R-CHOP/R-DHAP Compared to R-CHOP Induction Followed by High Dose Therapy with Autologous Stem Cell Transplantation Induces Higher Rates of Molecular Remission In MCL: Results of the MCL Younger Intergroup Trial of the European MCL Network

In the MCL younger trial of the European MCL Network, patients up to 65 years with stage II-IV mantle cell lymphoma were randomized to either a standard arm with 6 cycles of 3-weekly R-CHOP, stem cell mobilization with DexaBEAM and myeloablative treatment with 12 Gy TBI, 2×60mg/kg cyclophosphamide and autologous stem cell transplantation (ASCT) (Arm A), or an experimental treatment arm including 6 cycles of alternating R-CHOP/R-DHAP followed by a high dose Ara-C containing myeloablative therapy with 10 Gy TBI, 4×1.5 g/m² Ara-C, 140mg/m² melphalan and ASCT (Arm B). In addition to clinical response assessment, minimal residual disease (MRD) was prospectively monitored on the molecular level by real time quantitative (RQ-) PCR in both arms. MRD samples were collected at diagnosis, at midterm (after 4 induction cycles), after induction (6 cycles), and in 3-monthly intervals after ASCT until clinical progression. MRD results were evaluated according to ESG criteria (van der Velden, Leukemia 2007) and compared to clinical response and outcome. RQ-PCR was designed to reach a sensitivity of 10E-5, MRD negativity (MRD-) was defined as a negative RQ-PCR result with a technical assay sensitivity of at least 10E-04. Molecular response (MR) was defined as MRD- in peripheral blood (PB) and/or bone marrow (BM) at any sampling time point.

Until May 2010, 307/422 patients randomized in Germany or France had MRD samples available and a molecular marker for RQ-PCR (158 patients of the R-CHOP arm and 149 of the R-CHOP/R-DHAP arm). Overall 2374 samples, 1639 PB and 735 BM were evaluated for MRD. Clinical parameters as stage, LDH elevation, bone marrow infiltration and MIPI were distributed equally in both groups. Based on 173/307 (56%) patients with available midterm samples, MRD clearance was significantly higher in the experimental arm with 36/84 (43%) MRD- patients compared to only 12/89 (13%) in the standard arm; p<0.0001). This difference was confirmed in both, PB (50/80 (63%) vs. 18/84 (21%); p<0.0001) and BM (31/71 (44%) vs. 12/75 (16%); p=0.0003).

After completion of induction 90% of R-CHOP and 94% of R-CHOP/R-DHAP patients achieved a clinical response with a CR rate of 26% and 39%, respectively. The rate patients achieving a MR was significantly higher in the R-CHOP/R-DHAP arm (60/82 (73%) vs. 29/92 (32%) after R-CHOP; p<0.0001). BM clearance from lymphoma cells was inferior after R-CHOP only (MRD- 17/71 (24%) compared to R-CHOP/R-DHAP (MRD- 39/57 (68%)). Accordingly, MRD- in the PB was achieved after R-CHOP in only 40/86 patients (47%) compared to 63/79 (80%) in the R-CHOP/R-DHAP arm. Achievement of BM MR after induction was associated with a significantly improved remission duration in the pooled treatment arms (89% vs. 74% at 24 months, p=0.0017).

High-dose consolidation followed by ASCT demonstrated a high impact on tumor reduction in the pooled treatment arms and increased the BM MR rate from 50% to 75% (p = 0.0001, paired samples). This improvement was more prominent in the R-CHOP arm (29% to 65%; p = 0.0023) than in the experimental arm (76% to 88%; p=0.18). Remarkably, sustained PB MR during the first year after ASCT was predictive for outcome in both treatment arms (pooled cohort n = 135, 94% vs. 63% ongoing remissions at 2 years, p=0.0001) R-CHOP: 92% vs. 67%, p=0.0224 and R-CHOP/R-DHAP : 96% vs. 53%, p=0.0016).

RQ-PCR is an excellent tool to quantitatively determine the impact of different treatment modalities on tumor clearance and revealed the superiority of the high dose Ara-C containing treatment arm early during treatment. Furthermore it underlines the importance of ASCT consolidation in MCL.

Thus, MRD seems to be prognostically more relevant than clinical and morphological complete response assessment and was confirmed as a reliable early predictor of clinical outcome in MCL.

Ribrag:LFB: Honoraria, Research Funding; servier: Research Funding; celgene: Research Funding; pfizer: Honoraria; novartis: Honoraria.