Rosenthal, Allison

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 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.

Abstract Zanubrutinib is a second-generation Bruton Tyrosine Kinase (BTK) inhibitor, FDA-approved for Mantle Cell Lymphoma (MCL), designed to be more selective and potentially better tolerated than first-generation agents like Ibrutinib. Progressive multifocal leukoencephalopathy (PML), a rare but severe complication, has not previously been reported with Zanubrutinib. We report a 74-year-old woman with a germline CHEK2 mutation and asymptomatic MCL (CD5+, cyclin D1+, Ki67 10–20%) diagnosed in 2016, managed with surveillance. In 2023, she was also diagnosed with localized breast cancer treated with lumpectomy and exemestane. Later that year, she developed new headaches. Brain MRI revealed diffuse bilateral pachymeningeal enhancement, suspicious for lymphomatous spread, without parenchymal involvement. By early 2024, follow-up imaging showed stable pachymeningeal enhancement with new scattered punctate right frontal subcortical lesions, coinciding with systemic MCL progression. Spinal imaging revealed epidural and bone marrow involvement; CSF was negative for malignancy. Zanubrutinib was initiated in March 2024. By August 2024, new bilateral frontal and parietal fuzzy hyperintense and faintly enhancing white matter lesions emerged, while prior punctate lesions regressed. Biopsy confirmed PML with JC virus DNA by in situ hybridization and absence of B-cell clonality. Zanubrutinib was discontinued. Follow-up imaging showed regression of lesions without new enhancement, consistent with immune reconstitution. The initial subcortical punctate lesions remained stable. In 2025, she was diagnosed with localized pancreatic adenocarcinoma, precluding cytotoxic therapy initially due to concern for PML reactivation. However, as of May 2025, neuroimaging remains stable, and patient was started on palliative gemcitabine/paclitaxel. This is the first reported case of PML associated with Zanubrutinib. It underscores the importance of vigilance for PML even in patients without overt immunosuppression, especially those with overlapping malignancies and treatment exposures in the correct clinical context.

Abstract Secondary central nervous system lymphoma (SCNSL) is defined as the diagnosis of CNS lymphoma diagnosed concurrently with systemic lymphoma or after prior treatment. Due to the poor prognosis associated with SCNSL, the lack of randomized trial data, and the need for international consensus guidelines, there is a high unmet need for effective therapy options for SCNSL. Here we present safety and efficacy data on 2 SCNSL patients treated with the combination of emavusertib and ibrutinib. Both patients had directly progressed on their prior BTKi treatment. One patient achieved an unconfirmed complete response (CRu) and remained on treatment for over 4 mos, while the other patient maintained stable disease (SD) with a 38% reduction in disease burden from baseline and was on treatment for more than 8 mos. The patient with a durable SD, who received 5 prior lines of therapy along with an ASCT, presented with 3 related AEs Grade ≥ 3 that were reversible and manageable. These included elevated ALT, AST, and bilirubin levels that resolved. The patient received emavusertib 300 mg BID and ibrutinib 560 mg QD. The CRu patient received 6 prior lines of therapy and experienced CK elevation, fatigue, hypoglycemia, sepsis, urinary retention, neutropenia, and constipation that resolved with either a dose reduction and/or supportive care. The initial dose for this patient was 150 mg emavusertib BID and ibrutinib 560 mg QD. Subsequently, the dose of emavusertib was decreased to 150 mg BID due to Grade 4 neutropenia, then increased to 200 mg AM and 150 mg PM once resolved. This patient achieved CRu within 60 days on treatment. The 2 patients presented here are supportive data for using the combination of emavusertib and ibrutinib in SCNSL.

ABSTRACT Newly diagnosed patients with non‐Hodgkin lymphoma (NHL) often have a history of other diseases, and these comorbidities can impact patient treatment and management options, as well as overall survival (OS). We developed the Lymphoma Epidemiology of Outcomes (LEO) comorbidity index (LCI) as a sum of 10 comorbidities adapted from the Self‐Report‐Generated Charlson Comorbidity Index (SRG‐CCI) for use in the LEO cohort, a national prospective study of newly diagnosed NHL. Of the 5502 participants with self‐reported comorbidity data, 3107 (56.4%) were male and the mean age at diagnosis was 60.9 years (range, 18–99 years). The LCI ranged from 0 to 6, with 48.6% having 0, 30.2% having 1, 21.2% having 2 or more comorbidities. With a median follow‐up of 62.4 months among surviving participants, 2099 patients had an event and 1219 died. Continuous LCI similarly predicted both 1‐year mortality (c‐statistic = 0.654) and OS (c‐statistic = 0.655), while it showed a weaker but still statistically significant predictive ability for lymphoma‐specific (c‐statistics = 0.617) and event‐free (c‐statistic = 0.574) survival. Participants with 1 (HR = 1.21, 95% CI 1.05–1.39) and 2+ (HR = 1.80, 95% CI 1.56–2.08) comorbidities had inferior OS compared to those with no comorbidities after adjustment for age and sex (c‐statistic = 0.654), and performance strengthened after adjustment for the International Prognostic Index (c‐statistic = 0.672). LCI predicted OS most strongly in marginal zone (c‐statistics = 0.748) and weakest in T‐cell (c‐statistic = 0.579) lymphoma. The cumulative incidence of death due to lymphoma, lymphoma treatment, and other causes all increased with increasing comorbidities, with the greatest increase observed for death due to other causes. The LCI performs comparable to other published comorbidity indices, supporting its use in the LEO cohort to better model real‐world outcomes and more generally providing an approach to implementing comorbidity indices in cancer survivorship cohorts.

Evaluation of T-cell receptor (TCR) β-chain constant region 1 (TRBC1) expression is an alternative T-cell clonality assessment method. However, evaluation of TRBC1 immunohistochemistry (IHC) for distinguishing mycosis fungoides (MF)/Sezary syndrome (SS) from reactive inflammatory infiltrates in skin is incomplete. We evaluated the utility of a novel dual TRBC1-CD3 IHC stain in skin biopsies with MF/SS (n=40), reactive (n=24), or atypical T-cell infiltrates indeterminant for MF/SS (n=9). Twenty of 24 reactive cases showed clear polytypic TRBC1 expression (median percent TRBC1 positivity among CD3-positive T cells [%TRBC1+] 50% in dermis, 42.5% in epidermis among all cases), while 34/40 MF/SS were clearly monotypic (%TRBC1+ either ≤20% or ≥85%) (sensitivity 85.0%, specificity 91.7%, positive predictive value 94.4%, negative predictive value 78.6%). Discordance between TRBC1 expression and diagnosis was associated with few neoplastic/monotypic T cells and/or lack of physical separation between neoplastic and non-neoplastic populations. Among patch/plaque MF/SS, TRBC1 showed similar diagnostic sensitivity (80.0% vs. 86.7%) and high categorical correlation (monotypic vs. not monotypic, 80%) with TCR gene rearrangement results. TRBC1 interpretation was reproducible, with ≥2/3 and 3/3 pathologists rendering identical interpretations in 100% and 86% of cases, respectively, after independent review and 100% agreement following collective review. Digital image analysis confirmed visual %TRBC1+ accuracy ( r =0.9749, P <0.0001). On the basis of these results, we propose %TRBC1+ cutoffs of <25% or >75% for establishing T-cell monotypia in skin. Considering such thresholds, TRBC1-CD3 evaluation facilitated diagnostic refinement in 7/9 (78%) atypical cases. Overall, TRBC1-CD3 IHC clearly and rapidly aids diagnosis of cutaneous T-cell proliferations.

Autologous Chimeric antigen receptor (CAR) T-cell therapies have demonstrated substantial efficacy in patients with relapsed or refractory hematologic malignancies; however, their implementation has been constrained by regulatory barriers. Risk Evaluation and Mitigation Strategies (REMS), mandated by the U.S. Food and Drug Administration (FDA), were initially implemented to mitigate risks associated with cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and other treatment-related toxicities. On 27 June 2025, the FDA removed REMS requirements for all approved B-cell maturation antigen (BCMA) and CD19-directed autologous CAR T-cell therapies, citing that current product labeling sufficiently communicates safety information. Key regulatory changes include the elimination of site certification and tocilizumab stocking requirements, a reduction in the recommended post-infusion proximity period from four weeks to two weeks, increased flexibility regarding monitoring locations, and a shortened driving restriction from eight weeks to two weeks. This review examines the rationale for the REMS requirements for CAR T-cell therapies, synthesizes contemporary safety data from clinical trials and real-world practice, and explores the implications of this regulatory shift for access to care, particularly in rural and underserved populations. The removal of REMS requirements may facilitate broader implementation of CAR T-cell therapies and alleviate logistical and institutional barriers, offering the potential to expand access while preserving patient safety.

Abstract Although follicular lymphoma (FL) typically follows an indolent course, patients with FL who experience early events, such as transformation or progression, have increased risk of death related to lymphoma. The FL24Cx is an algorithm based on a 45-target gene expression profiling (GEP) assay, which was developed and trained using 265 formalin-fixed, paraffin-embedded tissue samples on a reliable platform to predict, at the time of diagnosis, whether a patient will experience an event within 24 months. The modeling also confirmed and relied upon previously reported synergy between immune response (IR) gene expression signatures IR1 and IR2. Once locked, the 5-factor logistic regression FL24Cx model was independently validated in a retrospectively assessed cohort of 232 patients from 2 immunochemotherapy-treated arms of SWOG Cancer Research Network S0016 phase 3 clinical trial, in which it assigned 169 patients to the low-risk group with 29 events before 24 months (17.2%) and 63 patients to the high-risk group with 24 events before 24 months (38.1%). The relative risk of an event within 24 months after registration among patients who were classified into the high-risk group relative to patients who were classified into the low-risk group was 2.2 (95% confidence interval, 1.41 to 3.51). An up-front GEP biomarker, such as the FL24Cx, rigorously validated in a clinical laboratory and with a clinically relevant turnaround time, could identify and steer enrollment of patients at high risk for early events in clinical trials, thus enabling timely interpretation of such trials and increasing the pace of innovation.

ABSTRACT Anaplastic lymphoma kinase‐positive large B‐cell lymphoma (ALK+ LBCL) is a rare, aggressive subtype of diffuse large B‐cell lymphoma with poor outcomes using standard chemotherapy. In this multi‐institutional retrospective study, we analyzed 39 cases of ALK+ LBCL identified at six US academic centers from 2002 to 2024, with treatment including conventional cytotoxic regimens in frontline and biologically informed and nonchemotherapy‐based strategies in the relapsed setting. Ninety‐two percent of patients received frontline anthracycline‐based chemotherapy; 43% received intensified regimens, and 15% underwent upfront autologous stem cell transplantation (ASCT). Despite these approaches, outcomes remained poor. At a median follow‐up of 5.4 years, median event‐free survival (EFS) was 0.6 years (95% CI, 0.4–0.9), and median overall survival (OS) was 1.5 years (95% CI, 1.3–NR). One‐ and five‐year EFS rates were 28% and 17%, while corresponding OS rates were 72% and 42%, respectively. Advanced stage and high IPI scores were associated with inferior outcomes. Twelve patients received ALK inhibitors, with alectinib showing more durable responses than crizotinib. Lenalidomide and immune checkpoint inhibitors also demonstrated activity, including durable complete responses. Five patients underwent allogeneic stem cell transplantation, with three achieving sustained remission. In conclusion, our findings highlight the limited benefit of chemotherapy, even when intensified or followed by ASCT, and support the integration of biologically targeted therapies, which may have contributed to improved OS in our cohort compared to historical outcomes. Prospective, collaborative studies are needed to better understand disease biology and define optimal use of modern therapies in this rare lymphoma.