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INTRODUCTION

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Rituximab has completely revolutionised our therapeutic paradigms for patients with B-cell malignancies. The results of a pivotal trial including 166 patients previously treated with chemotherapy demonstrated a response rate of 48% including 6% complete remissions (CRs) and a median duration of response of about a year [1]. These data led to the approval of rituximab by regulatory agencies such as the U.S. Food and Drug Administration, beginning in 1997. This level of activity, along with a favourable safety profile, encouraged investigators to identify ways to improve on the potential benefit of this important new agent. The most logical approaches to pursue included using the drug earlier in the course of the disease, or as maintenance following an induction regimen. The data from early studies suggested that the response rate to rituximab was higher in less heavily pre-treated patients [1]. Therefore, several groups studied this agent as initial treatment, primarily for indolent B-cell malignancies. Colombat and colleagues [2] reported their experience with 50 patients designated as having low tumour burden, CD20+ follicular non-Hodgkin’s lymphoma (NHL), characterised by the absence of B symptoms, no tumour mass >7 cm, a normal serum lactate dehydrogenase (LDH) and β2-microglobulin, no splenomegaly or organ compression, and no ascites or pleural effusion. Nevertheless, 46 had stage II or IV disease and two thirds had bone marrow involvement that was low in 45%, intermediate in 41%, and high in 14%. Patients received 4 weekly infusions of rituximab at a dose of 375 mg/m2. The response rate one month after treatment (day 50) was 73%, with 10 patients in CR, 3 patients in complete remission/unconfirmed (CRu), and 23 patients in partial remission; 10 patients had stable disease, and 3 experienced disease progression. One of 13 (8%) patients in CR, 9 of 23 (39%) patients in partial remission, and 5 of 10 (50%) patients with stable disease exhibited disease progression during the first year. There were 32 patients who were initially positive for polymerase chain reaction (PCR) data on bcl-2-J(H) rearrangement. On day 50, 17 of 30 patients (57%) were negative for bcl-2-J(H) rearrangement in peripheral blood, and 9 of 29 (31%) were negative in bone marrow; a significant association was observed between molecular and clinical responses (p < 0.0001). After 12 months, 16 of 26 patients (62%) were PCR negative in the peripheral blood. These results indicate that early molecular responses can be sustained for up to 12 months and that this response is highly correlated with progression-free survival. Thus, rituximab had a high level of clinical activity and a low level of toxicity with a high complete molecular response rate in patients with follicular lymphoma and a low tumour burden. In a recent long-term follow-up update (median 60 months), the overall response rate was 80% with 49% CR/CRu. The median progression-free survival was only 18 months, with a relapse-free survival of 27 months. There was no significant correlation between conversion to bcl-2 negative and relapse-free survival. This lack of durability of the responses in most patients is somewhat disappointing.

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In another trial, Witzig and co-workers [3] treated 37 newly diagnosed patients with advanced stage follicular NHL using 4 weekly infusions of rituximab. Patients were considered to be at low risk, with no B symptoms; 39% were considered low risk by the International Prognostic Index, 44% low-intermediate, and only 17% high-intermediate. The overall response rate was 72% with 36% CRs. The median time to progression was 2.2 years and 18 patients required subsequent treatment with chemotherapy. Patients with an elevated LDH had a poor prognosis with a median time to progression of only 6 months. Grade 3 or worse adverse events occurred in 15% of patients. Based on these ...

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