Rituximab zur Remissionsinduktion bei rezidivierten und refraktären indolenten Lymphomen und Mantelzell-Lymphomen

Hintergrund und Fragestellung: Eine Monotherapie mit Rituximab ist bei rezidivierten follikulären Lymphomen wirksam. Phase-II-Studien zeigten bei einer Kombination mit Chemotherapie eine wesentliche Verbesserung der Remissionsraten. Bislang gab es hierzu jedoch keine prospektiv randomisierten Studien.

Patienten und Methoden: 1998 wurde die multizentrische Phase-III-Studie der GLSG begonnen. Eingeschlossen waren Patienten mit rezidiviertem oder refraktärem indolentem Lymphom oder Mante^lzell-Lymphom (MCL). Zur Rezidivbehandlung wurde folgende Kombination gewählt: Fludarabin 25 mg/m²/d, Tag 1-3, Cyclophosphamid 200 mg/m²/d, Tag 1-3 und Mitoxantron 8 mg/m²/d an Tag 1 (FCM). Insgesamt wurden vier Zyklen im Abstand von 4 Wochen verabreicht. Die Patienten wurden prospektiv für eine alleinige Therapie mit FCM versus Immunochemotherapie mit R-FCM (375 mg/m² einen Tag vor FCM) randomisiert.

Ergebnisse: Von den 147 Patienten hatten 93 ein follikuläres Lymphom (FL), 40 Patienten ein MCL und 14 Patienten ein lymphoplasmozytisches/-zytoides Lymphom. Eine Zwischenauswertung von 94 evaluierbaren Patienten ergab mit dem sequentiellen Test einen signifikanten Vorteil für den R-FCM-Arm. Hier lag die Ansprechrate bei 83 % gegenüber 58% nach alleiniger Chemotherapie mit 35 % respektive 13 % kompletten Remissionen. Ein ähnlicher Vorteil zeigte sich in der Auswertung der einzelnen Subentitäten, besonders deutlich für die MCL (Ansprechraten: 65 % vs. 33 %). In beiden Therapiearmen traten hämatologische Toxizitäten Grad 3 und 4 auf; infektiöse Komplikationen waren selten und in beiden Gruppen gleichmäßig verteilt.

Folgerungen: Bezogen auf das Gesamtansprechen zeigt diese prospektiv randomisierte Studie erstmals einen signifikanten Vorteil einer kombinierten Immunochemotherapie bei Patienten mit rezidiviertem oder refraktärem indolentem Lymphom auf.

Background and objective: Rituximab has shown a high activity in relapsed follicular lymphomas when given alone. Further on, phase-II-studies indicate that its addition to chemotherapy may improve the response rate substantially. However, so far, prospective randomized studies have not been available.

Patients and methods: In 1998 the GLSG started a multicenter trial in patients with relapsed or refractory indolent lymphoma or mantle cell lymphoma. A fludarabine-containing regimen (FCM) was chosen for salvage therapy, with fludarabine 25 mg/m²/d 1-3, cyclophosphamide 200 mg/m² d 1-3 and mitoxantrone 8 mg/m² d 1. A total of four courses, every 4 weeks were given. Patients were prospectively randomized for FCM alone or the immunochemotherapy with R-FCM (375 mg/m² one day before FCM)

Results: About 147 randomized patients 93 had follicular, 40 mantle cell and 14 lymphoplasmocytic/-cytoid lymphoma. Statistical analysis was performed by sequential testing and indicated for 94 fully evaluable patients a significant advantage for the R-FCM-arm, with an overall response rate of 83 % as compared to 58%, when treated with FCM alone (CR: 35 % vs. 13 %). Similar improvements of remission rate were detected in the different lymphoma subgroups, especially in MCL (OR: 65 % vs. 33 %). Both treatment options were associated with hematological toxicities of grade III and IV, but well tolerated; infectious complications were rare, with no difference between the two treatment groups.

Conclusion: This prospectively randomized trial demonstrates for the first time a significant improvement of the combined immunochemotherapy related to the remission rate in patients with relapsed or refractory indolent lymphoma.

Literatur

• 1 Anderson K C, Bates M P, Slaughenhoupt B L, Pinkus G S, Schlossman S F, Nadler L M. Expression of human B cell-associated antigens on leukemias and lymphomas: a model of human B cell differentiation.  Blood. 1984;  63 1424-1433
• 2 Borisch B, Semac I, Soltermann A, Palomba C, Hoessli D C. Anti-CD20 treatments and the lymphocyte membrane: pathology for therapy.  Verh Dtsch Ges Pathol. 2001;  85 161 166
• 3 Bosch F, Perales M, Cobo F. et al . Fludarabine, cyclophosphamid and mitoxantrone (FCM) therapy in resistant or relapsed chronic lymphocytic leukemia or follicular lymphoma (abstr).  Blood. 1997;  90 2360
• 4 Cartwright R, Brincker H, Carli P M. et al . The rise in incidence of lymphomas in Europe 1985 - 1992.  Eur J Cancer. 1999;  35 627-633
• 5 Chow K U, Sommerlad W D, Boehrer S. et al . Anti-CD20 antibody (IDEC-C2B8, rituximab) enhances efficacy of cytotoxic drugs on neoplastic lymphocytes in vitro: role of cytokines, complement, and caspases.  Haematologica. 2002;  87 33-43
• 6 Coiffier B, Lepage M D, Briere J. et al . CHOP chemotherapy plus Rituximab compared with CHOP alone in elderly patients with diffuse large-b-cell lymphoma.  N Engl J Med. 2002;  346 235-242
• 7 Colombat P, Salles G, Brousse N. et al . Rituximab (anti-CD20 monoclonal antibody) as single first-line therapy for patients with follicular lymphoma with a low tumor burden: clinical and molecular evaluation.  Blood. 2001;  97 101-106
• 8 Czuczman M S. CHOP plus rituximab chemoimmunotherapy of indolent B-cell lymphoma.  Semin Oncol. 1999;  26 88-96 (Suppl 14)
• 9 Czuczman M S. Combination chemotherapy and rituximab.  Anticancer Drugs. 2001;  12 S15-19 (Suppl 2)
• 10 De Vita V, Jaffe E, Mauch P. Lymphocytic lymphomas. Philadelphia, PA: Lippincott-Raven In De Vita VT, Hellman S, RosenbergSA (eds): Cancer: Principlesand Practice of Oncology 1989: 1741-1808
• 11 Emmanouilides C, Rosen P, Telatar M. et al . Excellent tolerance of rituximab when given after mitoxantrone/cyclophosphamide: an effective and safe combination for indolent non-Hodgkin’s lymphoma.  Clin Lymphoma. 2000;  1 146-151; discussion 52-3.
• 12 Falkson C I. Fludarabine: a phase II trial in patients with previously treated low-grade lymphoma.  Am J Clin Oncol. 1996;  19 268-270
• 13 Feuring-Buske M, Kneba M, Unterhalt M. et al . IDEC-C2B8 (Rituximab) anti-CD20 antibody treatment in relapsed advanced-stage follicular lymphomas: results of a phase-II study of the German Low-Grade Lymphoma Study Group.  Ann Hematol. 2000;  79 493-500
• 14 Foran J M, Cunningham D, Coiffier B. et al . Treatment of mantle-cell lymphoma with Rituximab (chimeric monoclonal anti-CD20 antibody): analysis of factors associated with response.  Ann Oncol. 2000;  11 117-121 (Suppl 1)
• 15 Foran J M, Rohatiner A Z, Cunningham D. et al . European phase II study of rituximab (chimeric anti-CD20 monoclonal antibody) for patients with newly diagnosed mantle-cell lymphoma and previously treated mantle-cell lymphoma, immunocytoma, and small B-cell lymphocytic lymphoma.  J Clin Oncol. 2000;  18 317-324
• 16 Ghielmini M, Schmitz S F, Burki K. et al. Swiss Group for Clinical Cancer Research (SAKK) . The effect of Rituximab on patients with follicular and mantle-cell lymphoma.  Ann Oncol. 2000;  11 123-126 (Suppl 1)
• 17 Hainsworth J D. Rituximab as first-line systemic therapy for patients with low-grade lymphoma.  Semin Oncol. 2000;  27 25-29 (Suppl 12)
• 18 Hainsworth J D, Burris H A, Morrissey L H. et al . Rituximab monoclonal antibody as initial systemic therapy for patients with low-grade non-Hodgkin lymphoma.  Blood. 2000;  95 3052-3056
• 19 Hiddemann W, Unterhalt M, Herrmann R. et al . Mantle-cell lymphomas have more widespread disease and a slower response to chemotherapy compared with follicle-center lymphomas: results of a prospective comparative analysis of the German Low-Grade Lymphoma Study Group.  J Clin Oncol. 1998;  16 1922-1930
• 20 Hiddemann W, Unterhalt M, Pott C. et al . Fludarabine single-agent therapy for relapsed low-grade non-Hodgkin’s lymphomas: a phase II study of the German Low-Grade Non-Hodgkin’s Lymphoma Study Group.  Semin Oncol. 1993;  20 28-31 (Suppl 7)
• 21 Hiddemann W, Unterhalt M, Wandt H. et al . Myeloablative radiochemotherapy followed by blood-stemcell-transplantation significantly prolongs the disease-free intervall in patients with low-grade lymphomas as compared to standard maintenance with interferon alpha: results of a prospective randomized comparison by the German Low Grade Lymphoma Study Group (GLSG) (abstr).  Blood. 1999;  94 2715
• 22 Horning S J, Rosenberg S A. The natural history of initially untreated low-grade non-Hodgkin’s lymphomas.  N Engl J Med. 1984;  311 1471-1475 (23)
• 23 Howard O M, Gribben J G, Neuberg D S. et al . Rituximab and CHOP induction therapy for newly diagnosed mantle-cell lymphoma: molecular complete responses are not predictive of progression-free survival.  J Clin Oncol. 2002;  20 1288-1294
• 24 Johnston J B, Verburg L, Shore T, Williams M, Israels L G, Begleiter A. Combination therapy with nucleoside analogs and alkylating agents.  Leukemia. 1994;  S140-143 (Suppl 1)
• 25 Klasa R, Meyer R, Shustik C. et al . Fludarabine versus CVP in previously treated patients with progressive low grade non-Hodgkin`s lymphoma (lg-NHL) (abstr).  Proc Am Soc Clin Oncol. 1999;  18 28
• 26 Lazzarino M, Orlandi E, Montillo M. et al . Fludarabine, cyclophosphamide, and dexamethasone (FluCyD) combination is effective in pretreated low-grade non-Hodgkin’s lymphoma.  Ann Oncol. 1999;  10 59-64
• 27 Lossos I S, Paltiel O, Polliack A. Salvage chemotherapy using a combination of fludarabine and cyclophosphamide for refractory or relapsing indolent and aggressive non-Hodgkin’s lymphomas.  Leuk Lymphoma. 1999;  33 155-160
• 28 Maloney D G, Grillo-Lopez A J, Bodkin D J. et al . IDEC-C2B8: results of a phase I multiple-dose trial in patients with relapsed non-Hodgkin’s lymphoma.  J Clin Oncol. 1997;  15 3266-3274
• 29 Maloney D G, Grillo-Lopez A J, White C A. et al . IDEC-C2B8 (Rituximab) anti-CD20 monoclonal antibody therapy in patients with relapsed low-grade non-Hodgkin’s lymphoma.  Blood. 1997;  90 2188-2195
• 30 McLaughlin P, Grillo-Lopez A J, Link B K. et al . Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program.  J Clin Oncol. 1998;  16 2825-2833
• 31 McLaughlin P, Hagemeister F B, Rodriguez M A. et al . Safety of fludarabine, mitoxantrone, and dexamethasone combined with rituximab in the treatment of stage IV indolent lymphoma.  Semin Oncol. 2000;  27 37-41 (Suppl 12)
• 32 McLaughlin P, Hagemeister F B, Romaguera J E. et al . Fludarabine, mitoxantrone, and dexamethasone: an effective new regimen for indolent lymphoma.  J Clin Oncol. 1996;  14 1262-1268
• 33 McLaughlin P, Hagemeister F B, Swan F. et al . Phase I study of the combination of fludarabine, mitoxantrone, and dexamethasone in low-grade lymphoma.  J Clin Oncol. 1994;  12 575-579
• 34 Micallef I N, Lillington D M, Apostolidis J. et al . Therapy-related myelodysplasia and secondary acute myelogenous leukemia after high-dose therapy with autologous hematopoietic progenitor-cell support for lymphoid malignancies.  J Clin Oncol. 2000;  18 947-955
• 35 Park S, Brice P, Noguerra M E. et al . Myelodysplasias and leukemias after autologous stem cell transplantation for lymphoid malignancies.  Bone Marrow Transplant. 2000;  26 321-326
• 36 Rambaldi A, Lazzari M, Manzoni C. et al . Monitoring of minimal residual disease after CHOP and rituximab in previously untreated patients with follicular lymphoma.  Blood. 2002;  99 856-862
• 37 Reed J C, Kitada S, Kim Y, Byrd J. Modulating apoptosis pathways in low-grade B-cell malignancies using biological response modifiers.  Semin Oncol. 2002;  29 10-24 (Suppl 2)
• 38 Reff M E, Carner K, Chambers K S. et al . Depletion of B cells in vivo by a chimeric mouse human monoclonal antibody to CD20.  Blood. 1994;  83 435-445
• 39 Rohatiner A, Gregory W, Peterson B. et al . A meta-analysis of randomised trials evaluating the role of interferon (IFN) as treatment for follicular lymphoma (FL) (abstr).  Proc Am Soc Clin Oncol. 1998;  17 4a
• 40 Santini G, Contu A, Porcellini A. et al . Mitoxantrone alone or in combination chemotherapy (VeMP) as second-line treatment in relapsed or refractory poor-prognosis non-Hodgkin’s lymphoma. A report of the Non-Hodgkin’s Lymphoma Co-operative Study Group (NHLCSG).  Haematologica. 1991;  76 485-490
• 41 Santini G, Nati S, Spriano M. et al . Fludarabine in combination with cyclophosphamide or with cyclophosphamide plus mitoxantrone for relapsed or refractory low-grade non-Hodgkin’s lymphoma.  Haematologica. 2001;  86 282-286
• 42 Shan D, Ledbetter J A, Press O W. Signaling events involved in anti-CD20-induced apoptosis of malignant human B cells.  Cancer Immunol Immunother. 2000;  48 673-683
• 43 Silver R T, Case D C, Wheeler R H. et al . Multicenter clinical trial of mitoxantrone in non-Hodgkin’s lymphoma and Hodgkin’s disease.  J Clin Oncol. 1991;  9 754-761
• 44 Tobinai K, Kobayashi Y, Narabayashi M. et al. The IDEC-C2B8 Study Group . Feasibility and pharmacokinetic study of a chimeric anti-CD20 monoclonal antibody (IDEC-C2B8, rituximab) in relapsed B-cell lymphoma.  Ann Oncol. 1998;  9 527-534
• 45 Vose J M, Link B K, Grossbard M L. et al . Phase II study of rituximab in combination with chop chemotherapy in patients with previously untreated, aggressive non-Hodgkin’s lymphoma.  J Clin Oncol. 2001;  19 389-397
• 46 Zinzani P L, Tosi P, Visani G. et al . Apoptosis induction with three nucleoside analogs on freshly isolated B- chronic lymphocytic leukemia cells.  Am J Hematol. 1994;  47 301-306