Predictive Power of Early, Sequential MRD Monitoring in Peripheral Blood and Bone Marrow in Patients with Mantle Cell Lymphoma Following Autologous Stem Cell Transplantation with or without Rituximab Maintenance; Final Results from the LyMa-MRD Project, Conducted on Behalf of the Lysa Group

Abstract

INTRODUCTION : Minimal residual disease (MRD) has emerged as an important predictor of clinical outcome in patients with mantle cell lymphoma (MCL). Its use in everyday clinical practice, however, remains uncertain since standardized MRD monitoring strategies and response criteria are not yet formally established. To address this question, we conducted the LyMa-MRD project as an ancillary biology study in a prospective phase III trial in MCL patients < 66 years of age (NCI NCT00921414; LyMa Trial; Le Gouill et al, NEJM 2017). Briefly, in this trial all patients were previously untreated and received 4 courses of R-DHAP followed by ASCT. After ASCT, patients were randomized between observation (obs) versus Rituximab maintenance (RM) which was associated to superior event free, progression free and overall survival, respectively. Herein, we present the final MRD analysis. METHODS : The final MRD analysis was performed in a total of 220 MRD evaluable patients [defined as patients with an available MRD assay and appropriate follow-up sample in peripheral blood (PB) and/or bone marrow, (BM), at the time point of interest for statistical analyses] and aimed to assess MRD response rates and prognostic impact [progression free and overall survival, (PFS, and OS, respectively)] at the pre-ASCT (after induction phase) (n=195 ; 86 RM and 84 obs) or (2 ; 90 RM and 92 obs). Sequential MRD monitoring was a predefined secondary objective. An additional aim was to assess the value of combining molecular MRD and PET (positron emission tomography) for outcome prediction pre- and post-ASCT. MRD was quantitatively assessed in PB and / or BM after induction or after ASCT by using gold standard EURO-MRD RQ-PCR assays targeted to clonal immunoglobulin gene rearrangements, in 3 French national reference laboratories. MRD data for survival analysis was generated from assays with a minimal sensitivity of at least 10-4. MRD status was assigned according to EURO-MRD interpretation guidelines. MRD negativity at a given time point was defined as absence of RQ-PCR amplification product in the follow-up sample (minimal assay sensitivity of 10-4). Non evaluable MRD was mostly due to no follow-up sample, no MRD target or MRD assay failure. RESULTS: In a total of 195 MRD evaluable patients who completed R-DHAP induction therapy, MRD was found negative in 77% (n=144) and 64% (n=115) of PB and BM samples, respectively. MRD status pre-ASCT was predictive of PFS and OS: p< 0.0001, respectively, for PB; p= 0.0295 and 0.0407, respectively, for BM). Post-ASCT, MRD in PB and BM was negative in 94% (n=181) and 81% (n=137) of patients, respectively, and was predictive of PFS (but not OS) (PB, p= 0.0452 ; BM, p=0.0261). In patients that were MRD negative either pre (PB, p= 0.0260; BM, p=0.0405) or post-ASCT (PB, p=0.001; BM, p=0.007), RM was associated to improved PFS and also OS, albeit to a lesser extent [pre-ASCT BM MRD and post-ASCT PB MRD neg groups only ; p= 0.0395 and p =0.02, respectively]. Finally, combining PET and MRD status offered improved prediction of PFS both pre- (p< 0.0001, PB; p=0.0028, BM MRD) and post-ASCT (p<0.0001, PB; p=0.0082, BM). Likewise, combining either pre- or post-ASCT PET/MRD also provided improved prediction of OS [PB, but not BM, plus PET pre-ASCT, p=0.0002 ; PB or BM MRD plus PET, p<0.0001 and p=0.0474, respectively, post-ASCT). CONCLUSION: Pre-ASCT MRD status in both BM and PB is an early predictor of PFS and OS in younger MCL patients receiving ASCT. RM provides longer PFS and OS regardless of MRD status pre- and post-ASCT. Early sequential MRD monitoring at the pre-ASCT treatment phase and directly post-ASCT thus offers strong potential for early clinical outcome prediction, as a surrogate clinical end point, and for MRD-guided, risk-adapted treatment in MCL. Disclosures Delfau-Larue: MUNDIPHARMA: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); AMGEN: Honoraria; GILEAD: Honoraria; ROCHE: Honoraria. Thieblemont:Roche, Hospita: Research Funding; Roche, Amgen, Kyte Gilead, Celgene, Abbvie, Novartis, Cellectis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Cellectis: Speakers Bureau. Oberic:Roche, Janssen: Consultancy; Roche, Janssen: Other: Travel, Accommodations, Expenses; Roche: Honoraria. Bouabdallah:Gilead Sciences: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Roche: Consultancy, Honoraria. Casasnovas:MSD: Consultancy, Honoraria; AMGEN: Consultancy, Honoraria; BMS: Consultancy, Honoraria; abbvie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding. Ribrag:BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses; argenX: Current equity holder in publicly-traded company, Research Funding; Infinity: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Honoraria; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; arGEN-X-BVBA: Research Funding; BAY1000394 studies on MCL: Patents & Royalties; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Eisai: Honoraria; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Immune Design: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy, Current equity holder in publicly-traded company, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AZD: Honoraria, Other; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Institut Gustave Roussy: Current Employment; Nanostring: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses; Pharmamar: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Hermine:Alexion: Research Funding; AB Science: Consultancy, Current equity holder in publicly-traded company, Honoraria, Patents & Royalties, Research Funding; Novartis: Research Funding; Roche: Consultancy; Celgene BMS: Consultancy, Research Funding. Le Gouill:Roche Genentech, Janssen-Cilag and Abbvie, Celgene, Jazz pharmaceutical, Gilead-kite, Loxo, Daiichi-Sankyo and Servier: Honoraria; Loxo Oncology at Lilly: Consultancy.

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

“…Interestingly, such a phenomenon was not reported by the MRD substudy of the LyMa trial, exploring rituximab as a post-ASCT maintenance treatment, probably suggesting a wider efficacy of this drug across all patient subgroups. 9 Finally, we were not able to identify clear correlations between LEN dose intensity and MRD kinetics, even though the limited number of patients provided with complete MRD and LEN dosage data (n = 45) hampered an accurate subgroup analysis of this phenomenon.…”

“… 6 Even if prospective and standardized, these RQ-PCR results are usually derived from merged tissues (mainly PB), and systematic comparison between BM and PB samples at different time points (as well as between IGH and BCL-1/IGH markers) is lacking. Moreover, MRD data from the LyMA phase 3 trial, which have so far been presented only in abstract form, 9 are focused on only 2 early time points (before and after ASCT) and are not conclusive regarding the prognostic value of MRD after ASCT, as very few MRD-positive results were recorded. On the other hand, the phase 2 Nordic trials described highly predictive MRD data from a selection of patients derived from 2 phase 2 studies.…”

“…These modulating effects of maintenance therapy on MRD values need to be more extensively investigated in different maintenance contexts (eg, LEN, 12 rituximab, 9 and ibrutinib), but they might explain the suboptimal predictive role of punctual MRD analysis at very early time points in a small retrospective series of patients receiving rituximab maintenance. 29 Finally, many additional biological factors could influence patient sensitivity to LEN, as suggested, for example, by the pharmacogenomics substudies from the present FIL MCL0208 trial.…”

First-Line Autologous Stem Cell Transplantation for Mantle Cell Lymphoma: A Systematic Analysis and Treatment Recommendation

“…In the MRD analysis by Callanan et al. ( 33 ), RM provides longer PFS and OS regardless of MRD status pre- and post-ASCT in MCL pts who completed R-DHAP induction therapy. Sequential MRD monitoring during treatment offers strong potential for early clinical outcome prediction, as a surrogate clinical endpoint, and for MRD-guided, risk-adapted treatment in MCL.…”

The optimal time and clinical implications of measurable residual disease detection in mantle cell lymphoma

“…The concept of measurable residual disease (MRD) assessment has been well established in hematological neoplasms. Previously, several studies have shown its close correlation of MRD status with PFS and overall survival (OS) in MCL [9][10][11][12][13] . Its role in routine practice is yet to be de ned but will be in uenced by suitable modalities for real-world use 14 .…”