Predictive Power of Early, Sequential MRD Monitoring in Peripheral Blood and Bone Marrow in Patients with Mantle Cell Lymphoma Following Autologous Stem Cell Transplantation with or without Rituximab Maintenance; Final Results from the LyMa-MRD Project, Conducted on Behalf of the Lysa Group

INTRODUCTION : Minimal residual disease (MRD) has emerged as an important predictor of clinical outcome in patients with mantle cell lymphoma (MCL). Its use in everyday clinical practice, however, remains uncertain since standardized MRD monitoring strategies and response criteria are not yet formally established. To address this question, we conducted the LyMa-MRD project as an ancillary biology study in a prospective phase III trial in MCL patients < 66 years of age (NCI NCT00921414; LyMa Trial; Le Gouill et al, NEJM 2017). Briefly, in this trial all patients were previously untreated and received 4 courses of R-DHAP followed by ASCT. After ASCT, patients were randomized between observation (obs) versus Rituximab maintenance (RM) which was associated to superior event free, progression free and overall survival, respectively. Herein, we present the final MRD analysis.

METHODS : The final MRD analysis was performed in a total of 220 MRD evaluable patients [defined as patients with an available MRD assay and appropriate follow-up sample in peripheral blood (PB) and/or bone marrow, (BM), at the time point of interest for statistical analyses] and aimed to assess MRD response rates and prognostic impact [progression free and overall survival, (PFS, and OS, respectively)] at the pre-ASCT (after induction phase) (n=195 ; 86 RM and 84 obs) or (2 ; 90 RM and 92 obs). Sequential MRD monitoring was a predefined secondary objective. An additional aim was to assess the value of combining molecular MRD and PET (positron emission tomography) for outcome prediction pre- and post-ASCT. MRD was quantitatively assessed in PB and / or BM after induction or after ASCT by using gold standard EURO-MRD RQ-PCR assays targeted to clonal immunoglobulin gene rearrangements, in 3 French national reference laboratories. MRD data for survival analysis was generated from assays with a minimal sensitivity of at least 10-4. MRD status was assigned according to EURO-MRD interpretation guidelines. MRD negativity at a given time point was defined as absence of RQ-PCR amplification product in the follow-up sample (minimal assay sensitivity of 10-4). Non evaluable MRD was mostly due to no follow-up sample, no MRD target or MRD assay failure.

RESULTS: In a total of 195 MRD evaluable patients who completed R-DHAP induction therapy, MRD was found negative in 77% (n=144) and 64% (n=115) of PB and BM samples, respectively. MRD status pre-ASCT was predictive of PFS and OS: p< 0.0001, respectively, for PB; p= 0.0295 and 0.0407, respectively, for BM). Post-ASCT, MRD in PB and BM was negative in 94% (n=181) and 81% (n=137) of patients, respectively, and was predictive of PFS (but not OS) (PB, p= 0.0452 ; BM, p=0.0261). In patients that were MRD negative either pre (PB, p= 0.0260; BM, p=0.0405) or post-ASCT (PB, p=0.001; BM, p=0.007), RM was associated to improved PFS and also OS, albeit to a lesser extent [pre-ASCT BM MRD and post-ASCT PB MRD neg groups only ; p= 0.0395 and p =0.02, respectively]. Finally, combining PET and MRD status offered improved prediction of PFS both pre- (p< 0.0001, PB; p=0.0028, BM MRD) and post-ASCT (p<0.0001, PB; p=0.0082, BM). Likewise, combining either pre- or post-ASCT PET/MRD also provided improved prediction of OS [PB, but not BM, plus PET pre-ASCT, p=0.0002 ; PB or BM MRD plus PET, p<0.0001 and p=0.0474, respectively, post-ASCT).

CONCLUSION: Pre-ASCT MRD status in both BM and PB is an early predictor of PFS and OS in younger MCL patients receiving ASCT. RM provides longer PFS and OS regardless of MRD status pre- and post-ASCT. Early sequential MRD monitoring at the pre-ASCT treatment phase and directly post-ASCT thus offers strong potential for early clinical outcome prediction, as a surrogate clinical end point, and for MRD-guided, risk-adapted treatment in MCL.