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Abstract Introduction: Pirtobrutinib, a highly selective non-covalent BTK inhibitor, demonstrated encouraging efficacy in Richter transformation (RT) of chronic lymphocytic leukemia (CLL) in the BRUIN trial (Wierda et al, Lancet Haematology, 2024). However, a control arm was not included in this phase 1/2 trial, and how pirtobrutinib compares to usual care is unknown. To address this gap of knowledge, we sought to compare efficacy outcomes in BRUIN to that in a control cohort consisting of RT patients treated with usual care at Mayo Clinic. Methods: The study was approved by the Mayo Clinic IRB. Patient-level data from BRUIN (n=79; investigator-assessed) were obtained from the study sponsor. Patients with histologically confirmed RT (large B-cell lymphoma) who received at least one line of therapy (n=230) were identified from the Mayo Clinic CLL Database. Multivariable logistic regression was employed to calculate propensity scores for baseline covariates (ie, age at RT treatment line, number of prior lines of CLL treatment [truncated at 3], number of prior lines of RT treatment [truncated at 3], and LDH). For each Mayo patient, propensity scores for each line of RT therapy were calculated, and the line with the highest propensity score was chosen as the index RT treatment line. Using the inverse probability treatment weighting (IPTW) methodology, individual weights were computed, and standardized mean differences (SMDs) were examined for each of the unadjusted and weighted baseline covariates to ensure that balance was obtained between BRUIN cases and Mayo controls. Overall survival (OS; the primary endpoint) and progression-free survival (PFS) were analyzed using unweighted and weighted Cox proportional hazards models. Unweighted and weighted overall response rates (ORRs) and complete response (CR) rates were analyzed using logistic regression. Results: The final analysis dataset contained 79 BRUIN cases (median age 67 [range 26-95], 66% male) and 204 Mayo controls (median age 69 [range 30-89], 74% male). The BRUIN cohort had more patients with ECOG PS ≥1 (61% vs 40%, p=0.001) and elevated LDH (81% vs 63%, p=0.003) than the Mayo cohort. The proportion of patients with TP53 aberration was not statistically different in both cohorts (57% vs. 44%, p=0.15). The index line of RT treatment in the Mayo cohort included chemoimmunotherapy (n=167, 80%) and novel agent-based therapy (eg, cBTKi, venetoclax, PI3Ki, immune checkpoint inhibitor, etc; n=42, 20%). Median lines of prior CLL therapy were 2 (IQR 1-4) vs 1 (IQR 0-3) in the BRUIN and Mayo cohorts, respectively; median lines of prior RT therapy were 2 (IQR 1-2) vs 0 (IQR 0-2). The SMDs of the weighted baseline factors met pre-determined criteria (-0.25≤SMD≤0.25), indicating that balance between the two cohorts was achieved. The median follow-up was 18.3 months (range 0.7-32.9) in the BRUIN cohort and 122.8 months (range 0-280.2) in the Mayo cohort. The unweighted median OS was 12.5 months (95% CI 7.0-20.6) in the BRUIN cohort and 5.7 months (95% CI 3.9-10.7) in the Mayo cohort. The unweighted HR was 0.76 (95% CI 0.54-1.07, p=0.12). After IPTW, the weighted HR was 0.63 (95% CI 0.50-0.78, p<0.001), significantly favoring the BRUIN cohort. The unweighted median PFS was 3.6 months (95% CI 2.8-5.1) in the BRUIN cohort and 3.1 months (95% CI 2.5-4.3) in the Mayo cohort. The unweighted HR was 0.98 (95%CI 0.72-1.34, p=0.92). After IPTW, the weighted HR was 0.78 (95% CI 0.64-0.95, p=0.01), again favoring the BRUIN cohort. Response was evaluable/available in 69 patients in BRUIN and 182 patients in Mayo cohort. The unweighted ORR was 58% vs 53% in BRUIN and Mayo cohorts, respectively (OR=0.83, 95% CI 0.47-1.45, p=0.51), and the CR rate was 16% vs 36% (OR=2.94, 95% CI 1.43-5.88, p=0.003). After IPTW, the weighted OR was 0.65 (95% CI 0.45-0.93, p=0.02) for ORR, favoring the BRUIN cohort, and 1.89 (95%CI 1.23-2.86, p=0.02) for CR rate, favoring the Mayo cohort. Conclusions: This individual patient-level IPTW-based analysis demonstrated that single agent pirtobrutinib is associated with improved OS, PFS, and ORR compared to usual care in patients with RT. These results support the choice of pirtobrutinib over traditional therapies for RT. Although these results are encouraging, the durability of response to pirtobrutinib remains suboptimal. Ongoing trials and other future research will evaluate the efficacy of pirtobrutinib in combination with other treatments in this setting.

Abstract Introduction: Isocitrate dehydrogenase (IDH) mutations are observed in ~20% of patients with acute myeloid leukemia (AML). In the U.S., ivosidenib (ivo) is approved with or without azacitidine (aza) in the frontline (FL) and as monotherapy in relapsed/refractory (R/R) IDH1-mutated (mut) AML. Olutasidenib (oluta) is approved as monotherapy for R/R IDH1-mut AML. Enasidenib (ena) is approved as monotherapy for R/R IDH2-mut AML. This study describes real-world IDH inhibitor (IDHi) administration patterns and evaluates their outcomes in on-label settings. Methods: A retrospective review of patients with IDH1/2-mut AML who received ivosidenib, olutasidenib, or enasidenib was conducted at 12 academic institutions in the U.S. Best response at any time during treatment, including complete response (CR) and complete response with partial hematologic recovery (CRh), were graded using European Leukemia Net (ELN) 2022 criteria. Results: A total of 387 patients with IDH1- and IDH2-mut AML were treated with an IDHi in the FL or R/R setting. Median follow-up was 9.6 months (range, 0.03-90.7). Demographics include 79% White, 14% Black, 3% Asian, and 4% other/unknown race; 5% were Hispanic ethnicity; 46% were female; the median age was 70 years (range, 28-95). 70% had an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, 26% had secondary AML, and 10% had therapy-related AML. Per the ELN 2024 less-Intensive risk classification, 58% were favorable risk, 29% intermediate, 7% adverse, and 6% unknown. Overall, 209 of 387 patients (54%) received IDHi regimens on-label. In FL IDH1-mut AML (n=45), 11 received ivo monotherapy, 25 aza/ivo, and 9 used off-label combinations: 3 hypomethylating agent (HMA) + venetoclax (ven) + ivo, 5 decitabine/ivo, 1 intensive chemotherapy (IC)/ivo. Among R/R IDH1-mut AML (n=109), 47 received ivo monotherapy, 7 oluta monotherapy, and 55 off-label (31 HMA/ivo, 16 HMA/ven/ivo, 3 IC/ivo, and 5 other). 44 received off-label ena for FL treatment of IDH2-mut AML (25 ena monotherapy, 9 HMA/ena, 8 HMA/ven/ena, and 2 IC/ena). In R/R IDH2-mut AML (n=189), 119 patients received ena monotherapy and 70 received off-label combinations (25 HMA/ena, 30 HMA/ven/ena, 7 IC/ena, 6 ena/gilteritinib, and 2 other). In on-label treatment of FL IDH1-mut AML, one of four patients with response assessment of FL ivo monotherapy had a CR/CRh. Of 19 patients with response assessment on FL aza/ivo, 13 patients (68.4%) had a CR as best response (95% CI, 46.0-84.6%). Median OS was 14.9 mo (95% CI, 4.17-NR) for ivo monotherapy (n=11) and 31.9 mo (95% CI, 9.1-NR) for aza/ivo (n=25), with 0 and 2 patients receiving allogeneic stem cell transplant (allo-SCT), respectively. In R/R IDH1-mut AML, the rate of CR/CRh was 35.5% (95% CI, 21.1-53.1) for on-label ivo monotherapy. All 4 patients with response assessment for on-label oluta monotherapy had a CR. Median OS was 14.0 mo (95% CI, 10.1-22.4) for ivo monotherapy and NR for oluta monotherapy (95% CI, 10.1-NR), with 10 and 0 receiving allo-SCT, respectively. The CR/CRh rate for ivo was 38.1% (8 of 21 assessed; 95% CI, 20.8-59.1) in age < 70, and 30.0% (3 of 10 assessed; 95% CI, 10.8-60.3) in age ≥ 70. Median OS was 15.2 mo (95% CI 9.3-NR) in age < 70 (n=27) and 10.4 mo (95% CI 8.0-18) in age ≥ 70 (n=20). In R/R IDH2-mut AML, the rate of CR/CRh for on-label ena monotherapy was 38.2% (95% CI, 27.6-50.1). Median OS was 12.1 mo (95% CI, 8.2-16.6), with 5 having received allo-SCT. In demographic subgroups for ena monotherapy, 52 non-Hispanic White (NHW) patients with response assessment had a CR/CRh rate of 42.3% (95% CI, 0.30-0.56). Only 1 of 13 non-Hispanic Black (NHB) patients with response assessment had a CRh (7.7%; 95% CI, 1.4-33.0) as best response, with none attaining CR. Median OS was 13.7 mo (95% CI 10.3-26.3) in NHW (n=82), 11.2 mo (95% CI, 6.1-NR) in NHB (n=18), and 69.1 mo (95% CI, 52.6-NR) in Hispanic patients (n=8). The CR/CRh rate was 48.6% (17 of 35 assessed; 95% CI, 33.0-64.4) for age < 70, and 27.3% (9 of 33 assessed; 95% CI, 15.1-44.2) for age ≥ 70. Median OS was 12.0 mo (95% CI, 9.9-22.1) in age < 70 (n=48) and 5.8 mo (95% CI, 4.1-8.7) in age ≥ 70 (n=69). Conclusion: Practice patterns for IDH inhibitors in AML vary considerably, with high amounts of off-label use. Response rates for ivosidenib and enasidenib in the real-world setting are comparable to those of clinical trials. Descriptive analyses of demographic subgroups highlight areas in need of further research.

Aerosol viral transmission monitoring enables early, noninvasive detection of infectious disease spread by identifying airborne viral particles in shared environments. Integrating sampling, sensing, and data analysis, this perspective outlines an integrated framework for transforming epidemic responses from reactive testing to proactive surveillance. It synthesizes current technological advances and deployment experiences to identify key challenges in detection efficiency, data management, and societal trust. This marks a shift from clinical diagnosis to environmental surveillance, transforming epidemic responses from testing individuals to monitoring shared air. By enabling earlier interventions, these systems help reduce transmission, protect vulnerable groups, and limit disruptions to daily life and the economy.

Abstract Introduction: Patients (pts) with soft tissue plasmacytomas noncontiguous with bone (true extramedullary disease [EMD]) have poor outcomes with standard therapies shown by low overall response rates (ORRs), which are not durable. Talquetamab (Tal; anti-GPRC5D×CD3) and teclistamab (Tec; anti-BCMA×CD3) are first-in-class bispecific antibodies (BsAbs) approved as monotherapies for triple-class exposed (TCE) relapsed/refractory multiple myeloma (RRMM). Primary analysis from the RedirecTT-1 (NCT04586426) dedicated phase 2 EMD cohort (March 2025 data cut; median follow-up [mFU] 12.6 mo) showed Tal + Tec elicited an ORR of 78.9% (assessed by independent review committee) and a 12-mo progression-free survival (PFS) of 61.0%. Here, we report updated efficacy, using investigator assessment, and safety results from the phase 2 RedirecTT-1 EMD cohort with Tal + Tec. Importantly, we report EMD location and a novel analysis of tumor burden as a prognostic indicator of ORR. Methods: Pts had TCE RRMM and true EMD defined as ≥1 nonradiated soft tissue plasmacytoma noncontiguous with bone ≥2 cm in 1 dimension (with or without paramedullary plasmacytomas). Nonsecretory/oligosecretory disease was permitted. Prior CAR-T and non-BCMA/-GPRC5D BsAb therapies were permitted. Pts received Tal 0.8 mg/kg + Tec 3.0 mg/kg Q2W, preceded by step-up doses, with a permitted switch to monthly dosing at investigator's discretion after cycle 6 or after cycle 4 with confirmed ≥VGPR. Response was assessed per IMWG; EMD response was assessed by PET-CT or MRI whole-body scans. Tumor burden was assessed by total EMD tumor volume. Results: As of July 2025, 90 pts received Tal + Tec, with a median follow-up of 16.3 mo (range 0.5–23.7). Baseline characteristics were as previously reported; 39% had nonsecretory/oligosecretory disease, 20% had prior anti-BCMA CAR-T therapy, and 9% had prior BsAb therapy (all anti-FcRH5). The median number of plasmacytomas was 2 (range 1–7); 17 (18.9%), 29 (32.2%), and 74 (82.2%) pts, respectively, had ≥1 nodal, organ, or soft tissue EMD, while 11 (12.2%) also had ≥1 additional paramedullary plasmacytoma. Of 268 EMDs across all pts, 95 (35.4%) were nodal EMD, 77 (28.7%) were organ EMD (most commonly liver), and 64 (23.9%) were soft tissue EMD; 32 (11.9%) were paramedullary. Baseline EMD tumor volume was <25 cm2in 43 (47.8%) pts, 25–50 cm2 in 21 (23.3%) pts, and >50 cm2 in 26 (28.9%) pts. Per investigator assessment, ORR (95% CI) was 77.8% (67.8–85.9); 50.0% had a ≥CR. Median duration of response (DOR) was not estimable (NE; 12-mo DOR rate, 60.1%), 12-mo PFS was 55.6%, and median overall survival (OS) was NE (12-mo OS rate 73.8%). ORR was 90.7% (77.9–97.4; ≥CR 60.5%) in pts with EMD tumor volume <25 cm2, 66.7% (43.0–85.4; ≥CR 52.4%) for 25–50 cm2, and 65.4% (44.3–82.8; ≥CR 30.8%) for >50 cm2. Common adverse events (AEs) included CRS (77.8%; no grade [gr] 3/4) and neutropenia (72.2%; gr 3/4 62.2%). Taste changes (78.9%), non-rash skin AEs (68.9%), and nail AEs (55.6%) were all gr 1/2, and rash AEs (30.0%) were mostly gr 1/2. ICANS occurred in 11 (12.2%) pts (gr 3, 1.1%; gr 4, 1.1%). Infections occurred in 72 (80.0%) pts (gr 3/4 40.0%), most commonly upper respiratory tract infection (26.7%; gr 3/4 5.6%); IVIG was highly recommended to prevent and manage hypogammaglobulinemia and infection. Ten (11.1%) pts discontinued Tal + Tec due to treatment-emergent AEs (4 pts due to infections and 6 due to gr 5 AEs). Two pts discontinued Tal only due to AEs. In total, 11 (12.2%) pts had gr 5 AEs (6 due to infections), 6 of which were deemed to be drug related by investigators. Data will be updated with an additional 4 mo of follow-up for the presentation. Conclusions: With longer follow-up in pts with TCE RRMM with true EMD regardless of baseline tumor characteristics, Tal + Tec efficacy exceeded all approved therapies, including T-cell redirecting and cellular therapies, noting limitations of cross-study comparisons. Lower total EMD tumor volume was associated with a higher ORR but low pt numbers in each group and lack of statistical testing limits robust interpretation. The safety profile of Tal + Tec was generally consistent with each monotherapy; AEs were not exacerbated with the combination. These data continue to highlight the clinical benefit of the novel combination of Tal + Tec in pts with true EMD, a population with high disease burden and significant unmet need.

Abstract Background Despite CD19-directed chimeric antigen receptor T (CAR-T) therapy achieving remarkable remission rates in relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL), long-term survival remains constrained by T-cell exhaustion and immunosuppressive microenvironments. Dasatinib, a tyrosine kinase inhibitor (TKI), has been shown to alleviate T cell exhaustion and enhance CAR-T cell persistence, demonstrating therapeutic synergy in newly diagnosed ALL. However, it may also suppress CAR-T cytotoxicity and is ineffective against BCR-ABLT315I mutations. Third-generation TKIs, including ponatinib and olverembatinib, effectively overcome T315I-mediated resistance, yet their impact on CAR-T cell function and immune modulation remains insufficiently defined. Methods and Results: We first established in vitro co-culture models of CD19 CAR-T cells with the B-ALL cell line NALM6 to evaluate the effects of dasatinib, ponatinib and olverembatinib on resting and tumor antigen-activated CAR-T cells. At clinically relevant concentrations, none of the TKIs affected resting CAR-T viability. In contrast, upon activation, all three TKIs significantly inhibited CAR-T activation, cytotoxicity, and cytokine secretion (IL-2, TNF-α, IFN-γ), while reducing activation-induced CAR-T cell apoptosis. TKIs treatment also downregulated exhaustion markers (eg. PD-1, TIM3, LAG3) and promoted differentiation toward naïve (TN) and central memory (TCM) subsets, while reducing terminal effector T cells. After the drug elution, CAR-T cells regained their cytolytic function in response to tumor targets. Notably, ponatinib-treated CAR-T cells exhibited higher levels of IFN-γ, TNF-α and IL-2 post-washout compared to other groups. Importantly, the TN/TCM phenotype and low exhaustion marker expression were preserved after washout in all TKI-treated groups. Transcriptomic profiling of CAR-T cells in vitro revealed that all three TKIs downregulated key exhaustion-associated genes, including PDCD1, HAVCR2, CTLA4 and NR4A1, along with upregulation of stemness- and memory-associated genes (eg. CCR7, TCF7, LEF1, IL7R). Gene set enrichment analysis showed inhibition of T-cell activation, apoptosis, glycolysis, and TGF-β signaling by all TKIs. Remarkably, ponatinib uniquely activated the IFN-γ pathway, suggesting superior immunostimulatory effects. Mechanistically, all three TKIs suppressed the phosphorylation of AKT, p38 MAPK, and NF-κB p65, indicating shared inhibition of downstream TCR signaling. Based on these findings, we evaluated ponatinib in a clinical setting. A prospective study (No. ChiCTR2000036350) enrolled three R/R B-ALL patients with the BCR-ABLT315I mutation. All the patients received CD19 CAR-T cell therapy followed by ponatinib maintenance, initiated two months post-infusion. All three patients remained progression-free during ponatinib maintenance. Notably, the DNA copies of CAR-T cells remained detectable at months 5 and 9 after ponatinib treatment in two patients, respectively. To further explore the in vivo effects of ponatinib on T cells and other immune cells,peripheral blood mononuclear cells were collected from these patients before and one month after ponatinib initiation for single-cell RNA sequencing. Ponatinib exposure led to an increased proportion of CD8+T cells and a decreased abundance of myeloid cells subsets. Within T cells, effector cells expanded while Tregs and exhausted T cells decreased. Differential gene analysis showed suppression of activation, adhesion, apoptosis, and PD-1/PD-L1 signaling, aligning with in vitro results. Functional scoring revealed enhanced cytotoxicity, IFN-γ responses, and reduced glycolysis, exhaustion, TGF-β, and Treg signatures. Furthermore, analysis of NK cell subsets showed enhanced cytolytic scores and enrichment of proliferation and immune activation pathways, suggesting that ponatinib preserves innate immune responses in vivo. Conclusions: This study provides preclinical and preliminary clinical evidence that third-generation TKIs, particularly ponatinib, can effectively alleviate CAR-T cell exhaustion, promote memory phenotypes, and remodel the immune microenvironment. Compared to dasatinib and olverembatinib, ponatinib uniquely enhances effector cytokine production and activates the IFN-γ pathway. These findings support ponatinib as a promising combinatorial agent with CAR-T therapy, offering a rational strategy for improving outcomes in patients with T315I-mutated R/R B-ALL.

Abstract Background and Significance Diffuse large B-cell lymphoma (DLBCL) and other LBCLs account for 35–40% of non-Hodgkin lymphoma cases in North America, Europe, and East Asia. Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is the standard first-line treatment for DLBCL, achieving cure rates in approximately 60–70% of patients. However, 30–40% of patients will relapse or become refractory (R/R) to treatment, facing poor prognosis. Patients with high International Prognostic Index (IPI) scores (3–5) and those with IPI 1–2 who have bulky disease and/or very high lactate dehydrogenase (LDH) are recognized as high-risk (HR) subsets with suboptimal outcomes (Maurer et al, ASH 2023, #4512). Novel combination strategies are an area of focus for improving efficacy in this population. GOLCA is a potential, first-in-class, oral CELMoD agent designed for the treatment of lymphoma, with preferential distribution to lymphoid organs and enhanced activity in lymphoma cell lines. GOLCA drives the closed, active conformation of cereblon to induce rapid and deep degradation of Ikaros and Aiolos, leading to direct cell killing (agnostic of cell of origin [COO]) and immunomodulatory activity. In the Phase 1b study CC-220-DLBCL-001, GOLCA in combination with R-CHOP demonstrated a predictable and manageable safety profile with high rates of durable responses, irrespective of COO, in previously untreated aggressive B-cell lymphomas (BCL), including promising activity in HR patients (Amzallag et al, ASH 2024, #579). The median relative dose intensity for GOLCA and CHO components was high (97–99%), indicating uncompromised delivery of curative standard-of-care treatment and combinability. GOLCA ± rituximab has also shown encouraging efficacy and safety in patients with R/R DLBCL (Bachy et al, ICML, #148). These findings support the further study of GOLCA + R-CHOP combination in the Phase 3 setting. Study Design and Methods GOLSEEK-1 (NCT06356129) is a randomized, double-blind, placebo-controlled, Phase 3 study evaluating GOLCA + R-CHOP versus placebo + R-CHOP in patients with previously untreated HR LBCL. Approximately 850 patients with previously untreated LBCL will be randomized 1:1 to either GOLCA + R-CHOP or placebo + R-CHOP. Eligible patients include those with histologically confirmed LBCL per WHO 2022 criteria—including DLBCL (not otherwise specified [NOS], ABC/GCB), high-grade BCL with MYC and BCL2 rearrangements or NOS, T-cell/histiocyte–rich LBCL, or Epstein Barr Virus-positive DLBCL. HR status is defined by IPI ≥3, or IPI 1–2 with HR features: LDH >1.3× upper limit of normal and/or bulky disease (≥7 cm lesion). All patients must have measurable disease as defined by Lugano criteria. Key exclusion criteria are other lymphoma subtypes such as primary mediastinal LBCL; primary cutaneous DLBCL-leg type, grade 3b follicular lymphoma (FL); transformed indolent lymphoma; anaplastic lymphoma kinase (ALK) positive LBCL; primary effusion lymphoma; and Burkitt lymphoma and known or suspected central nervous system involvement. Randomization will be stratified by IPI score (HR 1–2 and 3 vs 4–5) and bulky disease status (≥7 cm vs <7 cm). After a screening period of ≤4 weeks, patients will receive either GOLCA (0.4 mg) or placebo orally once daily for 7 consecutive days in each of 6 cycles, combined with R-CHOP every 21 days. The primary endpoint is progression-free survival (PFS) by investigator assessment per Lugano Response Criteria. Key secondary endpoints include PFS in non–high-grade BCL, event-free survival, independently assessed complete metabolic response, undetectable minimal residual disease by PhasED-Seq (defined as undetectable circulating tumor DNA levels at end of treatment), and overall survival. Patients will be followed up for up to approximately 67 months after beginning treatment. This study is currently recruiting at 309 sites in 36 countries , across the United States, Europe, Latin America, and East Asia. Acknowledgement BMS Artificial Intelligence was used to revise existing text with human author oversight.

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 Background The benefit of high-dose chemotherapy and autologous stem cell transplantation (ASCT) as a consolidation strategy after initial chemotherapy in peripheral T-cell lymphoma (PTCL) is currently unclear, and a randomized trial (EA4232/PTCL-STAT) to answer this question is currently underway. Angioimmunoblastic T-cell lymphoma (AITL) is a rare, aggressive subtype of nodal PTCL with poor prognosis and unique features. Here, we report a large-scale, real-world evidence on the role of ASCT in frontline AITL management. Methods We analyzed a national cohort of 5,827 patients diagnosed with AITL between 2004 and 2020 from the National Cancer Database (NCDB). Baseline demographic, clinical, and socioeconomic characteristics were assessed. Treatment modalities included chemotherapy alone, chemotherapy with ASCT, and no treatment. Overall survival (OS) was evaluated using Kaplan-Meier method and multivariable Cox proportional hazards regression. Propensity score matching (PSM) was performed to validate ASCT's treatment effect. Results Among patients with complete treatment information (n = 5,224), the median age at diagnosis was 68 years (range 20–90). Frontline treatments included chemotherapy alone (68.6%, n = 3,584), chemotherapy with ASCT (14.6%, n = 761), and no treatment (16.8%, n = 879). Compared with patients who did not receive ASCT, those who underwent ASCT were significantly younger (median 60.0 vs 68.0 years), more frequently treated at academic centers (81.5% vs 57.9%, p < 0.001), and more likely to reside in areas with higher educational attainment (p < 0.001). They exhibited lower Charlson-Deyo comorbidity scores (CDS), with a higher proportion having a score of 0 (82.8% vs 73.6%, p < 0.001), and were more likely to have advanced-stage disease (93.0% vs 86.9%, p < 0.001). Furthermore, a higher proportion of patients who received ASCT were diagnosed in more recent years (p < 0.001). Sex, race, and IPI score distribution showed no significant baseline differences. Median follow-up time was 81.1 months (95% CI: 77.4–84.9), and the median OS was 23.3 months (95% CI: 21.3–25.2) for the entire cohort. For patients receiving chemotherapy with ASCT, the median OS was 139.2 months (95% CI: 104.2–174.2). In comparison, chemotherapy alone yielded a median OS of 23.6 months (95% CI: 21.4–25.8), while patients who received no treatment had a median OS of 4.0 months (95% CI: 2.7–5.2); overall p < 0.001. Median OS also significantly improved with more recent diagnosis eras: 20.1 months for patients diagnosed in 2004–2009 (95% CI: 16.8–23.4), 23.9 months for those diagnosed in 2010–2015 (95% CI: 21.0–26.7), and 26.7 months for patients diagnosed in 2016–2020 (95% CI: 23.1–30.4) (p < 0.001). Analyses consistently demonstrated longer median OS in female patients (27.5 vs. 20.7 months in males, p <0.001), and in patients treated at academic centers (27.5 vs. 16.4 months at non-academic centers, p < 0.001). Median OS varied by race (White: 24.0 months vs. Black: 15.2 months vs. Others: 30.3 months; p = 0.017). Patients with higher household income and higher educational attainment experienced significantly improved survival (p = 0.005 and p = 0.017, respectively). Patients with early-stage disease, lower IPI scores, and lower CDS also showed significantly longer survival (p < 0.001 for all comparisons). Multivariate Cox regression showed that chemotherapy with ASCT significantly reduced mortality risk compared to chemotherapy alone (HR = 0.438, 95% CI: 0.364–0.527, p < 0.001). No treatment significantly increased mortality risk (HR = 1.941, 95% CI: 1.634–2.305, p < 0.001). PSM analysis further validated that chemotherapy with ASCT significantly lowered mortality risk compared to chemotherapy alone (HR = 0.608, 95% CI: 0.503–0.736, p < 0.001), after matching for age at diagnosis, sex, race, income, education level, academic center, stage, CDS, and diagnosis era. Conclusion This large-scale, real-world analysis suggests that chemotherapy followed by ASCT is associated with significantly improved overall survival in patients with AITL, supported by unadjusted Kaplan-Meier analysis, adjusted multivariate Cox regression, as well as PSM analysis. These data support ASCT as an important consolidation strategy for AITL in real-world practice.

Abstract Background Primary central nervous system lymphoma (PCNSL) is a rare but aggressive non-Hodgkin lymphoma with limited prospective data to guide optimal therapy. This study evaluates real-world treatment patterns and survival outcomes using a large national cohort. Methods We analyzed data from the National Cancer Database (NCDB) for patients diagnosed with PCNSL between 2004 and 2020. Baseline demographics and treatment characteristics were analyzed using descriptive statistics. Survival outcomes were estimated using the Kaplan-Meier method and compared using log-rank tests. Multivariable Cox proportional hazards models were constructed to identify independent predictors of overall survival (OS). Results A total of 14,450 patients with PCNSL were included; 14,439 had first-line treatment data available, and 13,390 had survival data. Median age at diagnosis was 67 years (range 18-90), 49.2% were female, and 6.6% were African American. Chemotherapy alone was the modality of treatment for 81.6% (n=11,787), 12.2% (n=1,769) received chemoradiation, 3.8% (n=545) received chemotherapy and underwent autologous stem cell transplant (ASCT) but no radiation, and 2.4% (n=348) received radiation only. The median follow-up time was 73.5 months (95% CI 71.4-75.6), and the median OS for the group was 17.4 months (95% CI 16.2-18.6). Survival differed significantly by age group (median OS: <65 yrs, 46.1 months [95% CI 41.7 -50.6]; 65-79 yrs, 12.5 months [95% CI 11.2-13.7]; ≥80 yrs, 3.2 months [95% CI 2.9-3.5]; p<0.001), by year of diagnosis (median OS: 2004-2009, 11.0 months [95% CI 9.9-12.1]; 2010-2015, 20.0 months [95% CI 17.4-22.6], 2016-2020, 29.7 months [95% CI 26.0-33.4]; p<0.001), and by frontline treatment strategy (p<0.001). Patients treated with chemotherapy followed by ASCT had the longest median OS (not reached), while those receiving radiation alone had the poorest outcomes with a median OS of 3.9 months (95% CI 3.2-4.7); chemoradiation patients had a median OS of 31.8 months (95% CI 27.5-36.1), and chemotherapy only patients had a median OS of 13.9 months (95% CI 12.7-15.1)(p<0.001). African American patients had an inferior outcome with a median OS of 10.2 months [95% CI 7.2-13.1], compared to “other” races with a median OS of 36.9 months [95% CI 27.6-46.1] (p<0.001), although this is more similar to the median outcome for white patients (17.0 months [95% CI 15.8-18.3]). Treatment at an academic center (25.7 vs 11.0 months) and a high case-volume center (defined as >median number of cases per facility) (18.6 vs 10.5 months), and lower Charlson-Deyo comorbidity scores (CDS) (defined as CDS 0-1) (21.7 vs 6.8 months) were also associated with superior OS (p<0.001). In multivariable analysis, increasing age ( 65-79 y.o HR 1.60 [1.52-1.1.68], ≥80 y.o HR 2.95 [2.75-3.17]), CDS≥2 (HR 1.36 [1.28-1.44]), and African American race (HR 1.12 [1.02-1.24]) were adverse predictors of OS (all p<0.001), while treatment strategy (ASCT [HR 0.17], chemoradiation [HR 0.53], chemotherapy only [HR 0.68] compared to radiation alone), more recent year of diagnosis (2010-2015 [HR 0.81], 2016-2020 [0.70]), and treatment at an academic center [HR 0.81] remained predictors of superior OS (all p<0.001). Conclusion In this large national cohort of patients with PCNSL, treatment with chemotherapy followed by ASCT was associated with the most favorable survival outcomes. Patients treated with chemoradiation or multi-agent chemotherapy also demonstrated improved survival compared to those receiving radiation monotherapy or single-agent chemotherapy alone, respectively. Age, comorbidities, race, and treatment at academic centers were also significant independent predictors of OS. These findings highlight substantial disparities in outcomes and underscore the importance of optimizing treatment strategies, improving access to high-intensity therapies, and supporting timely referral to academic or high case-volume centers, particularly for younger and medically fit patients.

The emergence of state-of-the-art large language models (LLMs), which hold the ability to generalize to diverse natural language processing tasks, has led to new opportunities in health care. Oncology is especially well-suited to leverage these resources as the journeys of patients with cancer inherently yield extensive, longitudinal data sets comprising clinical narratives, pathology and radiology reports, and genomic sequencing reports. This review begins with an overview of the fundamental concepts behind LLMs, including the definitions, architecture, training paradigm, and performance optimization through prompt engineering and retrieval-augmented generation. We also take a moment to explore the newly emerging paradigm of LLMs in a multiagentic framework. We then synthesize current research on how LLMs may benefit stakeholders within the practice of oncology, including patients, oncologists, researchers, and learners. Finally, we address the limitations and risks of LLMs, including hallucinations, inherent biases, patient privacy, and clinician deskilling. While research thus far shows significant potential for LLMs to transform cancer care, necessary future directions include studies emphasizing patient stakeholder perspectives on LLM incorporation in clinical workflows, the development of relevant clinical benchmarks for LLM evaluation, a greater focus on real-world prospective testing, and deeper exploration of LLM reasoning capabilities.