How Much Rituximab Do We Need: A Multicenter, Randomized Trial Comparing 1, 3 or 6 Infusions of Rituximab Combined with 6 Cycles of CHOP Chemotherapy in Untreated Patients with Advanced Follicular Lymphoma (HD2000-Trial).

The addition of Rituximab to standard chemotherapy has substantially improved the prognosis of NHL. Over the last years, a trend towards intensified protocols with multiple applications of Rituximab has been observed. We are able to report a unique cohort that has also been treated with only 1 or 3 courses of Rituximab within a prospective randomized phase II trial, contrasting current standard procedures.

Between 2000 and 2005, 126 patients (pts) with stage III/ IV CD20+ follicular lymphoma (FL) were randomized in a prospective multicenter trial to receive 1, 3 or 6 courses Rituximab with 6 courses standard CHOP chemotherapy. The primary endpoint was to compare the three treatment arms with regards to molecular remission rates (mRR) among pts with positive PCR at diagnosis. Secondary endpoints were clinical remission rates, progression-free (PFS) and overall-survival (OS) and toxicity. After screening failure (n = 21) or protocol violation (n = 6) had occurred, 99 pts form the base for this analysis. Among those, only 28 pts were PCR positive at start of treatment and met the criteria for inclusion into the primary endpoint analysis.

Due to a limited number of evaluable pts, mRR and duration of molecular remission could not be analyzed. Among 99 pts eligible for the secondary endpoint analysis, 31 received 1 course of Rituximab (arm A), 36 received 3 courses (arm B) and 32 received 6 (arm C). 42% were male. The median age at diagnosis was 56 years (range 23–79). Histological grade was 1 in 49%, 2 in 35% and 3 in 12%. Stage according to Ann Arbor was 3 in 30% and 4 in 70% of pts. B symptoms were present in 36%. According to FLIPI, 21% were classified as low risk (0–1), 39% as intermediate risk (2), and 39% as high risk (3–5). At least one extranodal manifestation was detected in 81 pts, with over 60% of extranodal manifestations being located in the bone marrow. Bulky disease was detected in 57 pts. Following immunochemotherapy, 37% received consolidating involved-field radiotherapy. There was no difference between the three treatment arms with regards to presenting or demographic characteristics (p>.05). Treatment was terminated prematurely in 19 pts due to protocol violation (n = 10), stable disease/ disease progression (n=5), pts′ preference (n = 3) or death (n = 1). After completion of immunochemotherapy, 29 of 99 pts had achieved CR and 58 PR; no or minimal response or progression was observed in 6 pts, and 6 pts were not evaluable. There was no statistically significant difference of clinical remission status between pts in arm A and B compared to those in arm C (p = .66), and between pts in arm B and C compared to arm A (p = .07). There was no trend in clinical remission rates through different courses of Rituximab (p = .09). However, 3 courses were not inferior to 6 courses with regards to clinical remission rate. After a median follow-up of 60 months (range 4–90) 94% of pts in each arm had achieved at least PR. Relapse occurred in 36 pts, with no significant difference in remission duration between the three arms (p = .28). In comparison to 1 course, multiple courses did not significantly prolong the duration of remission (p = .12). 6-year PFS was 45% in arm A, 60% in arm B and 65% in arm C, with no difference between the three arms (p = .35). Neither 3 (p = .29) nor 6 courses (p = .18) did significantly alter PFS compared to 1 course. The difference in PFS between 1 course vs. 3 or 6 courses was not significant (p =.16). 6-year OS was 72% in arm A, 82% in arm B and 80% in arm C, with no significant difference between the three arms (p = .46). Neither 3 (p = .26) nor 6 courses (p = .36) significantly altered OS when compared to 1 course. The difference in OS between 1 course vs. 3 or 6 courses was also not significant (p = .22). Toxicities most frequently observed were grade 3/4 leucopenia. There was no difference with regards to infections (p = .67) and allergic reactions (p = .70). Death occurred in 18 pts.

There was no difference in remission rates, remission duration, PFS and OS between pts treated with different courses of Rituximab, with more frequent applications not differing from less frequent applications. In this study, a non-inferiority of fewer applications of Rituximab could not be detected. Therefore, the advantage of multiple courses of Rituximab remains uncertain. To our knowledge, this is the first study that randomized pts to receive fewer doses of Rituximab than currently applied in standard protocols.

No relevant conflicts of interest to declare.