MINIMAL RESIDUAL DISEASE (MRD) IN EARLY STAGE FOLLICULAR LYMPHOMA CAN PREDICT PROGNOSIS AND DRIVE RITUXIMAB TREATMENT AFTER RADIOTHERAPY

Abstract

Introduction: In stage I–II follicular lymphoma (FL), BCL2/IGH+ cells can be detected in the peripheral blood (PB) and/or bone marrow (BM) in a high proportion of cases. We analyzed the prognostic impact of MRD in localized FL and explored the possibility of a MRD-guided rituximab therapeutic approach after standard involved field-radiotherapy (IF-RT). Methods: Between 2000 and 2016, 67 consecutive patients with stage I/II FL were investigated for the BCL2/IGHrearrangement by qualitative PCR in the PB and BM, and (when available) in lymph nodes (LN). MRD was monitored every 6 months in patients positive at baseline. RQ-PCR and droplet digital PCR (ddPCR) were retrospectively performed in 30 MBR+ cases. All patients were treated with IF-RT (24-30 Gy); from 2005, patients who were MRD+ after IF-RT received rituximab (R) (375 mg/m2 x 4). The median follow-up is 67 months (17–183). Results: At baseline, 72% of patients were BCL2/IGH+: 54% MBR+, 9% mcr+, 9% minor BCL2 rearrangement+. Of the 13 evaluable LNs, 11 showed the same molecular marker identified in the PB/BM; 2 cases, negative in the PB/BM, showed a rearrangement in the LN. IF-RT induced an MRD negativity in 50% of baseline positive cases. R was administered to 19 MRD+ patients after IF-RT and an MRD− status was achieved in 16 (84%); 9/16 patients (56.3%) remain persistently MRD−, and none has so far relapsed (p = 0.02). Eight MRD+ patients did not receive R (pre-2005) and 6 (75%) have relapsed (p = 0.025). Progression-free survival (PFS) was significantly longer for MRD+ patients treated with R compared to untreated MRD+ patients (p = 0.0412) (Figure 1). Overall, of the 39 patients with molecular follow-up, 18 were persistently MRD+ and 21 MRD−. Ten of the 18 (55.5%) MRD+ patients relapsed, while this occurred only in 3/21 (14.3%) of the MRD− patients (p = 0.015). PFS was significantly better for MRD− patients (p = 0.0163). RQ-PCR-defined tumor burden at diagnosis predicted the MRD clearance after IF-RT (p = 0.0027), whilst it predicted PFS only when assessed by ddPCR (p = 0.026). The 10-year PFS and OS are 66% (95% CI: 51%–77%) and 96% (95% CI: 76%–99%), respectively. Conclusions: Early stage FL has a heterogeneous disease extension profile: 2 of our cases were truly localized, with a molecular marker only in the LN. On the contrary, when BCL2/IGH+ circulating cells are detectable at diagnosis, ddPCR is a powerful tool to quantify tumor circulating levels and to predict prognosis. IF-RT in localized FL is the undisputed first-line treatment, but alone it often does not clear circulating FL cells. R administration in MRD+ patients decreased significantly the risk of a subsequent relapse and improved PFS. We strongly suggest treating patients suffering from early stage FL through an MRD-guided treatment with R after IF-RT. Keywords: follicular lymphoma (FL); minimal residual disease (MRD); rituximab.