Mou, Eric

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 Background: Although progression-free survival (PFS) in early-stage (ES) classic Hodgkin Lymphoma (cHL) is high, there remains a subset of patients (pts) at higher risk of worse outcomes, particularly in those with unfavorable risk disease. Leveraging pt-level data from within the HoLISTIC (Hodgkin Lymphoma International STudy for Individual Care) Consortium, the E-HIPI was developed in clinical trial pts and validated in real-world registry pts to predict 2-year (y) PFS (Rodday. NEJM Evidence 2025). Continuous, objective, and readily measurable pre-treatment variables were considered, with sex, maximum tumor diameter, albumin, and hemoglobin included as significant predictors. Using the E-HIPI, interactive calculators for pt risk, comparison, and stratification were created (https://rtools.mayo.edu/holistic_ehipi/). Although the E-HIPI was developed and validated in both unfavorable and favorable ES cHL pts, the clinical predictors are primarily markers of unfavorable disease. In the development and initial validation cohorts, 2y PFS was 93.7% and 90.3%, respectively, the C-statistic was 0.63 in both cohorts, calibration was strong with slight underprediction of events in the validation cohort, and the E-HIPI outperformed the historic binary classification of patients as favorable or unfavorable using EORTC criteria. However, since pts in the original E-HIPI development and validation were primarily treated with ABVD chemotherapy protocols, additional validation is needed, particularly among pts with unfavorable ES cHL who were treated initially with more intensive chemotherapeutic platforms (e.g., BEACOPP-based). Thus, we conducted an external validation of the E-HIPI in pts treated on recent unfavorable ES cHL GHSG trials. Methods: The validation cohort included 2367 adults (ages 18 to 60y) with newly-diagnosed unfavorable cHL from randomized phase 3 trials conducted by the GHSG (HD14 von Tresckow. JCO 2012; and HD17 Borchmann. Lancet 2021). We calculated the predicted probability of 2y PFS events based on the E-HIPI model equation (scale 1-100%). Model performance was assessed using discrimination and calibration. Discrimination, which is the model's ability to separate high and low risk pts, was assessed using Harrell's C-statistic. Calibration, which is the model's ability to accurately predict absolute risk, was assessed by comparing observed and predicted probabilities of 2y PFS events within quintiles of predicted probabilities and estimating calibration-in-the-large (predicted minus observed event rate) and the calibration slope. Results: For pts treated on unfavorable GHSG trials, mean age was 33y, 95% had stage II disease, mean baseline E-HIPI score (i.e., predicted 2y PFS event rate) was 6.0% (SD=2.3%), and the observed 2y PFS rate was 96.2% (95%CI: 95.4-97.0%). The C-statistic was 0.65 (95% CI: 0.59-0.70), calibration-in-the-large was 0.02, and the calibration slope was 1.08 (95% CI: 0.52, 1.64). Within the lowest risk E-HIPI quintile, the observed 2y PFS event rate was 1.6%, compared with 6.1% in the highest risk quintile. Conclusions: In external validation of the recently published E-HIPI in pts with cHL treated on unfavorable GHSG trials using more intensive BEACOPP-based protocols, discrimination was similar to the original development and validation cohorts. Collectively, the E-HIPI is a treatment-agnostic prediction tool across varied treatment regimens for unfavorable ES cHL pts. Better 2y PFS in the GHSG trials than in the E-HIPI development and initial validation cohorts may have contributed to mild misclassification, likely reflecting differences in treatment regimens. This may be resolved with recalibration or incorporating granular treatment variables into future models. Additional research is needed to understand E-HIPI performance in pts with favorable disease who have even lower event rates as well as to more fully predict individualized pt outcomes across varied chemotherapy platforms and radiation received for all ES cHL pts.

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.

Abstract Anaplastic large cell lymphomas (ALCLs) are CD30+ T-cell lymphomas that share pathologic features but differ in presentation, outcome, and genetics. Current classification incorporates clinical presentation and anaplastic lymphoma kinase (ALK) status but inadequately addresses molecular heterogeneity and therapeutic vulnerabilities. We studied 689 patients with ALCL in the LLMPP (Lymphoma/Leukemia Molecular Profiling Project) and performed expert consensus review, genetic subtyping (ALK, DUSP22, TP63, and triple negative), and immunohistochemistry for phosphorylated STAT3Tyr705. RNA sequencing with unsupervised gene expression profiling in 393 patients identified 2 main molecular types of ALCL that could be predicted with 91% accuracy based on the presence (type I) or absence (type II) of phosphorylated STAT3Y705 expression. Type I ALCLs included ALK+ ALCL and a subset of triple-negative ALCLs (TN-I); type II ALCLs included tumors with DUSP22 and/or TP63 rearrangements and the remaining triple-negative ALCLs (TN-II). Type I ALCLs were enriched for JAK-STAT3, whereas type II ALCLs were enriched for non–tyrosine kinase pathways, particularly epigenetic regulators such as EZH2. Immunohistochemistry showed overexpression of EZH2 and its trimethylated substrate H3K27. Prognosis in systemic ALCL was favorable for DUSP22-rearranged ALCL (5-year overall survival, 95%) and ALK+ ALCL (88%), intermediate for triple-negative ALCL (TN-I, 52% and TN-II, 37%), and poor for TP63-rearranged ALCL (0%). We introduce an integrated molecular classification that preserves currently diagnosed ALCL entities but identifies 4 molecularly distinct ALK− ALCL subtypes (DUSP22-rearranged, TP63-rearranged, TN-I, and TN-II). This classification can be easily implemented on paraffin tissue in routine practice or clinical trials, and stratifies ALCL into diagnostically, prognostically, biologically, and potentially therapeutically relevant subtypes.