“Miro” Study, a FIL multicenter phase II trial combining local radiotherapy and MRD-driven immunotherapy in early-stage follicular lymphoma.
Authors: Pulsoni Alessandro , Tosti Maria Elena , Ferrero Simone , Luminari Stefano , Liberati Anna Marina , Cenfra Natalia , Renzi Daniela , Zanni Manuela , Boccomini Carola , Ferreri Andres J. , Rattotti Sara , Zilioli Vittorio R. , Bolis Silvia Anna Maria , Grapulin Lavinia , Della Starza Irene , Ricardi Umberto , Galimberti Sara , Ladetto Marco , Del Giudice Ilaria , Foà Robin 
Published: May 2020

e20073 Background: Early stage follicular lymphoma (FL) is usually managed with involved field radiotherapy (IFRT), allowing eradication of the disease in 40-50% of patients (pts). The aim of this multicenter phase II prospective study was to evaluate the role of minimal residual disease (MRD) in identifying pts unlikely to be cured by IFRT, for whom an immunotherapy-based consolidation could improve outcome. Methods: 110 pts with stage I/II FL were enrolled and treated with 24 Gy IFRT. Peripheral blood (PB) and bone marrow (BM) samples were centralized to the FIL (Federazione Italiani Linfomi) MRD Network of EuroMRD-certified laboratories. In BCL2/IGH+ pts at baseline, MRD was analyzed by nested PCR (NEST) and RQ-PCR (RQ) in BM and/or PB after IFRT and every 6 months over a 3-year period. Pts with positive MRD by both NEST and RQ in the BM and/or PB after IFRT or who became positive during the follow-up (FU) were treated with 8 weekly doses of the anti-CD20 MoAb ofatumumab (OFA). Primary objective: efficacy of immunotherapy in obtaining a negative MRD. Results: 49 of 106 pts were males. Median age was 55 y (29-83). 69% of pts had inguinal involvement. At baseline, 30% of pts had a BCL2/IGH rearrangement (30 MBR, 1 MBR and mcr, 1 mcr) in BM and/or PB; the concordance between compartments was 90%. All pts obtained a clinical response after IFRT, with persistence of BCL2/IGH+ cells in PB and/or BM in 60% of cases. MRD-positive pts, either after IFRT (n = 18) or in case of conversion to a positive signal during the FU (n = 7), received OFA, obtaining a conversion to MRD negativity, in 20/22 cases (91% - CI 65.1-97.1), significantly superior to the expected 50%. After a median FU of 25 months, all but 2 pts who achieved a negative MRD with OFA are still negative. A clinical relapse or progression was observed in 17 pts: 13 (18%) among the 73 “no marker” pts; 2 relapses (16%) were observed among the 12 MRD-negative pts after IFRT and 2 among the 25 treated with OFA (8%), 1 having achieved a MRD negativity and 1 not. No significant differences in PFS have so far been observed between the three groups. Conclusions: In early stage FL RT alone is often insufficient to eradicate the disease, inducing a negative MRD only in 40% of pts, long-lasting only in half of them. The primary objective of this study - MRD negativity after immunotherapy - was achieved. The strategy of an immunotherapy consolidation after IFRT in MRD-positive pts allowed to increase molecular responses. A longer FU and further studies will allow to define the impact of this MRD-driven strategy also on clinical outcome. Clinical trial information: EudraCT number: 2012-001676-11 .