Punctual and kinetic MRD analysis from the Fondazione Italiana Linfomi MCL0208 phase 3 trial in mantle cell lymphoma

Abstract

Minimal residual disease (MRD) analysis is a known predictive tool in mantle cell lymphoma (MCL). We describe MRD results from the Fondazione Italiana Linfomi phase 3 MCL0208 prospective clinical trial assessing lenalidomide (LEN) maintenance vs observation after autologous stem cell transplantation (ASCT) in the first prospective comprehensive analysis of different techniques, molecular markers, and tissues (peripheral blood [PB] and bone marrow [BM]), taken at well-defined time points. Among the 300 patients enrolled, a molecular marker was identified in 250 (83%), allowing us to analyze 234 patients and 4351 analytical findings from 10 time points. ASCT induced high rates of molecular remission (91% in PB and 83% in BM, by quantitative real-time polymerase chain reaction [RQ-PCR]). Nevertheless, the number of patients with persistent clinical and molecular remission decreased over time in both arms (up to 30% after 36 months). MRD predicted early progression and long-term outcome, particularly from 6 months after ASCT (6-month time to progression [TTP] hazard ratio [HR], 3.83; P < .001). In single-timepoint analysis, BM outperformed PB, and RQ-PCR was more reliable, while nested PCR appeared applicable to a larger number of patients (234 vs 176). To improve MRD performance, we developed a time-varying kinetic model based on regularly updated MRD results and the MIPI (Mantle Cell Lymphoma International Prognostic Index), showing an area under the ROC (Receiver Operating Characteristic) curve (AUROC) of up to 0.87 using BM. Most notably, PB reached an AUROC of up to 0.81; with kinetic analysis, it was comparable to BM in performance. MRD is a powerful predictor over the entire natural history of MCL and is suitable for models with a continuous adaptation of patient risk. The study can be found in EudraCT N. 2009-012807-25 (https://eudract.ema.europa.eu/).

Graphical abstract

Figure 1.

Molecular negativization rates. Results were obtained by nested PCR in (A) BM and (B) PB and by RQ-PCR in (C) BM and (D) PB. NEG, negative; PNQ, positive not quantifiable; POS, positive; R-CTX, rituximab-cyclophosphamide; R-HD-ARA-C, rituximab-high dose cytarabine.

Figure 2.

Effect of MRD positivity on TTP HR over time. Flexible parametric survival models with time-varying effect modeled using the restricted cubic spline transformation of time at different time points: BM by (A) nested PCR and by (B) RQ-PCR; PB by (C) nested PCR and by (D) RQ-PCR. M, months after ASCT; R-CTX, rituximab-cyclophosphamide; R-HD-ARAC, rituximab-high dose cytarabine.

Figure 3.

MRD impact on TTP, measured by RQ-PCR. Timepoints after ASCT, M6, and M12 were measured in BM (A,C,E, respectively) and in PB (B,D,F, respectively). M6, 6 months from transplant; M12, 12 months from transplant; NEG, negative; POS, positive.

Figure 4.

Time-varying AUCs of TTP. MIPI only (red) and different MIPI-adjusted kinetic MRD models are shown: BM by (A) nested PCR and by (B) RQ-PCR, PB by (C) nested PCR and by (D) RQ-PCR. M6, 6 months from transplant; MRD POS, positive minimal residual disease.

Figure 5.

MRD impact on TTP, stratified by randomization arm. MRD was measured by RQ-PCR in BM at different time points: here, the time points after (A) ASCT and (B) M12 are shown. M12, 12 months from ASCT; NEG, negative; POS, positive.