A Randomized Trial of Fludarabine and Mitoxantrone Plus Rituximab vs CHOP Plus Rituximab as First-Line Treatment in Patients With Follicular Lymphoma

The FM (fludarabine [Fludara], mitoxantrone [Novantrone]) combination is an effective strategy in follicular lymphoma. From October 1999, patients from 12 Italian centers were randomized for a comparative study of FM vs CHOP (cyclophosphamide [Cytoxan, Neosar], doxorubicin HCl, vincristine [Oncovin], prednisone) chemotherapy with the addition of rituximab (Rituxan) in selected cases.

To be eligible, patients were required to have a histologically proven diagnosis of CD20-positive follicular lymphoma, according to the Revised European-American Lymphoma (REAL) classification, and a positive polymerase chain reaction (PCR) analysis (bone marrow and/or peripheral blood) for bcl-2/IgH. Patients were required to be between 15 and 70 years old, to be in stage II-IV, and to have an Eastern Cooperative Oncology Group performance status of 0 or 1.

After randomization, patients were allocated to the FM arm (fludarabine at 25 mg/m²/d IV on days 1 to 5 and mitoxantrone at 10 mg/m² IV on day 1) or the CHOP arm (doxorubicin at 50 mg/m² IV on day 1, cyclophosphamide at 750 mg/m² IV on day 1, vincristine at 1.4 mg/m² IV on day 1, and prednisone at 100 mg/d orally on days 1 to 5). In both arms, patients were assigned to receive six cycles of chemotherapy. Thereafter, to be eligible for rituximab treatment, they had to have partial (PR) or complete clinical response (CR) and still be PCR positive in the bone marrow and/or peripheral blood in two molecular analyses performed 4 and 6 weeks after the sixth cycle. These patients were elected to receive four weekly IV infusions of rituximab (375 mg/m²).

Clinical response to treatment was defined according three categories: CR, PR, and failure. Of 102 patients registered, 69 were evaluable for response after completion of chemotherapy. The CR, PR, and failure rates were, respectively, 64%, 31%, and 6% in the FM arm (36 patients) vs 42%, 28%, and 9% in the CHOP arm (33 patients); P = .07 for CR. The molecular evaluation documented the clearance of the bcl-2/IgH chimeric gene in 34% and 10% for the FM and CHOP regimens, respectively (P = .007). After the rituximab courses, molecular evaluation documented clearance in 71% and 44% for the FM and CHOP subsets, respectively, with measurable improvement of the clinical response in 50% of the PR patients.

CONCLUSION: These results confirm the efficacy of FM for untreated FL patients in terms of clinical and molecular response, and also the role of rituximab in improving molecular and/or clinical response when added to chemotherapy for first-line treatment of FL.

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