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Two years of rituximab following bendamustine-rituximab induction does not add significant benefit in patients with Waldenström's macroglobulinemia

Results of a randomized phase III trial demonstrate that two years of rituximab maintenance following induction therapy with bendamustine-rituximab (BR) does not result in a significantly improved progression-free (PFS) or overall survival (OS) in patients with Waldenström’s macroglobulinemia. In an exploratory analysis, a higher age (>65 years) appears to be a critical factor for a potential benefit of rituximab maintenance. Despite the negative outcome of this trial, it does confirm the high activity of BR in this setting with a median PFS of 9-10 years.

Background

The StiL NHL1-2003 trial established BR as a highly effective treatment for patients with Waldenström’s macroglobulinemia (WM) achieving a median PFS of 69.5 months. Rituximab maintenance following rituximab-based chemo-immunotherapy results in a significant PFS improvement in patients with follicular lymphoma (FL) and mantle cell lymphoma (MCL). To date, there are no prospective data on the potential of rituximab maintenance following BR in patients with WM and, as such, the role of rituximab maintenance in this setting is unclear. To address this, the phase III StiL NHL 7-2008 trial compared the effect of 2 years of rituximab maintenance vs. observation following induction therapy with BR in 218 patients with previously untreated WM. In the induction phase, all patients were treated with up to 6 cycles of BR plus 2 additional rituximab cycles. Only patients responding to BR were randomized to either rituximab maintenance (q 2 months for 2 years) or observation.

Results

The median age of patients in the study was 66 years, 14% was older than 75 years and almost all included patients (99%) had stage IV disease. Approximately two thirds of patients (68%) had a baseline hemoglobin <11 g/dl, 15% had a lactate dehydrogenase (LDH) level of >240 U/L and the median IgM level was 32.7 g/L. A third of patients (34%) had B-symptoms and 6% had bulky disease. These patient and disease characteristics were well-balanced between both treatment arms.

After BR induction, 88% of patients obtained a major response (complete [CR], very good partial [VGPR] or partial response [PR]), while an additional 5% of patients had a minor response (MR). With respect to toxicity, rituximab maintenance was associated with lower rates of leukocytopenia (4% vs. 11%) and neutropenia (7% vs. 14%) compared to observation. Apart from that, no major differences with respect to toxicity were seen. After a median follow-up of 80 months, patients in the observation arm had a median PFS of 106.3 months as compared to 118.4 months for patients treated with 2 years of rituximab maintenance. In a statistical analysis, this 12 months difference in median PFS did not prove to be statistically significant (HR[95%CI]: 1.21[0.78-1.89]; p=0.3982). The median OS did not differ between both treatment arms (median not reached in both arms; HR[95%CI]: 0.85[0.46-1.55]; p=0.5962).

In a subgroup analysis in function of the international scoring system for WM (ISSWM) score, the benefit of rituximab maintenance seemed to be more pronounced in patients with ISSWM intermediate and high risk. In this subgroup, the median PFS in patients receiving 2 years of rituximab was 118.4 months as compared to 78.2 months with observation (HR[95%CI]: 1.55[0.94-2.57]; p=0.0867). Also an exploratory analysis in function of age revealed some differences. While rituximab maintenance did not lead to a better PFS in younger patients (<65 years) (median not reached in both arms; HR[95%CI]: 0.75[0.38-1.51]; p=0.4177), older patients (>65 years) did have a longer median PFS if they were treated with 2 years of rituximab (median PFS: 64.3 vs. 118.4 months; HR[95%CI]: 1.86[1.03-3.38]; p=0.0355). Finally, the results of this study again demonstrated that patients with disease progression within 24 months have a poor prognosis. In fact, the median OS in patients with a time to progression of less than 24 months was 23.1 months, while the median OS was not yet reached in patients with a longer time to progression (HR[95%CI]: 5.88[2.30-15.00]; p<0.0001).

Conclusions

Results of the StiL NHL 7-2008 trial confirm the clinical efficacy of BR in the frontline treatment of WM, with a median PFS of 9-10 years. The addition of 2 years of rituximab in patients with a response to BR did, however, not lead to a significant improvement in PFS and OS. In an exploratory analysis, rituximab maintenance did seem to induce a PFS benefit compared to observation in older patients, but more data are needed to make firm conclusions on this.

Reference

Rummel M, Lerchenmüller C, Hensel M, et al. Two years rituximab maintenance vs. observation after first line treatment with bendamustine plus rituximab (B-R) in patients with waldenström's macroglobulinemia (MW): results of a prospective, randomized, multicenter phase 3 study (the StiL NHL7-2008 MAINTAIN trial). Presented at ASH 2019; Abstract 343.

Speaker Mathias Rummel

Rummel1

Mathias J Rummel, MD, PhD, Med. Clinic IV, Hematology, Justus Liebig University, Giessen, Germany

 

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