Adding Anti-CD20 Antibody to First-Line Chemotherapy Improves Response in Previously Untreated NHL

PHILADELPHIA-The combination of fludarabine (Fludara) and mitoxantrone(Drug information on mitoxantrone) (Novantrone), the FM regimen, has demonstrated high response rates in newly diagnosed follicular lymphoma.[1] Previous studies with this combination chemotherapy have shown overall response rates ranging from 55% in intermediate/ high-grade non-Hodgkin's lymphoma (NHL) to 89% in low-grade NHL.[2,3] Adding rituximab(Drug information on rituximab) (Rituxan), a Bcell- depleting, anti-CD20 antibody, may further increase response rates while adding little additional toxicity to the FN regimen. This hypothesis was tested by Stephanie A. Gregory, MD, and colleagues at Rush-Presbyterian- St. Luke's Medical Center in Chicago, Boston Baskin Cancer Group in Memphis, and the Community Hospital of Munster, Indiana. Dr. Gregory reported that the FN regimen followed by rituximab achieves high response rates in previously untreated patients with lowgrade, advanced NHL (ASH poster 1401).[4] Phase II Study This phase II study evaluated and reported on 41 patients with CD20+ previously untreated NHL. Histologic diagnosis showed that 11 patients (27%) had small lymphocytic lymphoma; 18 (44%) had follicular small cleaved lymphoma; 6 (15%) had fol- licular mixed lymphoma; 3 (7%) had maltoma; 2 (5%) had mantle cell lymphoma; and 1 (2%) had marginal zone lymphoma. Patients were treated with four to six cycles (28 days per cycle) of fludarabine (25 mg/m² on days 1 to 3) and mitoxantrone (12 mg/m² on day 1) with no prophylactic antibiotic therapy. Patients who achieved a complete response after four or six cycles of the FN regimen received rituximab (375 mg/m²/week for 4 weeks) 4 to 6 weeks after cessation of chemotherapy. All patients had a Karnofsky performance status greater than or equal to 70. Overall, 33 patients (80%) had stage IV disease, 3 (8%) had stage III disease, and 5 (12%) had stage II disease. Clinical Response Of 31 evaluable patients, 30 (97%) achieved a clinical response, including 14 (45%) complete responses and 16 (52%) partial responses. These responses have been durable, with 50% of patients who achieved a complete response remaining in remission for more than 24 months and 31% of patients who achieved a partial response remaining in remission for more than 12 months. Serious adverse events reported during the study included grade 3 and 4 neutropenia (n = 64 events in 163 chemotherapy cycles), neutropenic fever (n = 7), dyspnea (n = 2), retinal detachment (n = 1), and thrombus formation (n = 1). Three patients required a 25% dose adjustment for prolonged neutropenia and two patients discontinued because of neutropenia. Although prophylactic antimicrobial therapy was not used, infections were rare, with only one case of pneumonia. Comparison With CHOP Another evaluation of the FN regimen followed by rituximab in treatment of low-grade lymphoma [5] was presented by Pier Luigi Zinzani, MD, on behalf of the Italian Cooperative Study Group on Lymphoma, Institute of Hematology and Medical Oncology, University of Bologna, Italy (ASH abstract 344). In this study, the efficacy and safety of the FM regimen followed by rituximab were compared with the efficacy and safety of cyclophosphamide(Drug information on cyclophosphamide) (Cytoxan, Neosar), doxorubicin(Drug information on doxorubicin), vincristine (Oncovin), and prednisone(Drug information on prednisone) (CHOP) followed by rituximab in patients with previously untreated follicular lymphoma. Patients with a histologically confirmed diagnosis of CD20+ follicular lymphoma (according to Revised European-American Lymphoma [REAL] classification standards) and a positive diagnosis of bcl-2/IgH rearrangement by polymerase chain reaction were randomized to receive six cycles of either fludarabine (25 mg/m²/day IV on days 1 to 3) and mitoxantrone (10 mg/m² IV on day 1) or CHOP (cyclophosphamide 750 mg/m² IV on day 1, doxorubicin 50 mg/m² IV on day 1, vincristine 1.4 mg/m² IV on day 1, and prednisone 100 mg/day on days 1-5). Other inclusion criteria included age 18 to 70 years, stage II to IV disease, and an Eastern Cooperative Oncology Group performance status less than or equal to 2. Patients who achieved partial or complete responses but were still positive in bone marrow and/or peripheral blood (as assessed by polymerase chain reaction at 4 and 6 weeks after chemotherapy) were eligible to receive four cycles of 375 mg/m² IV rituximab per week to determine if rituximab treatment could eliminate minimal residual disease. Of 159 randomized patients, 93 were evaluable for response. Rituximab improved the clinical and molecular response rates for both treatment regimens. The results are presented in Table 1.[5] These results suggest that the FM regimen may be more effective than CHOP for first-line treatment of patients with follicular lymphoma, and that addition of rituximab to either chemotherapy regimen improves response, in some cases dramatically. Further evaluation will be necessary to confirm these results. Overall, these studies show that the combination of FM followed by rituximab is a very promising regimen that leads to high response rates and durable remissions in previously untreated patients with low-grade or follicular NHL.