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40 Impact of Maintenance Arm on Prognostic Value of MRD after Induction Treatment in MCL R2 Elderly Trial , a Mantle Cell Lymphoma Network Study

Program: Oral and Poster Abstracts
Type: Oral
Session: 621. Lymphomas: Translational—Molecular and Genetic: Clinical Applications
Hematology Disease Topics & Pathways:
Translational Research
Saturday, December 11, 2021: 10:15 AM

Marie-Helene Delfau1,2,3*, Elizabeth A. Macintyre, PhD, MD4,5, Mary B. Callanan, PhD6*, Christiane Pott7*, Vincent H.J. Van Der Velden, PhD8*, Christa Homburg9*, Ramon Garcia-Sanz, MD10, Paula Gameiro11*, Maria Gomes Da Silva, MD, PhD12*, Wolfram Klapper13*, Lucie Oberic, MD14,15*, Pierre Feugier, MD16*, Violaine Safar, MD17*, Olivier Casasnovas, MD18*, Martin H. Dreyling, MD, PhD19 and Vincent Ribrag, MD20,21

1INSERMU955 équipe 9, University Hospital, Créteil, France
2Immunology Biology, Mondor University Hospital, Créteil, France
3Department of Immunology, University Hospital, Creteil, France
4Institut Necker Enfants Malades, Université de Paris (Descartes), Paris, France
5Laboratory of Onco-Hematology, Necker University Hospital, Paris, France
6Inserm UMR 1231, Centre Hospitalier Universitaire de Dijon, Dijon, France
7Department of Medicine II, University Hospital of Schleswig-Holstein, Kiel, Germany
8Department of Immunology, Erasmus University Medical Center, Rotterdam, Netherlands
9Sanquin Diagnostic Services, Amsterdam, NLD
10Hematology Department, Hospital Universitario de Salamanca, Salamanca, Spain
11Molecular Biology, Instituto Português de Oncologia, Lisboa, Portugal
12IPO, Lisboa, Portugal
13Department of Pathology, Hematopathology Section, University Hospital Schleswig-Holstein, Christian-Albrecht-University of Kiel, Kiel, Germany
14Institut Universitaire du Cancer—Oncopole Toulouse (IUCT-O), Toulouse, France
15Department of Hematology, Purpan University Hospital, Toulouse, France
16Department of Hematology, Henri Poincaré University, CHU NANCY BRABOIS, Vandoeuvre Les Nancy, France
17Department of Hematology, Lyon-Sud Hospital, Pierre-Benite, France
18Hematology Department, University Hospital F. Mitterrand and Inserm UMR 1231, Dijon, France
19Department of Internal Medicine III, LMU Hospital, Munich, Germany
20Département d'Innovation Thérapeutique et d'Essais Précoces (DITEP), Gustave Roussy Institute of Cancer, Villejuif, France
21Université Paris-Saclay, Gustave Roussy, INSERM U1170, Villejuif, France

Introduction

The prognostic value of minimal residual disease (MRD) in mantle cell lymphomas (MCL) has been reported in several clinical trials mainly in younger patients eligible for autologous transplantation and allows preemptive treatment of relapse. In elderly patients, the MCL R2 Elderly trial evaluated the benefit of a maintenance treatment combining rituximab plus lenalidomide (R2) compared to rituximab alone (R) in patients responding to the randomized induction treatment, either the reference treatment R-CHOP or alternate RCHOP/R-HAD regimen. The clinical results of the trial will be reported during the present ASH-2021 meeting. A secondary objective of the MCL R2 Elderly trial was to assess the ability of the experimental regimen to eradicate MRD, or the ability of the maintenance regimen to erase the poor prognostic value of MRD (+) at the end of induction treatment (EOI) or during maintenance.

Methods

Samples were collected at diagnosis, midterm, EOI and every 6 months during the 2 years maintenance period. Prospective quantitative MRD assessment on peripheral blood (PB) or bone marrow (BM) samples was performed in national reference laboratories in France, Germany, the Netherlands, Spain and Portugal (All members of Euro-MRD network), using the standardized gold standard real-time quantitative polymerase chain reaction (QPCR) of clonal immunoglobulin heavy chain VDJ junction (IGH) or IGH-BCL1 rearrangement. Samples with QPCR data below the quantitative range (BQR) were considered positive when 2 or 3 replicates were positive. Assay sensitivity ranged from 10-4 to 10-5. Depending of time point, MRD status was assigned from PB result alone or from both PB and BM. In the later case, MRD was judged (+) if at least one sample, PB or BM, was (+) by QPCR.

Results:

Tumoral marker was identified and MRD results were generated in 470 out of 532 tested patients (88% informativity). The analyses at 2 time-points are reported here: MRD at EOI in 401 patients who completed the induction treatment (R-CHOP n=192; R-CHOP/R-HAD, n=209) and MRD after one year under maintenance in 242 randomized patients (R n=114; R2 n=128). Clinical characteristics of the analyzed patients did not differ from the entire clinical cohort (Table 1). At the EOI, 157/401 (39%) patients were MRD(+), with no differences according to the induction regimen (81/192 [42.2%] in R-CHOP arm vs 76/209 [36.3%] in R-CHOP/R-HAD arm, p=0.23). With a median FU of 2.4 yrs from EOI, MRD(+) at EOI was significantly associated with a shorter median PFS (2.7yrs vs 4.7yrs, HR 1.78 [1.3-2.4] p=0.0002). However, the MRD status did not have the same impact in both maintenance arms (interaction test p=0.02). In the R arm, the 2 yr PFS was 64.8% and 61.7% for MRD(-) and MRD(+) patients, respectively (NS). In contrast, in the R2 arm, MRD did have a prognostic value: 84.3% vs 61.6% 2yr PFS for MRD(-) vs. MRD(+) patients, respectively (HR : 3 [1.78-5.1] p<0.0001) (Figure 1a), even when adjusted to MIPI. When only BM results were taken into account (n=320) HR increases (4 [2.2-7.3] p<0.0001).

MRD was analyzed both at EOI and after 1 year maintenance in 231 patients. In 191 patients (82.7%), the MRD status was identical at both time-points (35 (+)/(+) and 156 (-)/(-)). Only 3 patients converted from MRD (-) to MRD (+), 2 in the R and 1 in the R2 arm. MRD (+) to (-) conversion was observed in 16 (14.5%) and 21 (17.4%) patients in the R and R2 arms respectively (NS).

MRD status after one year of maintenance was obtained in 242 patients (203 MRD(-), 39 MRD (+)). MRD remained significantly associated with PFS, with a median PFS of 2.1 years and 4.9 years for MRD (+) and MRD (-) patients, respectively (HR 2.8 [1.6-5) p=0.0002) (figure 1b), with no interaction of maintenance arm.

Conclusion:

MRD assessment using standardized Euro-MRD QPCR demonstrated that the MRD status at EOI is of high prognostic value for PFS in elderly patients, but the observed effect is mainly due to the benefit provided by the R2 maintenance to the patients that are MRD(-) after induction. Whether undetectable MRD in these patients corresponds to very low disease levels (MRD<10-5), that can be immunologically controlled by the addition of lenalidomide to R, remains to be determined. A longer follow-up is needed to assess patient’s outcome after the end of maintenance. Finally, our results show that patients MRD positive under maintenance, are at high risk of relapse, irrespective of treatment arm.

Disclosures: Delfau: AMGEN: Honoraria; GILEAD: Honoraria; MUNDIPHARMA: Honoraria; ROCHE: Honoraria, Research Funding; CELGENE: Research Funding. Gomes Da Silva: Gilead Sciences: Research Funding; Astrazeneca: Research Funding; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; MSD: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Klapper: Regeneron: Consultancy, Research Funding; Amgen: Research Funding; Takeda: Consultancy, Research Funding; Roche: Consultancy, Research Funding. Oberic: Celgene: Honoraria; Janssen: Honoraria, Other: Support for attending meetings and/or travel; F. Hoffmann-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel; Gilead: Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel; AbbVie: Other: Support for attending meetings and/or travel; Incyte: Membership on an entity's Board of Directors or advisory committees. Feugier: ROCHE: Membership on an entity's Board of Directors or advisory committees, Other: Meeting travel funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel funding. Safar: roche: Consultancy, Honoraria; novartis: Consultancy, Honoraria. Casasnovas: Janssen: Consultancy; BMS: Consultancy; Gilead/Kite: Consultancy, Research Funding; TAKEDA: Consultancy, Research Funding; ROCHE: Consultancy, Research Funding; Amgen: Consultancy. Dreyling: Amgen: Speakers Bureau; BeiGene: Consultancy; Astra Zeneca: Consultancy, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Genmab: Consultancy; Celgene: Consultancy, Research Funding, Speakers Bureau; Gilead/Kite: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Roche: Consultancy, Research Funding, Speakers Bureau; Abbvie: Research Funding; Bayer HealthCare Pharmaceuticals: Consultancy, Research Funding, Speakers Bureau. Ribrag: Roche: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Epizyme: Honoraria, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees; Infinity Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; MSD Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; GSK: Research Funding; Astex Pharmaceuticals: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Nanostring: Membership on an entity's Board of Directors or advisory committees; PharmaMar: Honoraria, Membership on an entity's Board of Directors or advisory committees; Argen-X: Research Funding; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees.

*signifies non-member of ASH