The Addition of Rituximab to Combination Chemotherapy With Fludarabine, Cyclophosphamide, Mitoxantrone-Results of a Prospective Randomized Comparison by the German Low Grade Study Group

March 1, 2002

Rituximab (Rituxan) has shown high activity in relapsed follicular lymphomas when given alone, and phase II studies indicate that its addition to chemotherapy may further improve response rates substantially. Because prospective randomized studies have not been available so far, the German Low Grade Study Group (GLSG) started a multicenter national trial in patients with relapsed or refractory follicular cell lymphoma (FCL) or mantle cell lymphoma (MCL). As patients were treated for first-line therapy with CHOP (cyclophosphamide [Cytoxan, Neosar], doxorubicin HCl, vincristine [Oncovin], prednisone), the FCM (fludarabine [Fludara], cyclophosphamide, mitoxantrone [Novantrone]) combination was chosen for salvage chemotherapy.

Rituximab (Rituxan) has shown high activity in relapsed follicular lymphomaswhen given alone, and phase II studies indicate that its addition tochemotherapy may further improve response rates substantially. Becauseprospective randomized studies have not been available so far, the German LowGrade Study Group (GLSG) started a multicenter national trial in patients withrelapsed or refractory follicular cell lymphoma (FCL) or mantle cell lymphoma(MCL). As patients were treated for first-line therapy with CHOP(cyclophosphamide [Cytoxan, Neosar], doxorubicin HCl, vincristine [Oncovin],prednisone), the FCM (fludarabine [Fludara], cyclophosphamide, mitoxantrone[Novantrone]) combination was chosen for salvage chemotherapy.

The FCM combination included fludarabine at 25 mg/m2 days 1-3,cyclophosphamide at 200 mg/m2 days 1-3, and mitoxantrone at 8 mg/m² day 1.This treatment was repeated for four cycles every 28 days. Patients wereprospectively randomized to FCM alone or FCM plus rituximab at 375 mg/m² on theday before FCM therapy. Since November 1998, 147 cases were randomized, 80 ofwhom are currently evaluable for response. A total of 43 patients had FCL, and27 patients were diagnosed with MCL, and 10 patients presented with lymphocyticlymphoma. Statistically, both treatment arms were monitored by sequentialtesting, which indicated a significant difference between both treatment arms asof June 2001.

In patients treated with FCM alone 53% complete and partial remissions wereobserved (15% CR, 38% PR), whereas in the group receiving FCM plus rituximab anoverall response rate of 89% was obtained (36% CR, 53% PR) (P = .000715).Similar improvements in remission rates were detected in FCL (95% vs 68%) aswell as in MCL (77% vs 27%). Both treatment options were associated withhematologic toxicities of grades 2 to 4, but were well tolerated. Only onetreatment-related death was observed in the rituximab plus FCM arm, and three inthe FCM arm.

CONCLUSION: This study is, to our knowledge, the first prospective randomizedtrial investigating the addition of rituximab to combination chemotherapy in FCLand MCL. It demonstrates a significant improvement of the combined strategy inpatients with relapsed or refractory disease.

Click here to read Dr. Bruce Cheson's commentary on this abstract.