Minimal Residual Disease Evaluation in the Context of V-Rbac, a Risk-Tailored Phase II Trial of the Fondazione Italiana Linfomi (FIL)

Introduction. R-BAC (rituximan-bendamustine-cytarabine) is an highly effective first-line immunochemotherapy regimen for elderly fit patients with mantle cell lymphoma (MCL), allowing a considerable progression-free survival (PFS), particularly in low-risk (LR) patients, even without maintenance. On the other hand, outcomes in high-risk (HR) patients are still unsatisfactory, even with this therapy. To address this issue, the Fondazione Italiana Linfomi (FIL) designed the risk-tailored “V-RBAC” trial (NCT03567876), that showed how the addition of venetoclax to R-BAC in HR cases improved the performance of the induction strategy. Methods. This study is a multicenter, phase 2 trial for elderly (>64 years) fit MCL patients, offering consolidation (800 mg/day) and maintenance (400 mg/day up to 18 months) with venetoclax monotherapy after abbreviated R-BACx4 for HR patients; HR was defined as the presence of any risk factor among blastoid morphology, Ki67 ≥30%, or TP53 mutation/deletion. To investigate the efficacy of this novel regimen, HR patients were studied for minimal residual disease (MRD) both by standardized allele-specific oligonucleotide-droplet digital PCR (ddPCR), targeting either IGHV or IGH::BCL1 rearrangements, and by multiparametric flow cytometry (MFC). Bone marrow (BM) and peripheral blood (PB) samples were centralized in the four EuroMRD labs of the FIL MRD Network at baseline and at predetermined time points (before consolidation, after consolidation and at the end of treatment). Clinical data and primary endpoint of the trial were already reported[Visco, ASH 2023], we here describe in detail the MRD results. Results. Between September 2018 and July 2021, 54 HR MCL patients were prospectively enrolled in the trial. A reliable molecular marker for MRD by ddPCR was retrieved in 49 cases (91%), namely 29 IGHV only, 4 IGH::BCL1 only and 16 both markers. Overall, only 35 patients were evaluable for MRD in at least one timepoint, as 6 patients progressed during the induction and 8 interrupted the treatment due to toxicity or investigators decision. Nonetheless, the RBAC regimen resulted highly effective in clearing the MRD even in this HR population, with 25/33 (75%) patients achieving MRD negativity in BM and 28/35 (80%) in PB after four cycles of induction therapy. Moreover, after four cycles of venetoclax consolidation the rate of MRD negativity further raised to 86% (26/30) in BM and 90% (28/31) in PB, highlighting the activity of this drug in clearing the MRD at least in a subset of cases. Finally, after 18 months of venetoclax maintenance, the MRD negativity rate was 93% (13/14) in BM and 88% (15/17) in PB. Based on these data, we investigated the capacity of MRD to be a prognostic marker for PFS. Overall, MRD positivity at any timepoint was associated with an higher risk of relapse (HR 5.75, 95%CI 1.93-17.18, p=0.002 in BM and HR 7.89, 95%CI 2.65-23.53, p<0.001 in PB, respectively). In particular, the three patients still MRD positive after venetoclax consolidation experienced a dismal outcome with a relapse event after 7, 9 and 25 months, respectively. Finally, a direct comparison between ddPCR and MFC approach to detect MRD in PB was performed: detailed data are still under evaluation and will be presented during the meeting. Conclusion. We here described the MRD monitoring results in the risk-tailored phase II trial FIL V-RBAC. Four cycles of R-BAC regimen provided high rates of molecular MRD negativity in HR elderly fit MCL patients, further improved by a venetoclax consolidation. Patients MRD positive after induction or consolidation still experience dismal outcome and should be considered for alternative, experimental approaches.