Influence of Minimal Residual Disease on Survival of Patients with Mantle Cell Lymphoma

Background: The paradigm of the treatment mantle cell lymphoma (MCL) has changed due to development of newer agents (such as ibrutinib, lenalidomide, temsirolimus). Considering that the scheme of using the newer drugs implies permanent drug intake (before disease progression), which helps prevent the early relapses. With a high degree of probability, it can be assumed that MCL, in the future can be withdrawn from the group of aggressive and relapsing lymphomas. Evaluation and monitoring of the minimal residual disease (MRD) in patients with MCL allows to predict the course of the disease and optimize the strategy for maintaining this category of patients.

Aim: To assess influence of MRD negative (MRD^neg) status on the duration of progression free survival (PFS) and overall survival (OS).

Method: In this study were included 33 patients with MCL (male/female ratio 3:1), age 51 to 82 years (median 64 years). The median of follow-up duration is 80.7 months (range 0.7-147.1). Median of therapy lines - 1 (range 1-5). With rituximab-containing chemotherapy regimens were treated 25 patients (R-CHOP - 12, RFC - 5, RBV - 3, RB - 2, R-DHAP - 1, R-Hyper-CVAD - 1, RVc-CAP - 1); ibrutinib - 3, lenalidomide - 3 and temsirolimus - 1. Autologous stem cell transplantation (AutoSCT) was performed in 7 patients (21.2%). Maintenance therapy received 23 patients (69.7%): rituximab - 20, ibrutinib - 1, lenalidomide - 1 and temsirolimus - 1. During the follow-up period, 9 patients (27.2%) died: progression of the disease - 5, other reasons - 4. The evaluation of MRD status was carried out using 5-color flow cytometry on bone marrow samples after completion of induction therapy. The absent of MRD was detected when less than 1 tumor cell was detected per 10000 leukocytes (10^-4).

Results: Complete remission (CR) was achieved in 54.5% (n=18), partial remission (PR) - 45.5% (n=15). Patients were divided into two groups depending on MRD status: group MRD positive (MRD^pos) (n=12) and group MRD negative (MRD^neg) (n=21). The frequency of achievement of MRD^neg status was 63.6% (CR - n=15, PR - n=6). Noted, that all patients (n=7) who underwent AutoSCT achieved MRD^neg status after induction therapy and kept it after consolidation with AutoSCT. Disease progression in MRD^pos group was state in 11 patients (91.7%), in MRD^neg group - 6 (28.6%) (р=0.0005). Patients with MRD^pos status who underwent maintenance therapy achieved MRD^neg status in 8/12 cases. One patient, after completion R-CHOP + AutoSCT followed by a two-year maintenance program of rituximab, retained MRD^neg status. A year later, during the control survey, MRD^pos status was recorded. This patient was resumed maintenance therapy with rituximab. MRD^neg status is achieved after 6 months from the beginning of maintenance therapy. Median PFS in group MRD^neg was not achieved, in group MRD^pos - 12.5 months (р=0.001). Medians OS were not achieved in both groups. 5-year OS were: group MRD^neg - 83.8% and group MRD^pos - 73.3%. 10-year OS were: group MRD^neg - 64.4% and group MRD^pos - 58.7%. When comparing OS in patients among all groups no significant differences were found, which is probably due to a small number of events (р>0.05).

Conclusion: Our data demonstrate that achievement MRD^neg remissions determine duration of response on ongoing therapy and significant increase of PFS duration. Presently, MRD detection in patients with MCL is important part of complex assessment of effectiveness therapy and it need to be studied more.

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