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RiBVD regimen as first-line treatment for older MCL patients
pared to 28.6% for MRD-positive patients; (P<0.0001). While for peripheral blood this is broadly in keeping with findings of the EU-MCL network for other treatment reg- imens,20 results concerning the prognostic impact of bone marrow molecular MRD, in patients treated with RiBVD, differ.20 The prognostic impact of MRD in patients treated with the R-BAC500 regimen has not been reported as yet.24 One avenue of investigation for clarification of these issues will be testing of ‘next generation’ cellular and molecular methods of MRD detection. Multi-para- metric flow cytometry, although requiring very high lev- els of expertise, has been shown to be feasible and pro- vide satisfactory sensitivity, when compared to highly standardized quantitative polymerase chain reaction methods in MCL.29 For molecular MRD, droplet digital polymerase chain reaction analysis is gaining interest30 as is molecular MRD assessment in circulating cell-free DNA in B-cell non-Hodgkin lymphoma.31-33 Combinatorial approaches (metabolic, cellular/molecular) as reported here for MCL, and in follicular lymphoma,34 will also be useful. Ultimately, careful investigation of residual disease, particularly by combinatorial approach- es, will be needed to further refine MRD-driven precision medicine approaches in lymphoma, and other cancers.35
MRD positivity at the end of treatment or at 1 year of follow-up was found to be highly predictive for early relapse (at 11 and 26 months, respectively) in patients treated with the RiBVD regimen. Although numbers of MRD-negative patients were small, these findings add fur- ther weight to the notion that achieving durable molecular remission is an important goal in MCL. Indeed, mainte- nance therapy and/or pre-emptive treatment directed to patients in molecular relapse or remaining MRD-positive after treatment has been shown to play a significant role in prolonging clinical response in MCL.2,23,36,37 The choice of maintenance or a pre-emptive therapy strategy may depend on the nature of initial therapy, as highlighted by a
recent study that failed to show the benefit of rituximab maintenance after bendamustine.38
In conclusion, our results identify the combination of rituximab, bendamustine bortezomib and dexametha- sone, without maintenance therapy, as a promising treat- ment option in MCL patients ≥65 years old. The RiBVD regimen compares favorably with other treatment strate- gies used in this setting, although randomized trials are still lacking. Prolonged PFS appears to result from rapid clearance of (re)circulating tumor B cells in the post-induc- tion phase. Continued molecular remission in the blood was predictive of prolonged survival, indicating that molecular MRD monitoring and molecular response offer significant potential as precision medicine tools for early and late clinical decision-making in MCL.
Acknowledgments
We thank Dr Jean Marie Quésada, biostatistician at the Grenoble Clinical Investigation Center (INSERM CIC 1406), for his help in data analysis, Valérie Rolland-Neyret and Roseline Delepine, data coordinators of the trial, for their excellent work, and all of the clinicians, not mentioned in the author list, who enrolled patients. We also thank the hematopathologists of the LYSA Pathology Commission for their pathology review (Dr. Danielle Canioni, Dr. Barbara Burroni, Prof. Alexandra Traverse- Glehen, Prof. Antoine Martin) and staff of the LYSA-Pathology core facility for providing their expert assistance for immunohisto- chemistry. We thank Estelle Gimenez for excellent technical coordi- nation of the MRD work. We also thank our partners Mundipharma, Jannsen-Cilag, and Roche for funding. MBC acknowledges additional institutional support from the Université Grenoble-Alpes, Université Bourgogne-Franche Comté, INSERM and CNRS. Research funding via the French National Cancer Institute and the ITMO Cancer ‘Epigenetics and Cancer pro- gramme’ is also acknowledged. Finally, we thank Professor André Goy, chairman and executive director of the John Theurer Cancer Center, Hackensack for his critical review of the manuscript.
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