Half of follicular lymphoma patients receiving rituximab maintenance remain free of progression at 10 years
The intergroup PRIMA phase III study was designed to evaluate the potential benefit of 2 years of rituximab (R) maintenance after a response to first line R-chemotherapy induction therapy in patients with follicular lymphoma (FL) and a high tumour burden. During ASH 2017, the ten-year update of this trial was presented, confirming the previously reported progression-free survival (PFS) benefit observed with R maintenance. The trial did not demonstrate a survival benefit for R-maintenance but did indicate that patients with a high tumour burden have an 80% chance of being alive after 10 years. Importantly, half of the patients receiving R maintenance were free of progression after 10 years, representing a 38% risk reduction compared to observation. Half of the patients did also not receive any new anti-lymphoma treatment during the 10-year follow-up period.
Although FL is still considered to be an incurable disease, progress in response rates and response duration have translated into an improved survival and patients can now benefit from prolonged remission intervals. Previous studies have demonstrated a significant clinical benefit of using R maintenance therapy in relapsing patients following chemotherapy, R-chemotherapy or an autologous stem cell transplantation (ASCT) and in first-line patients following chemotherapy, or R monotherapy. The phase III PRIMA study evaluated the effect of rituximab maintenance therapy following first-line therapy with the combination of R and chemotherapy. In PRIMA, untreated FL patients with a high tumour burden received induction therapy with R in combination with CVP, CHOP, or FCM. Patients with at least a partial response (PR) after induction were then randomised to R maintenance (375mg/m2 every 8 weeks for 2 years), or observation. Induction therapy consisted of R-CHOP in 885 patients, while 272 and 45 patients received R-CVP, or R-FCM induction therapy, respectively. In the second step 1,018 patients were randomised (769 R-CHOP, 222 R-CVP and 28 R-FCM) to R maintenance (N=505), or observation (N=513). After three years, the PFS (primary endpoint) was shown to be significantly superior for R maintenance compared to observation (3-year PFS rate 75% vs. 58%; HR[95%CI]: 0.55[0.44-0.68]; p< 0.0001). After 6 years, this PFS benefit was confirmed with a HR of 0.58 in favour of R maintenance.
Results after 10 years follow-up
During ASH 2017, long-term results of this study, with 4 additional years of follow-up, were presented. The median follow-up for the 607 patients included in this long-term analysis was 9.8 years. The median PFS for patients in the observation arm was reached at 4.06 years as compared to 10.49 years in the R-maintenance arm (HR[95%CI]: 0.61[0.52-0.73]; p< 0.0001). At 10 years, 51% of the patients in the R-maintenance arm (versus 35% in the observation arm) were estimated to be free of disease progression. The benefit of R-maintenance for PFS was significant in all predefined subgroups, irrespective of age, gender, FLIPI index and the response to induction immunochemotherapy (CR or PR). The PFS benefit in favour of R maintenance was significant in patients who received R-CHOP induction therapy (HR[95%CI]:0.57[0.47-0.70]), while in patients treated with R-CVP or R-FCM induction, a non-significant trend in favour of R maintenance was seen (HR[95%CI]: 0.75[0.53-1.07], respectively HR[95%CI]:0.58[0.16-2.07]). The median time to new anti-lymphoma treatment was 6.6 years in the observation arm and was not yet reached in the R maintenance arm (HR[95%CI]:0.66[0.55-0.78]; p< 0.0001), with a 10-year estimate of 53% of the patients in the R arm not having received a new treatment (versus 41% in the observation arm). The 10-year OS rate was identical for both treatment arms at 80% (HR[95%CI]:1.04[0.77-1.40]; p= 0.795).
Adverse events
No new safety signals were seen during the additional 4 years of follow-up. Overall, 17% of patients in the observation arm experienced a grade 3/4 adverse event, as compared to 24% in the R maintenance arm. Serious adverse events were reported in 13% of patients in the observation arm and in 21% of patients treated with R maintenance. At data lock, 84 and 88 patients had died in the observation- and R-maintenance arm, respectively. Main causes of death in the observation- and R-maintenance arms were respectively: lymphoma progression in 38 and 39 patients, second cancer for 24 and 6 patients (with respectively 7 and 2 myeloid disorders), infections in 6 and 11 patients (1 PML in each arm) and cardiovascular disorders in 4 and 8 patients.
In summary, the long-term follow-up of PRIMA confirms the sustained PFS benefit of R maintenance over observation after induction immunochemotherapy for patients with FL and a high tumour burden. Despite the lack of OS benefit, it is noteworthy that more than half of the patients in the R arm remain free of disease progression and have not required new anti-lymphoma treatment beyond 10 years. With the prolonged life expectancy of patients with FL, it is important to consider long-term treatment-related toxicities and the risk of secondary malignancies.The long-term PRIMA data are reassuring in this respect.
Reference
Salles G, Seymour J, Feugier P, et al. Long Term Follow-up of the PRIMA Study: Half of Patients Receiving Rituximab Maintenance Remain Progression Free at 10 Years. Presented at ASH 2017; Abstract #486.
