A Multicenter Randomized Trial of Fludarabine and Mitoxantrone (FM) Plus Rituximab Versus CHOP Plus Rituximab as First-Line Treatment in Patients with Follicular Lymphoma (FL)

Reviewer: Ryan Smith, MD
Last Modified: December 9, 2002

Presenter: Pier Luigi Zinzani
Presenter's Affiliation: Italian Cooperative Study Group on Lymphoma
Type of Session: Scientific


    Follicular lymphoma is a low grade lymphoma that typically has a smoldering disease course. Many patients progress to more advanced disease with symptomatic problems. Different therapies have been employed in this case with various results. For example, historical results from CHOP chemotherapy has ranged from 15%-80% response rates. This study was done to compare CHOP chemotherapy with Fludarabine + Mitoxantrone chempotherapy, with adjuvant rituximab in both arms to determine the efficacy of these treatments.

Materials and Methods

  • 159 patients with CD-20 positive, Grade I-II follicular lymphoma comprised the study group.
  • Patients were required to be positive for the Bcl-2/IgH chimeric gene with Stage II-IV disease and an ECOG performance status of 0-2.
  • 66% of patients had stage IV disease with 60% with bone marrow involvement.
  • Fludarabine + Mitoxantrone (FM) group: Fludarabine 25 mg/m2/day days 1-3, mitoxantrone 10 mg/m2 day 1
  • CHOP group: doxorubicin 50 mg/m2 on day 1, cyclophosphamide 750 mg/m2 on day 1, vincristine 1.4 mg/m2 on day 1, prednisone 100 mg/day days 1-5.
  • Patients were restaged after 3 cycles. Those few patients without response were allowed to crossover
  • Patients received 6 cycles total. Those with PR/CR were eligible to receive 4 weekly doses of rituximab (375 mg/m2)
  • Endpoints of the study thus far were CR, PR, molecular response, and failure.


  • CR rates for the FM group was 67% vs. 38% for the CHOP group
  • Molecular response (representing the clearance of the Bcl-2/IgH chimeric gene) was 36% in the FM group vs. 20% in the CHOP group
  • After the addition of rituximab, the CR rate increased from 67% to 88% in the FM group and from 38% to 70% in the CHOP group
  • After the addition of rituximab, the molecular response rate increased from 36% to 58% in the FM group and from 20% to 42% in the CHOP group
  • Grade 3/4 toxicity was rare in each group, and nonhematologic toxicity was also mild
  • Patients in the CHOP group experienced more Grade 2 toxicity (55% nausea/vomiting, 95% alopecia, 45% peripheral neurotoxicity, and 38% constipation)

Author's Conclusions

  • This study demonstrates the efficacy of FM in terms of clinical CR and molecular response. The responses were greater in the FM group with less toxicity
  • The role of rituximab is demonstarted to be very important via CR rates and molecular response

Clinical/Scientific Implications

    The standard of care in the United States for patients with advanced stage low grade lymphomas is usually observation with treatment with chemotherapy for symptomatic disease. The chemotherapy employed is usually very tolerable chemotherapy, much like fludarabine. This study demonstrates the efficacy tolerable FM chemotherapy in this situation over a more aggressive CHOP regimen. The response rates in this regimen show that it should continue to be employed in this situation. Also, the use of rituximab demonstrates a high efficacy, increasing the CR rates and molecular response rates in both treatment arms. In fact, rituximab increases these rates to almost make up for the lack of efficacy in the CHOP arm. This points to the fact that rituximab alone may be used in the future to obtain responses and perhaps symptomatic relief, which could be studied next. Although symptomatology (which is the most common reason for treatment in the United States) was not shown in this presentation, given the amount of stage IV disease and bone marrow involvement, it is likely that most patients did have symptoms related to their disease. Finally, though these data are impressive, it should be pointed out that these are response data only, and no follow up data or reports on outcome or survival are shown. Therefore, the effect of these modalities on these important endpoints are not known.

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