Minimal Residual Disease in Mantle Cell Lymphoma

Ladetto, Marco; Tavarozzi, Rita; Pott, Christiane

doi:10.1016/j.hoc.2020.06.006

Cited by 11 publications

(6 citation statements)

References 65 publications

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“…The FIL MCL0208 clinical trial showed a PFS advantage of LEN compared with OBS. 23 Here, we add the observation that fewer relapses among MRD-positive patients were registered in the LEN arm ( Figure 5A and supplemental Figure 6). Moreover, MRD analysis preserved its predictive value during LEN, but its impact was modulated by maintenance therapy.…”

Section: Discussionmentioning

confidence: 86%

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

Ferrero

Grimaldi

Genuardi

et al. 2022

Blood

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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/

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Section: Discussionmentioning

confidence: 86%

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

Ferrero

Grimaldi

Genuardi

et al. 2022

Blood

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“…Other methods such as ddPCR 21 and particularly nextgeneration sequencing 26 will overcome limitations of qPCR 25 and will improve feasibility of MRD assessment for clinical decision making. In the meantime, qPCR results as those established here should serve as a strong reference.…”

Section: Discussionmentioning

confidence: 99%

“…In this trial, MRD was assessed by qPCR, a method that used to be the gold standard when the study was planned. 25 The fact that only 80% of patients with diagnostic samples scheduled for MRD assessment were finally evaluable was mainly due to low-infiltrated diagnostic samples (PB and/or BM) that resulted in either failure to detect a clonal marker (15%) or missing the EuroMRD criteria of technical requirements for limits of sensitivity and quantification (5%). This observation was also made by Ferrero et al 24 Therefore, for prospective design of MRD-guided trials, one would include FFPE-tissue to increase the number of evaluable patients to >90%.…”

Section: Discussionmentioning

confidence: 99%

Predictive Value of Minimal Residual Disease for Efficacy of Rituximab Maintenance in Mantle Cell Lymphoma: Results From the European Mantle Cell Lymphoma Elderly Trial

Hoster,

Delfau-Larue,

Macintyre

et al. 2024

JCO

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PURPOSE The outcome of older patients with mantle cell lymphoma (MCL) has improved by the introduction of immunochemotherapy, followed by rituximab (R)-maintenance. Assessment of minimal residual disease (MRD) represents a promising tool for individualized treatment decisions and was a prospectively planned part of the European MCL Elderly trial. We investigated how MRD status influenced the efficacy of R-maintenance and how MRD can enable tailored consolidation strategies. PATIENTS AND METHODS Previously untreated patients with MCL age 60 years or older have been randomly assigned to R versus interferon-alpha maintenance after response to rituximab, fludarabine, cyclophosphamide (R-FC) versus rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP). MRD monitoring was performed by real-time quantitative polymerase chain reaction (qPCR) following EuroMRD guidelines. RESULTS A qPCR assay with a median sensitivity of 1 × 10−5 could be generated in 80% of 288 patients in an international, multicenter, multilaboratory setting. More extensive tumor 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 progression-free survival (PFS; hazard ratio [HR], 0.38 [95% CI, 0.21 to 0.63]) and overall survival (OS; HR, 0.37 [95% CI, 0.20 to 0.68]), particularly in R-CHOP–treated patients (PFS-HR, 0.23 [95% CI, 0.10 to 0.52]; OS-HR, 0.19 [95% CI, 0.07 to 0.52]). R-maintenance appeared less effective in MRD-positive patients (PFS-HR, 0.51 [95% CI, 0.26 to 1.02]) overall and after R-CHOP induction (PFS-HR, 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. CONCLUSION The results confirm the strong efficacy of R-maintenance in patients who are MRD-negative after induction. Treatment de-escalation for MRD-negative patients is discouraged by our results. More effective consolidation strategies should be explored in MRD-positive patients to improve their long-term prognosis.

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“…The prog nos tic role of MRD assess ment, uti liz ing dif fer ent assays includ ing flow cytom e try, reverse-tran scrip tion polymer ase chain reac tion (PCR)-based tech niques, and immunosequencing plat forms, has been well established in MCL. 42 MRD sta tus post induc tion che mo ther apy and pre-ASCT has been shown to be an impor tant pre dic tor of PFS and a potential bio marker for risk-adapted treat ments. 43,44 Thus, the ongoing EA4151 study is com par ing main te nance rituximab alone vs ASCT con sol i da tion in MCL patients who achieve a remis sion and an MRD-unde tect able sta tus post induc tion.…”

Section: Clinical Case 1 (Con Tin Ued)mentioning

confidence: 99%

What is the role of up-front autologous stem cell transplantation in mantle cell lymphoma?

Kumar

2022

Hematology

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Up-front autologous stem cell transplantation (ASCT) is the established standard of care for younger, transplant-eligible MCL patients and is associated with a prolonged progression-free survival (PFS) benefit. However, there is no randomized controlled trial data, with therapy including rituximab and cytarabine, that has established a PFS and overall survival (OS) benefit with ASCT in the modern era. Multiple retrospective studies have failed to identify an OS benefit associated with ASCT in younger MCL patients. The high-risk patient subgroup with evidence of baseline TP53 mutation has a dismal outcome with intensive chemoimmunotherapy followed by ASCT, thus up-front ASCT is not optimal for this patient subset. Ongoing randomized clinical trials will help to clarify the role of up-front ASCT in the future. For example, the ongoing European MCL Network Triangle study incorporating ibrutinib into chemoimmunotherapy induction and maintenance with and without ASCT will help define the role of ASCT in the era of novel biologically targeted agents (ClinicalTrials.gov identifier: NCT02858258). Additionally, minimal residual disease (MRD) assessment is a powerful prognostic tool in MCL, and the ongoing Eastern Cooperative Oncology Group-American College of Radiology Imaging Network E4151 study is comparing maintenance rituximab alone vs ASCT consolidation in MCL patients who achieve remission and MRD-undetectable status post induction (ClinicalTrials.gov identifier: NCT03267433). ASCT remains a highly efficacious initial therapy for younger MCL patients; however, ultimately the decision to pursue ASCT requires discussion of risks vs benefits, incorporating patient preferences and values.

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Minimal Residual Disease in Mantle Cell Lymphoma

Cited by 11 publications

References 65 publications

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

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

Predictive Value of Minimal Residual Disease for Efficacy of Rituximab Maintenance in Mantle Cell Lymphoma: Results From the European Mantle Cell Lymphoma Elderly Trial

What is the role of up-front autologous stem cell transplantation in mantle cell lymphoma?

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