Polgárová, Kamila

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 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 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.

Background: SAR442257 (SAR'257) is a trispecific antibody that targets CD38, CD3 and CD28. Simultaneous CD3 and CD28 binding triggers T cell co-signaling, and additional CD38 recognition directs the T cells to CD38+ cancer cells such as multiple myeloma (MM) and non-Hodgkin lymphoma (NHL). This is a first-in-human phase 1 study investigating the safety, efficacy, pharmacokinetic (PK) and pharmacodynamic (PD) profile of SAR'257 in patients (pts) with refractory and relapsed (rr) MM and rrNHL. Methods: This is a multicenter, international, open-label, dose-escalation study (NCT04401020) of SAR'257 in pts with rrMM refractory to standard-of-care (SOC) options, including anti-CD38 monoclonal antibodies, and in pts rrNHL without any SOC options. SAR'257 was administered intravenously with lead-in doses (Day 1−5) in the first week, followed by twice weekly (BIW) or once weekly (QW) dosing; 11 target dose levels (TDLs) in pts with rrMM (9 TDLs: 0.06-11 µg/kg BIW; 2 TDLs: 18-27 µg/kg QW), and 2 TDLs in pts with rrNHL (2 µg/kg BIW and 4 µg/kg QW). Results: As of February 19, 2024, 47 pts (rrMM, n=40; rrNHL, n=7) received SAR'257. The median ages (years) were 64 (rrMM; range: 40−84) and 70 (rrNHL; range: 18−75). The median number of prior lines was 5 (range: 3−12) for rrMM and 5 (range: 2−7) for rrNHL cohort. In rrMM cohort, all (100%) pts had prior exposure to an anti-CD38 monoclonal antibody (MAb) and were refractory to anti-CD38 and in rrNHL cohort all were anti-CD38 naïve. The median time from last anti-CD38 dose was 2.7 (range: 1−65) months for rrMM cohort. Safety analysis revealed that 68% (n=32) pts had treatment-emergent adverse events (TEAEs; 26 pts in rrMM and 6 pts in rrNHL); 21.3% pts (n=10) Grade (G) ≥3 TEAEs (7 in rrMM and 3 in rrNHL). Cytokine release syndrome (CRS) was the most common TEAE, occurring in 52.5% of rrMM pts across all TDLs (n=21; G≥3 in 1 pt from 11 µg/kg BIW TDL) and in 57.1% of rrNHL pts (n=4; no G≥3) at the two TDLs tested. Repetitive CRS episodes (>1 episode) were more frequent at higher TDLs. Infusion-related reactions (IRRs; any G) were observed in 22.5% pts with rrMM (n=9; no G≥3) and in 28.5% pts with rrNHL (n=2; G≥3 in 1 pt). Epstein-Barr virus (EBV) infection/reactivation was reported in 17.5% (n=7; G≥3 in 4 pts) and 28.6% (n=2; no G≥3) pts with rrMM and rrNHL respectively. Further, 15% (n=6, G≥3 in 2 pts) from rrMM and 14.3% (n=1; G2 CMV reactivation) pts from rrNHL cohort reported cytomegalovirus (CMV) infection/reactivation. One case of immune effector cell-associated neurotoxicity syndrome (ICANS) was reported (G4) in the rrNHL cohort. Four dose-limiting toxicities (DLTs) were observed in the rrMM cohort [1 at 4 µg/kg BIW (G3 hepatotoxicity); 1 at 11 µg/kg BIW (G5 CRS−EBV reactivation; and 2 at 27 µg/kg QW (G3 CMV infection reactivation and G3 febrile neutropenia in same pt)]. Three DLTs were observed in the rrNHL cohort (2 at 2 µg/kg BIW [G4 neutropenia and G4 thrombocytopenia; same pt] and 1 at 4 µg/kg QW [ICANS G4]). For pts with rrMM, the maximum plasma concentration of SAR'257 reached within or above the theoretical efficacious range (0.1−1nM; extrapolated from ex vivo models), starting at 8 µg/kg BIW and 18 µg/kg QW in the first treatment cycle. As of July 08, 2024, the overall response rate (ORR), defined as partial response (PR) or better, was 5% (n=2) in the rrMM cohort: 1 pt exhibited stringent complete response (duration of response [DOR]=8.1 months, on-going) and 1 showed a complete response (CR) at 27 µg/kg QW TDL. In rrNHL cohort, the ORR was 14.3%, 1 pt achieved PR (DOR=7.1 months) at 2 µg/kg BIW TDL. The disease control rate (stable disease or better for >8 weeks) was 60% (n=24) and 28.6% (n=2) in the rrMM and rrNHL cohorts respectively. For both cohorts exploratory biomarker analysis revealed that: (1) SAR'257 treatment activated peripheral blood T cells and reduced regulatory T cell numbers and CD4/CD8 ratio; (2) CD38 expression on plasma cells positively corelated with time since the last anti-CD38 MAb dose; (3) Among the pts experiencing CRS, the peak values of cytokines (Interleukin (IL)-6, IL-8, and C-reactive protein) were significantly higher during the first cycle in comparison to subsequent cycles. Conclusion: This Phase 1 study of SAR'257 showed an anti-tumor response in a small number of pts from the rrMM and rrNHL cohorts. Due to safety concerns, in particular high rates of EBV and CMV reactivation and recurrent episodes of CRS in the higher dose levels, the study was terminated during dose escalation.