Utility of Baseline PET/CT As Surrogate of Molecular Features in Mantle Cell Lymphoma

Mantle cell lymphoma (MCL) shows substantial clinical and biological heterogeneity. Baseline ¹⁸F-FDG PET/CT is widely used for initial MCL evaluation but displays heterogeneous findings and its utility, prognostic value, and correlation with biological features of the tumor remain unclear. The aim of our study was to determine the relationship investigate the association between metabolic, volumetric and dispersion PET/CT parameters with and the molecular features of MCL at diagnosis.

We retrospectively studied 73 MCL patients consecutively diagnosed between June 2005 to August 2022 at Hospital Clínic and Hospital Universitario Mutua Terrassa. All patients underwent baseline PET/CT and had a histologically confirmed diagnostic sample (lymph node, extranodal tissue, peripheral blood, or bone marrow) before frontline treatment. Mutational profile and t(11;14)(q13;q32) were investigated using a MCL-oriented targeted next generation sequencing (NGS) panel (SureSelectXT, Agilent Technologies) and copy number alterations (CNA) were assessed using Oncoscan or CytoScan arrays. The proliferation signature and molecular MCL subtype were evaluated using MCL35 and L-MCL16 Nanostring assay, respectively. PET/CT images were analyzed using the MIM Software 7.3.6 (SUV ≥2.5 threshold) excluding physiological uptake. Recorded parameters included SUVmax, total metabolic tumor volume (TMTV), spleen MTV, total lesion glycolysis (TLG), spleen TLG, Dmax, and standardized Dmax (SDmax). Contrast-enhanced CT scans measured spleen size and recorded the sum of the product of the diameters (SPD) of the pathological lesions. Association between variables was assessed with Spearman correlation, Mann-Whitney U test, Kruskal-Wallis test, or Fisher's exact test.

Among 73 MCL patients (18% female, median age 64 years), 89% had III-IV Ann Arbor stages, 38% had high risk MIPI score, 6% had blastoid morphology, and 53% a high (≥30%) Ki67 index.

Regarding MCL molecular subtype (N=62), 82% of cases were conventional MCL (cMCL), 11% non-nodal MCL (nnMCL) and 7% were undetermined. By NGS (N=66) the most frequently mutated genes (>10%) were TP53, CCND1, NOTCH1/2 and NSD2. A median of 3.5 (0-23) CNAs per case were detected and chromothripsis was seen in 8% of cases. Using the MCL35 assay (N=40), 10% of cases had high proliferation, 30% standard and 60% low.

Radiologic splenomegaly was seen in 56% of patients (N=66) and their median spleen size was 158 mm (132-264). Of those with pathological spleen uptake (49%, N=72), median spleen SUVmax was 4.6 (2.6-12), median spleen MTV 823 mL (41.8-3370) and median spleen TLG 3040 (109.3-13642). At least one CT-measurable pathologic lesion was seen in 83% patients (N=64) with a median SPD of 1645 (160-12925), while 17% of patients did not show any pathologic lesions. PET/CT showed pathological uptake in 86% (N=72) of patients, with a median SUVmax of 7.1 (3.5-26), median TMTV 565 mL (1.7-6068), and median TLG 1494 (5.5-20626). More than one metabolically active lesion was seen in 83% of cases with a median Dmax of 482 mm (41-807) and median SDmax of 5160 mm (41-1471584).

As for clinical parameters, III-IV Ann Arbor stage, high MIPI risk, high LDH and high B2M values were associated with higher TMTV and TLG (P<0.05). There were no associations between morphological variants or Ki67 and PET/CT parameters.

Regarding MCL subtypes, nnMCL patients (86%, N=7) exhibited no CT-measurable lesions (excluding the spleen), whereas among all patients without CT-measurable lesions, only 55% were nnMCL. In terms of metabolic parameters, nnMCL showed lower SUVmax, TMTV, TLG and SPD (P<0.05) than cMCL, and in terms of dispersion parameters nnMCL also showed lower Dmax and SDmax than cMCL (P<0.05). No differences were observed between MCL subtypes regarding spleen metrics, metabolic parameters, or PET/CT-detected extranodal involvement. Tumor proliferation (MCL35) correlated with SUVmax (0.35; P=0.035), TLG (0.32; P=0.046), Dmax (0.46; P=0.007) and SDmax (0.46; P=0.003). Finally, we found no significant associations between TP53 mutation or CNA and PET/CT parameters.

Our findings suggest that besides previously described clinical associations with PET/CT, MCL molecular subtype and proliferation signature are also reflected in PET/CT parameters. These associations could have potential impact in comprehensively assessing MCL prognostic features.

Nadeu:Diagnóstica Longwood: Patents & Royalties: IgCaller algorithm to Diagnóstica Longwood; AbbVie: Honoraria; AstraZeneca: Honoraria; Gilead: Research Funding; SOPHiA Genetics: Honoraria; Janssen: Honoraria. Jimenez-Vicente:AbbVie: Speakers Bureau; AbbVie: Other: Travel Grants. Mozas:Kyowa Kirin: Honoraria, Other: Travel Grant; AstraZeneca: Honoraria, Other: Travel Grant; Beigene: Honoraria, Other: Travel Grant; Janssen: Honoraria, Other: Travel Grant; Abbvie: Honoraria, Other: Travel Grant; Takeda: Honoraria, Other: Travel Grant. Gaya:Sobi: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Alexion, AstraZeneca Rare Disease: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees. Lopez-Guillermo:Takeda: Consultancy; Janssen: Consultancy; Incyte: Consultancy; Abbvie: Consultancy; Genmab: Consultancy, Other: Safety Committee clinical trials; Gilead/Kite: Consultancy, Research Funding; Roche: Consultancy, Research Funding. Gine:Gilead/Kite: Honoraria; Lilly: Honoraria, Research Funding; Astra-Zeneca: Honoraria; Janssen: Honoraria, Research Funding; Roche: Honoraria.