Bendamustine Plus Rituximab Followed By Rituximab Maintenance for Patients with Untreated Advanced Follicular Lymphomas. Results from the StiL NHL 7-2008 Trial (MAINTAIN trial) (ClinicalTrials.gov Identifier: NCT00877214)

Background: The StiL Study NHL 7-2008 investigates the role of maintenance duration with rituximab after induction with bendamustine-rituximab (B-R) for first-line treatment of advanced follicular (FL), other indolent lymphoma, or mantle cell lymphoma.

Methods: Patients (pts) with FL were treated with a maximum of 6 cycles of B-R (bendamustine 90 mg/m² [days 1+2], rituximab 375 mg/m²) administered every 28 days plus 2 additional cycles of rituximab every 4 weeks. All responding pts (complete response [CR] or partial response [PR]) were then eligible for rituximab maintenance treatment and a subsequent randomization: all responding pts with FL received 2 years rituximab maintenance (375 mg/m²) administered every two months. Pts with an ongoing response were then randomized 1:1 to observation (no further treatment) or to 2 more years of rituximab maintenance (i.e. B-R plus 2 years vs 4 years rituximab maintenance). Here we report on the response to B-R and tolerability and safety of B-R followed by 2 years of rituximab maintenance in pts with FL only.

Patient Characteristics: To date, 612 pts (319 women and 293 men) with FL have been registered (first patient in April 2009, last patient registered July 2012). Median age was 61 years (range, 24-81); 352 (58%) pts had stage IV; median number of nodal areas was 5; bone marrow involvement was found in 322 (52%) pts; and 175 pts (28%) presented with splenomegaly. The median LDH was 210 U/l, with 197 pts (32%) having an LDH > 240 U/l. Median FLIPI was 3 and the median CD4 count was 491 per mm³at induction.

Results: To date, 546 pts of 612 are evaluable for response and safety. The overall response rate (ORR) was 93.6% with 511 pts achieving a remission after B-R induction therapy. The CR rate was 39.6%; nine pts (1.6%) had stable disease; and 27 (4.9%) did not respond to B-R and had progressive disease. Of these 511 pts achieving remission, 291 (56.9%) received the full planned 2 years rituximab maintenance treatment, and 281 pts were then randomized to observation only (n=140) or 2 additional years of rituximab maintenance (n=141). Seventy nine pts are still undergoing treatment with the planned 2-year standard rituximab maintenance and are not yet randomized.

Reasons for not receiving the full 2-year course of rituximab maintenance (n=141) included: death (n=6); relapse or progressive disease (n=50); transformation into aggressive lymphoma (n=4); infection during rituximab maintenance (n=4); infection during B-R induction (n=1); toxicity (e.g. neutropenia) (n=19); secondary malignancies during induction or during rituximab maintenance (n=3 and n=6, respectively); reactivated hepatits B (n=1); rituximab intolerance (n=3); removal of the patient from the trial by the investigator for any reason (n=16); withdrawal of patient consent during induction with B-R (n=2) and during the 2-year rituximab maintenance (n=14); non-compliance (n=2); lost to follow up (n=6); severe comorbidity (dementia) (n=1); and other reasons (n=3).

No unexpected toxicity and no progressive multifocal encephalopathy were observed. To date, 35/612 pts developed 38 secondary malignancies.

Conclusions: Results of this study confirm the efficacy of B-R in pts with previously untreated advanced FL. These results are in line with those of other studies such as StiL NHL 1-2003(1) or the “BRIGHT”-Study(2). Rituximab standard maintenance over 2 years for FL appears safe, with no new or unexpected toxicities.

1. Rummel et al. Lancet 2013;381:1203-10.

2. Flinn et al. Blood 2014;123:2944-52.