Molecular Remission after Combined Immunochemotherapy Is of Prognostic Relevance in Patients with MCL: Results of the Randomized Intergroup Trials of the European MCL Network

Two randomized intergroup trials of the European MCL Network investigating the impact of different combined immunochemotherapy protocols for patients with stage II-IV mantle cell lymphoma (MCL) followed by autologous stem cell transplantation for patients <65 yrs and a rituximab or interferon maintenance treatment for patients > 65 yrs are currently performed.

Patients and methods: 182 German patients with evidence for peripheral blood (PB) involvement as demonstrated by consensus IGH-PCR at diagnosis were analyzed for quantitative PB involvement and molecular response (MR) by Real Time Quantitative (RQ) IGH-PCR. The results were evaluated according to ESG criteria (van der Velden, Leukemia 2007) and were compared to clinical parameters at diagnosis and outcome.

Results: Patients had a median age of 61 years, an elevated LDH in 37%, B-symptoms in 42% and extranodal involvement in 36%. According to the MIPI prognostic index 20% had an adverse, 37% an intermediate and 43% a good prognosis. Median level of circulating MCL cells in PB at initial diagnosis were 6×10−2 (range 2×10-4 to 8×10-1) and correlated significantly with clinical parameters as advanced stage (p=0.0016), elevated LDH (p= 0.0026), bone marrow infiltration (p= 0.0001) and MIPI prognostic index (p<0.0001). MR after induction was achieved in 55% (67/121) of all evaluable patients and correlated with stage (p=0.058), the presence of B-symptoms (p=0.016) and BM infiltration at diagnosis (p=0.011). Interestingly, the rate of MR was higher in patients receiving the protocol for elderly than for young patients (69% vs. 45% p=0.0006). This effect was especially prominent in the BM with an MRD clearance of 65% in elderly compared to only 35% in younger patients (p<0.0001). BM was more sensitive for MRD detection compared to PB after rituximab containing treatment. Of 62 paired samples only 2 BM samples were BM MRD- with concomitant MRD+ in the PB, whereas 13 MRD- PB samples demonstrated MRD+ in the corresponding BM (p=0.045). Patients achieving a MR in the BM after induction demonstrated a significantly improved remission duration compared to MRD+ patients (100% vs. 66% at 24 months, p=0.0285, median observation time 15 months).

Conclusion: Quantitative detection of circulating MCL cells improves clinical risk assessment and staging accuracy. Furthermore RQ-PCR allows to evaluate the impact of different treatment modalities on tumor clearance in PB and BM. This is the first randomized trial demonstrating that achievement of MR by combined immunochemotherapy might be an early indicator for treatment outcome in MCL.