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; Interim Results from the LyMa-MRD Project, Conducted on Behalf of the Lysa Group

INTRODUCTION : Minimal residual disease (MRD) is emerging as an important predictor of clinical outcome in patients with mantle cell lymphoma (MCL). However, its utility in everyday clinical practice 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 (NCI NCT00921414; LyMa Trial).

METHODS : The present MRD analysis was performed in a subgroup of randomized patients (n=178) of the 299 MCL patients (<66yrs) enrolled in the LyMa trial (Sept 2008 to Aug 2012). Briefly, all patients were previously untreated and received 4 courses of R-DHAP followed by ASCT using an R-BEAM conditioning regimen (n=257). After ASCT, patients were randomized between observation (obs) (n=120) versus Rituximab maintenance (RM) (n=119). The first planned interim-analysis, with a median follow-up of 40.6 months was presented at ASH 2014 and indicated superior PFS in the RM versus Obs arms (Le Gouill et al. ASH 2014). Sequential MRD monitoring was a predefined secondary objective and was performed throughout. At interim analysis the aim was to determine if peripheral blood (PB) and/or bone marrow (BM) MRD status, pre- and post ASCT, can predict patient outcome in terms of PFS according to RM or Obs. MRD was quantitatively assessed in PB and / or BM after induction, after ASCT by using gold standard EURO-MRD RQ-PCR assays and interpretation guidelines, targeted to clonal immunoglobulin gene rearrangements, in 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 a given follow-up sample (minimal assay sensitivity of 10-4).

RESULTS: Among the 299 patients enrolled in the LyMa trial, MRD data in PB and / or BM was successfully generated pre- and/or post-ASCT phases, for a total of 178 randomized patients. Of the 61 out of 239 randomized patients without MRD data, 9 are ongoing and other reasons were no MRD target or MRD assay failure. Pre-ASCT MRD in BM and PB was negative in 66% (n=98) and 80% (n=120), of samples, respectively. Post-ASCT, MRD in BM and PB was found negative in 82% (n=122) and 95% (n=162), respectively. MRD status pre-ASCT in either BM or PB was predictive of longer PFS (respectively; p= 0.0451, p= 0.0016). In contrast, PB MRD status, post-ASCT failed to predict PFS while there was a trend for a better PFS for patients achieving MRD negativity in the BM (median PFS: NR vs 43.4 months ; p= 0.07 ). We next investigated patient outcome according to MRD status pre-ASCT and randomization arms. In BM and PB, respectively, 72% and 79% of patients in the obs arm were MRD negative compared to 59% and 80% in the RM arm, respectively. The estimated 3y-PFS for MRD pos/obs, neg/obs, pos/RM, neg/RM patients, according to BM and PB MRD status were: 61,6% (IC95%, 35.4-79.8) vs 83.9% (IC95%, 70.1-91.7) vs 86.2% (IC95%, 67.3-94.6) vs 91.8% (IC95%, 76.3-97.3) (p=0.0110) and 51.8% (IC95%, 24.4-73.6) vs 86.5% (IC95%, 73.5-93.4) vs 80% (IC95%, 50-93.1) vs 92.8% (IC95%, 81.6-97.3) ( p=0.0027), respectively.

CONCLUSION : Pre-ASCT MRD status in both BM and PB is an early predictor of PFS in younger MCL patients receiving ASCT. RM provides longer PFS regardless of MRD status pre-ASCT. Early sequential MRD monitoring at the pre-ASCT treatment phase thus offers strong potential for early clinical outcome prediction and MRD-guided, risk-adapted treatment in future MCL trials. Our preliminary results also suggest continued, clinically relevant, direct or indirect Rituximab-mediated anti-tumor activity, in rare residual circulating or 'tissue-resident' MCL cells.