The relapse-free survival benefit observed with rituximab maintenance added to autologous stem cell transplant suggests that the treatment strategy may help with disease eradication.
Rituximab (Rituxan) maintenance after autologous stem cell transplant (ASCT) for the treatment of relapsed follicular lymphoma (FL) sustained its benefit in relapse-free survival (RFS) for 12 months, according to long-term follow-up data from the prospective randomized EBMT LYM1 study (NCT00005589).
In the past, high remission rates have been achieved with the combination of rituximab and chemotherapy in patients with FL who were treatment naïve. But in the case of relapsed FL, response rates tend to plummet, and duration of response (DOR) in patients also decreases. In addition, disease progression is common in this patient population, occurring in roughly 20% of patients within their first 24 months of treatment. Those who experience disease progression within the first 24 months typically have an overall survival (OS) rate of less than 50% compared with 85% in those who do not progress within their first 2 years of treatment.
These prior results with rituximab both underscore a need to explore a better study end point.
The prospective study assessed the time to disease progression as its primary end point and response rate/survival, molecular remission rates, and safety as secondary end points. A total of 288 patients were enrolled and randomized to receive either rituximab purging at 375 mg/m2 once per week for 4 weeks or rituximab non-purging following the same dose strategy, and prior to rituximab maintenance and ASCT. The study also administered a high-dose regimen of carmustine, etoposide, cytarabine, and melphalan.
Twenty-nine percent of the study population withdrew, leaving 206 patients to receive ASCT and 99 patients to receive rituximab maintenance. To measure the study end points, all outcomes were deemed significant if they reached a 2-sided P value of .05.
Three patients were excluded from the 12-month analysis, leaving 203 patients evaluated for efficacy and safety. Patients were assessed based on whether they had received rituximab maintenance or not. In the maintenance population, most patients were male (53.4%) and were a median age of 52 years (range, 33–68). In the maintenance cohort, 18.% of patients had an ECOG performance status below 0, 78.3% had stage III/IV disease, 39% had a hemoglobin level of <12 g/dL at baseline, and 2 patients had a B2 macroglobulin level at baseline.
In terms of disease characteristics, some patients showed extranodal involvement (39.8%), bulky disease (23.3%), BCL2 positivity (59.2%), BM involvement (32%), and 27.2% of patients had unknown characteristics. The median number of months from diagnosis to randomization in the study was 35 (range, 7-135) for the rituximab maintenance group. Most of the patients (59.5%) received 3 prior lines of chemotherapy and had a low FLIPI score (43.3%). Before ASCT, the remission observed with patients was either complete remission (CR; 29.1%) or a very good partial response (VGPR; 70.9%).
Baseline characteristics were similar in the group that did not receive rituximab maintenance. The most significant difference in this cohort was that it had a large population of male patients (61%). Also, fewer patients in the non-maintenance cohort had extranodal involvement (28%), a difference of greater than 10%.
For all patients in the study, the 10-year non-relapse mortality rate was 7% (range, 4%-11%). There was no significant difference in NRM observed between the 2 cohorts (P = .001). Overall, relapse occurred in only 4 patients after 7.5 years. In the rituximab maintenance population, relapse after 10 years decreased by 35% (95% CI, 25%-44%) compared with 85% (95% CI, 48%-67%) in the non-maintenance cohort (HR, 0.50; 95% CI, 0.33-0.76; P = .001).
In terms of the secondary study end points, the 10-year PFS rate in the overall study population was 44% (95% CI, 38%-50%) at a median follow-up of 12 years (interquartile range, 10-13). Rituximab maintenance significantly prolonged PFS in the study, with a 12-year PFS rate of 55% (95% CI, 46%-66%) compared with 36% (95% CI, 27%-47%) in the non-maintenance arm (HR, 0.548; 95% CI, 0.37-0.80; P =.002). The median PFS in the rituximab maintenance population was 11.4 years compared with only 4.0 years in the non-maintenance group.
Patients in the study were followed for OS assessment for a median of 10 years. The OS rate in the overall population was 71% (95% CI, 65%-76%). After ASCT, the 10-year OS rate in the overall was 75% (95% CI, 69%-81%). In the rituximab maintenance group, the 10-year OS rate was 79% (95% CI, 72%-88%) compared with 70% (95% CI, 61%-80 %) in the non-maintenance cohort (HR, 0.716; 95% CI, 0.43-1.18).
Following ASCT, the study investigators led by Ruth Pettengell of St. George’s University in London evaluated progression of disease at 24 months, a secondary study end point. Data were available for 188 patients and 79% of those patients were in remission at 24 months, and 21% had disease progression. Pettengell et al also determined that having disease progression at 24 months negatively impacted OS. In patients who progressed compared with those who did not, the HR was 3.21 (95% CI, 1.77-5.80; P < .001). Among patients who progressed at 24 months, the 10-year OS rate was 60% (95% CI, 46%-79%) versus 85% (95% CI, 79.4%-91.0%) for those who did not progress at 24 months.
Regarding the efficacy of rituximab maintenance as observed through this prospective study, Pettengell wrote: This long-term follow-up of a randomized trial in patients with relapsed FL shows that the beneﬁt of 8 months of rituximab maintenance therapy after ASCT in terms of relapse prevention is sustained at 12 years.”
Pettengell et al concluded that the benefit observed suggests that rituximab maintenance added to ASCT may help with disease eradication and, therefore, has curative potential.
Petengell R, Uddin R, Boumendil A, et al. Durable benefit of rituximab maintenance post-autograft in patients with relapsed follicular lymphoma: 12-year follow-up of the EBMT lymphoma working party Lym1 trial. Bone Marrow Transplant. Published online January 15, 2021. doi: 10.1038/s41409-020-01182-w