Eva Hoster, PhD, on Mantle Cell Lymphoma: Predictive Value of Minimal Residual Disease on Efficacy of Rituximab Maintenance

Rituximab maintenance has become standard of care in the first line treatment of mantle cell lymphoma. The European MCL Elderly Trial has established rituximab maintenance after R-CHOP in older patients with mantle cell lymphoma. We assessed and analyzed MRD as part of the MCL Elderly Trial to investigate whether the MRD status at end of induction predicts the efficacy of rituximab maintenance and to find trigger points for MRD based treatment guidance. The European MCL Elderly Trial recruited patients with previously untreated and advanced stage mantle cell lymphoma older than 60 years and not suitable for autologous stem cell transplantation. Patients were first randomized between six cycles of R-FC and eight cycles of R-CHOP and responding patients were subsequently randomized between rituximab and interferon maintenance until progression. Minimal residual disease or MRD was assessed by real-time quantitative PCR according to standardized guidelines reaching a target sensitivity of 10 to the -5 and MRD time points were at mid-induction, end of induction and the two monthly intervals during maintenance and follow up. MRD assessment was possible and 80% of patients screened for a molecular marker and tumor dissemination enhanced the identification of a molecular marker. Induction with R-FC resulted in a deeper and more rapid MRD clearance compared with R-CHOP. And of note, the differences observed in MRD response were much larger than those seen for clinical remission. The efficacy of rituximab maintenance was clearly confirmed in patients MRD negative at end of induction and this was especially seen in patients pre-treated with R-CHOP. In contrast, in MRD positive patients at end of induction, the efficacy of rituximab maintenance seemed potentially reduced. In the two years after end of induction rituximab maintenance was associated with more frequent, constant MRD negativity and conversions to MRD negativity and less frequent conversions to MRD positivity. MRD positivity after end of induction and start of maintenance was associated with relatively short response duration and medium times from MRD positivity to clinical relapse and were rather short with around one to one and a half years. In conclusion, our results confirm the strong efficacy of rituximab maintenance in MRD negative patients which means that omitting rituximab maintenance in MRD negative patients is clearly discouraged by our results. MRD positivity after end of induction inside of maintenance seems to be an important trigger point for treatment intensification or novel treatment approaches. And these MRD guided treatment strategies should be studied in future clinical trials.