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Abstract Background Previous studies in aggressive B-cell lymphoma demonstrate that patients with shorter diagnosis-to-treatment intervals (DTI) represent those with higher risk disease. This suggests that patients enrolled in clinical trials may carry a selection bias as they often have longer DTI than patients in the general population. This has important implications for clinical research design and the generalizability of clinical trials in aggressive lymphomas. However, the prognostic implications of DTI have not been evaluated in peripheral T-cell lymphomas (PTCL). Therefore, we examined DTI and its association with clinical factors and outcomes in a prospective observational cohort of patients with PTCL from the United States within the LEO (Lymphoma Epidemiology and Outcomes) and MER (University of Iowa and Mayo Clinic Specialized Programs of Research Excellence Molecular Epidemiology Resource). Patients and Methods We evaluated patients enrolled to the MER (2002-2015) and LEO (2015-2020) cohorts with the following forms of PTCL: PTCL-not otherwise specified (PTCL-NOS, n=217), nodal T-follicular helper (TFH) cell lymphoma (nTFHL, n=153), anaplastic large cell lymphoma (ALCL), ALK positive (ALCL, ALK+, n=74), ALCL, ALK negative (ALCL, ALK-, n=95), enteropathy associated T-cell lymphoma (n=18), and monomorphic epitheliotropic intestinal T-cell lymphoma (n=2). Associations of DTI with clinical factors and outcomes were examined using Kaplan Meier and Cox models. Event free survival (EFS) was defined as the time from start of treatment to relapse/progression, start of 2nd line therapy, or death from any cause. Overall survival (OS) was defined as the time from start of treatment until death from any cause. DTI was defined as the number of days between the first diagnostic biopsy and the start of therapy. Patients who were initially observed or had DTI > 100 days were excluded. Results In 559 patients (229 MER and 330 LEO), median age was 60, 34% had IPI>2 and 71% were stage III/IV. 472 (84%) patients initially received anthracycline-based chemotherapy. Median DTI was 23 days (interquartile range (IQR): 12-39) and was similar in MER (21 days, IQR: 11-33) and LEO (25 days, IQR: 14-42). 168 (30%) patients had DTI 0-14 days, 178 (32%) 15-28 days, and 213 (38%) 29-100 days. Overall in the cohort, shorter DTI was associated with a worse 5-year OS (DTI 0-14 days: 43%; DTI 15-28 days: 53%; DTI 29-100 days: 58%, p<0.001) and 5-year EFS (DTI 0-14 days: 31%; DTI 15-28 days: 39%; DTI 29-100 days: 45%, p<0.001). In multivariable analyses, the association of DTI with outcomes remained consistent after adjusting for age and International Prognostic Index (IPI). Shorter DTI was strongly associated with adverse clinical factors, including elevated lactate dehydrogenase levels, poor performance status, B-symptoms, and higher IPI in both cohorts (all P < .003). DTI was not associated with age, sex, or distance from the LEO/MER center (all p>0.3). 6% patients with DTI of 0-14 days received 1L treatment on a clinical trial, compared to 11% with DTI 15-28 days and 13% with DTI 29-100 days, underscoring that patients with lower DTI may be underrepresented in clinical trials. When examining within PTCL subtypes, the association between short DTI (0-14 days) and inferior outcomes was most prominent in PTCL, NOS (OS HR=2.13, 95% CI: 1.52-2.94; EFS HR =1.49, 95% CI: 1.19-1.85). Associations between short DTI and outcomes were weaker in other subtypes: nTFHL (OS HR=1.28, 95% CI: 0.83-2.00; EFS HR =1.22, 95% CI: 0.82-1.81), ALCL, ALK-, (OS HR=1.30, 95% CI: 0.59-2.86; EFS HR =1.32, 95% CI: 0.68-2.56), ALCL, ALK+, (OS HR=1.05, 95% CI: 0.26-4.17; EFS HR =2.12, 95% CI: 0.84-5.26). Conclusion Shorter DTI is associated adverse prognostic clinical factors (LDH, stage, high IPI) and inferior EFS and OS in newly diagnosed PTCL. Patients with DTI ≤ 14 days, which represents approximately 1/3 patients with PTCL, may be underrepresented in clinical trials. Understanding of this selection bias should inform clinical trial design and interpretation. Future studies should consider strategies to minimize barriers to enrollment for patients with low DTI.

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 Background: Covalent Bruton tyrosine kinase inhibitors (cBTKi) have dramatically changed the treatment (tx) landscape of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), especially in the first-line setting. However, cBTKi resistance or intolerance eventually occurs. Pirtobrutinib is a highly selective, non-covalent BTKi that inhibits BTK with low nM potency throughout the daily dosing interval. Pirtobrutinib demonstrated safety and efficacy in the phase 1/2 BRUIN study among patients (pts) with R/R CLL/SLL, including pts previously treated with a BTKi. Pirtobrutinib is approved for treating CLL in adults in the EU after prior tx with a BTKi, and in the USA for adults with CLL/SLL who have received at least 2 prior lines of therapy, including a BTKi and a BCL-2i. Here, we report the final results from the phase 1/2 BRUIN study (NCT03740529) with more than 5 years (yrs) follow-up (f/u), focusing on efficacy and safety of pirtobrutinib in pts with CLL/SLL in the post-cBTKi setting. Methods: Pts with prior cBTKi-exposed CLL/SLL were eligible for tx with pirtobrutinib. Endpoints included overall response rate (ORR) per 2018 iwCLL criteria, ORR including partial response with lymphocytosis (PR-L), duration of response (DOR), and progression-free survival (PFS), assessed by independent review committee (IRC; presented herein) and investigator, overall survival (OS), and safety. Data cut was 27 January 2025, providing a median study f/u of 34.1 months (mos; range, 0.5-69.8). Results: Among the 282 pts with CLL/SLL who were cBTKi-exposed and treated with pirtobrutinib, of which 84.4% (238/282) received 200 mg as the starting dose, the median age was 69 yrs (range, 36-88). The median number of prior therapies was 4 (range, 1-11), with 45.4% of pts having received prior BCL2i, and 77.0% having discontinued prior cBTKi due to progressive disease (PD), 19.5% due to toxicity, and 3.5% due to other reasons/missing. High-risk features were frequent: unmutated IGHV in 85.8% (193/225), mutated TP53 in 40.4% (99/245), and del(17p) in 29.2% (59/202). The ORR was 72.3% (95% CI, 66.7-77.5). ORR including PR-L was 81.6% (95% CI, 76.5-85.9), which was consistent across subgroups including BCL2i-exposed (80.5%; 95% CI, 72.5-86.9), BCL2i-naive (82.5%; 95% CI, 75.5-88.1), unmutated IGHV (82.9%; 95% CI, 6.8-87.9), del(17p) (88.1%; 95% CI, 77.1-95.1), and prior cBTKi discontinuation due to PD (79.7%; 95% CI, 73.8, 84.9) or toxicity (87.5%; 95% CI, 76.8-94.4). The median DOR was 18.4 mos (95% CI, 14.82-20.27), with 36-mos DOR rate of 28.0% (21.6-34.7). The median PFS was 18.7 mos (95% CI, 16.6-21.8) among all pts and the 36-mos PFS rate was 25.0% (95% CI, 19.4-31.0) with 44 mos of f/u. Further, the median PFS was 22.3 mos (95% CI, 19.3-27.6) for BCL2i-naive pts, and 15.9 mos (95% CI, 13.6-17.5) for BCL2i-exposed pts; 16.6 mos (95% CI, 13.8-19.4) among those who discontinued prior cBTKi therapy due to PD, and not estimable (NE) (95% CI, 25.2-NE) in those who discontinued due to toxicity. Among all pts with CLL/SLL, with a median f/u of 46.5 mos, the median OS was NE (95% CI, 47.8-NE), with the 36-mos OS rate of 62.0% (95% CI, 55.8-67.7). Median time on pirtobrutinib was 20.0 mos (range, 0.2-69.8), and 43 (15.2%) pts were still on tx at data cutoff. The most frequent TEAEs, regardless of attribution, were fatigue (38.7%), neutropenia/neutrophil count decreased (35.8%), diarrhea (30.5%), cough (29.8%), COVID-19 (28.4%), and contusion (27.7%). The most frequent grade ≥3 TEAEs were infection (36.5%) and neutropenia/neutrophil count decreased (29.8%). Low rates of grade ≥3 TEAE of hypertension (5.3%), hemorrhage/hematoma (2.5%), and atrial fibrillation/flutter (2.1%) were observed. Grade 5 TEAEs, regardless of attribution, occurred in 35 (12.4%) pts. Overall, 11 (3.9%) pts had a TRAE leading to a dose reduction, and 9 (3.2%) pts had a TRAE leading to pirtobrutinib discontinuation. Conclusion: In heavily pretreated R/R post-cBTKi CLL/SLL pts, pirtobrutinib continues to show favorable and durable efficacy. Pirtobrutinib is well-tolerated, with low rates of hypertension, hemorrhage/hematoma, and atrial fibrillation/flutter, which can be frequently observed with cBTKi. Additionally, dose reductions/discontinuations due to pirtobrutinib TRAEs were low. No new pirtobrutinib safety signals were identified with more than 5 yrs of f/u.

Abstract Introduction: cBTKi have made a substantial impact in pts w/ MCL, but pts who develop PD while on treatment w/ cBTKi have historically had poor responses to subsequent lines of therapy (LOT). Brexucel, lisocel, and the non-covalent BTKi pirto have been approved in this population. While two RW studies have substantiated the benefit of brexucel, similar data for pirto are lacking. Accordingly, we aimed to evaluate the outcomes of pts treated w/ pirto in the RW setting. Methods: We performed a multi-center retrospective cohort study of adult pts w/ a diagnosis of MCL who experienced PD after any approved cBTKi and subsequently received pirto. Pts who received pirto w/ bridging intent and those who switched to pirto due to intolerance of cBTKi were excluded. The 95% exact binomial confidence intervals (CI) were calculated for overall response rate (ORR) and complete response rate (CRR). Progression-free survival (PFS) and overall survival (OS) were defined as the time from pirto start to PD or death, whichever occurred first, and the time from pirto start to death, respectively, and calculated w/ the Kaplan-Meier method. The log-rank test was used to compare survival curves. A multivariate (MV) Cox proportional hazard model was built to calculate adjusted hazard ratio (aHR). Analyses were performed w/ SAS, version 9.4. Results: Data on 111 pts w/ MCL treated across 21 institutions were collected. Median (mdn) age was 72 (range 33 – 93) years. Twenty-seven pts (24%) were female, 3 (3%) were Asian, 5 (5%) Black, 9 (8%) Hispanic, 86 (77%) White. Among the 53 (48%) pts w/ available MIPI-c at diagnosis, 28 (53%) pts were high-risk. Ki67 at diagnosis was available in 84 (76%) pts: of those, 58 (69%) had a Ki67 ≥30%, and 41 (49%) ≥50%. TP53 mutational status was available in 70 (63%) pts: 33 (47%) had documented TP53 mutation and 10/52 (19%) pts had a disease w/ complex karyotype. Pts had a mdn of 3 (range 1 – 9) prior LOT (n=106). Ninety-one pts (86%) received chemo-immunotherapy (CIT), 16 (15%) autologous stem cell transplant, 19 (18%) venetoclax (ven), 29 (27%) chimeric antigen receptor T-cell, 4 (4%) allogeneic stem cell transplant. For cBTKi, 39 (35%) pts received ibrutinib, 56 (50%) pts acalabrutinib, 33 (30%) pts zanubrutinib, and 17 (15%) pts received more than one cBTKi. The mdn time from the last dose of cBTKi to pirto start was 55 (range 0 – 2587) days, w/ 51 (46%) pts who switched from a cBTKi directly to pirto. Thirty (27%) pts had no response (stable disease or PD as best response) to cBTKi, and 40 (36%) pts had no response to the last LOT. Two (2%) pts received pirto in combination w/ CIT, 8 (7%) w/ an anti-CD20 monoclonal antibody (mAb), 11 (10%) w/ ven ± a mAb, while 86 (77%) pts as single agent. In 104 (94%) pts, pirto was given at full dose, 10 (9%) pts had a subsequent dose reduction. A total of 35 serious (grade ≥3) adverse events (AE) were documented in 27 (24%) pts: 4 (4%) pts had a serious bleeding AE, 5 (5%) pts a serious cardiac AE, 10 (9%) a serious GI AE, and 16 (14%) a serious infectious AE. Ninety-eight (88%) pts were evaluable for response. The ORR was 40% (95% CI 30% – 50%) w/ a CRR of 29% (95% CI 20%– 39%). At the last follow-up, 29 (26%) pts remained on pirto w/ a mdn treatment duration of 15.1 months (range 0.4 – 26). Fifty-eight (52%) pts died, 35 (78%) because of PD. At a mdn follow-up of 15.8 (range 0.4 – 26) months among survivors, the mdn PFS was 4.7 months (95% CI 3.3 – 8.2) and the mdn OS was 13 months (95% CI 9.2 – not available). Using the log-rank test, age (quartile groups), number of LOT (1-2 vs. 3-4 vs. 5+), time from cBTKi to pirto (quartile groups), Ki67≥30%, and high MIPI-C did not result in a statistically significant difference in PFS (p>0.05). Presence of TP53 mutation was associated w/ a non-statistically significant adverse trend in PFS (p=0.0585). No response to cBTKi and Ki67≥50% were associated w/ a statistically significant inferior PFS in log-rank test (p=<0.05), which persisted in a MV Cox regression model (aHR 2.4, 95% CI 1.4-4.2, and aHR 2.6, 95% CI 1.6-4.4, respectively). Conclusions: This is the first RW report on pirto in MCL pts. In this high-risk population, ORR to pirto was comparable to the BRUIN trial, while PFS was significantly worse, especially in pts w/ no response to cBTKi and w/ a high Ki67. However, prolonged remissions were seen in a subset of pts, suggesting that a better characterization of this population w/ durable benefit from pirto is needed.

Abstract Background: Prognostication for patients with non-transformed relapsed/refractory (R/R) follicular lymphoma (FL) is not well defined. Progression of disease within 24 months (POD24) and number of lines of prior therapy are commonly used to benchmark outcomes and for trial eligibility in this space. However, a comprehensive model for risk prediction in R/R FL is lacking. Here we utilize patients from the LEO Consortium for Real World Evidence (CReWE) and Iowa/Mayo Clinic Lymphoma SPORE MER to develop a clinical prediction model for R/R FL. Methods: Patients with grade 1-3A FL were prospectively enrolled at diagnosis in the MER and/or initiated second line or later therapy (2L+) for non-transformed FL at one of the 8 LEO Centers from a previous LEO CReWE study (Casulo et al, Lancet Haem 2022). All available lines of therapy were abstracted; lines of therapy after histologic transformation were not used in the analyses. A management plan of observation was considered as a type of therapy in the 1L setting but not in the 2L+ setting. Clinical variables and outcomes were abstracted at each line of therapy. Variables considered for modeling included demographics, clinical labs, treatment history, and pertinent clinical variables (including FLIPI and FLIPI24 components). Multiple imputation was used to address missing data in modeling; beta-2 microglobulin (B2M) was unable to be imputed due to the amount of missing data. Index therapy was defined as the date of initiation of a line of therapy (2L, 3L or 4L) for non-transformed FL. The primary endpoint for model development was the time from index therapy until the histologic transformation or lymphoma-related death (HT/LD). Cox proportional hazards models were used for model development. Modeling was first performed separately for each line of therapy and then evaluated across lines. Bootstrapping on imputed datasets was used to assess optimism in model performance. Results: N=1001 patients initiated 2L+ therapy and were utilized for modeling. Of these patients, N=654 initiated 3L and N=344 initiated 4L therapy. Median age at index therapy was (60, 61, and 62) for lines 2-4, respectively. Median follow-up by line of therapy was 8.2, 6.1, and 6,1 years and number of HT/LD events for modeling was 272, 154, and 88, respectively. Observed outcomes decreased modestly as the line therapy increased: median event-free (1.6, 1.5, and 1.2 years) and overall survival (17.6 years, 14.5 years, and 12.3 years), for lines 2-4, respectively. 5-year estimates of HT/LD by line of therapy were 21.6% (95% CI: 18.9-24.3), 23.7% (95% CI: 19.9-27.4) and 29.3% (95% CI: 23.3-34.7), respectively. A clinical prediction model was independently developed for each line of therapy; the final model for each line consisted of the same variables: increasing age, male sex, higher LDH, lower hemoglobin, higher white blood cell count, prior immunochemotherapy exposure, and shorter time since initial diagnosis. The parameter estimates for these variables were broadly similar across the different lines of therapy. The model output is an individual patient's risk of HT/LD. Patients with high-risk FLP-R, as defined using the upper quartile of FLP-R risk scores for each line, had observed 5 year HT/LD rates of 43%, 44% and 51% in lines 2-4, respectively. In contrast, patients with the lower quartile of FLP-R risk scores had observed 5 year HT/LD rates of 10%, 6% and 8% in lines 2-4, respectively. The optimism-corrected c-statistic for the FLP-R model across all lines of therapy was 0.685. This added significant information beyond FLIPI diagnosis (c=0.533) FLIPI at index line (c=0.563), the line of therapy (c=0.525), POD24 status (c=0.578), or all 4 variables combined (c=0.614). Conclusions: The FLP-R model identifies a group of patients with non-transformed FL in the R/R setting who are at very high risk of transformation and/or lymphoma-related death across lines of therapy. FLP-R features 4 of the 5 components of the 1L FLIPI24 prediction model (B2M was unavailable for modeling) with the addition of sex, treatment history and time since initial diagnosis. The number of prior therapies is not sufficient to identify high-risk populations for clinical trial enrichment in the R/R FL setting and model discrimination for FLP-R was greatly improved over FLIPI and/or POD24 across lines of therapy. A Shiny app will be provided for model implementation; external validation is planned.

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 Background: Despite the efficacy of covalent Bruton tyrosine kinase inhibitors (cBTKi) in R/R MCL, patients (pts) ultimately discontinue treatment due to intolerance or development of resistance and disease relapse. Pirtobrutinib is a highly selective, non-covalent BTKi that inhibits BTK with low nM potency throughout the daily dosing interval. Pirtobrutinib was safe and effective in the phase 1/2 BRUIN study in pts with R/R B-cell malignancies, including those previously treated with a BTKi. Pirtobrutinib is approved in the EU for adults with R/R MCL after prior treatment with a BTKi (EMA Conditional Approval, Oct 2023), and in the USA for adults with R/R MCL after ≥ 2 lines of systemic therapy, including a BTKi (FDA Accelerated Approval, Jan 2023).Here, we report the final results from the phase 1/2 BRUIN study (NCT03740529), with a follow-up period of up to 5 yrs, focusing on the efficacy and safety of pirtobrutinib in all R/R MCL pts. Methods: Pts with R/R MCL who received ≥1 prior lines of therapy (including BTKi) were eligible for treatment with pirtobrutinib monotherapy. Key endpoints included overall response rate (ORR), duration of response (DOR) and progression-free survival (PFS), all assessed by independent review committee (IRC) per Lugano 2014 criteria (presented here) and investigator, overall survival (OS), and safety. Pts were included across the range of doses evaluated in dose escalation and expansion (25-300 mg/day). A data cutoff on 27 January 2025 was utilized, with a median study follow-up of 17.5 months (range, 0.5-69.6). Results: Among the 166 pts with R/R MCL, 153 (92%) received the pirtobrutinib approved dose of 200 mg/day, 152 (92%) had received prior cBTKi, of which 128 (84.2%) discontinued any prior cBTKi due to progressive disease (PD), and 15 (9.9%) due to toxicity. The cBTKi-pre-treated pts had a median age of 70 yrs (range, 46-88), 52% had intermediate-risk and 28.3% had high-risk sMIPI scores. The median number of prior lines of therapy was 3 (range 1-9), with most pts having received a prior anti-CD20 antibody (96.7%) and chemotherapy (90.1%). Additional prior therapies included hematopoietic stem cell transplantation (21.7%; 19.7% auto and 4.6% allo), BCL-2 inhibitor (15.8%), CAR-T cell therapy (8.6%). As of the data cutoff, 11 (7.2%) pts who received a prior cBTKi and 6 (42.9%) cBTKi naïve pts remained on treatment. The cBTKi pre-treated pts had an ORR of 49.3% (95% CI, 41.1-57.6), including 15.8% complete responses (CR) (n=24) and 33.6% partial responses (PR) (n=51). The 75 responding pretreated pts had a median DOR of 21.6 months (95% CI, 9.2-27.2) at a median follow-up of 24 months. The ORR among 128 pts who had discontinued any prior cBTKi due to PD and 15 pts who discontinued due to toxicity was 43.0% and 93.3%, respectively. The median PFS and OS for cBTKi pre-treated pts were 5.6 months (95% CI, 5.3-9.2) and 23.9 months (95% CI, 17.3-51.5), respectively. Fourteen pts (9.2%) were censored for PFS due to subsequent anticancer therapy without documented PD, including 8 pts who received CAR-T. The cBTKi naïve pts (n=14) had an ORR of 85.7% (95% CI, 57.2-98.2), including 50.0% CR (n=7) and 35.7% PR (n=5). The 12 responding naïve pts had a median DOR of 42.7 months (95% CI, 25.8-NE) at a median follow-up of 43 months. The median PFS and OS in the cBTKi naïve pts were 44.6 months (95% CI, 16.7-NE) and not reached (95% CI, 33.5-NE), respectively. Among all R/R MCL pts (n=166), the most frequent treatment-emergent adverse events (TEAE), regardless of attribution, were fatigue (31.9%), diarrhea (22.9%), anemia (18.1%), and dyspnea (18.1%). The most common Grade ≥3 TEAE was neutropenia/neutrophil count decreased (13.3%), and the rate of Grade ≥3 infections was 21.1%. Grade ≥3 hemorrhage/hematoma (2.4%) and all-grade atrial fibrillation/flutter (3.6%) were infrequent. In total, 13 (7.8%) pts had a fatal TEAE, with 4 (2.4%) classified as infections. Overall, 8 pts (4.8%) had treatment-related AE leading to dose reductions, and 6 (3.6%) had treatment-related AE leading to pirtobrutinib discontinuation. Conclusion: Pirtobrutinib continues to demonstrate efficacy in pts with heavily pre-treated R/R MCL including both those who previously received a cBTKi and those who were BTKi-naïve. The safety profile of pirtobrutinib remained favorable with a low-rate of dose reductions/discontinuations due to drug-related toxicity. No new safety signals were identified after up to 5 yrs of follow-up.

Abstract Introduction There is currently no standard-of-care for patients (pts) who cannot tolerate full dose anthracycline regimens in frontline large B-cell lymphoma (LBCL). R-miniCHOP is a commonly used regimen that provides curative intent treatment with manageable toxicity. Despite this, lymphoma and treatment-related mortality are the leading causes of death in these pts. Additionally, many pts may not be eligible to receive R-miniCHOP due to comorbidity or frailty. There are limited clinical trial and real-world data focused on this population. Methods Pts with LBCL age 18 years (yrs) and older were identified from the Lymphoma Epidemiology of Outcomes (LEO) cohort, a prospective study of newly diagnosed pts with non-Hodgkin lymphoma enrolled from 2015-2020 at 8 academic medical centers in the US. Pts with LBCL were included in this analysis if they had received R-miniCHOP or a regimen that did not include an anthracycline (nonAC). NonAC regimens included R-CVP, BR, rituximab, radiation and lenalidomide and rituximab. Pts completed the Vulnerable Elders Survey (VES-13) and were considered vulnerable if they had a score >3. Event-free survival (EFS) was defined as the time from start of treatment until progression/relapse, retreatment, or death due to any cause; EFS at 24 months (EFS24) was a secondary endpoint. Overall survival (OS) was defined as the time from start of treatment until death due to any cause. EFS and OS for R-miniCHOP and non-IC groups, as well as vulnerable and not vulnerable by VES-13 were estimated using Cox models. Results A total of 190 pts received R-miniCHOP (N=139) or nonAC (N=51). R-miniCHOP-treated pts were older (median 82 vs 72 yrs) and more commonly female (55% vs 35%). The majority in both groups (86% vs 78%) received their treatment at a LEO center and did not receive therapy on a clinical trial (89% vs 100%). Most pts receiving R-miniCHOP had high-intermediate (32%) or high (30%) international prognostic index (IPI) score, while both high-intermediate (22%) and high (20%) IPI were lower in the nonAC-treated pts. Cell of origin was determined by immunohistochemistry as available clinically, with GCB 42% vs 31%, non-GCB 32% vs 29%, and not done/unknown 26% vs 39% in R-miniCHOP vs nonAC pts. Double-hit status by FISH was known in 115 pts and was positive in 13% of R-miniCHOP pts and 10% of nonAC pts. The diagnosis-to-treatment interval (DTI) was ≤14 days in 30% of R-miniCHOP pts and 24% of nonAC pts. Of pts who had a VES-13 score (N=119), vulnerable status trended higher in the R-miniCHOP (66%) vs the non-IC group (50%; p=0.15). With a median follow-up of 50.5 months, the median EFS was 37.1 months and median OS was 50.0 months. R-miniCHOP, compared with non-IC, was associated with improved EFS (unadjusted HR=0.54, 95% CI 0.36-0.81; p=0.003) and OS (unadjusted HR=0.58, 95% CI 0.38-0.88; p=0.011). When adjusted for age, IPI, LBCL subtype (diffuse large B-cell lymphoma, not otherwise specified vs other), DTI and VES-13, R-miniCHOP was strongly associated with improved EFS (HR=0.26, 95% CI 0.14-0.50; p<0.001) and OS (adjusted HR=0.29, 95% CI 0.15-0.57; p<0.001). EFS24 rate was 56% in all pts and was superior in pts treated with R-miniCHOP vs non-IC (62.7% vs 34.1%; p=0.001). In the R-miniCHOP group, vulnerable status (adjusted for IPI) was associated with inferior OS (HR=2.22, 95% CI 1.09-4.50; p=0.028) and trended towards inferior EFS (HR=1.76, 95% CI 0.93-3.32; p=0.083). In a competing-risk cumulative-incidence analysis, lymphoma was the leading cause of death for pts receiving R-miniCHOP at 2 (0.16, 95% CI 0.11-0.24) and 5 (0.20, 95% CI 0.14-0.28) yrs, as well as for those receiving non-IC at 2 (0.35, 95% CI 0.24-0.53) and 5 (0.38, 95% CI 0.26-0.56) yrs. Treatment-related mortality was similar in both groups. In the R-miniCHOP group, the 2-yr (0.20 vs 0.03) and 5-yr (0.20 vs 0.11) lymphoma-related mortality was higher in pts who were vulnerable vs not by VES-13, while there were no differences for mortality due to therapy or other causes by vulnerable status. Conclusions These data support R-miniCHOP as a curative regimen in older and frail pts with the majority achieving EFS24. R-miniCHOP compared to non-IC use is strongly associated with improved EFS and OS when adjusted for disease and patient related variables. Within the R-miniCHOP group, vulnerable status is associated with inferior OS. Additional research efforts are needed to optimize outcomes for this group of pts.

Abstract Background: Rural/nonmetropolitan (nonmetro) counties face known barriers to comprehensive cancer care compared with metropolitan (metro) counties, which may impact the outcomes for lymphoma patients. We evaluated the impact metro vs nonmetro status on outcomes after a diagnosis of non-Hodgkin lymphoma (NHL) in the context of clinical, demographic, and lifestyle factors. Methods: Of 7724 participants enrolled in the prospective LEO cohort study from 2015-2020, 7610 (98.5%) had their county of residence at diagnosis assigned a RUCC (2013) code. We compared outcomes of participants from metro (defined as RUCC 1-3, which are central counties with ≥1 urban areas of ≥50,000) vs nonmetro counties (RUCC 4-9, which are counties with smaller urban areas as well as completely rural). We estimated hazard ratios (HRs) and 95% confidence intervals (CI) from univariable and multivariable Cox models for associations of metro status with overall survival (OS). Cause of death (lymphoma [including treatment related], non-lymphoma, unknown) was assessed using a competing risk approach. Results: Compared with metro counties (N=6096), LEO participants from nonmetro counties (N=1514) were older (median age 64 vs 62 years; p<0.001), more likely to be non-Hispanic white (94% vs 75%; p<0.001) and married (84% vs 75%; p<0.001), and less likely to have completed graduate or professional school education (16% vs 27%; p<0.001). There were no notable differences (>5%) by metro status for sex, employment status, NHL subtype, stage, performance status, abnormal lactate dehydrogenase (LDH), international prognostic index (IPI), number of comorbidities, time from diagnosis to treatment interval (DTI) or participation in a clinical trial. Compared with LEO participants from metro counties, those from nonmetro counties had inferior OS at 5 years (74.5% vs 78.4%; HR=1.23, CI 1.10-1.37; p<0.001). The OS association only slightly attenuated after adjustment for age, sex, race/ethnicity and NHL subtype (HR=1.20, CI 1.07-1.34; p=0.002), and held in models that adjusted for clinical prognostic factors (stage, NHL subtype, IPI, DTI), socioeconomic status (SES; education, marital status), health status (comorbidity, frailty), or lifestyle factors (smoking, body mass index). Using a competing risk model, the cumulative incidence of death at 5 years due to lymphoma (16.9% vs 14.1%; p=0.002) and non-lymphoma (5.9% vs 3.9%; p=0.002) was higher for participants from nonmetro vs metro counties, respectively. For participants <65 years, nonmetro vs metro status had inferior OS (HR=1.40, CI 1.17-1.67; p<0.001). This association remained after adjustment for age, sex, race/ethnicity and NHL subtype (HR=1.36, CI 1.14-1.63; p<0.001), as well as after adjustment for clinical prognostic, SES, health status, or lifestyle factors. The cumulative incidence of death at 5 years due to lymphoma was higher in participants from nonmetro vs metro counties (15.1% vs 11.5%; p=0.002), while there was no difference by metro status for non-lymphoma related deaths (2.1% vs 1.7%; p=0.47). In contrast, for participants age 65+ years, there was no differences by metro status for OS (HR=1.04, CI 0.91-1.20; p=0.56). After adjustment for age, sex, race/ethnicity and NHL subtype, participants from nonmetro areas had inferior OS (HR=1.12, 0.97-1.29) although this was not statistically significant (p=0.13), and was attenuated in models adjusting for clinical, health status, or lifestyle factors. The cumulative incidence of death at 5 years due to lymphoma was no different in participants from nonmetro vs metro counties (18.9% vs 18.0%; p=0.37), while non-lymphoma related deaths were higher in nonmetro counties (9.9% vs 6.8%; p=0.017). Conclusion: LEO participants from nonmetro vs metro counties had inferior OS overall, although this was predominately observed for younger (<65 years) participants. These associations did not appear to be explained by demographic, NHL subtype, clinical, SES, health status, or lifestyle factors. Of particular note, the risk of death due to lymphoma was higher in nonmetro areas for participants <65 years but not those 65+ years, while the risk of death due to other causes was higher in nonmetro areas for participants 65+ years but not those <65 years. These findings require further study, particularly related to barriers to care, and suggest the potential need for age-specific strategies to optimize outcomes for NHL patients from nonmetro/rural areas.

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.