Rummel M, et al. ASH 2017:483

Four versus two years of rituximab maintenance following BR in patients with previously untreated FL: Results of the StiL NHL 7-2008 MAINTAIN trial

Background

Rituximab maintenance (R-maintenance) is an established consolidation regimen in patients with follicular lymphoma (FL) following first-line treatment with bendamustine plus rituximab (BR), despite the fact that there is no proven evidence for its efficacy in this scenario. The StiL NHL 7-2008 MAINTAIN trial was developed to demonstrate the improvement in progression-free survival (PFS) with four years of R-maintenance compared to two years of R-maintenance after induction with BR in patients with untreated FL. Results from this study were presented at the 2017 ASH Annual Meeting.1

Study design

  • The StiL NHL 7-2008 MAINTAIN trial was an investigator-initiated, prospective, randomized, multicentre, phase III study conducted in 120 centres in Germany and Austria.
  • A total of 611 patients with FL were registered between April 2009 and July 2012.
  • Median follow-up was 75 months since registration.
  • Inclusion criteria were:
    • Untreated grade 1 or 2 FL that was histologically proven no more than six months before registration;
    • Stage III/IV disease, or stage II with bulky disease and indication for treatment;
    • Age 18–80 years;
    • Eastern Cooperative Oncology Group performance status of 0–2; and
    • Written informed consent.
  • The primary endpoint was PFS.
  • Secondary endpoints included overall survival (OS), time to next treatment (TTNT), response rates, adverse events (AEs), short- and long-term toxicities, second primary malignancies (SPM), and the comparison of two years of R-maintenance (from this study) to no maintenance following BR (from the StiL NHL 1-2003 study).
    • In the cross-study comparison, all patients from the NHL 7-2008 study were compared to all patients with FL who received BR in the NHL 1-2003 study.2

Study design

Key findings

Baseline characteristics and disposition

  • Of the 611 patients registered, 350 patients were randomized to receive either two years of R-maintenance (n = 172) or four years of R-maintenance (n = 178) following induction with BR.
    • Reasons that patients were not randomized included death (n = 11), progressive disease or stable disease (n = 63), transformation (n = 26), intolerance to BR (n = 15), withdrawn consent (n = 39), protocol violation (n = 26), neutropenia/cytopenia (n = 21), infections (n = 9), secondary malignancy (n = 16), other histology (n = 8), and other reasons (n = 27).
  • Baseline patient characteristics were similar between the two groups.
    • Median age was 59 years and 61 years in the two years R-maintenance and four years R-maintenance groups, respectively.
    • A similar percentage of both groups were >70 years of age (17% and 21%, respectively).
    • The majority of patients had stage III/IV disease (87% and 89%, respectively).
    • Approximately half of patients had bone marrow involvement (50% and 51%, respectively).
  • During induction, 94% of patients received the full dose of bendamustine in a median of six cycles.
  • In the two years R-maintenance group, 97.7% of patients completed maintenance with a median of 12 cycles.
  • In the four years R-maintenance group, 98.7% of patients completed two years of maintenance with a median 12 cycles, and 62.9% of patients completed four years of maintenance with a median of 12 cycles.
  • In the cross-study comparison, baseline characteristics were similar between groups.
    • Median age was 61 years and 60 years in the NHL 7-2008 and NHL 1-2003 studies, respectively.
    • The majority of patients had stage IV disease (59% and 69%, respectively) and bone marrow involvement (54% and 60%, respectively).

Efficacy

  • In the intent-to-treat population (n = 595), median PFS and OS were not reached after 96 months.
  • PFS was not significantly different between the two years and four years R-maintenance groups (HR = 0.73, 95% CI: 0.44–1.21; one-sided p = 0.1125). (Figure 1)
  • OS was also not significantly different between these groups (HR = 0.91, 95% CI: 0.42–1.96; p = 0.8036).
  • In the cross-study comparison, PFS was significantly prolonged in the NHL 7-2008 cohort (who received R-maintenance) compared to the NHL 1-2003 cohort (who did not receive maintenance). (Figure 2)
    • OS was not different between these two cohorts. (Figure 3)

Figure 1. Progression-free survival from randomization (n = 350)

Figure 2. PFS comparison: NHL 1-2003 vs. NHL 7-2008

Figure 3. OS comparison: NHL 1-2003 vs. NHL 7-2008

Safety

  • At the time of randomization, notable grade 3/4 AEs included neutropenia (16% in patients not randomized, 20% in the two years group, and 17% in the four years group), infections (10% in patients not randomized, 6% in the two years group, and 3% in the four years group), and pneumonia (7% in patients not randomized, 3% in the two years group, and 2% in the four years group).
    • These AE rates remained comparable between treatment arms after randomization (neutropenia: 10% in the two years group, 7% in the four years group; infections: 6% in the two years group, 2% in the four years group; pneumonia: 5% in the two years group, 2% in the four years group).
  • Causes of death are listed in Table 1.
  • A total of 17 patients (2.8%) died from infection (13 not randomized, one in the two years group, and three in the four years group).
    • The median age of these patients at registration was 71 years.
    • Nine of the patients died after a relapse and a second-line treatment.
    • Seven of the patients were primary refractory and died early.
    • Ten patients died in ongoing remission.
    • The types of infection were pneumonia (n = 8), sepsis (n = 6), fungal (n = 1), pneumocystis pneumonia (n = 1), and progressive multifocal leukoencephalopathy (n = 1).
  • Cluster of differentiation 4 and immunoglobulin G levels were similar between groups.
  • The incidence of SPM did not differ between groups (12% in patients not randomized, 10% in the two years group, and 8% in the four years group).

Table 1. Causes of death

Key conclusions

  • This study confirmed the high anti-lymphoma activity of BR.
  • Four years R-maintenance following BR did not statistically prolong PFS or OS compared to two years R-maintenance.
  • After randomization, fewer AEs were observed than expected.
  • With the limitation of a cross-trial comparison, it was demonstrated that BR plus R-maintenance could improve PFS compared to no maintenance, but did not impact OS.

References: 1. Rummel M, Buske C, Hertenstein B, et al. Four versus two years of rituximab maintenance following bendamustine plus rituximab in patients with previously untreated follicular lymphoma: results of the prospective, randomized, multicenter phase 3 study StiL NHL 7-2008 MAINTAIN trial. ASH Annual Meeting Abstracts 2017:483. 2. Rummel MJ, Niederle N, Maschmeyer G, et al. Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial. Lancet 2013;381(9873):1203–10.