Of 8644 patients registered with DLBCL in LYFO in the inclusion period, 6075 patients with DLBCL were treated with rituximab-based therapy and were considered potential candidates for the current study. Data to calculate prognostic indices of interest were available for 5126 patients who fulfilled inclusion criteria and were selected for the final analysis (Fig. 1). Data on missing variables among 6075 potential candidates is provided in Supplementary Fig. 1.

DLBCL diffuse large B-cell lymphoma, IPI International Prognostic Index, NCCN-IPI National Comprehensive Cancer Network IPI, LYFO Danish Lymphoma Register, R rituximab, R-CHOP rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone.

Table 1 summarizes baseline patient characteristics. The median age was 68 years (range 18–95), with 71.0% older than 60. There was a slight male predominance (57.3%) and patients with advanced stage III and IV disease (68.1%) (Table 1).

We identified 13 clinical and two laboratory models from 11 studies [3, 7, 8, 12, 28,29,30,31,32,33,34]. All models except IPI and age-adjusted IPI (aaIPI) were developed for patients treated with rituximab-based regimens. Table 2 summarizes the variables included in each model. Tables 3 and 4 provide calculations and distributions of patients within each risk group and among our cohort according to models with four- (n = 8) and three-risk groups (n = 5) [3, 7, 8, 12, 28,29,30,31,32,33,34]. All studies except two included DLBCL patients from retrospective cohorts [3, 28]. Slight differences in inclusion criteria with variable follow-up under 60 months were reported across the studies. The number of patients from the original populations used to develop current models ranged from 88 to 2031 [3, 28]. The largest study population was used to develop IPI, followed by DLBCL Prognostic Index (DLBCL-PI), and NCCN-IPI with 2031, 1803, and 1650 patients, respectively [3, 8, 12]. Five models were developed in populations larger than 500 patients [3, 8, 12]. All studies proposing models with three risk groups analyzed less than 400 patients (range 88-365) [7, 28, 32,33,34]. The median age in analyzed studies ranged from 57 to 70 years [8, 29, 31, 32]. Three studies reported the median age of the analyzed population over 68 years [29, 31, 32].

The most commonly used variables in analyzed models were the IPI variables, including Ann Arbor stage (9/13), ECOG PS (9/13), LDH (9/13), age (6/13), and extranodal sites (5/13) (Table 2). In contrast to the IPI, three models stratified extranodal involvement by high-risk localizations and not the absolute number of involved sites [8, 30, 31]. Additionally, four laboratory variables (hemoglobin, platelet [PLT] count, and absolute lymphocyte count [ALC]) were used in individual models, while albumin was used in four models. Different cut-offs for age, LDH, hemoglobin, PLT, ALC, and albumin were used across different studies (Table 2).

Variables were commonly dichotomized, while age and LDH were divided into several groups in NCCN-IPI, Modified NCCN-IPI, and Kyoto Prognostic Index (KPI) [8, 30, 31].

All patients were categorized into risk groups according to the prognostic models used in this analysis. Distributions of patients according to risk categories in original models and current study are provided in Tables 3 and 4.

IPI classified 26.2% of patients into low-risk groups, whereas 21.3% were in high-risk groups. aaIPI, R-IPI, and NCCN-IPI classified 19.8, 6.4%, 8.1%, respectively, in the low-risk group and 19.4%, 49.1%, and 13.9% in the high-risk group.

As presented in Suppl. Table 1, when IPI was used as the reference model and compared to other models with four-risk groups, it showed substantial agreement (weighted κ between 0.61-0.80) with aaIPI (weighted κ = 0.76), NCCN-IPI, Modified NCCN-IPI, DLBCL-PI, and age-adjusted DLBCL-PI (aaDLBCL-PI). When NCCN-IPI was used as the reference model, it showed substantial agreement with the IPI and Modified NCCN-IPI. The highest number of differently grouped patients with only fair agreement (weighted κ between 0.21–0.40) was observed between the NCCN-IPI vs. KPI (weighted κ = 0.35) and Modified-3-factor Model (weighted κ = 0.37). When models with three risk categories were compared with the R-IPI as the reference model, they showed poor (weighted κ < 0.00) to slight agreement (weighted κ = 0-0.20) with only ALC/R-IPI showing fair agreement with R-IPI (weighted κ = 0.24) (Suppl. Table 2).

The median follow‐up of the study population was 58.2 months, and the maximum follow-up of 244.7 months. There were 2190 deaths (42.7%). The median survival of the whole study population was 135.1 months (95% CI 127.2–143.0).

Univariate analysis of parameters included in each model showed the prognostic significance of all included variables in the evaluated prognostic models (Suppl. Table 3). As several models used laboratory variables (e.g., hemoglobin, PLT, ALC, albumin) with different cut-offs of the same variable included in some models, we compared the laboratory biomarkers’ hazard ratios (HR) at different cut-offs. We then applied the cut-offs producing the highest HR in multivariate analysis. Five IPI/NCCN-IPI variables were further combined with four laboratory variables (hemoglobin<120 g/L, PLT < 100 × 109/L, ALC < 0.84 × 109/L, and albumin<35 g/L) in multivariate analysis. No significant correlations (collinearity) between models included in multivariate analysis were observed. In multivariate analysis with IPI parameters, only the number of extranodal sites was insignificant, while when combining five NCCN-IPI parameters with four laboratory variables, all parameters retained prognostic significance with extranodal sites marginally significant (Suppl. Table 3).

Figure 2 presents Kaplan–Meier curves for all 13 models. Moreover, we calculated 3- and 5-year OS rates for all models, as shown in Tables 3 and 4. Five-year OS estimates in the respective high-risk groups ranged from 31.7%, 33.4%, and 38.5% for Modified NCCN-IPI, NCCN-IPI, and DLBCL-PI, respectively, to 43.6% and 53.9% for IPI and R-IPI. In the respective low-risk groups, 5-year OS was 89.5%, 92.8%, and 97.1% for DLBCL-PI, Modified NCCN-IPI, and NCCN-IPI, while a lower estimate of 85.8% was registered for IPI, but not for R-IPI (97.5%).

The shaded color areas around curves represent confidence intervals.

The median PFS was 129.5 months (95% CI, 120.8–138.2 months), and the maximum PFS was 244.7 months. Suppl. Table 4 provides HRs for PFS for risk groups within each prognostic model. Moreover, measures of model fitness and discrimination are also provided in Suppl. Table 4. Kaplan–Meier and calibration curves were similar to those of OS (data not provided).

The lowest AIC was registered for NCCN-IPI (34002), Modified NCCN-IPI (34039), and DLBCL-PI (34100). The highest AIC was registered in aaIPI (34748), along with laboratory models (Table 5). IPI and R-IPI had AIC values in the middle of the group (34340, 34380). Regarding BIC, similar results were obtained as AIC (Table 5).

The highest CPE values were found for NCCN-IPI (0.670), Modified NCCN-IPI (0.664), and DLBCL-PI (0.660). The lowest CPE was registered for the Matsumoto model (0.580), aaIPI (0.585), and two laboratory models (0.577, 0.584) (Table 5).

Models that provided the highest c-index were DLBCL-PI, NCCN-IPI, and Modified NCCN-IPI, with values of 0.700, 0.693, and 0.684, respectively. When these models were compared to NCCN-IPI as the reference model, there was no statistical difference between the NCCN-IPI and DLBCL-PI. However, NCCN-IPI had statistically better discriminative ability than Modified NCCN-IPI. Additionally, NCCN-IPI performed significantly better than IPI and R-IPI, for which the c-indexes were 0.673 and 0.643, respectively. Other models with three risk groups had significantly inferior discriminative ability than NCCN-IPI with a c-index lower than R-IPI (Fig. 3).

Calibration curves of 13 prognostic models in diffuse large B-cell lymphoma patients concerning overall survival.

Additionally, when AUC was calculated, DLBCL-PI, NCCN-IPI, and Modified NCCN-IPI showed the highest values (0.661, 0.657, and 0.651, respectively). In contrast, the lowest AUC values were found in three-risk models and aaIPI.

Calibration curves for 5-year survival are provided in Fig. 3. Models with the highest c-index had calibration curves close to a 45-degree line, indicating good calibration.