HIGH TOTAL METABOLIC TUMOR VOLUME AT BASELINE ALLOWS TO DISCRIMINATE FOR SURVIVAL PATIENTS IN RESPONSE AFTER R‐CHOP: AN ANCILLARY ANALYSIS OF THE REMARC STUDY

Abstract

Introduction: High total metabolic tumor volume (TMTV) measured on 18F-FDG PET/CT before R-CHOP has been shown to be significantly associated with inferior progression-free survival (PFS) and overall survival (OS) in patients with diffuse large B-cell lymphoma. The REMARC study (NCT01122472) showed a significantly better progression-free survival (PFS) in 650 patients responding to R-CHOP treated with maintenance therapy with lenalidomide (LEN) versus placebo (PBO), but no difference in OS was observed. The aim was to analyze the prognostic impact of baseline TMTV together with biological profile. Methods: TMTV was computed on baseline PET/CT using the 41% SUVmax method. The optimal TMTV cut-off for PFS and OS was determined by Receiver Operating Curve and X-tile analyses and confirmed by a training validation method. A subset of patients (n = 192) was classified as GCB or non-GCB profile, and with MYC or BCL2 by FISH. Survival was estimated using Kaplan Meier (KM) curves. Analyses were performed on the evaluable population (n=301/650) and each arm, with 146 pts on PBO and 155 pts on LEN. Results: Clinical characteristics were similar to the overall population. After a median 5 years follow-up, 4y-PFS was 73% and 4y-OS was 85%. Median baseline TMTV was 238 cm3 (Q1-Q3;78,523). The optimal TMTV cut-off was 220 cm3 for PFS and OS. Patients with TMTV >220 vs ≤220 cm3 presented with worse ECOG performance status (ECOG ≥2: 21% vs 11.5%, p=0.029), higher Ann Arbor stage (stage III-IV: 94% vs 87%, p=0.043), more extra-nodal sites (>1: 63.5% vs 39%, p<0.001), more frequently elevated LDH (74% vs 45%, p<0.001), higher IPI (IPI 3-5: 85% vs 58%, p=10-3), and higher aaIPI (score 2-3: 74% vs 40%, p=10-3). In all evaluated patients, a significant impact of TMTV was observed for PFS (p=2.10-4) and OS (p=10-4). Patients with high TMTV>220 vs low TMTV≤220, had a 4-year PFS of 56% vs 82% and OS of 74% vs 92% respectively. This prognostic impact of a high baseline TMTV on PFS (HR=2.2; 95% CI, 1.4-3.5) and OS (HR=3.2; 95% CI, 1.5-6.6) was maintained in both PBO and LEN arms. As demonstrated in the original report, GCB/nonGCB profile had no significant impact on PFS and OS, regardless of TMTV. BCL2 impacted PFS and could be stratified by TMTV. MYC had no impact on PFS and OS. In multivariate analysis, baseline TMTV was the most powerful parameter associated with inferior PFS and OS, compared to aaIPI and treatment arm. Conclusion: TMTV measured on baseline PET/CT is the strongest prognosticator of outcome in DLBCL, even in patients in responding after R-CHOP. High TMTV at baseline was significantly associated with inferior PFS and OS in patients receiving either PBO or LEN. Keywords: diffuse large B-cell lymphoma (DLBCL); positron emission tomography (PET).