Rituximab maintenance improves outcomes in young MCL patients after ASCT – A phase III trial

On 28^th September 2017, a study published in The New England Journal of Medicine by Steven Le Gouill, from Nantes University Hospital, France, and colleagues explored rituximab maintenance therapy in young patients with Mantle Cell Lymphoma (MCL) after Autologous Stem-Cell Transplantation (ASCT). The publication follows an oral abstract presented by Professor Le Gouill at American Society of Hematology (ASH) 2016 that was previously reported by the Lymphoma Hub in an article last year.

The trial included 299 patients aged 18–65 with untreated MCL, who were eligible for ASCT. Patients received induction chemotherapy of four 21-day cycles of rituximab, dexamethasone, high-dose cytarabine and a platinum derivative (R-DHAP). Following ASCT the patients were randomized to receive either rituximab maintenance therapy (375mg/m² body surface area of rituximab every 2 months for 3 years) or were observed. The primary endpoint was Event-Free Survival (EFS) and secondary endpoints included Progression-Free Survival (PFS) and Overall Survival (OS).

Key Findings

• Median follow-up = 50.2 months (46.4–54.2)
• After exclusions, 240 patients were randomized to either rituximab (n = 120) or observation (n = 120)
• Results for rituximab group vs observation:
  • EFS = 79% (95% CI, 70–86) vs 61% (95% CI, 51–70), P = 0.001
    • HR = 46 (95% CI, 0.28 to 0.74), P = 0.002
  • Progression-Free Survival (PFS) = 83% (95% CI, 73–88) vs 64% (95% CI, 55–73), P < 0.001,

• HR = 0.40, (95% CI, 0.23–0.68) P <0.001

• Overall Survival (OS) = 89% (95% CI, 81–94) vs 80% (95% CI, 72–88) P = 0.04,
  • HR = 0.50 (95% CI, 0.26–0.99) P = 0.04
• Median PFS and OS were not reached in either group
• Total patient deaths (unrelated to treatment) = 13 rituximab vs 24 observation group, major cause of death was lymphoma and no deaths were related to treatment
• The most frequent grade 3–4 Adverse Event (AE) was neutropenia

In summary, the results of this phase III study showed the benefits of rituximab maintenance therapy in young MCL patients after ASCT. EFS, OS and PFS were significantly improved with regard to Event-Free Survival (EFS) and secondary endpoints included Progression-Free Survival (PFS) and it was also noted that cytarabine-based induction regimens were found to be efficacious. Rituximab was found to be well tolerated with a good safety profile and the results suggest that rituximab maintenance may be a good option for this group of patients.

Abstract

Background: Mantle-cell lymphoma is generally incurable. Despite high rates of complete response after initial immunochemotherapy followed by autologous stem-cell transplantation, patients have relapses. We investigated whether rituximab maintenance therapy at a dose of 375 mg per square meter of body-surface area administered every 2 months for 3 years after transplantation would prolong the duration of response. Methods: In a phase 3 trial involving 299 patients who were younger than 66 years of age at diagnosis, we randomly assigned 240 patients to receive rituximab maintenance therapy or to undergo observation after autologous stem-cell transplantation (120 patients per group); 59 patients did not undergo randomization. The primary end point was event-free survival (with an event defined as disease progression, relapse, death, allergy to rituximab, or severe infection) after transplantation among patients who underwent randomization. Results: After four courses of immunochemotherapy induction (rituximab, dexamethasone, cytarabine, and a platinum derivative [R-DHAP]), the overall response rate was 89%, and the complete response rate 77%. Transplantation was performed in 257 patients. The median follow-up from randomization after transplantation was 50.2 months (range, 46.4 to 54.2). Starting from randomization, the rate of event-free survival at 4 years was 79% (95% confidence interval [CI], 70 to 86) in the rituximab group versus 61% (95% CI, 51 to 70) in the observation group (P=0.001). The rate of progression-free survival at 4 years was 83% (95% CI, 73 to 88) in the rituximab group versus 64% (95% CI, 55 to 73) in the observation group (P<0.001). The rate of overall survival was 89% (95% CI, 81 to 94) in the rituximab group versus 80% (95% CI, 72 to 88) in the observation group (P=0.04). According to a Cox regression unadjusted analysis, the rate of overall survival at 4 years was higher in the rituximab group than in the observation group (hazard ratio for death, 0.50; 95% CI, 0.26 to 0.99; P=0.04). Conclusions: Rituximab maintenance therapy after transplantation prolonged event-free survival, progression-free survival, and overall survival among patients with mantle-cell lymphoma who were younger than 66 years of age at diagnosis. (Funded by Roche and Amgen; LyMa ClinicalTrials.gov number, NCT00921414).