Laurent Camille, Trisal Preeti, Tesson Bruno, Seth Sahil, Beyou Alicia, Roulland Sandrine, Lesne Bastien, Van Acker Nathalie, Cerapio Juan-Pablo, Chartier Loïc, Guille Arnaud, Stokes Matthew E, Huang C Chris, Huet Sarah, Gandhi Anita K, Morschhauser Franck, Xerri Luc
Department of Bio-Pathology, Institut Universitaire Cancer-Oncopole, Centre de Recherches en Cancérologie de Toulouse INSERM U1037, Toulouse, France.
Division of Hematology Translational Medicine, Bristol Myers Squibb, Summit, NJ.
Blood. 2024 Dec 12;144(24):2503-2516. doi: 10.1182/blood.2024024496.
A robust prognostic and biological classification for newly diagnosed follicular lymphoma (FL) using molecular profiling remains challenging. FL tumors from patients treated in the RELEVANCE trial with rituximab-chemotherapy (R-chemo) or rituximab-lenalidomide (R2) were analyzed using RNA sequencing, DNA sequencing, immunohistochemistry (IHC), and/or fluorescence in situ hybridization. Unsupervised gene clustering identified 2 gene expression signatures (GSs) enriched in normal memory (MEM) B cells and germinal center (GC) B-cell signals, respectively. These 2 GSs were combined into a 20-gene predictor (FL20) to classify patients into MEM-like (n = 160) or GC-like (n = 164) subtypes, which also displayed different mutational profiles. In the R-chemo arm, patients with MEM-like FL had significantly shorter progression-free survival (PFS) than patients with GC-like FL (hazard ratio [HR], 2.13; P = .0023). In the R2 arm, both subtypes had comparable PFS, demonstrating that R2 has a benefit over R-chemo for patients with MEM-like FL (HR, 0.54; P = .011). The prognostic value of FL20 was validated in an independent FL cohort with R-chemo treatment (GSE119214 [n = 137]). An IHC algorithm (FLcm) that used FOXP1, LMO2, CD22, and MUM1 antibodies was developed with significant prognostic correlation with FL20. These data indicate that FL tumors can be classified into MEM-like and GC-like subtypes that are biologically distinct and clinically different in their risk profile. The FLcm assay can be used in routine clinical practice to identify patients with MEM-like FL who might benefit from therapies other than R-chemo, such as the R2 combination. This trial was registered at www.clinicaltrials.gov as #NCT01476787 and #NCT01650701.
利用分子谱分析对新诊断的滤泡性淋巴瘤（FL）进行可靠的预后和生物学分类仍然具有挑战性。对在RELEVANCE试验中接受利妥昔单抗化疗（R-化疗）或利妥昔单抗-来那度胺（R2）治疗的患者的FL肿瘤进行了RNA测序、DNA测序、免疫组织化学（IHC）和/或荧光原位杂交分析。无监督基因聚类分别鉴定出在正常记忆（MEM）B细胞和生发中心（GC）B细胞信号中富集的2种基因表达特征（GSs）。将这2种GSs合并为一个20基因预测指标（FL20），以将患者分为MEM样（n = 160）或GC样（n = 164）亚型，这两种亚型也表现出不同的突变谱。在R-化疗组中，MEM样FL患者的无进展生存期（PFS）显著短于GC样FL患者（风险比[HR]，2.13；P = 0.0023）。在R2组中，两种亚型的PFS相当，表明R2对MEM样FL患者比R-化疗更有益（HR，0.54；P = 0.011）。FL20的预后价值在接受R-化疗治疗的独立FL队列（GSE119214 [n = 137]）中得到验证。开发了一种使用FOXP1、LMO2、CD22和MUM1抗体的IHC算法（FLcm），其与FL20具有显著的预后相关性。这些数据表明FL肿瘤可分为MEM样和GC样亚型，它们在生物学上不同，临床风险特征也不同。FLcm检测可用于常规临床实践，以识别可能从R-化疗以外的治疗（如R2联合治疗）中获益的MEM样FL患者。该试验已在www.clinicaltrials.gov上注册，注册号为#NCT01476787和#NCT01650701。
