A comprehensive analysis of minimal residual disease (MRD) data from the mantle cell lymphoma (MCL) Elderly study of the European MCL network shows that the efficacy of rituximab (R)-maintenance was clearly confirmed in MRD-negative patients after R-CHOP induction by substantially prolonged progression-free survival (PFS) and overall survival (OS). Consequently, treatment de-escalation by omitting R-maintenance in MRD-negative patients is strongly discouraged.
MRD positivity after start of R-maintenance was associated with short time to progression and represents an important trigger for treatment intensification to be developed in future studies. The findings are reported by Dr. Christiane Pott of the Medizinische Klinik II, Hämatologie und Internistische Onkologie Universitätsklinikum Schleswig-Holstein in Kiel, Germany, and colleagues of the European MCL MRD Working Group and the European MCL Network on 22 November 2023 in the JCO.
The authors explained in the background that variability of outcome in advanced-stage MCL can be partly explained by clinical variables and the Ki-67 index of proliferation. Treatment decisions are mainly guided by clinical characteristics. MRD detection allows a highly sensitive longitudinal monitoring of tumour load and residual disease during and after treatment in different mature B-cell malignancies, including MCL.
The European MCL Elderly study was an international, double-randomised phase III study that established R-maintenance in older patients with MCL responding to first-line R-CHOP based on PFS and OS. Furthermore, compared with R-CHOP, induction treatment with R-FC was not superior in terms of response rates and failure-free survival and was inferior in terms of OS, mainly because of increased early and late toxicity.
Within the European MCL Network, MRD monitoring has been established as a standard correlative programme for clinical studies. For MCL Elderly, the primary aim was to investigate whether and how the MRD status at the end of induction influenced the efficacy of R-maintenance and particularly to answer the question whether treatment de-escalation in MRD-negative patients should be encouraged. Secondary aims were to confirm the feasibility of MRD assessment for prognostic analyses in a multicentre, multinational study setting, to evaluate the use of MRD status as a dynamic indicator for induction treatment efficacy, and to establish optimal MRD time points for treatment modification.
Previously untreated patients with MCL age 60 years or older have been randomly assigned to R- versus interferon-alpha maintenance after response to R-FC versus R-CHOP. MRD monitoring was performed by real-time quantitative polymerase chain reaction (qPCR) following EuroMRD guidelines.
A qPCR assay with a median sensitivity of 1 × 10−5 could be generated in 80% of 288 patients in an international, multicentre, multilaboratory setting. More extensive tumour dissemination facilitated the identification of a molecular marker. The efficacy of R-maintenance in clinical remission was confirmed for MRD-negative patients at the end of induction in terms of PFS (hazard ratio [HR] 0.38, 95% confidence interval [CI] 0.21 to 0.63) and OS (HR 0.37, 95% CI 0.20 to 0.68), particularly in R-CHOP–treated patients (HR for PFS 0.23, 95% CI 0.10 to 0.52; and HR for OS 0.19, 95% CI 0.07 to 0.52).
R-maintenance appeared less effective in MRD-positive patients where HR for PFS was 0.51 (95% CI 0.26 to 1.02) overall and after R-CHOP induction HR for PFS was 0.59 (95% CI 0.28 to 1.26). R-FC achieved more frequent and faster MRD clearance compared with R-CHOP. MRD positivity in clinical remission after induction was associated with a short median time to clinical progression of approximately 1-1.7 years.
The authors concluded that in addition to the known prognostic role of MRD in MCL, their results show how MRD information can affect treatment decisions and future research. The results are in line with observations from the LYSA-LYMA study in younger patients with MCL. As a consequence, treatment de-escalation by omitting R-maintenance in MRD-negative patients is strongly discouraged. In contrast, intensified maintenance for MRD-positive patients after induction, including additive treatments as soon as MRD persistence or reappearance is observed, should be investigated in the context of clinical studies.
Beyond the application for pure prognostic purposes, the results also show the utility of and advocate for the assessment of MRD for treatment efficacy monitoring and establishing novel risk-adapted treatment strategies.
The findings were previously presented in part at the 2022 ASH Annual Meeting (10-13 December 2022, New Orleans, LA, US).
The study was supported by the European Commission within the European MCL Network and by the Lymphoma Research Foundation Correlative Research grant, Association de recherche contre le Cancer, Fondation de France comité Leucémie, Association de recherche sur le traitement, la genétique et l'immunologie des lymphomes. Banking support was provided by the CARPEM SIRIC.
Reference
Hoster E, Delfau-Larue M-H, Macintyre E, et al. on behalf of the European MCL MRD Working Group and the European MCL Network. Predictive Value of Minimal Residual Disease for Efficacy of Rituximab Maintenance in Mantle Cell Lymphoma: Results From the European Mantle Cell Lymphoma Elderly Trial. JCO; Published online 22 November 2023. DOI: 10.1200/JCO.23.00899