MabThera first-line in CLL
MabThera is approved for use in combination with chemotherapy in first-line CLL. This approval is supported by breakthrough data from the CLL8 trial showing that MabThera 500mg/m2 plus chemotherapy provides the longest remission for first-line CLL patients compared with chemotherapy alone.1
MabThera 500mg/m2 plus chemotherapy significantly improves PFS compared with chemotherapy alone in first-line CLL
CLL8 is a phase III trial involving 817 previously untreated CLL patients who were randomised to treatment with 6 cycles of MabThera plus fludarabine and cyclophosphamide (R-FC) or fludarabine and cyclophosphamide (FC) alone.
• The primary endpoint of CLL8 was progression-free survival (PFS).
• Secondary endpoints included overall survival (OS), rates of molecular, complete (CR) and partial response (PR), response rates and survival times in biological subgroups and rates of treatment-related adverse events.
The choice of the 500mg/m2 dose was based on initial dose escalation studies of MabThera monotherapy, which showed dose-dependent activity in CLL.2
After a median follow-up of 20.7 months, PFS was significantly improved with R-FC compared with FC alone (39.8 months versus 32.2 months, respectively; p<0.0001). The risk of progression or death was reduced by 44% in the R-FC arm (hazard rate [HR]: 0.56; 95% confidence interval [CI]: 0.43–0.72; p<0.0001). The magnitude of the PFS benefit meant that the trial was stopped early after a planned interim analysis (long-term follow-up is ongoing).
The PFS benefit was consistent across nearly all subgroups analysed, including patients with 17p deletions and those with unmutated IgVh (both of which predict poor survival).
Significant improvements in overall response rates (ORR) and CR rates were seen in the R-FC arm compared with FC alone (ORR: 86% versus 73%, respectively; p<0.0001; CR: 36% versus 17.2%; p<0.0001).
The analysis of OS also showed improved survival in favour of the R-FC arm (estimated 24-month survival rates: 92% versus 87%; p=0.0427), but longer follow up is needed to confirm this observation.
The risk of death was reduced by 36% in the R-FC arm (HR: 0.64; 95% CI: 0.41–1.00; p=0.0487). In addition, flow cytometric analysis of peripheral blood showed that R-FC significantly improved the proportion of patients achieving minimal residual disease negativity (66% in the R-FC arm versus 37% with FC alone, p<0.0001). The elimination of residual disease is a key short-term marker of efficacy and it is known to predict for long-term survival with R-FC.3,4
References
1. Hallek M, Fingerle-Rowson G, Fink A-M, et al. Blood 2008;112 (Abstract 325).
2. O’Brien SM, Kantarjian H, Thomas DA, et al. J Clin Oncol 2001;19:2165–2170.
3. Tam CS, O’Brien S, Wierda W, et al. Blood 2008;112:975–980.
4. Bosch F, Ferrer A, Villamor N, et al. Clin Cancer Res 2008;14:155–161.
