Lachowiez CA, Zeidner JF, Othman J
… +48 more, Kaempf A, Yun S, Heiblig M, Heuser M, Shahswar R, Madero Marroquin R, Cannova JM, Žučenka A, Marvin-Peek J, Senapati J, Abaza Y, Swaroop A, Zacheo I, Monaco F, Belhabri A, Tauveron-Jalenques U, Tavernier E, Carré M, Aspas Requena G, Cook RJ, Traer E, Saultz JN, O'Nions J, Basheer F, Laurie J, Handa S, Stein EM, Baer MR, Olin R, Blum W, Schiller G, Lin T, Curran E, Yocum A, Madarang E, Daver N, Kadia TM, Marconi G, Madanat Y, Dillon R, DiNardo CD, Swords R, Arango Ossa JE, Watts J, Loghavi S, Pollyea DA, Bernard E, PRISM-AML Investigators
PURPOSE: As risk stratification for patients with AML treated with lower-intensity venetoclax-based therapy remains suboptimal, we developed and validated a prognostic model integrating clinical, cytogenetic, and molecul...PURPOSE: As risk stratification for patients with AML treated with lower-intensity venetoclax-based therapy remains suboptimal, we developed and validated a prognostic model integrating clinical, cytogenetic, and molecular features. METHODS: We assembled a multinational data set comprising 2,092 adults with newly diagnosed AML treated with hypomethylating agents plus venetoclax (HMA + VEN). One thousand nine hundred eighteen patients with complete data were randomly divided into training (70%) and internal validation (30%) cohorts. Two independent external validation cohorts were assembled (n = 500 and n = 222). Modeling overall survival (OS), Elastic Net regression was applied in 1,000 bootstrap samples from the training cohort to select variables for a Ridge regression, which generated a continuous Prognostic Risk Integration for Survival Modeling (PRISM) score and risk categories based on tertiles (PRISM-3: low, moderate, high). These PRISM indices were then computed for the validation cohorts and compared with the 4-gene classifier (based on mutations in -ITD, , and ). RESULTS: PRISM integrated 17 clinical and genomic variables and demonstrated a linear association with OS. PRISM-3 stratified survival consistently across all cohorts (median OS: 25.1-28.8 months for low risk, 12.5-14.7 months for moderate risk, and 5.8-6.7 months for high risk; < .001). Compared with the 4-gene classifier, PRISM-3 reassigned approximately 40% of patients (and >50% of those with favorable risk) and demonstrated significantly better discrimination in validation cohorts (C-index 0.63-0.65 0.59-0.61; < .05). CONCLUSION: PRISM is a validated prognostic model for patients with AML receiving HMA + VEN that improves survival risk stratification beyond current standard tools and supports individualized, risk-adapted clinical decision making. The model is publicly available at prism-aml.com.
PURPOSE: Prognosis in low-grade gliomas (LGGs) remains highly variable, and treatment-related late toxicity is a concern. This trial was comparing single-modality therapies in patients who often survive for years or deca...PURPOSE: Prognosis in low-grade gliomas (LGGs) remains highly variable, and treatment-related late toxicity is a concern. This trial was comparing single-modality therapies in patients who often survive for years or decades and investigating differential responses according to molecular markers. METHODS: Four hundred seventy-eight patients with clinical high-risk LGG (WHO grade 2) were randomly assigned to standard radiotherapy (RT; 28 × 1.8 Gy) or dose-dense temozolomide (TMZ; 75 mg/m once daily × 21/28 days, up to 12 cycles). RESULTS: There was no significant difference in progression-free survival or overall survival (OS) between study arms. Analyzable tumor tissue in 73% (351/478) of patients allowed for post hoc reclassification according to the 2021 WHO pathologic criteria. In astrocytoma, IDHmt/1p/19q noncodeleted (n = 178), median OS was similar, 6.6-6.7 years irrespective of arm (0.67-1.44, = .93). In oligodendroglioma, IDHmt/1p/19q codeleted (n = 109), median OS was 12.9 years (9.4-not reached) with RT and 14.9 years (10.1-number of events not reached) with TMZ (hazard ratio [HR], 0.88 [0.52-1.49], = .63). In 64 tumors without isocitrate dehydrogenase (IDH) mutations, survival favored the TMZ arm: OS 2.5 (1.8-3.3) versus 4.7 (2.2-7.2) years (HR, 0.47 [0.27-0.82], = .0068). Patients age 40 years and older fared better than patients younger than 40 years, challenging the current notion of age alone as a negative prognostic factor. CONCLUSION: The assigned initial treatment modality did not affect progression-free survival or OS, regardless of the molecular subtype. Combined-modality therapy was not tested in this trial but has since become a standard of care for IDH-mutant astrocytoma. With emerging novel therapeutic options, rational treatment strategies tailored at the individual clinical and pathologic recurrence risk profiles will be needed. The validity of an age cutoff as prognostic factor is challenged when tumors are molecularly classified.
Cleary JM, Springfeld C, Arnold D
… +17 more, Hollebecque A, Gbolahan O, Nagasaka M, Siena S, Opdam F, Sunakawa Y, Cassier PA, Trikha G, Gort EH, Florou V, Greil R, La Porte PF, Gandhi PJ, Garner F, Wasserman E, Adeyemi S, Schram AM
PURPOSE: Presently, to our knowledge, there are no approved targeted therapies for neuregulin 1 gene fusion-positive (+) cholangiocarcinoma. Zenocutuzumab, a HER2 × HER3 bispecific antibody, is approved for previously tr...PURPOSE: Presently, to our knowledge, there are no approved targeted therapies for neuregulin 1 gene fusion-positive (+) cholangiocarcinoma. Zenocutuzumab, a HER2 × HER3 bispecific antibody, is approved for previously treated, advanced/metastatic + non-small cell lung cancer and pancreatic adenocarcinoma. Here, we report results for 22 patients with + cholangiocarcinoma in the eNRGy trial. METHODS: eNRGy is a single-arm, phase II study of zenocutuzumab in advanced + solid tumors. Patients were age 18 years and older and previously treated with or unsuitable for standard therapy. Zenocutuzumab 750 mg was administered intravenously once every 2 weeks. The primary end point was investigator-assessed overall response rate (ORR; RECIST v1.1). Secondary end points included duration of response (DOR), clinical benefit rate (CBR), progression-free survival (PFS), and safety. RESULTS: As of July 31, 2025, 22 patients (median age 57.5 years) with advanced + cholangiocarcinoma were enrolled and had received a median of 1.0 (range, 0-6) prior therapies. In the 18 patients with tumor subtype data available, all had intrahepatic cholangiocarcinoma. Three patients did not meet the protocol-defined criteria for inclusion in the efficacy analysis. Seven of 19 patients achieved a response, resulting in an ORR of 36.8% (95% CI, 16.3 to 61.6). The median DOR was 7.4 months and the median time to response was 1.9 months. The CBR was 57.9% (95% CI, 33.5 to 79.7). Median PFS was 9.2 months (95% CI, 3.9 to 11.1). Most treatment-related adverse events (TRAEs) were grade 1 and 2, and the most common were diarrhea (27.3%), fatigue (18.2%), and nausea (13.6%). One patient had a grade 3 TRAE of anemia. No patients discontinued treatment due to an AE. CONCLUSION: Zenocutuzumab demonstrated clinically meaningful and durable antitumor activity with a favorable safety profile in patients with advanced cholangiocarcinoma.
Eyre TA, Song Y, Hermine O
… +13 more, Shuang Y, Jurczak W, Farias JS, Mahuad C, Özcan M, Jachimowicz RD, Chen T, Ivanova E, Li X, Man G, Bourquelot P, Vezan R, Wang M
PURPOSE: Mantle cell lymphoma (MCL) is a rare and typically aggressive B-cell non-Hodgkin lymphoma characterized by recurrent relapse after short remissions. Sonrotoclax (BGB-11417) is a next-generation B-cell lymphoma 2...PURPOSE: Mantle cell lymphoma (MCL) is a rare and typically aggressive B-cell non-Hodgkin lymphoma characterized by recurrent relapse after short remissions. Sonrotoclax (BGB-11417) is a next-generation B-cell lymphoma 2 inhibitor with greater selectivity and potency than venetoclax, a shorter half-life, and no drug accumulation. Sonrotoclax monotherapy was evaluated in Bruton tyrosine kinase inhibitor-pretreated patients with relapsed/refractory (R/R) MCL. METHODS: BGB-11417-201 (ClinicalTrials.gov identifier: NCT05471843) is an ongoing global, open-label, phase I/II trial. Sonrotoclax was orally administered once daily with gradual, 4-week ramp-up to 160 mg or 320 mg to mitigate tumor lysis syndrome (TLS). The primary end point was overall response rate by the independent review committee (ORR-IRC) per Lugano classification; secondary end points included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Overall, 125 patients were enrolled and assigned to receive sonrotoclax 160 mg (n = 10) or 320 mg (n = 115) target doses once daily. Most patients had advanced disease (stage IV, 78.3%) and were heavily pretreated (median prior therapies, 3). In efficacy-evaluable patients (n = 103), the ORR-IRC was 52.4% (95% CI, 42.4 to 62.4), a statistically significant increase versus the historic control ORR (30%; < .0001); the complete response rate was 15.5%. Responses were seen across high-risk subgroups, including patients with mutation (59.1%). With a median study follow-up of 14.2 months, the median DOR-IRC was 15.8 months, and the median PFS-IRC was 6.5 months. Median OS was not reached. The most common all-grade/grade ≥3 treatment-emergent adverse events were neutropenia (35.7%/19.1%), thrombocytopenia (24.3%/9.6%), and anemia (24.3%/7.8%). TLS occurred in 7.0% of patients; all cases resolved without sequelae. CONCLUSION: Sonrotoclax demonstrated rapid, durable responses and manageable safety in heavily pretreated patients with R/R MCL, including high-risk subgroups, supporting its further clinical evaluation as an oral therapy for R/R MCL.
Living guidelines are developed for selected topic areas with rapidly evolving evidence that drives frequent change in recommended clinical practice. Living guidelines are updated on a regular schedule by a standing expe...Living guidelines are developed for selected topic areas with rapidly evolving evidence that drives frequent change in recommended clinical practice. Living guidelines are updated on a regular schedule by a standing expert panel that systematically reviews the health literature on a continuous basis, as described in the . ASCO Living Guidelines follow the . Living Guidelines and updates are not intended to substitute for independent professional judgment of the treating clinician and do not account for individual variation among patients. See appendix for disclaimers and other important information ( and ). Updates are published regularly and can be found on the .
Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have revolutionized the management of type 2 diabetes and obesity by providing sustained improvements in glycemic control, weight loss, and cardiovascular outcomes. Th...Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have revolutionized the management of type 2 diabetes and obesity by providing sustained improvements in glycemic control, weight loss, and cardiovascular outcomes. These benefits have led to increasing interest in their potential role in cancer treatment. Obesity and metabolic dysfunction are well-known factors that promote the development, progression, and resistance to therapy in various cancers, suggesting that drugs targeting these pathways may have anticancer effects. Emerging epidemiologic and clinical evidence shows that GLP-1RA therapy is linked to a lower risk of several obesity-related cancers, including GI, breast, endometrial, ovarian, prostate, and hematologic malignancies. Mechanistic studies also reveal effects on insulin signaling, long-term inflammation, angiogenesis, and immune system modulation. This comprehensive review integrates current knowledge of GLP-1RAs in cancer care, covering drug action, epidemiology, underlying mechanisms, and clinical application. We evaluate evidence for cancer prevention, their use as complementary treatments, and outcomes in patients with existing cancer. Overall, the evidence suggests that GLP-1RAs could become a novel class of agents linking metabolic health and cancer therapy, with potential applications in neoadjuvant treatment strategies, particularly in settings where prolonged neoadjuvant intervals allow for metabolic optimization before definitive surgical intervention.
Tahara M, Kiyota N, Kodaira T
… +30 more, Nishino H, Asada Y, Mitani H, Hirayama Y, Onozawa Y, Nishio N, Hanai N, Ohkoshi A, Hara H, Monden N, Nagaoka M, Minami S, Tanaka K, Fujii T, Yoshimoto S, Ueda T, Kishimoto Y, Homma A, Oridate N, Okami K, Uemura H, Katagiri K, Yamazaki T, Asakage T, Saito Y, Murono S, Mizusawa J, Nakamura K, Hayashi R, Head and Neck Cancer Study Group of the Japan Clinical Oncology Group (JCOG-HNCSG)
The interim analysis of JCOG1008 demonstrated that chemoradiotherapy with cisplatin 40 mg/m once a week for seven cycles (weekly cisplatin) was noninferior in terms of overall survival (OS) compared with chemoradiotherap...The interim analysis of JCOG1008 demonstrated that chemoradiotherapy with cisplatin 40 mg/m once a week for seven cycles (weekly cisplatin) was noninferior in terms of overall survival (OS) compared with chemoradiotherapy with cisplatin 100 mg/m once every 3 weeks for three cycles (3-weekly cisplatin) for postoperative high-risk locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN). This report presents the long-term follow-up results of JCOG1008. In this phase II/III trial, patients with postoperative high-risk LA-SCCHN were randomly assigned to receive either chemoradiotherapy with 3-weekly cisplatin or with weekly cisplatin. A total of 261 patients were enrolled. At the final analysis, with a median follow-up of 5.6 years, 5-year OS was 58.7% in the 3-weekly arm and 71.2% in the weekly arm (hazard ratio, 0.76 [95% CI, 0.52 to 1.12 [<1.32]]), confirming the noninferiority of the weekly regimen. Both 5-year relapse-free survival (RFS) and 5-year local RFS were numerically better in the weekly arm. No late adverse event showed more than a 10% difference between the two arms. In conclusion, 5-year follow-up confirmed that chemoradiotherapy with weekly cisplatin is noninferior in OS to chemoradiotherapy with 3-weekly cisplatin in patients with postoperative high-risk LA-SCCHN. These results further support the use of weekly cisplatin plus radiotherapy as a reasonable alternative for this patient population.
Li S, Liu Z, Liu Y
… +22 more, Li K, Cong L, Cao F, Liu A, Liu H, Li L, Qu L, Zhai Y, Wang F, Zhou D, Yi Q, Wang P, Li J, Shi D, Chu J, Zhang D, Xu Q, Nie S, Ma M, Song S, Wang P, Liu L
PURPOSE: Clinical data for first-line combination of antibody-drug conjugates (ADC) and immune checkpoint inhibitors in human epidermal growth factor receptor 2 (HER2)-overexpressing advanced gastric or gastroesophageal...PURPOSE: Clinical data for first-line combination of antibody-drug conjugates (ADC) and immune checkpoint inhibitors in human epidermal growth factor receptor 2 (HER2)-overexpressing advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma remain limited. We evaluated the efficacy and safety of disitamab vedotin (a HER2-directed ADC) combined with tislelizumab (a PD-1 inhibitor) and oral fluoropyrimidine S-1 as first-line therapy for patients with advanced HER2-overexpressing (immunohistochemistry [IHC] 3+ or 2+, regardless of in situ hybridization [ISH] status) G/GEJ adenocarcinoma. METHODS: In this single-arm, multicenter, phase II trial, patients received disitamab vedotin (2.5 mg/kg, once on day 1), tislelizumab (200 mg, once on day 1), and S-1 (40-60 mg, twice daily, days 1-14) in 21-day cycles. The primary end point was confirmed objective response rate (ORR) by independent central review (RECIST v1.1). Secondary end points included progression-free survival (PFS), overall survival (OS), duration of response (DoR), and safety. RESULTS: Fifty-seven patients (median age 65; IHC 3+ 71.9%, IHC 2+/ISH+ 17.5%, IHC 2+/ISH- 10.5%; PD-L1 combined positive score [CPS] <1 54.4%) were enrolled. The confirmed ORR was 89.5% (95% CI, 78.5 to 96.0). At a median follow-up of 28.2 months, the median PFS (mPFS) was 13.8 months (95% CI, 10.3 to 24.0), the median OS (mOS) reached 31.9 months (95% CI, 22.1 to not reached), and the median DoR was 13.3 months (95% CI, 9.6 to not reached). Patients with CPS ≥1 achieved an ORR of 92.3%, mPFS of 16.7 months, and mOS of 31.9 months; in the CPS <1 subgroup, the ORR was 87.1% with an mPFS of 10.0 months, and mOS of 25.4 months. Grade ≥3 treatment-related adverse events occurred in 64.9% of patients, primarily hematologic and peripheral neuropathy. CONCLUSION: First-line disitamab vedotin with tislelizumab and S-1 demonstrated remarkable antitumor activity and a manageable safety profile in HER2-overexpressing advanced G/GEJ adenocarcinoma, warranting validation in randomized controlled trials.
Fleischhauer K, Toffalori C, Cugnata F
… +48 more, Hofmann JA, Orofino G, Lorentino F, Ahci-Hanci M, Lange V, Müller CR, Kunadt D, Bornhäuser M, Sanz G, Soiffer R, Waterhouse M, Giaccone L, Ali H, Nachtkamp K, Bacigalupo A, Bonifazi F, Luznik L, Facchini L, Bramanti S, Nagler A, Saccardi R, Milano F, Zallio F, Pierini A, Mohty M, Flomenberg N, Takaori-Kondo A, Vey N, Teshima T, Kröger N, Laperche CM, Andreani M, Lupo Stanghellini MT, Peccatori J, Di Serio C, Kobbe G, Al Malki MM, Bruno B, Zeiser R, Lindsley RC, Sanz J, Beelen D, Stölzel F, Sauter J, Schmidt AH, Ciceri F, Vago L, HLALOSS Consortium
PURPOSE: For patients with hematologic malignancies, relapse is the leading cause of death after allogeneic hematopoietic cell transplantation (allo-HCT). Frequently, relapses are explained by immune evasion through alte...PURPOSE: For patients with hematologic malignancies, relapse is the leading cause of death after allogeneic hematopoietic cell transplantation (allo-HCT). Frequently, relapses are explained by immune evasion through alterations of human leukocyte antigens (HLAs), but determinants and clinical consequences remain poorly defined. METHODS: We analyzed 533 relapses of hematologic cancers after allo-HCT from different donor types, conducted at 27 centers worldwide. Genomic loss of mismatched HLA (HLA loss) was assessed using a newly developed next-generation sequencing pipeline. Clinical and immunogenetic factors associated with HLA loss were evaluated. Using HLA data from approximately 5 million individuals, a web-based tool to infer HLA incompatibility phasing was developed. RESULTS: HLA loss occurred in 15.6% of relapses, with significant variation according to donor type (28.7% haploidentical family, 7.2% unrelated adult, 2.7% cord blood, < .0001). The distribution of HLA mismatches across the patient's haplotypes, predicted through the phasing tool, was strongly associated with HLA loss, with an incidence of 27.6% when HLA mismatches were in the same haplotype, compared with 5.4% if present on different haplotypes ( < .0001). HLA loss affected postrelapse outcomes, abrogating the efficacy of original donor lymphocyte infusions, with significant survival advantage by second allo-HCT from a different donor. CONCLUSION: The likelihood of HLA loss varies significantly according to the number and positioning of HLA mismatches between patient and donor. A newly developed phasing tool enables reliable prediction of its risk, supporting informed donor selection. Routine assessment of HLA loss at relapse is warranted, as it critically affects the success of immunologic salvage therapies.
This piece reflects on the unseen emotional burden carried within oncology, where each clinical encounter leaves a lasting imprint beyond measurable outcomes.This piece reflects on the unseen emotional burden carried within oncology, where each clinical encounter leaves a lasting imprint beyond measurable outcomes.
Sharma MR, Powderly J, Kuboki Y
… +23 more, Strickler JH, Perets R, Cohen JE, Raimboaurg J, Nakajima TE, Yamamoto N, Cruz-Correa M, O'Neil B, Ghiringhelli F, Raghav K, Cecchini M, Bar J, Hunter Z, Burns M, Blaney M, Morrison-Thiele G, Aristide MN, Freise KJ, Li R, Li M, Vasilopoulos A, Biesdorf C, Sommerhalder D
Barac A, Guha A, Fleming TR
… +10 more, Bonaca M, Thavendiranathan P, Deswal A, Amiri-Kordestani L, Bhatnagar V, Cordoba R, Hurvitz S, Adjei AA, Agarwal N, American Heart Association Cardio-Oncology Committee of the Council on Clinical Cardiology and Council on Genomic and Precision Medicine; Council on Cardiovascular and Stroke Nursing; and Council on Peripheral Vascular Disease
The unprecedented expansion of approved oncology therapies has prolonged survival and transformed the prognosis for many patients diagnosed with cancer. However, cancer treatments may be associated with cardiovascular to...The unprecedented expansion of approved oncology therapies has prolonged survival and transformed the prognosis for many patients diagnosed with cancer. However, cancer treatments may be associated with cardiovascular toxicities that manifest through vascular, myocardial, or metabolic pathways, potentially limiting the use of cancer therapeutics and adversely affecting outcomes. Oncology clinical trials provide an important opportunity to evaluate cardiovascular safety signals by generating data on the incidence, timing, and spectrum of toxicities. However, progress has been limited by inconsistent definitions and variable approaches to event characterization. This scientific statement aligns the advances in cardiovascular medicine and cardiovascular clinical trials to provide criteria for systematic selection, rigorous characterization, and adjudication of cardiovascular endpoints in contemporary oncology trials. The proposed framework links drug-specific mechanisms to endpoint selection and standardizes the approach to definitions of adverse cardiovascular events, including heart failure, arrhythmias, myocarditis, and thrombotic events. Definitions of major adverse cardiac events, clinical events, and surrogate endpoints are discussed, along with strategies for alignment with the Common Terminology Criteria for Adverse Events and patient-reported outcomes. Practical guidance is provided for prospective surveillance, decentralized and hybrid clinical trial designs, independent endpoint adjudication, and statistical approaches to competing risks and late-emerging toxicities. By harmonizing cardiovascular endpoint assessment across oncology trials, this scientific statement aims to enhance risk stratification, facilitate regulatory acceptance, and inform clinical decision making, ultimately improving patient safety while supporting innovation in cancer therapeutics.
Wilson MR, Lewis KL, Kirkwood AA
… +36 more, Cwynarski K, Cheah CY, El-Galaly TC, Villa D, Savage KJ, Ghione P, Bobillo S, Smedby KE, Harrysson S, Trneny M, Klanova M, Puckrin R, Fox CP, Bishton M, Thanarajasingam G, Wong Doo N, Hapgood G, Soussain C, Choquet S, Dickinson M, Talaulikar D, de Mel S, Preston G, Ahearne M, Hawkes EA, Schorb E, Clavert A, Ku M, Guidetti A, Narkhede M, Calimeri T, Durot E, Smith J, Renaud L, McKay P, Eyre TA
PURPOSE: In large B-cell lymphoma (LBCL), use of high-dose methotrexate (HD-MTX) to prevent CNS relapse (so-called CNS prophylaxis) remains controversial. International guidelines continue to recommend HD-MTX in patients...PURPOSE: In large B-cell lymphoma (LBCL), use of high-dose methotrexate (HD-MTX) to prevent CNS relapse (so-called CNS prophylaxis) remains controversial. International guidelines continue to recommend HD-MTX in patients deemed ultra high risk (UHR) because of a lack of robust data specific to these subgroups. This study was designed to examine the impact of HD-MTX specifically in UHR patients. METHODS: Data from two previous retrospective analyses were combined to produce a cohort of UHR patients (≥1 of the following criteria: CNS international prognostic index score 5-6; testicular, renal/adrenal, or breast involvement; ≥3 extranodal sites), treated with or without HD-MTX. The primary outcome was CNS relapse rate (isolated or concurrent with systemic relapse) measured from diagnosis with additional landmark analysis of all responding patients with no progression event at 6 months. RESULTS: Analyses were performed on 1,923 patients meeting UHR criteria. No significant difference in 3-year CNS relapse rate was observed between no HD-MTX (n = 1,051) versus HD-MTX patients (n = 872), including in multivariable analyses adjusting for baseline characteristics (3-year rate, 9.3% 8.1%; adjusted hazard ratio [HR], 1.13 [95% CI, 0.82 to 1.57]). Analyses restricted to isolated CNS relapse also confirmed no difference (5.9% 5.7%; adjusted HR, 1.03 [95% CI, 0.69 to 1.53]). In the landmark analysis (no HD-MTX n = 782, HD-MTX n = 773), no difference in 3-year CNS relapse was observed (6.7% 6.6%, adjusted HR, 0.95 [95% CI, 0.62 to 1.44]). CONCLUSION: To our knowledge, this is the largest international comparative data set of patients with LBCL with UHR features showing no significant reduction in CNS relapse with HD-MTX in all UHR or in any individual subgroup. Despite inherent limitations of retrospective analyses, the data strongly support previous studies in suggesting HD-MTX prophylaxis has no meaningful benefit for most patients.