# Prognostic Value of the CALLY Index in Diffuse Large B-Cell Lymphoma: Linking Inflammation, Nutrition, and Tumor Biology

## TL;DR

The CALLY index, a blood-based score, can predict survival and treatment outcomes in diffuse large B-cell lymphoma patients, offering a new tool for risk assessment.

## Contribution

The study demonstrates the CALLY index's independent prognostic value in DLBCL, outperforming standard indices in identifying high-risk patients.

## Key findings

- A low CALLY index is independently associated with worse overall and event-free survival in DLBCL patients.
- The CALLY index outperforms standard prognostic scores in identifying patients at risk of relapse or refractory disease.
- CALLY index is a low-cost, accessible biomarker that correlates with adverse clinical features and treatment response.

## Abstract

Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma, but many patients experience relapse or resistance to standard frontline treatment. Better and easily available biomarkers are needed to improve risk assessment. The C-reactive protein–albumin–lymphocyte (CALLY) index is a simple score based on blood markers reflecting inflammation, nutritional status, and immune function. While the CALLY index has shown prognostic value in solid tumors, its relevance in hematologic malignancies remains unexplored. In this multicenter retrospective study, we analyzed 180 newly diagnosed DLBCL, NOS (not otherwise specified) patients treated with rituximab-based immunochemotherapy. A low CALLY index at diagnosis was independently associated with inferior overall and event-free survival, and a higher risk of refractory or relapsed disease, independent of established prognostic scores. Our findings suggest that the CALLY index is an inexpensive, accessible tool that may help identify high-risk patients and guide more personalized treatment strategies in DLBCL.

Background/Objectives: Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma and remains incurable in approximately 30–40% of patients despite advances in immunochemotherapy. Although gene expression profiling has improved risk stratification, there is an ongoing need for non-invasive, cost-effective, and clinically practical biomarkers to identify patients at high risk of treatment resistance or relapse (R/R). Systemic inflammation plays a pivotal role in DLBCL pathogenesis, impacting both tumor progression and treatment response. The C-reactive protein–albumin–lymphocyte (CALLY) index, integrating markers of inflammation, nutritional status, and immune competence, has demonstrated prognostic relevance in solid tumors; however, its relevance in hematologic malignancies remains unexplored. Methods: We retrospectively analyzed 180 adults with newly diagnosed DLBCL, NOS (not otherwise specified) who received frontline rituximab-based immunochemotherapy (R-CHOP or CHOP-like regimens) between January 2014 and December 2019 at three tertiary centers in Serbia. The median age was 67 years (IQR 59–73), and 56.1% were female. Receiver operating characteristic (ROC) analysis determined 6.5 as the optimal CALLY index cut-off (AUC 0.744, 95% CI 0.670–0.817; p < 0.001). Results: A low CALLY index (<6.5) was significantly associated with adverse clinical features, including anemia, elevated lactate dehydrogenase and β2-microglobulin, poor ECOG performance status, bulky disease, advanced stage, and unfavorable IPI, R-IPI, and NCCN-IPI scores (all p < 0.001). In contrast, no associations were observed with tumor subtype, immunophenotype, or comorbidities. Furthermore, patients with CALLY <6.5 showed lower overall response rates to treatment (59.6% vs. 85.5%, p < 0.001) and higher relapse rates (21.0% vs. 6.2%, p = 0.014). They also experienced reduced 3- and 5-year overall survival (OS) and event-free survival (EFS) (all p < 0.001). In multivariate analysis, a low CALLY index independently predicted poorer OS (HR 2.04, 95% CI 1.13–3.67; p = 0.017) and EFS (HR 1.89, 95% CI 1.13–3.14; p = 0.015). In addition, it independently identified patients at risk of relapsed/refractory (R/R) disease (OR 2.50, 95% CI 1.02–10.10; p = 0.04), outperforming standard prognostic indices. Conclusions: The CALLY index is a simple, low-cost, and widely accessible biomarker that independently predicts prognosis in DLBCL, NOS. It outperforms standard indices in identifying R/R cases. The CALLY index may enhance risk stratification and guide individualized treatment strategies.