Punctual, Kinetic MRD Analysis May Be MCL Natural History, Progression, and Outcomes Indicator

Punctual and kinetic minimal residual disease analysis could be a robust predictor of mantle cell lymphoma’s natural history and could represent an adaptable model for continuous patient risk assessment.

Minimal residual disease (MRD) appears to be a notable indicator of the natural history of mantle cell lymphoma (MCL) and could be a good fit for models that continuously adapt to patient risk, according to data derived from the FIL-MCL0208 trial (NCT02354313) published in Blood.

Investigators noted that MRD was predictive of both early progression and long-term outcomes in patients with MCL who were treated with lenalidomide (Revlimid) maintenance or observation following autologous stem cell transplant (ASCT), especially at the 6-month time point (ASCT; HR, 3.83; P <.001). Moreover, findings from a single time point analysis indicated that bone marrow was more reliable than peripheral blood. Additionally, while quantitative real-time polymerase chain reaction (RQ-PCR) was found to be reliable, nested PCR was applicable to a large group of patients (176 vs 234, respectively).

Kinetic MRD analysis across 2 or more times points—most notably at ASCT, month 6, and month 12—were more useful than assessing any individual timepoints. Sustained MRD positivity (HR, 6.93; 95% CI, 1.74-27.6; P = .006) or an alternating MRD pattern after ASCT (HR, 5.51; 95% CI, 2.02-15.0; P < .001) was consistently better at predicting time to progression vs achieving a complete response.

It was theorized that MRD performance could be improved by developing a time-varying kinetic model that was based on updated MRD findings and the Mantle Cell Lymphoma International Prognostic Index with an area under the receiver operating characteristic (ROC) curve upwards of 0.87 in the bone marrow. Area under the ROC curve was 0.81 in peripheral blood, and was similar with kinetic analysis.

The study was performed by way of several biological sub-studies, including 4351 analytical findings that allowed for methods, tissues, and predictive values at different time points to be compared. This also allowed for the development of a kinetic model for outcome prediction to circumvent a handful of limitations seen in single time point analyses.

FIL-MCL0208 assessed the efficacy of 24-month maintenance lenalidomide compared with observation in a population of young, fit patients with MCL following first-line high-dose chemoimmunotherapy and ASCT. Both the clinical trial and MRD study were approved by the ethics committees across all enrollment centers.

A total of 300 patients were included in the study from 2010 to 2015. Over 99% of baseline samples were centralized to the MRD lab successfully. A total of 1184 bone marrow samples and 1170 peripheral blood samples were collected during treatment and follow-up periods. Compliance ranged from 90% to 95% post ASCT and 65% to 70% during the latest time points. Suitable detection of MRD was achieved in 83% of cases (n = 250/300). In the population of 250 patients with detectable MRD, 6% did not have follow up samples because of early treatment interruption.

Among the remaining patients, 225 had available diagnostic material that could be used to set a standard curve for RQ-PCR and 184 had an acceptable standard curve. Within this population, 96% had at least 1 follow-up sample available for MRD analysis by RQ-PCR. Conversely, 25% were evaluable by nested PCR. Investigators generated 2351 nested PCR and 2000 RQ-PCR evaluable results.

In the population included in the MRD molecular analysis (n = 250), 23% presented with IGH and BCL1/IGH, 61% with IGH only, and 16% with BCL1/IGH only. Among these patients, 98 time to progression events were reported. Patients with no marker or BCL1/IGH only were found to have significantly lower tumor infiltration of baseline samples in bone marrow histology and 4-color flow cytometry of bone marrow vs other groups (1% vs 12%; P <.001) as well as in peripheral blood (0.7% vs 7%; P <.001). Additionally, these patients had consistently better clinical features, such as less stage IV and bulky disease, lower ECOG performance status, and lower MCL International Prognostic Index. This translated to a more favorable 3-year TTP rate at 86% vs 65%, respectively (P = .002). IGH rearrangements were preferentially used for MRD analysis when both markers were available.

In terms of other findings, investigators noted that bone marrow MRD negative rates increased from 30% following rituximab (Rituxan) plus cyclophosphamide (R-CTX) to 53% with rituximab and high-dose cytarabine (R-HD-ARA-C) and 56% with ASCT. A more robust MRD clearance was noted in the peripheral blood (47%) compared with paired bone marrow (79%) samples. The rates of MRD negativity after each treatment were 36% after R-CTX, 74% after R-HD-ARA-C, and 83% following ASCT in the bone marrow vs 49%, 88%, and 91%, respectively, in the peripheral blood (P <.05).


Ferrero S, Grimaldi D, Genuardi E, et al. Punctual and kinetic MRD analysis from the Fondazione Italiana Linfomi MCL0208 phase III trial in mantle cell lymphoma. Blood. Published online June 23, 2022. doi:10.1182/blood.2021014270