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Abstract Background Primary plasma cell leukemia (pPCL) is a rare and aggressive variant of multiple myeloma (MM), characterized by the presence of more than 5% circulating plasma cells on a peripheral blood smear. Despite advancements in therapy, including novel agents and autologous stem cell transplantation (ASCT), pPCL remains associated with markedly poorer survival outcomes compared to newly diagnosed MM. Although disease progression is common in pPCL, individual courses vary widely upon relapse and thereafter. We aim to describe the natural history of pPCL, focusing on clinical features and survival outcomes at the time of relapse or disease progression. Methods Patients with pPCL who were followed at our institution's cancer center between 2006-2024 were included for retrospective analysis. The electronic health record was reviewed to provide detailed information on patient demographics, disease characteristics, treatment regimens, and clinical outcomes. Time to next treatment (TTNT) and overall survival (OS) analysis were performed using the Kaplan-Meier method. Statistical analyses were performed using the SAS biostatistical software JMP 17.0.1 (SAS Institute Inc). Results We analyzed a cohort of 106 patients with relapsed pPCL after first-line therapy, all of whom received induction with novel agents. To date, 64 patients (60%) have died. Across the entire cohort, median OS is 39 months (mos) (95% CI: 25-68). 59 patients (56%) were diagnosed after 2015. Baseline FISH cytogenetics were available for 100 patients; 57 (57%) had one or more high-risk cytogenetic abnormality. Nearly all patients (96%) had ≥50% clonal plasma cells on initial bone marrow biopsy. While most patients (n = 61; 58%) were planned to undergo upfront ASCT, 20 (33%) experienced disease progression during induction therapy and required a more intensive salvage regimen (often infusional chemotherapy) prior to ASCT. The median TTNT after first-line therapy (TTNT#1) for the entire cohort was 10.4 mos (95% CI: 8–14). The median TTNT after second-line therapy (TTNT#2) for the entire cohort was 5.7 mos (95% CI: 4.3–7.1). Clinical details at first relapse, prompting initiation of second-line therapy, were available for 91 patients. Of these, 26 patients (29%) had symptomatic relapses—due to CRAB features or extramedullary disease—while 65 patients (71%) experienced asymptomatic biochemical progression. Symptomatic relapses were followed by significantly shorter TTNT#2 (3.9 vs. 7.0 mos; p = 0.039) and inferior OS from the start of second-line therapy (7.5 vs. 31.2 mos; p <0.0001) compared to asymptomatic relapses. The median TTNT#2 for patients who relapsed during induction and received salvage ASCT was 6.9 mos (n=20). In contrast, those treated after relapse with non-ASCT regimens (n = 86) fared worse; those receiving novel agent-based combinations, including doublets, triplets, or quadruplets (n=64) had respective median TTNT#2 of 3.3, 6.0, and 3.3 mos. Patients treated with infusional chemotherapy (n = 9) had the poorest outcomes, with a median TTNT#2 of just 1.4 mos. The median TTNT diminished with each subsequent line of therapy: TTNT#3 (n = 73) was 5.8 mos, TTNT#4 (n = 53) was 4.0 mos, and TTNT#5 (n = 35) was 2.6 mos. Patients with pPCL harboring the t(11;14) cytogenetic abnormality who were treated with venetoclax-based regimens (n = 8) during any line of therapy had a longer corresponding median TTNT of 15.0 mos. Additionally, 23 patients received anti-BCMA CAR-T cell therapy as a post-relapse line of therapy. At last follow-up, 15 of these patients (65%) had not relapsed, and after a median 20.7 mos of follow-up, the median TTNT following CAR-T cell therapy had not yet been reached. Patients who received CAR-T after 1-3 prior lines (n=15) had a median TTNT that was not reached; those who had received 4 or more prior lines (n=8) had a median TTNT of 20 mos. ConclusionsDespite the use of novel agent-based combination regimens and ASCT as first-line therapy, most patients with pPCL eventually experience disease progression. Consistent with MM, symptomatic relapse in pPCL is associated with poorer outcomes compared to asymptomatic biochemical progression. Additionally, the duration of response shortens with each successive line of therapy. Notable exceptions include venetoclax-based regimens in patients with t(11;14), and anti-BCMA CAR-T cell therapies: each appear to confer more durable responses than historical treatments in patients with relapsed pPCL.

Abstract Background: Splenic Marginal Zone Lymphoma (SMZL) is a rare B-cell lymphoma with heterogeneous clinical behavior. Although typically indolent, survival outcomes are modestly inferior to those of other indolent lymphomas, with 5-year overall survival (OS) rates of 70–80% compared to 85–95% in follicular or nodal marginal zone lymphoma. Additionally, 5–10% of patients present with aggressive disease, highlighting the need for better prognostic tools and treatment strategies. While rituximab (RTX) has become central to SMZL management, often replacing splenectomy as first-line therapy, it remains unclear whether survival outcomes have improved during this era of increased RTX use. We conducted a national analysis to characterize treatment patterns, prognostic factors, and survival trends over time. Methods: We conducted a retrospective cohort study of SMZL cases diagnosed between 2004 and 2020 using the National Cancer Database (NCDB). Descriptive statistics characterized baseline features. OS was estimated via Kaplan-Meier methods and compared using log-rank tests. Cox proportional hazards models assessed prognostic factors. To evaluate changes in survival over time, we stratified cases by year of diagnosis into early (2004–2009), mid (2010–2014), and recent (2015–2020) RTX-era cohorts. Differences in survival between eras were compared using the log-rank (Mantel–Cox) test. Results: Among 7,228 patients with SMZL, treatment data were available for 7,176 (99.2%). Median age at diagnosis was 69 years (IQR: 60 to 77), with 4.9% identifying as African American. Of 4,167 patients with stage data, 64% had advanced-stage (III or IV) disease. Among patients with available risk scores, 37% were classified as high-risk by IPI (4-5) and 43% had a Charlson-Deyo (CD) comorbidity score of 3 or higher. Treatment patterns included splenectomy alone in 1,381 patients (19%), RTX monotherapy in 2,068 (28.5%), and combined RTX and splenectomy in 3,727 (51.9%). Chemotherapy was administered to 1,834 patients (25%), radiation to 29 (0.4%), and autologous transplant to 3. Treatment modalities overlapped due to multimodal approaches; Patients undergoing splenectomy tended to be younger (≤65 years), have earlier-stage disease, lower CD scores, and low-risk IPI (all p < 0.001). Sixty-eight percent received care at academic centers. Median follow-up was 130 months (95% CI: 123.2 to 136.4). Three- and five-year OS rates were 81.5% and 73.6%, respectively. Despite increased RTX use over time, no significant improvement in OS was observed across eras (log-rank p = 0.35). Survival varied significantly by treatment strategy (p < 0.001). Patients who received neither RTX nor splenectomy had the poorest outcomes, with a median OS of 19.3 months (95% CI not estimable to 70.7). Splenectomy alone was associated with the longest median OS of 148.8 months (95% CI: 137.9 to 159.7), though this likely reflects favorable patient selection. Median OS was not reached for RTX monotherapy patients, suggesting similarly favorable, if not superior long-term outcomes. Combined RTX and splenectomy were associated with similarly prolonged survival (median OS 119.4 to 120.6 months). Addition of chemotherapy in sequential treatment did not significantly affect OS (121 vs. 131 months; p = 0.07). On multivariable analysis, factors independently associated with inferior OS included older age at diagnosis (HR 1.07; 95% CI: 1.06–1.08; p < 0.001) and higher CD comorbidity score (HR 1.29; 95% CI: 1.18–1.42; p < 0.001). In contrast, female sex (HR 0.66; 95% CI: 0.56–0.78; p < 0.001), treatment at an academic center (HR 0.84; 95% CI: 0.71–0.99; p = 0.04), and receipt of RTX (HR 0.48; 95% CI: 0.32–0.74; p < 0.001) were associated with prolonged OS. Conclusion: In this large national cohort of SMZL, receipt of RTX, alone or with splenectomy, was associated with improved OS. Favorable prognostic factors included younger age, female sex, lower comorbidity burden, and treatment at academic centers. However, despite greater RTX use over time, population-level survival in the recent RTX era has not significantly improved, likely reflecting poor outcomes in relapsed or refractory disease. These findings highlight the need to optimize frontline therapy and develop novel strategies to improve long-term outcomes in SMZL.

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 Background Red blood cell distribution width (RDW) is an easily accessible diagnostic test that is underutilized as a prognostic marker, despite substantial supporting evidence in cancer, cardiovascular diseases, and helathy individuals (Pilling et al. PLoS One 2028;13:e0203504). The association between increased RDW and incident acute myeloid leukemia (AML) has long been suggested in healthy volunteers (Abelson et al. Nature 2019;559:400). We looked into a similar phenomenon in patients with polycythemia vera (PV) or essential thrombocythemia (ET) in large discovery and validation cohorts. Methods A machine learning (ML) approach was used to identify baseline clinical and laboratory parameters that were predictive of leukemic transformation (LT) and develop a predictive model in a large discovery cohort of PV and ET, obtained from electronic medical records of the Maccabi Healthcare Services (MHS; Tel-Aviv, Israel). Receiver operating characteristic (ROC) curve analysis was utilized to determine the optimal cutoff points for RDW and other continuous variables. Mayo Clinic databases (Rochester, MN, USA) for patients with PV and ET were utilized as validation cohorts. Identification of study patients in the latter was according to the International Consensus Classification (Arber et al. Blood 2022; 140:1200) while in the discovery cohort was based on presence of ICD-9 codes associated with documentation of disease-specific driver mutations or treatment records that are consistent. Statistical analyses were performed using the R statistical software 4.4.2 (November, 2024) (Foundation for Statistical Computing, Vienna, Austria) or JMP Pro 18.0.0 software (SAS Institute, Cary, NC, USA). Results The discovery cohorts from Israel included 4,592 patients with PV (median age 63 yesrs; 53% males) and 5,968 with ET (median age 61 yesrs; males 40%). The validation cohorts from the Mayo Clinic included 633 PV (median 65 years; 51% males) and 634 ET (median 60 years; females 64%) patients that were informative for RDW. In the discovery cohorts, median follow-up (incident AML) was 6.1 years (N=186; 4.1%) in PV and 6.1 years (N=85; 1.4%) in ET. The corresponding values for the validation cohorts were 6.6 years (N=24; 3.8%) in PV and 7.0 years (N=22; 3.5%) in ET. Discovery cohort analyses Covariate-adjusted Cox regression analysis was utilized to estimate associations between LT and several clinical variables followed by machine learning pipeline to predict LT in a given timeframe. Conversion from continuous to binary variables was accompliched by ROC analysis. Shapley Additive exPlanations (SHAP) application enabled selection of top-ranked features that included RDW >15.5 (HR 3.2, 1.1-9.5; p=0.03), age >60 years (HR 2.9, 1.4-5.9; p<0.01), and LDH >1.5 x UNL (HR 4.0 (1.6-10.0; p<0.01). A similar analysis in ET also identified RDW >15.5 (p<0.01), age >60 years (p=0.01) as well as male sex (p=0.03) as independent risk factors for LT. Subseqent risk models based on these risk factors were externally validated and enabled robust risk stratification with 10-20 year AUCs rangening from 0.75 to 0.81. Validation cohorts analyses The indpendent predictive value of increased RDW observed in the discovery cohort was confirmed in the validation cohorts for both PV and ET and further gender-specified: female/male RDW ≥16.4/15.8 in PV (HR 7.9, 1.9-33.8) and ≥16.1/14.4 in ET (HR 5.1, 2.2-11.9). Also confirmed were the additional prognostic contributions of age ≥60 years (HR 3.8, 1.3-10.9) and LDH >1.5 x UNL (HR 3.9, 1.6-9.4), in PV, while no other clinical risk factor showed RDW-independent prognostic relevance in ET. The prognostic impact of RDW in ET was most apparent in females (p<0.01), as opposed to males (p=0.32) while the effect was equally significant in PV. In multivariable analysis that included previously recognized high risk mutations in PV (SRSF2) and ET (SF3B1), both RDW and mutations sustained significance (p<0.05). Conclusion The current study identifies higher RDW as a key risk factor for LT in both PV and ET, independent of other clinical or genetic risk factors. Possible underlying mechanisms include increased RDW as a marker of long-term pre-leukemic clones with sub-clinical ineffective erythropoiesis or an associated pro-leukemic inflammatory state.

Abstract Introduction Elevated levels of fetal hemoglobin (HbF) ameliorate sickle cell disease (SCD) manifestations. BEAM-101 is an investigational cell therapy comprising ex vivo base-edited autologous CD34+ hematopoietic stem and progenitor cells (HSPCs) that directly target the HBG1/2 promoters to disrupt BCL11A binding, switching production from sickle (HbS) to majority anti-sickling HbF. We present ongoing data from the BEACON study (NCT05456880), a Phase 1/2, single-arm, open-label study evaluating a single dose of BEAM-101 in individuals with SCD and severe vaso-occlusive crises (sVOCs). Methods Eligible patients were aged 12–35 years with SCD and ≥4 sVOCs in the 2-year period prior to informed consent. After mobilization with weight-based or tiered fixed-dose plerixafor, autologous CD34+ HSPCs were collected by leukapheresis and genetically modified with an adenine base editor. Following conditioning with pharmacokinetically adjusted myeloablative busulfan (target cumulative AUC 80 hr*mg/L), patients received a single dose of BEAM-101 (≥3.0×106 viable CD34+ cells/kg). Patients were then monitored for neutrophil and platelet engraftment, adverse events (AEs), total Hb, Hb fractions, % F-cells, hemolysis markers, sVOCs, and additional protocol endpoints for up to 24 months. Results As of June 16, 2025, enrollment has been completed and 46 patients have initiated mobilization. Of the 26 patients who have received BEAM-101, mean duration of follow-up was 6.2 (range 1.0–18.7) months. Baseline demographics were: age 18–34 years, 24 βS/βS genotype, 21 self-reported Black/African American, and 11 female. One patient, who successfully engrafted and obtained stable HbF levels >60%, withdrew consent 5 months post-infusion. For the 26 treated patients, the median number of stem cell collection cycles was 1 (range 1–4); 18 (69.2%) required a single cycle, 4 required 2 cycles, and 4 required >2 cycles. Target cell dose was achieved with a median of 3 (1–12) collection days. Patients received a mean BEAM-101 dose of 8.4 (range 3.2–23.4) ×106 viable CD34+ cells/kg. By the data cut, patients achieved neutrophil (n=26) and platelet (n=24) engraftment at a median of 18 (12–30) days and 19 (11–50) days, respectively, with a median duration of 7 (4–17) days of neutropenia. Of the 24 evaluable patients, 9 (37.5%) achieved platelet engraftment without requiring platelet transfusion through the transplant process. No patients had ≥Grade 3 AEs or serious AEs related to BEAM-101. One patient died due to respiratory failure, assessed as likely related to busulfan conditioning, 4 months post-infusion as previously reported. Mean total Hb increased to 12.1 (range 9.0–14.7) g/dL by Month (M) 1 (n=24), 15.6 (11.9–18.6) g/dL by M6 (n=11), and was sustained through follow-up. Four patients had total Hb levels above the normal range beyond M6 without any associated clinical manifestations or need for therapeutic intervention. Erythropoietin levels trended towards normal in all patients, including those with elevated total Hb. Mean endogenous HbF (HbF/[HbF+HbS]) was >60% and HbS was <40% by M1, which was sustained through last follow-up. At M6, mean % F-cells were 99.2% (97.0–99.9; n=10) and mean HbF/F-cell was 20.8 (18.0–23.9; n=9) pg, exceeding the protective threshold of 10 pg against sickling. Peripheral blood editing was at a mean of 68.5% by M3 (n=16), 69.6% by M6 (n=10), and 72.8% by M12 (n=5). Hemolysis markers and sickling parameters normalized or improved for all patients. No patients experienced any investigator-reported sVOCs post-engraftment. Conclusions The BEAM-101 treatment process is characterized by a low number of mobilization and collection cycles and high editing efficiency, resulting in rapid neutrophil and platelet engraftment and robust pancellular HbF expression, with durability observed up to 18 months. Additionally, there is a corresponding reduction in HbS levels to <40%, and improvements or resolution of hemolysis parameters and anemia, along with resolution of investigator-reported sVOCs post-engraftment. The safety profile of the BEAM-101 treatment regimen is consistent with busulfan conditioning, autologous HSCT, and underlying SCD. These results demonstrate the potential for base editing of the HBG1/2 promoters as a safe and effective therapeutic modality for the treatment of SCD that also has the potential to minimize hospitalization and treatment process burden for patients, families, and sites.

Abstract Background: De novo secondary central nervous system (CNS) lymphoma (SCNSL), characterized by concurrent systemic and CNS aggressive B-cell lymphoma at diagnosis, is a rare entity with a dismal prognosis. The prognostic significance of the initial anatomical compartment of CNS involvement (parenchymal vs. leptomeningeal) is not well-defined. We sought to analyze outcomes based on CNS localization in a single-institution cohort. Methods We retrospectively reviewed 34 patients with de novo SCNSL (including diffuse large B-cell lymphoma [DLBCL], high-grade B-cell lymphoma, not otherwise specified (HGBCL NOS), and double-/triple-hit lymphoma) treated at the Mayo Clinic between 2002 and 2025. Clinicopathological features, radiologic findings, treatment details, and survival outcomes were abstracted from the medical records. Patients were categorized by the primary site of CNS involvement. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method, and groups were compared with the log-rank test. Results The study cohort had a median age of 61.5 years (range 19-79) and a median International Prognostic Index score of 3 (range 2-4). Pathological subtypes included double-/triple-hit lymphoma (n=14, 41.2%), non-germinal center B-cell like (non-GCB) DLBCL (n=11, 32.4%), germinal center B-cell like (GCB) DLBCL (n=8, 23.5%), and HGBCL NOS (n=1, 2.9%). Among patients with available data, 14 (43.8%) were positive for MYC rearrangement, 13 (54.2%) for BCL2 rearrangement, and 10 (45.5%) for BCL6 rearrangement. First-line regimens received by patients included MR-CHOP (n=18, 52.9%), DA-R-EPOCH (n=5, 14.7%), combined CODOX-M/IVAC (n=4, 11.7%), R-CHOP with intrathecal methotrexate (n=3, 8.8%), miscellaneous therapies (n=3, 8.8%), and MRT (n=1, 2.9%). The complete response rate was 58.8% (n=20). Intrathecal chemotherapy was administered to 61.8% of patients, and consolidation with autologous stem cell transplant was performed in 35.3%. Based on the CNS compartment involved, de novo SCNSL (DN-SCNSL) were classified into two subtypes: the leptomeningeal subtype, defined as leptomeningeal involvement with or without parenchymal CNS disease (LM-DN-SCNSL; n=22, 64.7%), and the parenchymal subtype, defined as parenchymal-only CNS involvement (P-DN-SCNSL; n=12, 35.3%). Parenchymal disease was multifocal in 75% of cases, supratentorial in 58.3%, and associated with a midline shift in 30%. Although no tested factors (including pathological subtype, age, sex, and bone marrow involvement) were significantly associated with the anatomical compartment, a non-significant trend was noted for BCL6 rearrangement to be more common in the leptomeningeal group (8/13, 61.5%) than the parenchymal group (2/8, 25.0%) (P = 0.18). Survival outcomes were analyzed for both anatomical and pathological classifications. For the parenchymal versus leptomeningeal cohorts, 2- and 5-year Overall Survival (OS) rates were 75.0% vs. 45.1% and 41.0% vs. 38.7%, respectively (P = 0.34). For Progression-Free Survival (PFS), the 2- and 5-year rates were 48.6% vs. 32.5% and 29.2% vs. 26.0%, respectively (P = 0.53). The 2-year OS rates by pathological subtype were 81.8% for non-GCB DLBCL, 45.8% for DHL/THL, and 37.5% for GCB DLBCL (P = 0.27). Survival outcomes (OS/PFS) were not significantly associated with patient age, sex, pathological subtype, or anatomical compartment. Conclusion DN-SCNSL can be anatomically classified into two subtypes: LM-DN-SCNSL and P-DN-SCNSL. While a prognostic trend favoring the parenchymal subtype was observed, the difference did not achieve statistical significance, a finding likely attributable to the small cohort size. This classification may hold clinical utility for guiding risk stratification, and larger studies are needed to validate these findings and identify the most optimal treatments for each subtype of DN-SCNSL.

Abstract Background: In R/R DLBCL/FL, T-cell engager therapy (TCET) using chimeric antigen receptor T-cell therapy (CART) or bispecific antibodies (BsAbs) are promising options. Patients (pts) with R/R disease post TCET experience dismal outcomes with overall survival (OS)< 5 months (mos). Lonca, an antibody drug conjugate (ADC) targeting CD19 (FDA approved for R/R DLBCL and beneficial in R/R FL) has been increasingly used post-TCET. RWDA of Lonca is limited, especially regarding: 1) impact of CD19 expression on activity, 2) adverse events (AEs) in non-clinical trial setting, and 3) impact of sequencing Lonca and TCET. Thus, we conducted a RWDA of Lonca efficacy and toxicity in R/R DLBCL and FL pre- and post-TCET. Methods: We conducted a multicenter retrospective study of R/R DLBCL or FL pts ≥18 years who received Lonca from 2017 to 2025 at 10 US academic sites. Demographic, pathological, treatment, and AEs were collected. Efficacy outcomes included overall response rate (ORR), complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD). Progression-free survival (PFS) and OS were analyzed by Kaplan-Meier method. CD19 expression by immunohistochemistry (IHC) and/or flow cytometry (FC) prior to Lonca administration was correlated to outcomes. Results: Among 120 pts (DLBCL n= 101, FL n=19), all but 2 pts received Lonca monotherapy. At a median follow-up of 6.1 mos, median PFS and OS were 2.6 mos and 6.7 mos, respectively for the entire cohort. For DLBCL, median age was 66 years (18-89). Median prior lines of therapy (LOT) were 4 (1-11). ORR was 37.7% (CR: 17%, PR: 20.7%), SD: 6%, and PD: 56%. Median PFS was 2.1 mos, and median OS was 5.8 mos. For FL, median age was 62 years (28-88). Median prior LOT was 6 (2-8). ORR was 49.4% (CR: 28%, PR: 21.4%), SD: 14%, and PD: 35.7%. Median PFS was 6.7 mos, and median OS was 6.8 mos. OS by best response (entire cohort) was 11.3 mos and 11.8 mos in those who had CR and PR, respectively, 10.6 mos in SD and 3.5 mos in those with PD. Lonca LOT (2nd-12th line) was not associated with improved OS (p=0.58). Bulky disease (>7.5 cm) was not associated with worse OS (p=0.07). PD to Lonca was associated with PD at 2nd line treatment (OR: 4.3; 95% CI: 1.7–10.9) and 3rd-line treatment (OR: 4.2; 95% CI: 1.5–11.5), elevated lactate dehydrogenase (OR: 1.9; 95% CI: 1.2–2.9), and each subsequent increase of extranodal sites >1 prior to Lonca (OR: 1.5; 95% CI: 1.04–2.1). Among pts with available CD19 status prior to Lonca administration, 28 were FC-positive and 22 were IHC-positive. Of the CD19 FC-positive pts (n=23), 22% (5/23) achieved CR, 26% (6/23) had PR, 8% (2/23) had SD, and 43% (10/23) developed PD. Of the CD19 IHC-positive pts (n=20): 15% (3/20) achieved CR, 20% (4/20) had PR, 5% (1/20) had SD, and 60% (12/20) developed PD. Among all CD19-negative pts (n=7), two achieved CR, one had SD, and four with PD. Any grade AE was seen in 84% of pts. Any grade ≥3 (G3) AE was seen in 62% of pts. Notable G3 AEs included: anemia (35%), lymphopenia (34%), neutropenia (21.6%), thrombocytopenia (20%), infection (17%), fatigue (9%), peripheral edema (5%), pleural effusion (4%), photosensitivity (2.5%), and pruritus (2.5%). Treatment discontinuation due to AEs occurred in 17% (n=21) of pts. Fifty-five pts (50 DLBCL, 5 FL) received both Lonca and CD19 directed CART (Pre-Lonca n=54; Post-Lonca n=1). There was no significant difference in PFS or OS between pts who received CART and those who did not (PFS: 2.7 mos vs 3 mos; OS: 7.4 mos vs 5 mos). BsAb was used in 41 pts (34 DLBCL, 7 FL) (Pre-Lonca n=30; Post-Lonca n=11). No significant difference in PFS or OS was observed between pts who received BsAb pre- or post-Lonca. There was also no significant difference in PFS between pts who received a BsAb (2.2 mos) and those who did not (2.9 mos), nor in OS.Conclusion: In this large RWDA of Lonca, pts who achieved any form of clinical response experienced a significantly longer OS than previously reported for heavily pre-treated pts. Lonca was predominantly administered after TCET; however, there was no significant difference in efficacy between pts who received CART and BsAbs and those who did not. CD19 positivity and earlier utilization of Lonca did not appear to have an impact on response rates. Our findings support a role for Lonca in the treatment of R/R DLBCL pts not candidates for TCET. This RWDA highlights the need to further investigate the sequencing of Lonca in R/R DLBCL and FL.

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 Pronounced disparities in pediatric B-lymphoblastic leukemia (B-ALL) outcomes by race and ethnicity persist in the contemporary era. Gaps in overall survival (OS) from initial diagnosis are wider than event-free survival, suggesting that post-relapse mechanisms may contribute. However, data on treatment and outcomes after relapse are lacking. In a large, multicenter, real-world cohort of children and young adults with high-risk 1st relapse of B-ALL, we sought to (1) define survival outcomes by race/ethnicity and (2) explore if differences in therapy utilization drive outcomes. Methods We conducted an analysis within the Retrospective Study of Contemporary Approaches to 1st Relapse in B-ALL (ReCALL-1) cohort, which includes patients <30 years who initiated 1st relapse therapy between 2018-2022. This analysis was restricted to patients treated at US centers for “high-risk” 1st relapse, defined as relapse for which hematopoietic cell transplant (HCT) is generally standard-of-care: Early relapse (medullary <36m; isolated extramedullary <18m), late relapse with persistent end of reinduction disease, Ph+ B-ALL or age ≥18 years. Patients with Trisomy 21, those who received cell therapy before relapse and those who died during reinduction were excluded. The primary exposure was race/ethnicity categorized as Hispanic, non-Hispanic Black (NHB), non-Hispanic White (NHW), and other/unknown. The primary outcome was OS from relapse. Multivariable Cox regression models were constructed to include other social drivers of health (SDOH; health insurance, preferred language) and disease characteristics. Results Of 479 patients in ReCALL-1, 311 from 31 centers met inclusion for this analysis (41% Hispanic, 7% NHB, 46% NHW, 5% NH-other/unknown). With a median follow-up of 47m, OS differed by race/ethnicity (log-rank p=0.017): Hispanic, 4y OS 59%; NHB, 37%; NHW, 68%. Compared to NHW patients, NHB patients had an increased hazard of death (HR 2.3, 95% CI 1.3-4.3, p=0.006), while Hispanic patients were more similar to NHW patients (HR 1.3, 95% CI 0.9-2.0, p=0.16). Adjustment for SDOH only marginally attenuated the risk for NHB patients (aHR 2.0, 95% CI, 1.1-3.7, p=0.031) and led to equivalent outcomes for Hispanic patients (aHR 0.9, 95% CI, 0.5-1.5, p=0.66). Adjusting for disease characteristics that differed by race/ethnicity at p<0.2 (time to relapse, Ph+, Ph-like, KMT2Ar, age ≥18, or relapsed infant ALL) did not diminish the risk for NHB patients (aHR 2.0, 95% CI, 1.1-3.7, p=0.032) while outcomes remained equivalent for Hispanic patients (aHR 1.2, 95% CI, 0.8-1.8, p=0.40). Point estimates of cumulative incidence of non-relapse mortality (NRM) were highest in NHB patients (Hispanic, 4y NRM 13%, NHB 22%, NHW 11%), but this trend was not statistically significant (Gray’s p=0.52). Only 17% of patients initiated therapy for relapse on a clinical trial with no differences observed by race/ethnicity. Most patients received definitive treatment for relapse with either CAR T cell therapy (CART) or HCT: 79% overall, 74% Hispanic, 91% NHB, and 83% NHW. CART and HCT were utilized equally (39% and 40%, respectively) and the proportion that received each therapy did not vary by race/ethnicity. Time to CART/HCT, external referral for treatment, receipt of investigational v commercial CART, and use of post-CART consolidative HCT revealed no differences by race/ethnicity. Of the 66 patients (21%) who did not receive cell therapy, 26 had planned for CART or HCT, but did not receive due to disease progression or NRM (n=24; 12 Hispanic, 10 NHW), or insurance barriers (n=2, both Hispanic). After HCT, OS was worse for NHB patients (log-rank p=0.03) with 4y OS of 42% v 85% for NHW and 75% for Hispanic. Post-CART, 4y OS was 40% for NHB v 59% for NHW and 51% for Hispanic, but this difference was not statistically significant. Conclusion In a large real-world cohort of children with high-risk 1st relapse of B-ALL, we found a two-fold increased hazard of death for NHB patients compared to NHW patients, even after adjustment for other SDOH factors and high-risk disease features. In contrast to previous studies of adult patients, children appeared to have equal access to cell therapies across races/ethnicities. We found that Hispanic patients, who comprised >40% of the cohort, had similar survival to NHW children, suggesting that availability of cellular and immunotherapies may be mitigating historically observed disparities for children with relapsed B-ALL.

Abstract Introduction: Patients diagnosed with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) exhibit an elevated risk of developing other cancers (OC) relative to the general population. Historically, chemoimmunotherapy (CIT) represented the cornerstone of CLL/SLL management. A systematic review of clinical trials of CIT for CLL that included 28 studies reported 352/3297 (12.6%) patients developed OC (Csanadi 2022). The introduction of targeted agents beginning in the mid-2010's, including Bruton tyrosine kinase inhibitors (BTKi) and BCL2 inhibitors, has shifted the standard of care toward these novel therapies. In this study, we determined the risk of OC in newly diagnosed CLL/SLL patients cared for at the US Department of Veteran Affairs (VA), The University of Texas MD Anderson Cancer Center, and Mayo Clinic in Rochester, MN. Methods: We identified patients with newly diagnosed CLL/SLL after 1/1/2016 using the VA Central Cancer Registry, MD Anderson, and the Mayo Clinic CLL Databases. The baseline clinical characteristics, CLL treatments, and the occurrence of OC were abstracted by electronic health record (EHR) review. Receipt of CLL directed therapy was categorized into a) CIT only; b) targeted therapy only; c) CIT and targeted therapy; and d) other (including monotherapy with monoclonal antibody therapy). The occurrence of OC was modeled using CLL treatment as a time-dependent variable. Prior and concurrent OC diagnosed within 3 months of CLL/SLL were excluded from analyses, to reduce ascertainment bias. Results: We identified 6844 patients with CLL/SLL who met inclusion criteria. Median follow up was 3.6 years (interquartile range [IQR] 1.9-5.8). The median age at diagnosis of CLL/SLL was 71 years (range, 23 - 102); most patients were white (81%) and male (90%). Although many patients had missing values, among those with available information, IGHV genes were unmutated in 884 (51%), CLL FISH panel showed del17 in 213 (7%), del11q in 389 (13%), trisomy 12 in 674 (23%), and del13q in 1508 patients (50%). A total of 2344 patients received CLL directed therapy during follow-up: 278 (12%) received CIT only, 1809 (77%) received targeted therapy (+/- monoclonal antibody), only 99 (4%) received CIT and targeted therapy and 150 (6%) monoclonal antibody therapy only. Among patients treated with targeted therapies, 950 (50%) received ibrutinib, 381 (20%) received acalabrutinib, 164 (9%) received zanubrutinib, 4 (<1%) received orelabrutinib, 280 (15%) received venetoclax, and 3 (<1%) received sonrotoclax. Other treatments included combinations of a covalent BTKi (cBTKi) and BCL2i in 52 (3%) patients, among others. A total of 583 patients were diagnosed with OC during the study period. Types of OC observed included neoplasms of the prostate (n=129, 22%), lung (n=118, 20%), hematologic malignancies (n=91, 16%), gastrointestinal tract (n=68, 12%), melanoma (n=66, 11%), kidney and bladder (n=44, 8%), head and neck (n=19, 3%), and other/unknown (n=48, 8%). Estimated risk of occurrence of OC was 4.2% (95%CI 3.8-4.8%) at 24 months and 9.7% (95%CI 8.9-10.6%) at 60 months after a diagnosis of CLL/SLL. Multivariable analyses demonstrated that older age (HR: 1.013, 95%CI: 1.00-1.021), male sex (HR: 1.6, 95%CI: 1.1-2.3), and receipt of CLL directed therapy (HR: 1.4, 95%CI: 1.2-1.7) were associated with an increased risk of OC. When considering different types of CLL directed treatments, those who received CIT with or without targeted therapies had the highest risk of development of OC (HR: 1.6, 95%CI: 1.2-2.1). Risk of OC were also increased for those who received CIT only (HR: 1.41, 95%CI: 0.97-2.05) and those who received targeted treatments alone (HR: 1.27, 95%CI: 1.02-1.58). Conclusion: In this large dataset of newly diagnosed patients with CLL/SLL in the past ten years, approximately 10% patients developed OC at 5 years. Receipt of CLL directed therapy was associated with a 40% increased risk of development of OC compared to those patients who did not receive therapy. The risk was highest among patients who received CIT with or without targeted therapy and was still elevated in those who received CIT only or targeted therapy only.