Vodička, Prokop

Abstract A short diagnosis-to-treatment interval independently predicts inferior outcomes in follicular lymphoma. Using international discovery and validation cohorts, we demonstrate its prognostic value beyond established prognostic indices, with implications for risk stratification, clinical trial design, and interpretation.

Summary Family history of haematological malignancy (FHHM) reflects inherited susceptibility to non‐Hodgkin lymphoma (NHL), but its prognostic significance remains poorly understood. We used a cohort study of 1994 NHL patients to evaluate associations between FHHM and clinical outcomes across lymphoma subtypes. We estimated associations, adjusted for sex and lymphoma‐specific prognostic index, of self‐reported FHHM in a first‐degree relative with overall survival (OS), event‐free survival (EFS) and lymphoma‐specific survival (LSS) using multivariable Cox regression models and with failure to achieve EFS at 24 months (EFS24) using logistic regression. FHHM prevalence was 12.8%, and the median follow‐up among survivors was 12.0 years. FHHM was not associated with OS. In subtype‐specific analyses, FHHM was associated with inferior LSS (hazard ratio [HR] = 1.98, 95% confidence interval [CI] 1.11–3.53) in follicular lymphoma (FL); this association and the association with EFS24 failure strengthened among those treated with front‐line immunochemotherapy (EFS24 failure odds ratio = 2.57, 95% CI 1.08–5.99; LSS HR = 2.68, 95% CI 1.09–6.58). In mantle cell lymphoma, FHHM was associated with inferior EFS (HR = 1.70, 95% CI 1.02–2.85). Interaction testing did not demonstrate significant heterogeneity of FHHM effects by lymphoma subtype. FHHM may be associated with adverse outcomes in select NHL groups, particularly FL. These findings warrant further investigation of germline and environmental factors potentially contributing to more aggressive FLs.

Abstract Introduction The International Prognostic Index (IPI) is widely used to stratify risk in large B-cell lymphoma (LBCL) across all ages, with age-adjusted (aa)IPI applied to younger patients. While there have been efforts to develop prognostic indices (PIs) tailored to older patients, few are adopted in clinical practice due to their complexity and reliance on functional assessments, which are not routinely collected in real-world registry datasets. Recently proposed SENIOR-IPI (Dubois, ASH 2024) was developed for older patients with LBCL receiving anthracycline (A)-based therapy. We assessed the performance of standard and novel PIs in patients aged 80+ years and externally validated the SENIOR-IPI. Methods We harmonized and pooled data of patients aged 80+ years with newly diagnosed LBCL from a national registry and two prospective cohorts: NiHiL (Czech Republic, enrolled 2010–2023), LEO (USA; n=222, 2015–2020), and MER (USA; n=77, 2010–2015), forming a cohort of 819 individuals. We included 536 individuals with complete data on IPI components and albumin, including 485 treated with chemotherapy and 397 with A-based regimens (primary cohort). Following PIs were evaluated: IPI, NCCN-IPI, (aa)IPI, and SENIOR-IPI (age per year, aaIPI components, LDH >3x ULN as extra point, and albumin, all weighted six-fold; extranodal involvement excluded due to lack of prognostic significance). Multivariable hazard ratios (HR) were estimated using Cox proportional hazards models; discriminative ability was assessed using C-index and calibration plots. The primary endpoint was overall survival (OS); event-free survival results were consistent (230/357 events were deaths) and are not reported here. Results Among the 397 A-treated patients (median age 82 years, range 80–99), ECOG performance status (PS) 2–4 was observed in 35% of patients, clinical stage III–IV in 67%, elevated LDH in 65% (8% with >3x ULN), >1 extranodal (EN) site in 32%, and albumin levels < 3.5 g/dL in 27%. In multivariable modeling, only age per year (HR=1.07, P<0.01), and clinical stage (HR=1.36, P=0.048) were independent predictors of OS, whereas ECOG PS (HR=1.27, P=0.12), trichotomized LDH by ULN (HR=1.23, P=0.08) and albumin (HR=1.17, P=0.35) were not significant. SENIOR-IPI had the highest discrimination (C-index 0.631) in A-treated patients, outperforming IPI (0.617), NCCN-IPI (0.591), and aaIPI (0.620), with consistent results across cohorts: NiHiL (0.633), LEO (0.619), and MER (0.621). SENIOR-IPI stratified patients into low- (L-Risk, 0–9 points, 28%), low-intermediate (L-Int, 10–19 points, 42%), high-intermediate (H-Int, 20–29 points, 23%), and high-risk (H-Risk, 30–40 points, 7%) categories, with OS medians of 6.3, 3.8, 2.4, and 1.4 years, respectively (P<0.01), and significant separation between L-Int and H-Int (HR=1.47, P=0.02). By comparison, IPI categorized patients as L-Risk (12%), L-Int (24%), H-Int (27%), and H-Risk (37%), with median OS of 8.7, 4.6, 4.8, and 1.9 years, resp. (P<0.01). aaIPI yielded following distributions: 13%, 29%, 37%, and 21%; and median OS: 8.7, 5.3, 3.4, and 1.5 years; P<0.01. NCCN-IPI stratified patients into three groups: L-Int (13%), H-Int (49%), and H-Risk (39%), with respective OS medians of 8.7, 4.1, and 2.5 years (P<0.01). All PIs showed modest overestimation of mortality (calibration slopes: SENIOR-IPI 1.36; IPI 1.24; aaIPI 1.30; NCCN-IPI 1.26; intercept: -0.97, -0.87, -0.92, -0.87, resp.). In the entire cohort (n=536), SENIOR-IPI showed highest C-index (0.651 vs IPI 0.622, aaIPI 0.631, NCCN-IPI 0.606), and stratified patients into L-Risk (26%, 2-year OS: 6.4 years), L-Int (40%, 3.2 years), H-Int (24%, 1.5 years), and H-Risk (10%, 0.6 years). Calibration slope was 1.18 (intercept -0.33). Among patients not receiving chemotherapy, SENIOR-IPI also performed best (C-index 0.759 vs IPI 0.738, aaIPI 0.757, NCCN-IPI 0.728). Conclusion SENIOR-IPI enables effective risk stratification of patients aged 80+ years with LBCL into four prognostically distinct groups, outperforming traditional indices (IPI, NCCN-IPI, aaIPI) in patients receiving A-based therapy, as well as in the entire cohort and in patients not receiving chemotherapy. While its discrimination is superior, modest miscalibration suggests that future recalibration may improve precision. These findings support SENIOR-IPI as a clinically relevant prognostic tool for the elderly LBCL patient population. Funding: NU21-03-00411, P50 CA97274, U01 CA195568.

Abstract Over the past decade, classification systems using high-throughput genetic data have been developed to identify molecular subtypes of DLBCL. Although not a primary goal, these classifiers were also proposed as prognostic factors in their respective publications. To date, however, no study has directly compared these classifiers' ability to predict overall (OS) and event-free survival (EFS) in the same cohort. Herein, we sought to systematically compare predictive performance, benchmarked against the IPI, of several current established molecular classifiers and evaluate if any add significant independent prognostic information beyond the IPI. WES (including paired germline filter) and RNAseq data from newly diagnosed DLBCL patients (N=432; 2018 WHO criteria) in the Mayo Clinic/University of Iowa Lymphoma Molecular Epidemiology Resource (MER) were available for analysis (WES n=112, RNAseq n=40, or both n=280). The number of cases able to be classified (including as unclassified) for each classifier was as follows: IPI (432, 100%), cell-of-origin (COO, by Hans algorithm; 346, 80.1%), refined COO (by gene expression with Dark Zone Signature; 320, 100%), Haematological Malignancy Research Network (HMRN; 349, 89.0%), B-cell state (320, 100%), Lymphoma Ecotype (320, 100%), Lymphoma Microenvironment (LME; 320, 100%), Tumor microenvironment (TME26; 320, 100%), SubLymE (312, 97.5%), LymphGen (358, 91.3%), and DLBclass (223, 58.2%). OS was defined as time from diagnosis to all-cause death while EFS was defined as time from diagnosis to disease progression, initiation of second-line treatment, or all-cause death. We calculated Harrell's c-statistics for each Cox proportional hazards model evaluating the discriminative performance of each classifier in predicting OS/EFS. Using bootstrap validation, we obtained optimism-corrected c-statistics, which we report in the results. We performed likelihood ratio tests (LRT) comparing a univariable Cox model with IPI alone and models including both IPI and a given classifier to assess if a classifier provided independent prognostic information beyond the IPI. All patients were treated with immunochemotherapy (IC) with curative intent, 247 (57%) were male, median age at diagnosis was 65 years (IQR 55-72 years), 390 (96%) were White, 209 (60%) had GCB subtype by Hans, 22 (5.1%) had MYC double-hit by FISH (MYC and BCL2 or BCL6), and 162 (37.9%) had an IPI ≥ 3. The median follow-up was 7.0 years, 167 (39%) experienced an event, and 137 (32%) died. In a univariable Cox model, the c-statistic for IPI predicting OS was 0.66 (95% confidence interval [CI] 0.61-0.70). All other classifiers had c-statistics of ≤0.56. The c-statistic for IPI predicting EFS was 0.64 (95% CI 0.60-0.69), and all other classifiers had c-statistics of ≤0.58. The univariate DLBclass results for OS and EFS were not significantly impacted when restricted to cases with confidence >0.7 (n=136). In Cox models of IPI alone versus IPI plus an individual classifier, the only classifier that provided statistically significant, independent information for OS was TME26 (LRT p=0.02). Adjusting for IPI, patients who were TME26-negative had significantly inferior OS compared to TME26-positive cases (HR 1.63, 95% CI 1.07-2.47; p=0.02). For EFS, DLBclass (restricted to confidence >0.7) added significant prognostic information beyond IPI (LRT p=0.02). This finding was largely driven by C5 subtype; relative to C1 subtype and adjusting for IPI, C5 subtype had significantly inferior EFS (HR 5.53, 95% CI 1.81-17.0; p=0.003). In summary, we compared prognostic performance of multiple DLBCL molecular classifiers with respect to OS and EFS in a single real-world, prospective cohort of newly diagnosed, IC-treated DLBCL. Our data supports two key findings: all classifiers had modest performance for prognosis, and none individually outperformed the IPI in predicting OS nor EFS. Second, only TME26 and DLBclass (confidence >0.7) provided additional prognostic information beyond that captured by the IPI for OS and EFS, respectively. This finding suggests that the tumor immune microenvironment and characteristics of C5 DLBCLs (ABC-subtype, CD79B mutations) can potentially offer significant independent information for predicting survival and response to front-line immunochemotherapy. If replicated, these findings could inform risk-adapted treatment approaches and aid in identifying high-risk patients for enrollment in genomically-informed clinical trials.

Abstract Introduction: THRLBCL is a rare disease accounting for less than 10% of all diffuse large B-cell lymphoma (DLBCL) subtypes. THRLBCL was associated with poor outcomes in the pre-rituximab era, with limited contemporaneous data. Optimal frontline treatment remains unclear with some studies advocating for intensive regimens. The goal of this international study is to analyze the survival and treatment-related outcomes in patients with newly diagnosed THRLBCL treated with rituximab-containing chemotherapy and to compare with a DLBCL, not otherwise specified (NOS) cohort. Methods: THRLBCL and DLBCL patients prospectively enrolled in the Lymphoma Epidemiology of Outcomes (LEO) (NCT02736357) (7/2015 to 5/2020), Molecular Epidemiology Resource (1/2010 to 6/2015), and Czech Lymphoma Study Group project (NiHiL) (NCT03199066) (2/2010 to 11/2023) were analyzed. Diagnosis was made in dedicated hematopathology centers in both registries. We excluded patients with prior nodular lymphocyte-predominant Hodgkin lymphoma, central nervous system involvement, and not treated with rituximab-containing therapy. Event-free survival (EFS) and overall survival (OS) were estimated by Kaplan-Meier.Univariate associations were derived via Cox model and multivariate models were constructed by forward selection of significant variables with P≤0.05. Propensity score matching (1:5, caliper 0.2) between THRLBCL and DLBCL NOS patients was performed using IPI score components and treatment as covariates. Results: We identified 158 patients (LEO: 67 and NiHiL: 91) with THRLBCL. Among them, 140 patients received rituximab-containing regimens and were included in this analysis. Median age was 58 years (range, 19-89) with 57% aged ≤60 years. Most patients were male (n= 88; 63%) and had ECOG performance status (PS) of 0-1 (n= 111; 79%), stage III-IV (n= 111; 79%), elevated LDH (n= 92; 66%), and B symptoms (n= 84; 60%). Fifty (36%) patients had ≥2 extranodal (EN) sites, mostly liver (n= 39; 28%) and lung (n= 16; 11%), bone marrow (BM) involvement was observed in 26% (n= 37). Bulky disease (≥7.5cm) was present in 50 (36%) and IPI score ≥3 in 68 (48%) patients. The median diagnosis-to-treatment interval was 23 days (IQ range, 13-38.5). Frequent regimens were R-CHOP (n= 106; 75.7%), followed by intensive regimens such as R-MegaCHOP/ESHAP, R-HyperCVAD/MA, and R-CODOX-M/IVAC (n= 15; 10.7%), and R-CHOEP/EPOCH-R (n= 10; 7.14%). With a median follow-up of 3.92 years, the 4-year EFS & OS were 71% and 80%, respectively. Lymphoma was the main cause of death (n= 15; 11%) among 30 events. No difference in 4-year EFS (70% vs. 76%; P= 0.55) & OS (80% vs 82%; P= 0.96) were observed between R-CHOP and intensive regimens. Factors associated with shorter EFS and OS in univariate analysis for THRLBCL were ECOG PS 2-4: (HR= 3.3; P<.001 & HR= 5.97, P<.001, respectively); ≥2 EN sites (HR= 1.85, P= 0.043 & HR= 2.54, P= 0.014, respectively); B symptoms (HR= 2.35, P= 0.014 & HR= 2.84, P= 0.023) and IPI score (HR= 1.5, P= 0.002 & HR= 2.16, P<.001). Stage III-IV and BM involvement were associated with shorter OS only (HR= 7.36, P= 0.05 & HR= 2.18, P= 0.036, respectively). Among them, only ECOG PS 2-4 (OS: HR= 3.6, P= 0.003) and B symptoms (EFS: HR= 2.3, P= 0.046) were independent predictors of survival in multivariate analysis. Finally, we compared baseline characteristics and survival between THRLBCL (n= 140) and DLBCL NOS (n= 6099; LEO/MER: 2069 & NiHiL: 4030) treated with rituximab-containing regimens. Patients with THRLBCL were younger (≤60 years: 57% vs. 38%; P<.001), more frequently had ECOG PS 0-1 (79% vs 76%; P= 0.012), stage III-IV (79% vs 63%; P<.001), B symptoms (60% vs 38%; P<.001), and liver involvement (28% vs 7%; P<.001), compared to DLBCL NOS. Subtype was not associated with survival (OS HR= 0.79, P= 0.262 & EFS HR= 0.93, P= 0.662) when adjusted for IPI score. With a median follow-up of 4.89 years in the DLBCL NOS cohort, we observed similar 4-year EFS (71% vs 67%; P= 0.197) & OS between histologies (80% vs 77%; P= 0.125). These results were confirmed in propensity matching for EFS (HR= 0.98, P= 0.897) and OS (HR= 1.07, P= 0.732). Conclusions: In this large international analysis of patients with newly diagnosed THRLBCL contemporaneously treated, we observed similar survival rates compared to DLBCL NOS treated with R-CHOP and intensive regimens. ECOG PS and the presence of B symptoms were independent factors associated with survival.

Abstract Introduction Although chemo-free regimens are increasingly used in elderly patients with large B-cell lymphoma (LBCL), most still receive conventional chemoimmunotherapy. Patients up to 75–80 years old are usually treated with full-dose R-CHOP, while 80+ patients receive the attenuated R-miniCHOP regimen as standard of care. Prior studies have shown that in patients aged 65+ years, R-CHOP was associated with improved survival based on propensity score matching (PSM) analysis (Al-Sarayfi, Am J Hematol, 2023), though this did not include comorbidity data. Furthermore, no formal studies have focused specifically on 80+ patients. We aimed to perform a PSM comparison of R-CHOP versus R-miniCHOP to better inform treatment decisions in this population. Methods We harmonized and pooled data from 237 LBCL patients receiving chemotherapy with rituximab (out of all 263 80+ patients) from the prospective LEO cohort (USA, n=147; 2015–2020) and NiHiL registry (Czech Republic, single center, n=116; 2010–2023). Of them, 205 (86%) receiving anthracycline(A)-based regimens were included. Baseline characteristics, comorbidities, treatments, and outcomes were collected. PSM (1:1, caliper 0.2) was performed to compare R-CHOP and R-miniCHOP using age, ECOG performance status (PS), clinical stage, lactate dehydrogenase (LDH), and major comorbidities (heart disease, history of stroke, and other recent cancer) as matching variables. The endpoints were overall survival (OS), event-free survival (EFS), and lymphoma-specific survival (LSS, defined as death attributed to lymphoma progression). Results Among 205 A-treated patients, median age was 83 years (range 80–99); 30% had ECOG PS 2–4, 67% clinical stage III–IV, 34% ≥2 involved extranodal sites, 59% elevated LDH, and 58% had International Prognostic Index (IPI) scores 3–5. Median follow-up was 5.5 years; median OS and EFS were 4.1 and 3.4 years, resp. A-based regimens comprised full-dose R-CHOP-like (n=79; 39%; R-CHOP n=74, DA-EPOCH-R n=5) and R-miniCHOP (n=126; 61%). Patients receiving R-CHOP-like regimens had more favorable baseline characteristics (median age 82 vs 83 years, P=0.04; ECOG PS 2–4: 16% vs 39%, P<0.01; IPI 3–5: 46% vs 66%, P=0.03) and a lower, though not statistically significant, comorbidity burden (mean 1.14 vs 1.39; heart disease 35% vs 45%, P=0.22; history of stroke 4% vs 6%, P=0.64; other cancer 6% vs 5%, P=0.87). R-CHOP-like regimens vs R-miniCHOP had superior OS (median 6.3 vs 3.4 years; HR=0.61, 95% CI 0.42–0.90; P=0.01) and EFS (median 5.3 vs 2.1 years; HR=0.58, 95% CI 0.40–0.83; P<0.01), with no significant difference in LSS (2-year 89% vs 82%, HR=0.77, 95% CI 0.39–1.54, P=0.46). To mitigate selection bias, we performed PSM on patients with available baseline characteristics treated with R-CHOP (n=69) and R-miniCHOP (n=121), resulting in 63 matched pairs. Matched cohorts were well-balanced on age (median 82 years in both cohorts; P=0.68), ECOG PS 2–4 (17% vs 19%; P=0.82), IPI 3–5 (52% vs. 59%; P=0.41), and comorbidity burden (mean 1.10 vs. 1.29; P=0.30). The presence of heart disease (40% in both cohorts), history of stroke (5% vs 6%), and cancer (5% vs 6%) were similar. Survival modestly favored R-CHOP, but differences were not significant: median OS 5.3 vs 3.5 years (HR=0.73; 95% CI 0.46–1.15; P=0.17), median EFS 3.8 vs 2.8 years (HR=0.76; 95% CI 0.49–1.18; P=0.23), and 2-year LSS 88% vs 84% (HR=1.09; 95% CI 0.45–2.63; P=0.85). Treatment-related mortality was similar in both cohorts (16%). Among R-miniCHOP patients, survival outcomes did not differ between matched (n=63) and unmatched (n=63) groups (OS P=0.72; EFS P=0.23; LSS P=0.27). Unmatched (n=16) R-CHOP patients had a trend toward improved survival compared to matched (n=63) individuals (OS P=0.10; EFS P=0.049; LSS P=0.24). Conclusion This is the first PSM-based analysis comparing R-CHOP and R-miniCHOP in LBCL patients 80+ years old. Despite inherent limitations of a non-randomized design and limited number of matched patients, our findings – derived from two prospective cohorts – suggest that R-miniCHOP may offer outcomes comparable to R-CHOP, particularly with respect to LSS. While these results support R-miniCHOP as an appropriate frontline option, treatment decisions remain highly individualized. These data may help inform clinical decision-making and provide a basis for designing future trials targeting this population, where R-miniCHOP could serve as a comparator arm. Funding: NU21-03-00411, U01 CA195568.

Abstract Introduction Short diagnosis-to-treatment interval (DTI) is associated with aggressive disease biology and inferior outcomes in diffuse large B-cell lymphoma (DLBCL), and is recognized as a potential source of selection bias in clinical trials if not properly addressed. However, its prognostic significance in follicular lymphoma (FL) remains poorly characterized. We aimed to evaluate the prognostic significance of DTI in newly diagnosed FL patients who received frontline (1L) immunochemotherapy (IC), using a large international dataset and an independent external validation cohort. Methods For the discovery dataset, we evaluated patients diagnosed between 2002 and 2018 from ten observational cohorts as part of the FLIPI24 Consortium. External validation was conducted using data from patients enrolled in the Lymphoma Epidemiology of Outcomes (LEO) Cohort between 2010 and 2015. All patients had FL grade 1–3A and received 1L IC within 100 days of diagnosis. Patients with a concurrent DLBCL were excluded. Missing baseline laboratory values were addressed via multiple imputation. The primary endpoint was event-free survival at 24 months (EFS24); secondary endpoint was 5-year overall survival (OS), both calculated from treatment initiation. DTI was analyzed as continuous (via splines) and dichotomized variable (≤14 vs >14 days; as defined in DLBCL). Results In the discovery cohort (n=3,907), median age was 61 years (IQR 53–69), and 50% were male; 49% of patients were high-risk according to FLIPI, 26% according to PRIMA-PI, and 38% according to FLIPI24. Included patients received R-CHOP (54%), R-CVP (26%), or B-R (20%) as 1L treatment, followed by anti-CD20 maintenance in 60%. The median DTI was 30 days (IQR 17–48). Using the 14-day cut-off, 851 patients (22%) had short DTI. These patients had more adverse baseline characteristics, including B symptoms (42% vs 32%, P<0.01), ECOG performance status ≥2 (15% vs 8%, P<0.01), elevated LDH (51% vs 40%, P<0.01), hemoglobin <12 g/dL (30% vs 17%, P<0.01), and elevated β2-microglobulin (56% vs 44%, P<0.01). Prognostic indices (PIs) were also more frequently high-risk in the short-DTI group: FLIPI (56% vs 47%), PRIMA-PI (36% vs 24%), and FLIPI24 (51% vs 34%, all P<0.01). Spline modeling showed a decreasing EFS24 rate with increasing DTI, reaching a plateau at 30–40 days. In logistic regression model, each additional week of DTI improved EFS24 (OR 0.92, P<0.01). DTI attenuated but remained prognostic after adjusting for PIs (OR 0.93 for FLIPI, 0.95 for PRIMA-PI, 0.96 for FLIPI24, all P<0.01). When analyzed as a dichotomized variable, short DTI was associated with inferior EFS24: OR 1.74 adjusted for FLIPI, 1.63 for PRIMA-PI, and 1.53 for FLIPI24 (all P<0.01). The 2-year EFS of short vs long DTI groups was 71% vs 82% (HR 1.50, 95% CI 1.34–1.67, P<0.01), 5-year OS was 80% vs 86% (HR 1.38, 95% CI 1.21–1.56, P<0.01), and the 5-year cumulative risk of histologic transformation was 7.7% vs. 5.4% (P<0.01). In the validation cohort (n=516), median age was 61 years (IQR 52–69 years), 55% were male; 36% of patients were high-risk according to FLIPI; 29% according to PRIMA-PI, and 33% according to FLIPI24. Patients received B-R (59%) or R-CHOP (41%) as 1L treatment. The median DTI was 31 days (IQR 19–48), 84 patients (16%) had DTI ≤14 days. Similar patterns were observed; patients with short DTI had adverse baseline characteristics, PIs, and shorter 2-year EFS (72% vs 84%, HR 1.69, 95% CI 1.13–2.55, P=0.01). DTI remained associated with EFS24 when analyzed as a continuous variable (per week: OR 0.88 unadjusted, 0.90 with FLIPI, 0.89 with PRIMA-PI, and 0.89 with FLIPI24), and dichotomized (≤14 vs >14 days: OR 1.83 adjusted for FLIPI, 1.88 for PRIMA-PI, and 1.73 for FLIPI24). Conclusion Short DTI, defined as ≤14 days (observed in 22% of FL patients vs 46% in DLBCL), is a strong and independent predictor of inferior outcomes in newly diagnosed FL patients treated with IC. While DTI correlates with adverse baseline features and established PIs, it retains independent prognostic value. Although a 14-day threshold is reasonable for risk modeling, DTI contains greater informational value when modeled as a continuous variable. Among PIs, FLIPI24 most strongly attenuated the DTI effect, underscoring its superior discriminative power over FLIPI and PRIMA-PI. Clinical trials designs should mitigate any potential barriers to enrollment of FL patients requiring urgent therapy.

Abstract Introduction Marginal zone lymphoma (MZL) is an indolent and heterogenous disease. Several prognostic models have been proposed to assess outcomes in MZL, including FLIPI, IPI (primarily designed for overall survival [OS]), and MZL-specific scores such as MALT-IPI (event-free survival [EFS]) and MZL-IPI (progression-free survival). FLIPI24 is a recently developed prognostic index for patients with follicular lymphoma (FL) treated with first-line (1L) immunochemotherapy (IC), identifying a high-risk population with inferior survival and increased risk of lymphoma-related death. FLIPI24 has also demonstrated robust performance in the entire FL population, including patients under observation. This study aimed to evaluate the prognostic utility of FLIPI24 in patients with MZL and to compare its performance with other established indices (FLIPI, MZL-IPI, IPI, MALT-IPI). Methods We pooled harmonized data from newly diagnosed MZL patients with complete available FLIPI24 variables (age, white blood cell count [WBC], hemoglobin [HGB], serum lactate dehydrogenase [LDH], and beta-2-microglobulin [B2M] levels) treated with 1L IC. Data were collected from three prospective international cohorts: NiHiL (Czech Republic; n=897; enrolled 2005–2023), LEO (USA; n=62; 2015–2020), and MER (USA; n=32; 2010–2015), forming a pooled cohort of 991 1L IC-treated patients. The analysis was then extended to include all newly diagnosed MZL patients (n=2,116), regardless of treatment. The primary endpoint in the 1L IC-treated cohort was EFS at 24 months (EFS24), and for all MZL patients, it was OS. Secondary endpoints included OS24 for 1L IC treated cohort, lymphoma-related mortality by FLIPI24 risk groups, and comparative prognostic performance of FLIPI, IPI, and MALT-IPI, by C-statistics; performance of MZL-IPI was assessed on a subgroup of NiHiL patients with available data (n=877 all MZL, n=485 1L IC-treated). Results Among the 991 1L IC-treated patients, the median age at diagnosis was 66 years (range 22–94); 47% were male; 11% had ECOG performance status ≥2, 68% clinical stage III–IV, 42% elevated LDH, 40% IPI 3–5, 42% FLIPI 3–5, and 62% MALT-IPI 2–3. The median B2M level was 2.8 mg/L, WBC 7.0 × 10⁹/L, and HGB 13.1 g/dL. MZL subtypes were: 64% extranodal (EMZL), 22% nodal (NMZL), and 14% splenic (SMZL). Most common 1L IC regimens were R-CVP (46%), R-CHOP-like (32%), R-chlorambucil (9%), and B-R (9%). FLIPI24 stratified patients into low- (18%), intermediate- (37%), and high-risk (45%) groups. High-risk patients were older (median 54 vs 65 vs 71 years for low-, intermediate-, and high-risk groups, respectively; P<0.01), had more frequent adverse baseline features, and were more likely to have the SMZL subtype (2% vs 7% vs 25% for low-, intermediate-, and high-risk groups, respectively; P<0.01). After a median follow-up of 7.2 years, EFS24 was 89%, 85%, and 65% (P<0.01) across low-, intermediate-, and high-risk groups; OS at 2 years was 98%, 97%, and 79%; and OS at 5 years was 96%, 91%, and 62%, resp. (P<0.01). The 5-year cumulative incidence of lymphoma-related death was 13% in high-risk vs 6% in low-/intermediate-risk groups. FLIPI24 showed better prognostic accuracy for EFS compared with FLIPI, MZL-IPI, IPI and MALT-IPI (C-index: 0.640 vs 0.630, 0.622, 0.620 and 0.603, resp.), as well as for OS (C-index: 0.710 vs 0.672, 0.641, 0.663, 0.652, resp.). Prognostic performance was consistent across MZL subtypes. In the extended cohort of 2,116 newly diagnosed MZL patients (47% receiving IC, 17% rituximab monotherapy, 11% radiotherapy, 8% surgery, 2% antibiotics; 15% observed), FLIPI24 stratified patients into low- (24%), intermediate- (39%), and high-risk (37%) groups. OS at 2 year was 99%, 97%, and 83%, at 5 years it was 96%, 91%, and 62%, resp. (P<0.01). The 5-year cumulative incidence of lymphoma-related death was 12% in high-risk vs 4% in low-/intermediate-risk patients. FLIPI24 outperformed other indices (OS C-index: 0.754 vs MZL-IPI 0.654, FLIPI 0.700, MALT-IPI 0.694, IPI 0.699). Conclusion FLIPI24 demonstrates strong and consistent prognostic performance across all MZL subtypes, identifying ~40% of patients as high-risk with significantly worse survival and increased lymphoma-related mortality. The FLIPI24 outperforms FLIPI, MZL-IPI, IPI, and MALT-IPI in predicting outcomes and may serve as a practical tool to guide risk-adapted management and selection of patients for novel therapies in MZL. Funding: NU21-03-00411, P50 CA97274, U01 CA195568.

Abstract Introduction The International Prognostic Index (IPI, NEJM, 1993) has guided risk stratification in large B-cell lymphoma (LBCL) for over three decades. Its simplicity and clinical utility have driven its widespread adoption, even in the era of precision medicine. However, the prognostic value of the IPI and its components may not be uniform across the age spectrum of LBCL patients. We evaluated the contemporary prognostic performance of the IPI in a large international cohort, focusing on age-stratified performance and the relative contributions of its individual components, grouped as patient- and disease-related factors. Methods We harmonized and pooled data from 6,941 patients with newly diagnosed systemic LBCL treated with R-CHOP-like regimens (R-CHOP, R-miniCHOP, DA-EPOCH-R, R-CHOEP, R-CHOP+X) with complete IPI data from three prospective cohorts: NiHiL (Czech Republic, n=4,590; 2010–2023), LEO (USA, n=1,789; 2015–2020), and MER (USA, n=562; 2010–2015). IPI components included age, ECOG performance status (PS) as patient-related, and Ann Arbor clinical stage, serum lactate dehydrogenase (LDH), and extranodal (EN) involvement as disease-related factors. Prognostic performance was evaluated using multivariable Cox regression models and C-statistics. Age-stratified analysis was performed for: ≤40 years (7%; n=492), 41–60 years (28%; n=1,909), 61–80 years (59%; n=4,080), and >80 years (7%; n=460). The primary endpoint was overall survival (OS). Results In the pooled cohort, the median age was 66 years (range 18–95). Compared to the original IPI cohort (n=3,273), our cohort was older (age >60 years: 66% vs 41%) but otherwise comparable: ECOG PS 2–4 (25% vs 24%), clinical stage III–IV (63% vs 66%), elevated LDH (60% vs 52%), and >1 EN involvement (32% vs 30%). In multivariable analysis, age (≤60 vs >60 years) was the strongest predictor of OS (HR=2.78; vs HR=1.96 in original IPI report), followed by ECOG PS (HR=2.07; vs 1.80), clinical stage (HR=1.50; vs 1.47), LDH (HR=1.41; vs 1.85, all P<0.01); EN involvement was not significant (P=0.50, HR=1.03 vs 1.48). Risk group distribution shifted from the original IPI: 28% were low-risk (0–1 factor; vs 35%), 23% low-intermediate (2; vs 27%), 24% high-intermediate (3; vs 22%), and 25% high-risk (4–5; vs 16%). Corresponding 2-year OS rates were 95%, 86%, 78%, and 63%, superior to those of the original IPI cohort (87%, 67%, 55%, 44%; pre-rituximab era). Age was associated with an increasing risk of mortality, with a more pronounced rise beyond 60 years. In a piecewise Cox model, the HR per year was 1.04 for ages ≤60 (linear), 1.05 for 61–69 (accelerated), and 1.06 for ≥70 years (exponential, all P<0.01). ECOG PS retained prognostic significance across age groups: HRs were 1.87 (P=0.06) for ≤40 years, 1.63 (P<0.01) for 41–60, 2.22 (P<0.01) for 61–80, and 1.43 (P<0.01) for >80 years. The strength of other IPI components declined with age. Clinical stage showed decreasing impact: HR 2.08 (P=0.09), 1.97 (P<0.01), 1.49 (P<0.01), and 1.31 (P=0.05). LDH was significant only up to age 80 years: HRs were 2.07 (P=0.04), 1.96 (P<0.01), 1.32 (P<0.01), and 1.21 (P=0.13). EN involvement was non-significant across all groups: HRs were 1.37 (P=0.34), 1.26 (P=0.05), 0.98 (P=0.74), and 1.06 (P=0.67). The IPI C-statistics was 0.676 overall and declined with age: ≤40 years (0.708), 41–60 years (0.683), 61–80 years (0.641), and >80 years (0.598). We next stratified the IPI factors into patient- (age, ECOG PS) and disease-related (clinical stage, LDH, EN involvement). In patients ≤40 years, disease-related factors outperformed patient-related (C-index 0.693 vs 0.602), as in the 41–60 group (C-index 0.677 vs 0.589). In patients aged 61–80, predictive values were comparable (0.613 vs 0.622). In >80-year-olds, both declined substantially (0.580 vs 0.568). Conclusion The IPI remains a valuable prognostic tool in LBCL, particularly among younger patients. However, its overall predictive accuracy declines with age. In patients ≤60 years old, prognosis is primarily driven by disease-related factors, suggesting a role for molecular classifiers to enhance risk stratification. In older patients, incorporation of additional patient-level factors, such as comorbidities and nutritional status could be considered. These findings underscore the need for more individualized prognostic tools for LBCL patients. Funding: NU21-03-00411, P50 CA97274, U01 CA195568, Charles University Haematology-Oncology Cooperatio Program.

Abstract Introduction The LEO Comorbidity Index (LCI), comprising ten equally weighted comorbidity categories (respiratory, cardiovascular, digestive, hepatic, renal, autoimmune, diabetes, cancer history, HIV, and stroke), has demonstrated prognostic utility in patients with non-Hodgkin lymphomas. However, its predictive accuracy may vary with increasing age, due to age-related rises in comorbidity burden and physiological vulnerability. To investigate these dynamics, we evaluated the age-stratified predictive performance of LCI in patients with large B-cell lymphoma (LBCL), with a focused analysis on individuals aged 80+ years. We also examined which specific comorbidities most strongly influenced overall survival (OS) and developed a simplified, clinically applicable index tailored to this population. Methods We first included adults ≥40 years with newly diagnosed LBCL and recorded comorbidities from the LEO registry (USA, 2015–2020; n=1,652) to assess age-stratified predictive performance of LCI using the C-index. Next, we focused on patients 80+ years (n=263), pooled from the LEO cohort (n=147) and NiHiL registry (restricted to General Hospital, Prague, Czech Republic, 2010–2023; n=116). Comorbidities were collected from patient self-reports (LEO) and/or medical records (LEO/NiHiL). Univariate and multivariate Cox models were used. The primary endpoint was OS. Results Among the total LBCL population (n=1,652), LCI predictive performance improved by age category with C-index for patients <65 of 0.584, 65–79 years 0.579, and ≥80 years 0.647, indicating stronger discrimination in the 80+ group. Subsequent analysis focused on patients aged 80+ years (n=263; median age 83). Within this cohort, 34% had ECOG performance status (PS) 2–4, 66% stage III–IV disease, 59% elevated lactate dehydrogenase, 35% >1 extranodal site involved, and 58% International Prognostic Index (IPI) score of 3–5. A total of 377 comorbidities were reported, averaging 1.43 per patient (1.22 in LEO; 1.61 in NiHiL). LCI distribution was: 0 points in 24% (n=62), 1 point in 33% (n=88), and 2–5 points in 43% (n=113). Higher LCI scores had worse ECOG PS 2–4: 19% (LCI=0), 33% (LCI=1), and 43% (LCI ≥2; P=0.01), and inferior OS (median 6.9 years LCI=0, 3.0 years LCI=1, and 2.8 years LCI≥2, resp.; P=0.02). Presence of ≥1 comorbidity was associated with shorter OS compared to no comorbidities (HR=1.67, P=0.01). The LCI was an independent predictor of OS after adjusting for age (HR=1.18, P=0.01, C-index 0.623), IPI (HR=1.16, P=0.03, C-index 0.628) as well as for recently proposed SENIOR-IPI (HR=1.14, P=0.049, C-index 0.665). When evaluating individual comorbidities, heart disease (HR=1.54, P=0.01), stroke (HR=1.89, P=0.03), and recent malignancy (HR=1.99, P=0.02) were independent predictors of OS. Based on these findings, we developed a simplified LCI (sLCI) for use in 80+ patients incorporating only the three comorbidities (1 point each). Patients were categorized as sLCI: 0 (49%, n=129), 1 (44%, n=115), and 2–3 points (7%, n=19). sLCI scores 0, 1, 2–3 were associated with ECOG PS 2–4 27%, 37%, and 63%, respectively (P=0.01) and inferior OS: median 5.3 years (0), 2.5 years (1), and 1.4 years (2–3; P<0.01). sLCI remained an independent and strong predictor of OS after adjusting for age (HR=1.71, P<0.01, C-index 0.636), IPI (HR=1.66, P<0.01, C-index 0.635), and SENIOR-IPI (HR=1.60, P<0.04, C-index 0.659). The results were consistent in both NiHiL and LEO cohorts and remained significant among patients treated with anthracyclines (sLCI adjusted for age: HR=1.58, P<0.01, C-index 0.607; for IPI: HR=1.53, P=0.01, C-index 0.623; for SENIOR-IPI: HR=1.51, P=0.01, C-index 0.633). Conclusion Comorbidity burden becomes increasingly prognostic with higher age in LBCL patients. In the 80+ individuals, comorbidities – particularly heart disease, recent cancer, and stroke – have an independent impact on OS. While the original LCI captures the impact of broadly defined comorbidities, its prognostic utility attenuates in the 80+ patients, likely reflecting limited relevance of indolent chronic conditions in this population's constrained survival horizon. The sLCI, focused on the most prognostically relevant comorbidities, offers practical risk stratification. Incorporation of sLCI into clinical decision-making – alongside other prognostic indices – could better identify high-risk individuals and guide treatment strategies. Funding: NU21-03-00411, U01 CA195568.