Molecular Monitoring after Autologous Stem Cell Transplantation and Preemptive Rituximab Treatment of Molecular Relapse; Results from the Nordic Mantle Cell Lymphoma Studies (MCL2 and MCL3) with Median Follow-Up of 8.5 Years

Abstract

The main objectives of the present study were to monitor minimal residual disease (MRD) in the bone marrow of patients with mantle cell lymphoma (MCL) to predict clinical relapse and guide preemptive treatment with rituximab. Among the patients enrolled in 2 prospective trials by the Nordic Lymphoma Group, 183 who had completed autologous stem cell transplantation (ASCT) and in whom an MRD marker had been obtained were included in our analysis. Fresh samples of bone marrow were analyzed for MRD by a combined standard nested and quantitative real-time PCR assay for Bcl-1/immunoglobulin heavy chain gene (IgH) and clonal IgH rearrangements. Significantly shorter progression-free survival (PFS) and overall survival (OS) was demonstrated for patients who were MRD positive pre-ASCT (54 patients) or in the first analysis post-ASCT (23 patients). The median PFS was only 20 months in those who were MRD-positive in the first sample post-ASCT, compared with 142 months in the MRD-negative group (P < .0001). OS was 75% at 10 years and median not reached in the MRD-negative group, compared with only 35 months in the MRD-positive group (P < .0001). Of the 86 patients (47%) who remained in continuous molecular remission, 73% were still in clinical remission after 10 years. For all patients, the median time from ASCT to first molecular relapse was 55 months, with a continuous occurrence of late molecular relapses. Fifty-eight patients who experienced MRD relapse received rituximab as preemptive treatment on 1 or more occasions, and in this group, the median time from first molecular relapse to clinical relapse was 55 months. In most cases, rituximab converted patients to MRD negativity (87%), but many patients became MRD-positive again later during follow-up (69%). By multivariate analysis, high-risk Mantle Cell Lymphoma International Prognostic Index score and positive MRD status pre-ASCT predicted early molecular relapse. In conclusion, preemptive rituximab treatment converts patients to MRD negativity and likely postpones clinical relapse. Molecular monitoring offers an opportunity to select some patients for therapeutic intervention and to avoid unnecessary treatment in others. MRD-positive patients in the first analysis post-ASCT have a dismal prognosis and thus are in need of novel strategies.

Mantle cell lymphoma: 2019 update on the diagnosis, pathogenesis, prognostication, and management

“…This study demonstrated that rituximab maintenance can improve survival after SCT. MRD assessment in MCL has not been systematically implemented in clinical practice; however, a few studies have shown the critical clinical significance of MRD‐positive disease status and risk of predicting future relapses . Another issue for MRD assessment in MCL is optimization of the technique according to the tissue type used to test MRD, as not all patients have bone marrow involvement at diagnosis and not all patients have peripheral blood lymphocytosis sufficient enough for testing MRD by either flow cytometry or PCR (allele specific quantitative oligonucleotide polymerase chain reaction).…”

Potential loss of prognostic significance of minimal residual disease assessment after R‐CHOP‐based induction in elderly patients with mantle cell lymphoma in the era of rituximab maintenance

“…The data suggest that patients, who do not achieve PET negativity or patients with quantifiable MRD in PB after the induction, might benefit from a different (more intensive or innovative) maintenance therapy than rituximab only, eg, obinutuzumab or rituximab plus lenalidomide or other (Figure D, Supplemental Figure 3). In addition, it was demonstrated that a molecular relapse precedes the clinical one, and it could be treated with a preemptive rituximab in the cohort of patients without rituximab maintenance . However, the role of molecular relapse and its management in the cohort of patients on rituximab maintenance remains to be evaluated.…”

Minimal residual disease in mantle cell lymphoma: are we ready for a personalized treatment approach?

“…In a number of prospective reports, a pre-emptive rituximab treatment of MRD positive patients was able to reconvert them to MRD negativity, with the possibility of also prolonging their PFS. 8,17 Nevertheless, some limitations still hamper the widespread use of MRD analysis in clinical routine. The two major obstacles as far as methodology is concerned are the need for patient-specific primers and standardization issues.…”

“…Finally, although the predictive role of MRD has been established in MCL, [3][4][5] evidence for the usefulness of subsequent treatment tailoring based on the MRD results is unfortunately still scarce due to the lack of MRD-driven phase III trials in MCL. 8,17 Moreover, no MRD data are available yet in the context of the new targeted treatments, such as the Bruton's tyrosine kinase inhibitor ibrutinib.…”

“…Moreover, convincing data on the real usefulness of such an MRD-based treatment modulation are not yet available in lymphoma, with only retrospective evidence or evidence derived from a single, phase II trial available so far. 8,17 Some MRD-driven phase II and III trials are ongoing in MCL and also in follicular lymphoma to assess the clinical impact of personalized treatment, with first results eagerly awaited in the near future (reviewed by Dogliotti and Ferrero 27 and summarized for MCL in Table 1B). In conclusion, given that there is compelling evidence as to the predictive role of MRD in MCL, and ongoing standardization and methodological efforts are highly advanced, MRD analysis in MCL is already included in the majority of prospective trials.…”