Outcomes of Primary Mediastinal B-Cell Lymphoma Patients Treated with a PET-Guided Strategy in the Randomized Phase 3 Gained Study Conducted By Lysa

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Introduction: The GAINED study (NCT01659099) was a randomized phase 3 trial comparing obinutuzumab (G) to rituximab (R) plus ACVBP or CHOP14 induction, followed by PET-guided consolidation. No significant survival differences were found between the arms (Le Gouill et al. 2021). This post-hoc analysis aimed to detail the outcomes of primary mediastinal B-cell lymphoma (PMBL) patients included in the trial, verified through expert pathological review and the use of a molecular gene-expression profiling-based (GEP) classifier. Methods: Conducted by LYSA across 99 centers in Belgium and France from 2012 to 2015, the GAINED study had the following key inclusion criteria : patients aged 18-60 years, CD20+ diffuse large B-cell lymphoma (DLBCL) according to the 2008 WHO classification, aaIPI ≥1, and eligibility for autologous stem cell transplant (ASCT). Patients with a ΔSUVmax >66% after cycle 2 and >70% after cycle 4 (PET2−/4−) received standard consolidation chemotherapy, while those with PET2+/4− received intensive treatment with ASCT. PET4+ patients (ΔSUVmax ≤70%) were given salvage therapy. We here focused on clinical characteristics, treatment responses, and outcomes, incorporating metabolic tumor volume (MTV, fixed SUV4 method) and biological data including cell-free DNA (cfDNA) and soluble PDL1 (sPDL1) levels, mutational landscape (custom targeted NGS panel), and GEP (LymphoSign test). Primary endpoints included were progression-free survival (PFS) and overall survival (OS). False discovery rate correction was applied for multiple testing. Results: Of the initial 670 patients, 138 (20.6%) confirmed PMBL cases were analyzed. Baseline characteristics included a median age of 33.5 years, 63.8% female, 55.1% stage III-IV, 90.6% elevated LDH, 87% ECOG 0-1, 62.3% extranodal involvement, 52.2% aaIPI 2-3, 50.7% MTV ≥360 cm³, and 53.6% with bulky (>10cm) mediastinal masses. Induction regimens were R/G-CHOP14 (56.5%) and R/G-ACVBP (42.8%). Post-induction treatments, based on interim PET (iPET) results, included: consolidation chemotherapy (55.1%), ASCT (24.6%), and salvage therapy (12.3%). After a median follow-up of 39.5 months, 2-year PFS and OS rates were 86.2%, and 93.2%. PET2−/4− had superior PFS (p<0.001) but similar OS (p=0.123) compared to PET2+/4− and PET4+ patients; the 2-year PFS and OS were: 93.5% vs 82.4% vs 58.8% and 96% vs 90.9% vs 85.6% respectively. ACVBP plus ASCT (n=38) and CHOP14 plus ASCT (n=38) had similar 2-year PFS and OS: 94.6% vs 92.1% and 97.1% vs 94.7%. ACVBP plus sequential consolidation chemotherapy and CHOP14 8 cycles had also comparable 2-year PFS and OS: 81.8% vs 82.6% and 90.9% vs 90.9%. Among patients with GEP data (n=107), 38 (35.5%) were PDL1high/PDL2high. Key somatic mutations data (n=87) included SOCS1 (70.1%), B2M (56.3%), STAT6 (49.4%), TNFAIP3 (47.1%), GNA13 (39.1%), CIITA (37.9%), CD58 (36.8%), and TP53 (29.9%). Univariate analysis highlighted that bulky mass (HR 4.37 [95%CI: 1.48-12.92]), stage III-IV (HR 4.06 [1.38-12.01]), and PET4+ (HR 3.18 [1.07-9.48]) were associated with shorter PFS, whereas PET2- and ΔSUVmax PET4 (continuous variable) where associated with longer PFS (HR=0.48 [0.16-1.44] and 0.26 [0.15-0.43], respectively). Additionally, stage III-IV (HR 9.9 [1.28-76.57]) was linked to shorter OS, whereas ΔSUVmax PET4 was associated with longer OS (HR=0.36 [0.21-0.62]). None of the other factors assessed (aaIPI, induction chemotherapy regimen, R or G, cfDNA and sPDL1 level, PDL1high/PDL2high status, B2M,CD58, TP53 alterations, MTV) were significantly associated with outcomes. Finally, in multivariate models, bulky mass adjusted on aaIPI remained significantly associated with inferior PFS (HR 3.84 [1.11-13.27], p=0.034). When MTV and ΔSUVmax PET2 and PET4 were also included, only ΔSUVmax PET4 was associated with longer PFS (HR=0.21 [0.08-0.55], p=0.001) and OS (HR=0.46 [0.23-0.93], p=0.032). Conclusion: This analysis highlights the strong representation, distinct characteristics and excellent outcomes of PMBL patients in the GAINED trial, emphasizing the importance of expert histopathological and molecular characterization for accurate diagnosis. The iPET response, especially ΔSUVmax PET4, emerged as the primary predictor of outcomes in this selected clinical trial population. Tailoring consolidation treatments based on iPET results may have mitigated the impact of baseline adverse characteristics.

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