Prognostic value of baseline FDG PET/CT total metabolic tumor volume and MYC/BCL2 double expression status in patients with diffuse large B-cell lymphoma Free

Double-expressor lymphoma (DEL) is a distinct entity of diffuse large B-cell lymphoma (DLBCL), characterized by immunohistochemical co-expression of MYC and BCL2 proteins. DLBCL with DEL (DE-DLBCL) has a poor prognosis following standard R-CHOP induction therapy, regardless of the MYC/BCL2 rearrangement status. Although a previous study demonstrated DE-DLBCL with limited stage did not have inferior outcome; the only significant factor on multivariable analysis was bulky disease. This finding suggests that tumor burden, rather than the DEL phenotype itself, may be the primary determinant of prognosis. We measured total metabolic tumor volume (TMTV) using positron emission tomography-computed tomography (PET/CT) to quantify the overall tumor burden. Several studies have shown that TMTV is a strong prognostic factor of survival in various malignancies including malignant lymphoma. In this study, we aimed to evaluate the prognostic value of TMTV and DEL status in DLBCL.

We conducted a retrospective study of patients with histologically confirmed DLBCL between April 2013 and December 2024, who had undergone pretreatment PET/CT evaluation in Akita University Hospital. The immunohistochemical criteria for DEL status were defined as MYC expression in ≥ 40% and BCL2 expression in ≥ 50% of malignant cells, as previously described. All patients received rituximab plus anthracycline-based regimen. Patients who underwent dose-intensified chemotherapy or stem cell transplantation in first remission were excluded. Patients who received polatuzumab vedotin-based regimen were not included in this analysis due to the short follow-up time. Mediastinal lymphoma, lymphomas associated with immune deficiency, central nervous system disease or histologic transformation from low-grade lymphoma were excluded. In this study, progression was defined as either standard disease progression based on the Lugano 2014 criteria, or a treatment change to a more intensive therapy, regardless of the patient's disease status at that time. TMTV was quantified using SYNAPSE VINCENT software. Consistent with previous reports, TMTV was defined as the total volume of all lesions with a standardized uptake value (SUV) of ≥ 2.5. For survival analysis, Kaplan-Meier curves were compared using the log-rank test, and a multivariate Cox proportional hazards model was used to identify independent predictors of outcomes.

A total of 94 patients were included, with median age 66 years (range, 26-87). Forty-one patients (44%) had non-GCB subtype, and 44 (47%) had DEL status. DE-DLBCL was more common in non-GCB subtype (28/41, P < 0.001). The median TMTV value was 418 cm³ (range, 3.0–7067.6). ROC curve analysis showed the optimal TMTV cutoff for PFS was 255.8 cm³. This threshold is similar to the TMTV cutoff reported in the REMARC study (220 cm³) for prognostic assessment in patients with DLBCL. The median follow-up period was 42.0 months. Median PFS, OS were not reached. The multivariable analysis was performed testing baseline TMTV (< 255.8 cm³ vs. ≥ 255.8 cm³), DEL status, and IPI score (≤ 2 vs. > 2). Among them, high TMTV and DE-DLBCL were significant independent predictors for both PFS (HR 3.71, 95%CI 1.60-8.60 and HR 4.62, 95%CI 1.97-10.81, respectively) and OS (HR 3.12, 95%CI 1.26-7.73 and HR 4.56, 95%CI 1.70-12.24, respectively). IPI score was significant only for OS (HR 2.91, 95%CI 1.21-6.93). Kaplan-Meier analysis revealed that in patients with a low TMTV level, DEL status did not significantly affect 2-year PFS (82.4% vs. 94.1% for non-DEL; P= 0.188). However, among patients in the DE-DLBCL cohort, a high TMTV was associated with a significantly poorer prognosis compared to a low TMTV (2-year PFS: 18.8% vs. 82.4%; P< 0.001).

Our study demonstrates that in the rituximab era, baseline TMTV is a powerful independent predictor for patients with DE-DLBCL. Those with a high TMTV face a significantly poorer prognosis, whereas patients with low TMTV do not experience these adverse outcomes. In this cohort, patients treated with polatuzumab vedotin were excluded from the current analysis due to the small sample size and short follow-up period. Nevertheless, an exploratory analysis of this subgroup revealed a promising trend, suggesting that this treatment may overcome the poor prognosis of DE-DLBCL with high TMTV. Further investigation with a larger cohort and longer follow-up is warranted to confirm these findings.