Citations

Background/Objectives: Characterizing spinal cord multiple sclerosis (MS) lesions in MRI is critical for diagnosis, monitoring, and treatment evaluation. However, current automated approaches for lesion detection and segmentation are typically designed for specific MRI contrasts or acquisition sites, limiting their generalizability in real-world clinical settings where imaging protocols vary widely. This work proposes a robust multi-site, multi-contrast segmentation framework for spinal cord lesions. Methods: The segmentation model was trained and evaluated on a large-scale dataset comprising 4428 annotated images from 1849 persons with MS across 23 imaging centers, encompassing six MRI contrasts (T1w, T2w, T2*w, PSIR, STIR, and UNIT1) acquired at 1.5 tesla (T), 3 T, and 7 T. Results: Likert-type assessment performed by neuroradiologist ratings demonstrated superior generalization of the model compared to existing contrast-specific pipelines ( p < 0.01). Additional experiments evaluated robustness across spinal levels, acquisition resolutions, binarization thresholds, and quantitative evaluation on external labeled datasets. Conclusions: The proposed model can achieve accurate and reliable spinal cord MS lesion segmentation across heterogeneous MRI data, addressing a key barrier to clinical translation. The model is available in the Spinal Cord Toolbox v7.2 and higher. Code repository: https://github.com/ivadomed/seg-sc-ms-lesion-multicontrast

Abstract Hairy cell leukemia (HCL) and HCL variant (HCLv) are distinct, rare, and chronic splenic B-cell lymphomas/leukemias that partially overlap in clinicopathologic presentation but differ in genetic basis, prognosis, and management. HCL is caused by the BRAF-V600E kinase–activating mutation in &gt;95% of the patients, usually has excellent responses to chemotherapy with purine analogues, and is also amenable to BRAF inhibitor–based targeted treatments. In contrast, HCLv lacks BRAFV600E mutation, requires combined therapy with purine analogues in addition to rituximab, and generally shows less durable responses. Here, an international team of hematologists, experts on these rare diseases, was convened by the Hairy Cell Leukemia Foundation to update the previous guidelines (published in 2017) by providing a summary of current methods to diagnose and manage patients with HCL and HCLv as well as a prospective on newer targeted therapies to further improve outcomes.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non-Small Cell Lung Cancer (NSCLC) provide recommendations for the treatment of patients with NSCLC, including diagnosis, primary disease management, surveillance, and subsequent treatment. The panel has updated the list of recommended targeted therapies based on recent FDA approvals and clinical data. This selection from the NCCN Guidelines for NSCLC focuses on treatment recommendations for advanced or metastatic NSCLC with actionable biomarkers.

Background: While much of cancer research has historically centered on innovations within clinical or laboratory settings, most of the factors shaping equity in cancer outcomes reside outside hospital walls—in neighborhoods, workplaces, and community networks. This reality underscores the need for community-involved and community-living interventions: programs co-designed and delivered within communities to meet people where they live, work, and socialize . Such interventions hold the greatest promise for sustainability because they are embedded in the daily lives, cultures, and resources of the populations they serve. Methods: This special collection brings together research that illuminates the power of community-centered and community co-led strategies for prevention, early detection, treatment, and survivorship across diverse settings. Results: The articles in this series illustrate how innovation, cultural humility, and local engagement can bridge persistent gaps in cancer care. Conclusion: Together, they highlight how communities themselves are essential partners in dismantling disparities and achieving lasting cancer control.

Abstract Pyroptosis is a form of programmed cell death characterized by the cleavage of the gasdermin (GSDM) family proteins that form pores in the plasma membrane, cell rupture, and the release of proinflammatory cytokines. In this study, we performed immunohistochemistry for cleaved gasdermin D (GSDMD), gasdermin E (GSDME) N-terminus, and gasdermin C (GSDMC) in 2 different cohorts of diffuse large B-cell lymphoma (DLBCL) and analyzed the impact of GSDM expression on prognosis and immunity. The results showed frequent cleaved GSDMD (N-terminal) expression. Only cytoplasmic GSDMD N-terminal expression correlated with significantly better patient survival in the 2 cohorts. In contrast, GSDME was mainly expressed in the vascular endothelium, and correlated with significantly adverse prognostic effect. Correlating with the multiplex fluorescent immunohistochemistry results, we found that cytoplasmic GSDMD N-terminal expression was associated with increased CD38+ (activated) M1 macrophages in both cohorts, cognate interactions between live DLBCL cells and activated M1 macrophages (and T cells), and lower PD-1/PD-L1 expression in the analyzed cases. In contrast, T-cell pyroptosis, lymphoma cell-resistance to cell death, and phagocytosis by M2 macrophages were observed in tissues with predominantly nuclear GSDMD N-terminal expression. Bulk gene expression profiling and deconvolution analysis revealed associations of cytoplasmic GSDMD N-terminal expression with downregulation of “Don’t eat me”–signaling genes, upregulation of many RNA genes, decreased frequency of “inflammatory” lymphoma microenvironment subtype, increased frequencies of prognostically favorable cell states and ecotypes, and decreased frequency of T-cell exhaustion state. In summary, this study showed distinct cellular and subcellular patterns of 3 GSDM proteins and their associated immune response phenotypes and prognostic effects, with implications for novel therapeutic strategies for B-cell lymphoma.

Abstract Introduction Bruton tyrosine kinase inhibitors (BTKis) have changed the treatment algorithm for patients with high-risk relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). Efficacy was demonstrated for zanubrutinib and ibrutinib in high-risk R/R CLL patients in the ALPINE (NCT03734016) trial, for ibrutinib and acalabrutinib in the ELEVATE-RR (NCT02477696) trial, and for acalabrutinib in the ASCEND (NCT00135226) trial. While there is limited head-to-head comparative trial data of all covalent BTKis in the treatment of high-risk R/R CLL, a previously published network meta-analysis (NMA) used data from the ALPINE, ELEVATE-RR, and ASCEND trials, and reported that zanubrutinib demonstrated significantly improved relative efficacy compared to ibrutinib and acalabrutinib in high-risk R/R CLL (Shadman 2025). Within this NMA, high-risk R/R CLL populations were defined based on the prespecified definitions within each trial, including patients with del(17p) and/or TP53 mutations in the ALPINE and ASCEND trials, and del(17p)/del(11q) in the ELEVATE-RR trial. This study aimed to compare zanubrutinib versus ibrutinib and acalabrutinib in high-risk R/R CLL by calculating the number needed to treat (NNT) to avoid one progression or death. Methods A model was developed to evaluate the NNT among high-risk R/R CLL patients to avoid a progression or death. Progression free survival (PFS) data for zanubrutinib in high-risk patients were extracted from the ALPINE trial. PFS values for ibrutinib and acalabrutinib were derived from the previously published NMA study. PFS for ibrutinib and acalabrutinib were calculated by applying PFS hazard ratio from the NMA results to the zanubrutinib PFS value for the high-risk population in the ALPINE trial. 24-month PFS (72.6% for zanubrutinib, 52.0% for ibrutinib, and 55.9% for acalabrutinib) were used for the base case analysis of the model. Sensitivity analyses were conducted to examine the impact of alternative PFS inputs for ibrutinib, derived directly from the high-risk populations in ALPINE trial (unadjusted). Results The base case results from the NNT model indicate that for the treatment of patients with high-risk R/R CLL over 24-months, every five patients treated with zanubrutinib instead of ibrutinib results in the avoidance of one disease progression or death and every six patients treated with zanubrutinib instead of acalabrutinib results in the avoidance of one disease progression or death. Applying the model result to a hypothetical scenario of 100 patients with high-risk R/R CLL treated with zanubrutinib versus ibrutinib for two years finds approximately 20 patients will avoid disease progression events or deaths. Treating the same population with zanubrutinib versus acalabrutinib for two years will result in the avoidance of 17 disease progression events or death. Sensitivity analysis showed consistent NNT results.Conclusions The NNT analysis suggests that among high-risk R/R CLL patients, zanubrutinib is associated with more favorable clinical outcomes compared to ibrutinib and acalabrutinib. Over 24 months, zanubrutinib demonstrated a NNT of five to prevent one disease progression or death compared to ibrutinib, and an NNT of six compared to acalabrutinib, in high-risk R/R CLL patients. Study findings should be interpreted based on modeling assumptions and potential patient population differences across trials.

Abstract Background: Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma (NHL), accounting for approximately 30% of all NHL cases. DLBCL diagnosis relies on histologic examination, immunophenotyping, molecular and fluorescence in situ hybridization (FISH) analysis to differentiate it from similar NHL subtypes with overlapping morphological features, including more high-grade lymphomas like double-hit lymphoma. Because FISH is performed in a panel of single- or dual-target test format and analyzed through microscopy and manual image analysis, assessment of multiple target biomarkers can be cumbersome and expensive. As additional biomarkers for diagnosis, subtyping, prognosis, and therapeutic decision-making become available, target panels will become larger, posing additional challenges to clinical laboratories. Patients and Methods In this study, Hi-C sequencing of FFPE samples was performed to identify all genomic rearrangements by a single sequencing analysis for an unselected DLBCL case series of 159 patients, and the results were compared to FISH for the detection of clinically important variants. Results Hi-C sequencing showed superior performance compared to FISH: standard FISH for DLBCL includes testing for MYC, BCL2, and BCL6. Between FISH and Hi-C, these biomarkers were detected 105 times, of which, FISH detected 80/105 (76%) and Hi-C detected 102/105 (97%). The cohort included 4 double-hit lymphomas by FISH but Hi-C sequencing detected five. Besides DLBCL diagnostic biomarkers (MYC, BCL2, BCL6), many additional biomarkers were detected by Hi-C sequencing including variants not tested by FISH because the clinical suspicion was ambiguous and the relevant FISH probes were not used, and those not tested because the biomarkers were not thought to be common and, hence, left out of the FISH panel. In total, Hi-C sequencing detected additional biomarkers in 42 (26%) cases, including (1) variants targeted by FISH (i.e. MYC, BCL2, BCL6) but negative, (2) classification biomarkers for other lymphomas (CCND1, MALT, IRF4), and (3) those not tested because the biomarkers are not common and not included in the FISH panel. These additional biomarkers were supportive of suspected diagnosis of DLBCL versus double-hit lymphoma (24 cases), prompted reconsideration of a different diagnosis that may have led to different treatments (6 cases, e.g. mantle cell lymphoma), or biomarkers such as PDL1, ALK, and ATM which have implications for targeted therapies and/or inclusion in clinical trials (5 cases). Conclusion The Hi-C FFPE sequencing technology has the potential to improve the workflow of pathology labs for detection of a wide range of structural variants informing precision diagnosis and treatment for lymphomas.

Abstract Introduction: The first-generation BCL2 inhibitor,venetoclax, is an effective treatment for CLL/SLL, but its usage may be limited by toxicity. Sonrotoclax, a next-generation BCL2 inhibitor, is a more selective and pharmacologically potent inhibitor of BCL2 than venetoclax, with a shorter half-life and no drug accumulation. BGB-11417-101 (NCT04277637) is an ongoing, phase 1/1b, dose-escalation/expansion study in patients with B-cell malignancies. Presented here are preliminary data for sonrotoclax + obinutuzumab in patients with treatment-naive (TN) CLL/SLL in BGB-11417-101. Methods: Obinutuzumab is administered intravenously at 100 mg on day (D) 1, 900 mg on D2, 1,000 mg on D8 and D15 of cycle (C) 1, and then 1,000 mg on D1 of C2-6 of each 28-day cycle. Beginning on C2D1, sonrotoclax is administered orally once daily with ramp-up to the target doses, 160 or 320 mg. Patients can continue treatment until progressive disease (PD), unacceptable toxicity, or undetectable minimal residual disease (uMRD4; &lt;1 CLL cell per 10,000 leukocytes [&lt;0.01%]) in peripheral blood (PB) by next-generation sequencing (NGS; ClonoSEQ) after 15 treatment cycles. Study endpoints include safety per NCI-CTCAE v5.0, overall response rate (ORR) per iwCLL guidelines, and MRD status in PB per modified ERIC flow cytometry (FC) assay or NGS, depending on the timepoint. Tumor lysis syndrome (TLS) is assessed per Howard (2011) criteria. Results: As of May 16, 2025, 55 patients with TN CLL/SLL were enrolled (160 mg, n=20; 320 mg, n=35), and 21 patients (all 320 mg) have discontinued sonrotoclax + obinutuzumab (due to uMRD4 per NGS as protocol-mandated [n=17], PI decision uMRD4 per FC [n=2], and PD [n=2]). Four patients discontinued obinutuzumab only per PI decision (160 mg, n=1), thrombocytopenia (320 mg, n=2), and prostate cancer prior to starting sonrotoclax (160 mg, n=1). For all patients, the median age was 62 y, 65% were male, and 89% were White. At baseline, 14% of patients (8/55) had high tumor burden and 58% (31/53) had unmutated IGHV. Median study follow-up was 8.9 months (range, 0.4-25.4 months) for all patients; 6.4 months (range, 0.4-9.0 months) for 160 mg; and 16.0 months (range, 2.9-25.4 months) for 320 mg. Maximum tolerated dose was not reached. The most common any-grade treatment-emergent AEs (TEAEs) were thrombocytopenia (56%), infusion-related reaction (56%), and neutropenia (49%). Neutropenia was the most common grade ≥3 TEAE (38%). No deaths due to TEAEs occurred, and no TEAEs led to sonrotoclax discontinuation. Two cases of laboratory TLS occurred after C1D1 of obinutuzumab prior to starting sonrotoclax; no clinical or laboratory TLS occurred during sonrotoclax ramp up. No meaningful safety differences were observed among sonrotoclax dose cohorts. In 37 efficacy-evaluable patients (160 mg, n=7; 320 mg, n=30), the ORR was 89%; for the 320-mg cohort, ORR was 93% (28/30). Complete response (CR) rates (CR + CR with incomplete marrow recovery [CRi]) were 46% (all patients) and 43% (320 mg). For 23 patients in the 320 mg cohort who reached the C15 MRD assessment, the best C15 uMRD4 rate per FC was 87% (20/23; 2 not evaluable; 1 missing); per NGS, the uMRD4 rate at C15 was 78% (18/23; 5 missing). All patients with an available C15 MRD assessment achieved uMRD4 and remain in remission as of the data cutoff date. The median time from reaching sonrotoclax target dose to uMRD4 was 2.3 months (range, 1.4-5.6 months) in the 320-mg cohort. Three patients experienced PFS events: 1 died from an indeterminate cause (160 mg, discontinued treatment after C1D9 of obinutuzumab) and 2 had PD (320 mg; both Richter's transformation at C6 and C2). Conclusions: Sonrotoclax + obinutuzumab was generally well tolerated in patients with TN CLL/SLL, with no sonrotoclax discontinuations or deaths due to TEAEs. No laboratory or clinical TLS events occurred during sonrotoclax ramp-up. Encouraging antitumor activity was observed with sonrotoclax 320 mg. High rates of blood uMRD4 occurred early and deepened over time. All patients with an available C15 MRD assessment by NGS or FC achieved uMRD4 and remain in remission. A registrational phase 3 study (CELESTIAL-RRCLL, BGB-11417-303) assessing this combination with sonrotoclax 320 mg is currently recruiting.

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