MRD Eradication Should be the Therapeutic Goal in Mantle Cell Lymphoma and May Enable Tailored Treatment Approaches: Results of the Intergroup Trials of the European MCL Network
Authors: Pott Christiane , Macintyre Elizabeth , Delfau-Larue Marie-Helene , Ribrag Vincent , Unterhalt Michael , Kneba Michael , Hiddemann Wolfgang , Dreyling Martin , Hermine Olivier , Hoster Eva 
Published: October 2019

Abstract
Background: Minimal residual disease (MRD) measurement is an increasingly recognized tool for response assessment in B-cell malignancies and represents a useful surrogate marker for prognosis, allowing prediction of the clinical course prior to clinical study endpoints. Based on the randomized intergroup trials of the European MCL Network for patients with stage II-IV mantle cell lymphoma (MCL) investigating immuno-chemotherapy followed by autologous stem cell transplantation (ASCT) for patients <65 yrs and rituximab or interferon maintenance for patients > 65 yrs, we prospectively monitored MRD.
Methods: According to the protocols MRD analyses were performed after completed induction and subsequently in 3-monthly intervals after ASCT or 2-monthly during maintenance until progression. MRD results were evaluated according to ESG criteria (van der Velden, Leukemia 2007) and compared with clinical outcome. RQ-PCR was designed to reach a sensitivity of 10E-5, MRD negativity was defined as a negative RQ-PCR result with a sensitivity of at least 10E-4. Patients in complete or partial remission 6 months after ASCT/end of induction (MCL Younger/MCL Elderly) were included in this analysis. During follow-up MRD status in peripheral blood (PB) was assessed and defined as negative, if there were only negative MRD values, or positive in case of at least one positive MRD value during a 6-months period. Landmark analyses were performed for progression-free survival (PFS) according to MRD status for each 6-months period until 4 years of follow-up and PFS was compared between PB positive and PB negative patients.
Results: Among patients in remission 6 months after ASCT/end of induction, MRD results during follow-up were available in 406 patients (255 MCL Younger,151 MCL Elderly). The distribution into low, intermediate, and high risk MIPI of 44%, 34% and 22%, respectively, was similar to the total study population. During follow-up period, percentage of patients with evaluable MRD status dropped from about 50%-55% during the first two years to 40%-45% during years 3-4, and less than 40% afterwards. The rate of MRD positive samples was about 20-25% during the first 3 years, and less than 20% in the subsequent follow-up.
In each landmark analysis, a positive MRD status in PB was highly associated with a shorter PFS. This association was independent of baseline MIPI score, treatment arm or protocol (Figure 1). Thus, the prognostic value of MRD positivity was maintained in both trials MCL Younger and MCL Elderly. Remarkably, landmark analyses at all time points indicated a strong association also of low-level MRD with a shortened PFS. Finally, MRD analyses in 76 patients at relapse confirmed the close association of clinical relapse to MRD positivity, with only 10 patients (13%) being PB-negative.
Conclusion: Our data demonstrate that achievement and preservation of MRD negativity is the strongest independent predictor of prognosis in patients with MCL. Applying MRD status as tool for tailored treatment, therapeutic approaches should focus on a maximum MRD response to improve long term outcome.
Figure 1 Landmark analyses for PFS in remission after ASCT (MCL Younger) or end of induction (MCL Elderly). For each landmark time point only patients in follow-up at the landmark are included and stratified according to MRD status in PB in the 6 months period preceding the landmark. Figure 1. Landmark analyses for PFS in remission after ASCT (MCL Younger) or end of induction (MCL Elderly). For each landmark time point only patients in follow-up at the landmark are included and stratified according to MRD status in PB in the 6 months period preceding the landmark.

Disclosures
No relevant conflicts of interest to declare.