma: results of a prospective, randomized trial of the German Low-Grade Lymphoma Study Group. Blood. 2004 Nov 1;104(9):2667-74. Epub 2004 Jul 6.
• Forstpointner R, Unterhalt M, Dreyling M, Böck HP, Repp R, Wandt H, Pott C, Seymour JF, Metzner B, Hänel A, Lehmann T, Hartmann F, Einsele H, Hiddemann W; German Low Grade Lymphoma Study Group (GLSG). Maintenance therapy with rituximab leads to a significant prolongation of response duration after salvage therapy with a combination of rituximab, fludarabine, cyclophosphamide, and mitoxantrone (R-FCM) in patients with recurring and refractory follicular and mantle cell lymphomas: Results of a prospective randomized study of the German Low Grade Lymphoma Study Group (GLSG). Blood. 2006 Dec 15;108(13):4003-8. Epub 2006 Aug 31.
• Kluin-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, Procházka V, Di Raimondo F, Ribrag V, Uppenkamp M, André 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.
• Hoster 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.
• Pott C, Hoster E, Delfau-Larue MH, Beldjord K, Böttcher 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.

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

• German Low Grade Lymphoma Study Group
• Lymphoma Study Association
• HOVON - Dutch Haemato-Oncology Association
• Nordic Lymphoma Group