Early MRD Monitoring in Younger Patients With MCL Posttransplant Predicts Outcomes

Minimum residual disease (MRD) negativity in the bone marrow and peripheral blood prior to autologous stem cell transplant (ASCT) predicts better progression-free survival (PFS) and overall survival (OS) in younger patients with mantle cell lymphoma (MCL), according to a final analysis of the phase 3 LyMa-MRD project that was presented during the 2020 ASH Annual Meeting and Exposition.

Post-ASCT MRD status was not quite as predictive for outcomes, particularly OS, but its predictive capacity was enhanced when combined with the results from positron emission tomography (PET), said presenting author Mary B. Callanan, PhD, from University Hospital F. Mitterand and Inserm UMR 1231.

In addition, the study shows that “rituximab maintenance provides longer PFS and OS regardless of MRD status pre- or post-ASCT, suggestive of continued, clinically relevant antitumor activity of rituximab against very rare residual circulating and/or ‘tissue-resident’ MCL cells,” she said.

Achieving MRD negativity in the bone marrow pre-ASCT was associated with significantly superior PFS compared with MRD positivity (median, 56.2 months vs 49.9 months; P = .0295) as well as significantly better OS (median, 60.8 months vs not reached; P = .0407).¹

Achieving MRD negativity in the blood pre-ASCT was also associated with prolonged PFS compared with MRD-positive status (median: 60.8 vs. 34.9 months; P < .0001) as well as OS (median, 60.8 months vs. 39.6 months; P < .0001).

The LyMa study enrolled 299 patients aged 18 to 65 years old with untreated newly diagnosed MCL who were treated with induction rituximab, dexamethasone, high-dose cytarabine, and salt platinum (R-DHAP) and ASCT, followed by randomization to rituximab maintenance every 2 months for 3 years or observation. The main outcome from LyMa was an improvement in event-free survival, PFS, and OS with rituximab maintenance compared with observation.²

In LyMa-MRD, 220 patients for whom MRD was evaluable pre- and posttransplant formed the cohort for the final analysis. MRD analysis was performed by gold standard quantitative polymerase chain reaction assays and interpreted according to EURO-MRD standardized guidelines in 3 French reference laboratories. MRD data for the survival analysis was generated from assays with a minimal sensitivity of 10-4.

In 1042 samples from the 220 patients, MRD negativity in peripheral blood after induction therapy by R-DHAP was 77%, which increased to 94% posttransplant. “Likewise, in bone marrow, MRD negativity is at 64% postinduction by R-DHAP and reaches 81% after transplant,” she said.

Outcomes according to post-ASCT MRD status were also assessed. Post-ASCT MRD negativity in the blood was associated with improved PFS vs MRD-positive status (median, 59.2 months vs 34.4 months; P = .0452) but had no significant impact on OS (P = .1661). Similarly, post-ASCT status in the bone marrow had a significant impact on PFS (P = .0261) but not on OS.

Effect of maintenance rituximab

The addition of maintenance rituximab therapy improved outcomes in the patients who achieved MRD negativity in the bone marrow pre-ASCT. With maintenance, median PFS improved to a median of 58.2 months compared with 48.8 months in those patients who achieved MRD negativity pre-ASCT but were randomized to observation (P = .0405), and median OS improved from 52.2 months to 58.2 months with maintenance (P = .0395).

Maintenance therapy with achievement of MRD negativity in the blood pre-ASCT significantly extended median PFS (58.2 vs. 52.2 months; P = .0260) and median OS (58.2 months vs. not reached; P = .01326) compared with observation.

In patients with MRD-negative status in the blood post-ASCT, maintenance rituximab significantly prolonged median PFS from 48.8 months to 58.2 months (P = .001) and median OS from 52.2 months to 58.2 months (P = .02).

Maintenance therapy in patients with MRD-negative status in the bone marrow post-ASCT significantly prolonged median PFS (P = .0072) but had no significant impact on median OS compared with observation.

MRD Status Plus PET

The predictive power of integrating pre-ASCT molecular MRD status and results from PET was also assessed. “Quite strikingly…patients that achieved double negativity status for PET and MRD, whether this is in the bone marrow or the blood, show a significantly superior [PFS] outcome compared with those patients who remain double positive for PET and MRD…in the bone marrow or the blood,” she said.

Double negativity in the blood was also a predictor of significantly superior median OS in the blood (P = .0002) but not the bone marrow compared with double positivity.

Significantly improved predictive power for both median PFS and median OS was also achieved by combining post-ASCT MRD status in the blood and bone marrow with PET findings.

Reference

1. Callanan MB, Macintyre E, Delfua M-H, et al. 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. Presented at: 62nd American Society of Hematology (ASH) Annual Meeting and Exposition; December 5-9, 2020. Abstract 120.
2. Le Goiull S, Thieblemont C, Oberic L, et al. Rituximab after autologous stem-cell transplantation in mantle-cell lymphoma. N Engl J Med. 2017;377(13):1250-1260. doi: 10.1056/NEJMoa1701769