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 III MCL0208 prospective clinical trial assessing lenalidomide maintenance vs observation after autologous 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 timepoints. 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 timepoints. ASCT induced high rates of molecular remission (91% in PB and 83% in BM, by quantitative real-time PCR [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 TTP HR 3.83, p<0.001). 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 Mantle Cell Lymphoma International Prognostic Index, showing an area under the ROC 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 suitable for models with continuous adaptation of patient risk. Study can be found in EudraCT N. 2009-012807-25 https://eudract.ema.europa.eu/

Research Topic: Measurable Residual Disease in Hematologic Malignancies. Can digital droplet PCR improve measurable residual disease monitoring in chronic lymphoid malignancies?

“…Several large studies sustain the predictive role of MRD in MCL ( 52 – 56 ). Among the most recent, the FIL MCL0208 trial compared maintenance with lenalidomide vs. observation after an intensive chemo-immunotherapeutic regimen and autologous stem cell transplant (ASCT) in 300 young MCL patients ( 54 ). A molecular marker ( BCL1::JH and/or IGH rearrangements) was found in 83% of patients, and a MRD negativity was achieved in 78% of patients after high-dose chemotherapy and in 79% after ASCT ( 54 ).…”

“…Among the most recent, the FIL MCL0208 trial compared maintenance with lenalidomide vs. observation after an intensive chemo-immunotherapeutic regimen and autologous stem cell transplant (ASCT) in 300 young MCL patients ( 54 ). A molecular marker ( BCL1::JH and/or IGH rearrangements) was found in 83% of patients, and a MRD negativity was achieved in 78% of patients after high-dose chemotherapy and in 79% after ASCT ( 54 ). A time-varying kinetic model, combining the MRD status at two or more consecutive time points (post-ASCT, months +6, +12) was conceived.…”

“…A time-varying kinetic model, combining the MRD status at two or more consecutive time points (post-ASCT, months +6, +12) was conceived. The combination of the MRD status with the MIPI (Mantle Cell Lymphoma International Prognostic) index proved to be an informative tool in predicting relapse and determining time-to-progression (TTP) ( 54 ).…”

“…Also in this setting, the pitfalls of RQ-PCR, especially the contamination risk, the presence of disease levels below the quantitative range and the requirement of a standard curve offer the possibility to improve MRD monitoring by the employment of ddPCR ( 29 , 54 ).…”

“…The gold standard approach for MRD monitoring relies on BCL1:: IGH and IGH rearrangements monitored by RQ-PCR, capable of detecting up to 1 clonal cell among 100,000 analyzed (1 × 10 −5 ) (52-56). Several large studies sustain the predictive role of MRD in MCL (52)(53)(54)(55)(56). Among the most recent, the FIL MCL0208 trial compared maintenance with lenalidomide vs. observation after an intensive chemo-immunotherapeutic regimen and autologous stem cell transplant (ASCT) in 300 young MCL patients (54).…”