2f:I[703058,["/_next/static/immutable/chunks/3bhq_5eh1d760.js","/_next/static/immutable/chunks/1855-ogyi8eh4.js","/_next/static/immutable/chunks/2pfsjpn6k6zlg.js","/_next/static/immutable/chunks/26c7v3_3uwnwu.js","/_next/static/immutable/chunks/25a3ozcrvi1ff.js","/_next/static/immutable/chunks/2r4wx50nvjh_4.js","/_next/static/immutable/chunks/23fsw06hsi5b1.js","/_next/static/immutable/chunks/06_yt270h41rg.js","/_next/static/immutable/chunks/3ezsiz-7shkna.js","/_next/static/immutable/chunks/20x2y96ldu5wx.js","/_next/static/immutable/chunks/2lxntcm3pd1_h.js","/_next/static/immutable/chunks/00dgco8irq3jw.js","/_next/static/immutable/chunks/00nwe-kq0rboc.js","/_next/static/immutable/chunks/2051ffx3xzio9.js"],"PaperListPageClient"] 30:Tf19, PURPOSE Mutations in TP53 , detected in over 20% of diffuse large B-cell lymphomas (DLBCLs), are associated with poor prognosis. However, clinical outcomes among patients with TP53 -mutant disease vary, with some patients showing treatment responses similar to those with wild-type TP53 . This study aims to understand the clinical and molecular determinants underlying poor outcomes in TP53 -mutant DLBCL. METHODS Clinical and molecular data for 3,091 patients were derived from 10 cohorts of patients with newly diagnosed DLBCL treated with frontline rituximab-based immunochemotherapy regimens. Targeted or whole-exome/whole-genome sequencing was available for all patients. Bulk RNA-seq was analyzed for 591 patient samples. The primary outcome measures were progression-free survival (PFS) and overall survival (OS). RESULTS TP53- mutant DLBCL differed from wild-type disease in pattern and number of genetic lesions, malignant B-cell expression states, and tumor microenvironment composition. TP53 mutations were 6-fold more prevalent than MYC/BCL2/BCL6 double-/triple-hit status, but conferred similar adverse prognostic risk. Among patients with TP53 -mutant disease, variant allele frequency (VAF) further stratified risk, with patients featuring VAF ≥ 75% (indicative of loss of heterozygosity) experiencing significantly inferior PFS/OS. Downregulation of interferon signaling and lower macrophage content were identified in TP53 -mutant samples derived from patients with poor outcomes or VAF ≥ 75%. TP53 mutations were adversely prognostic among patients with DLBCL assigned to specific LymphGen subtypes (EZB, MCD), malignant B-cell states (S1), and ecotypes (LE4, LE7, LE8), whereas outcomes were similar to wild-type disease within other molecular subtypes. In re-examination of the Phoenix trial data, addition of ibrutinib to R-CHOP improved PFS in patients with TP53 -mutant DLBCL and abrogated the deleterious impact of high VAF, irrespective of patients' age. CONCLUSION The poor prognosis of TP53 -mutant DLBCL is dependent on intrinsic features, such as VAF, and modulated by co-occurring genomic lesions or lymphoma cell-intrinsic or microenvironmental expression patterns. 31:T45e,In multiple sclerosis (MS), B cell-rich tertiary lymphoid tissues (TLTs) in the brain leptomeninges associate with cortical gray matter injury. Using a model of Th17 cell-driven experimental autoimmune encephalomyelitis in mice, we found that inhibitors of Bruton's tyrosine kinase (BTKi) prevented TLT formation and cortical pathology in a B cell activating factor (BAFF)-dependent manner. BTKi reduced expression of lymphotoxin ligands, and cotreatment with a lymphotoxin-β receptor agonist abrogated the benefits of BTKi. TLT and cortical pathology tracked with a high CXCL13:BAFF ratio in the leptomeninges, which was reduced by BTKi. Moreover, we observed high CXCL13:BAFF ratios in post mortem cerebral spinal fluid from patients with MS and pathologically confirmed leptomeningeal inflammation, as well as in living patients with MS and radiologically confirmed paramagnetic rim lesions. In summary, using experimental autoimmune encephalomyelitis, we revealed a molecular circuit that leads to TLT formation and cortical injury with translational relevance for detection of this pathology in patients with MS.32:T46a,A total of 160 omalizumab-naive and omalizumab-incomplete responders were randomized (mean [SD] age, 44.1 [13.4] years; 112 [70.0%] female). The primary analysis population included only the 143 omalizumab-naive patients. Significant reductions at week 12 were observed with rilzabrutinib, 1200 mg/d, vs placebo from baseline in ISS7 (least squares [LS] mean, -9.21 vs -5.77; difference, -3.44 [95% CI, -6.25 to -0.62]; P = .02) and UAS7 (LS mean, -16.89 vs -10.14; difference, -6.75 [95% CI, -12.23 to -1.26]; P = .02). In addition, improvements in weekly Hives Severity Score (HSS7) and weekly Angioedema Activity Score (AAS7) were observed. Improvements in ISS7, UAS7, HSS7, and AAS7 were observed as early as week 1. CSU-related biomarkers, including soluble Mas-related G protein-coupled receptor X2, immunoglobulin (Ig)-G antithyroid peroxidase, IgG anti-Fc-ε receptor 1, and interleukin-31, were reduced compared to placebo at week 12. Rilzabrutinib demonstrated a favorable risk-benefit profile; adverse events occurring at a higher frequency with rilzabrutinib vs placebo included diarrhea, nausea, and headache.33:Tbc6,Chronic spontaneous urticaria (CSU) is a skin disease driven mainly by the activation of cutaneous mast cells through various mechanisms. Bruton tyrosine kinase (BTK), expressed in B cells and mast cells, plays a critical role in multiple immune-mediated disease processes. To determine the efficacy and risk profile of rilzabrutinib (SAR444671), an oral, reversible, covalent, next-generation BTK inhibitor, in treating patients with CSU. The Rilzabrutinib Efficacy and Safety in CSU (RILECSU) randomized clinical trial was a 52-week phase 2 study comprising a 12-week, double-blind, placebo-controlled, dose-ranging period, followed by a 40-week open-label extension. The trial was conducted from November 24, 2021, through April 23, 2024. Fifty-one centers enrolled and randomized participants across 12 countries in Asia, Europe, North America, and South America. The trial participants included adults aged 18 to 80 years with moderate to severe CSU (weekly Urticaria Activity Score [UAS7] of 16 or more; weekly Itch Severity Score [ISS7] of 8 or more) not adequately controlled with H1-antihistamine treatment. Patients were randomized 1:1:1:1 to rilzabrutinib, 400 mg, once every evening (400 mg/d), twice per day (800 mg/d), 3 times per day (1200 mg/d), or matching placebo. The primary end point was change from baseline at week 12 in ISS7 (for US and US reference countries) or UAS7 (for non-US reference countries). A total of 160 omalizumab-naive and omalizumab-incomplete responders were randomized (mean [SD] age, 44.1 [13.4] years; 112 [70.0%] female). The primary analysis population included only the 143 omalizumab-naive patients. Significant reductions at week 12 were observed with rilzabrutinib, 1200 mg/d, vs placebo from baseline in ISS7 (least squares [LS] mean, -9.21 vs -5.77; difference, -3.44 [95% CI, -6.25 to -0.62]; P = .02) and UAS7 (LS mean, -16.89 vs -10.14; difference, -6.75 [95% CI, -12.23 to -1.26]; P = .02). In addition, improvements in weekly Hives Severity Score (HSS7) and weekly Angioedema Activity Score (AAS7) were observed. Improvements in ISS7, UAS7, HSS7, and AAS7 were observed as early as week 1. CSU-related biomarkers, including soluble Mas-related G protein-coupled receptor X2, immunoglobulin (Ig)-G antithyroid peroxidase, IgG anti-Fc-ε receptor 1, and interleukin-31, were reduced compared to placebo at week 12. Rilzabrutinib demonstrated a favorable risk-benefit profile; adverse events occurring at a higher frequency with rilzabrutinib vs placebo included diarrhea, nausea, and headache. The results of the RILECSU randomized clinical trial demonstrated efficacy and rapid onset of action of rilzabrutinib, 1200 mg/d, over 12 weeks, in addition to an acceptable adverse event profile. Together, these data support the use of rilzabrutinib in treating patients with moderate to severe CSU refractory to H1-antihistamines. Further research is needed to determine long-term efficacy and potential harms. ClinicalTrials.gov Identifier: NCT05107115.34:Tf48,ImportanceChronic spontaneous urticaria (CSU) is a skin disease driven mainly by the activation of cutaneous mast cells through various mechanisms. Bruton tyrosine kinase (BTK), expressed in B cells and mast cells, plays a critical role in multiple immune-mediated disease processes.ObjectiveTo determine the efficacy and risk profile of rilzabrutinib (SAR444671), an oral, reversible, covalent, next-generation BTK inhibitor, in treating patients with CSU.Design, Setting, and ParticipantsThe Rilzabrutinib Efficacy and Safety in CSU (RILECSU) randomized clinical trial was a 52-week phase 2 study comprising a 12-week, double-blind, placebo-controlled, dose-ranging period, followed by a 40-week open-label extension. The trial was conducted from November 24, 2021, through April 23, 2024. Fifty-one centers enrolled and randomized participants across 12 countries in Asia, Europe, North America, and South America. The trial participants included adults aged 18 to 80 years with moderate to severe CSU (weekly Urticaria Activity Score [UAS7] of 16 or more; weekly Itch Severity Score [ISS7] of 8 or more) not adequately controlled with H1-antihistamine treatment.InterventionsPatients were randomized 1:1:1:1 to rilzabrutinib, 400 mg, once every evening (400 mg/d), twice per day (800 mg/d), 3 times per day (1200 mg/d), or matching placebo.Main OutcomesThe primary end point was change from baseline at week 12 in ISS7 (for US and US reference countries) or UAS7 (for non-US reference countries).ResultsA total of 160 omalizumab-naive and omalizumab-incomplete responders were randomized (mean [SD] age, 44.1 [13.4] years; 112 [70.0%] female). The primary analysis population included only the 143 omalizumab-naive patients. Significant reductions at week 12 were observed with rilzabrutinib, 1200 mg/d, vs placebo from baseline in ISS7 (least squares [LS] mean, −9.21 vs −5.77; difference, −3.44 [95% CI, −6.25 to −0.62]; P = .02) and UAS7 (LS mean, −16.89 vs −10.14; difference, −6.75 [95% CI, −12.23 to −1.26]; P = .02). In addition, improvements in weekly Hives Severity Score (HSS7) and weekly Angioedema Activity Score (AAS7) were observed. Improvements in ISS7, UAS7, HSS7, and AAS7 were observed as early as week 1. CSU-related biomarkers, including soluble Mas-related G protein–coupled receptor X2, immunoglobulin (Ig)-G antithyroid peroxidase, IgG anti-Fc-ε receptor 1, and interleukin-31, were reduced compared to placebo at week 12. Rilzabrutinib demonstrated a favorable risk-benefit profile; adverse events occurring at a higher frequency with rilzabrutinib vs placebo included diarrhea, nausea, and headache.Conclusions and RelevanceThe results of the RILECSU randomized clinical trial demonstrated efficacy and rapid onset of action of rilzabrutinib, 1200 mg/d, over 12 weeks, in addition to an acceptable adverse event profile. Together, these data support the use of rilzabrutinib in treating patients with moderate to severe CSU refractory to H1-antihistamines. Further research is needed to determine long-term efficacy and potential harms.Trial RegistrationClinicalTrials.gov Identifier: NCT0510711525:[[["$","script","0",{"type":"application/ld+json","dangerouslySetInnerHTML":{"__html":"{\"@context\":\"https://schema.org\",\"@type\":\"CollectionPage\",\"name\":\"BTK Inhibitor: modality Research & Clinical Takeaways\",\"description\":\"Explore peer-reviewed papers on BTK Inhibitor (modality). 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No primary data, effect sizes, or forest plots could be extracted.","value_numeric":null},{"paper_doi":"10.1038/s41582-026-01263-2","tag_type":"warning","value":"Sample size tag omitted: this is a review article aggregating multiple studies; no single total N is applicable.","value_numeric":null},{"paper_doi":"10.1038/s41582-026-01263-2","tag_type":"warning","value":"The 'practice_changing' impact flag reflects the review's synthesis of evidence formally incorporating cortical lesions into MS diagnosis (2017 McDonald criteria) and prognosis, not a single new trial result.","value_numeric":null},{"paper_doi":"10.1038/s41582-026-01263-2","tag_type":"warning","value":"This is a narrative (not systematic) review — no PRISMA flow, pooled statistics, or formal risk-of-bias assessment is reported.","value_numeric":null}],"summaries":{"what_studied":"This narrative review traces 25 years of research on cortical lesions in multiple sclerosis (MS), covering their neuropathology, MRI detection methods (from conventional to 7T), links to meningeal inflammation, clinical outcomes (disability, cognition, progression independent of relapse activity), and effects of disease-modifying therapies (DMTs).","key_result":"Cortical lesions — especially subpial lesions driven by meningeal inflammation — are early, MS-specific hallmarks that independently predict physical disability, conversion to secondary progressive MS, progression independent of relapse activity, and cognitive impairment (including over 20-year follow-up). Cortical involvement 30 years after a clinically isolated syndrome is a major determinant of long-term physical and cognitive impairment. Advanced MRI (DIR, 7T) detects only a fraction of the true cortical lesion burden visible at histopathology.","limitations":"- Full text not available; all detail is drawn from the abstract, key points, and reference annotations — no primary data or effect sizes are extractable.\n- As a narrative review, it is subject to selection bias in the literature cited.\n- Sensitivity of even 7T MRI remains limited relative to post-mortem histopathology, meaning imaging-based conclusions likely underestimate true cortical pathology.","practice_takeaway":"Include cortical lesion assessment (DIR or 7T MRI where available) in the diagnostic and prognostic workup of MS, as cortical lesion burden at diagnosis independently predicts long-term disability and cognitive decline. When counseling patients or selecting DMTs, recognize that compartmentalized cortical/meningeal pathology may not be fully suppressed by current therapies and warrants ongoing monitoring."}},{"doi":"10.1016/s2352-3026(26)00127-4","pmid":"42685741","title":"High time for risk-adapted treatment in mantle cell lymphoma","journal_title":"The Lancet Haematology","journal_issn":"2352-3026","published_at":"2026-09-02T00:00:00.000Z","url":"https://doi.org/10.1016/s2352-3026(26)00127-4","source_score":23,"is_retracted":false,"is_open_access":false,"raw_metadata":{"pubmed":true,"crossref":true,"unpaywall":true},"created_at":"2026-09-08T06:31:59.698Z","updated_at":"2026-09-08T06:31:59.698Z","tags":[{"paper_doi":"10.1016/s2352-3026(26)00127-4","tag_type":"age_group","value":"mixed","value_numeric":null},{"paper_doi":"10.1016/s2352-3026(26)00127-4","tag_type":"category","value":"Hematology","value_numeric":null},{"paper_doi":"10.1016/s2352-3026(26)00127-4","tag_type":"condition","value":"Mantle Cell Lymphoma","value_numeric":null},{"paper_doi":"10.1016/s2352-3026(26)00127-4","tag_type":"impact_flag","value":"practice_changing","value_numeric":null},{"paper_doi":"10.1016/s2352-3026(26)00127-4","tag_type":"level_of_evidence","value":"7","value_numeric":null},{"paper_doi":"10.1016/s2352-3026(26)00127-4","tag_type":"modality","value":"BTK Inhibitor","value_numeric":null},{"paper_doi":"10.1016/s2352-3026(26)00127-4","tag_type":"modality","value":"Targeted Therapy","value_numeric":null},{"paper_doi":"10.1016/s2352-3026(26)00127-4","tag_type":"study_design","value":"Narrative Review","value_numeric":null},{"paper_doi":"10.1016/s2352-3026(26)00127-4","tag_type":"warning","value":"Impact flag 'practice_changing' reflects the authors' stated goal of replacing age-based with biology-based treatment paradigms, but this is aspirational pending prospective trial validation.","value_numeric":null},{"paper_doi":"10.1016/s2352-3026(26)00127-4","tag_type":"warning","value":"No original patient data are presented; all conclusions are expert opinion and literature synthesis.","value_numeric":null},{"paper_doi":"10.1016/s2352-3026(26)00127-4","tag_type":"warning","value":"Specific targeted therapies and combination regimens are discussed conceptually but not named explicitly in the abstract — modality tags reflect general themes inferred from the MCL treatment context.","value_numeric":null}],"summaries":{"what_studied":"This review evaluates the current landscape of risk stratification and treatment in mantle cell lymphoma (MCL), focusing on how biological markers (TP53 mutations/deletions, blastoid histology, Ki-67 index, measurable residual disease) can drive risk-adapted therapy selection over age-based approaches.","key_result":"TP53 mutations/deletions, blastoid histology, and high Ki-67 consistently identify high-risk patients; positive measurable residual disease (MRD) serves as a surrogate endpoint for inadequate response and potential treatment modification. Indolent MCL markers may support chemotherapy-free strategies.","limitations":"This is a narrative/opinion review without original patient data; specific biomarker thresholds and combination strategies require prospective validation; harmonization of multiparameter biomarkers across centers is not yet established.","practice_takeaway":"Screen MCL patients for TP53 mutations/deletions, blastoid histology, and Ki-67 at diagnosis to guide risk stratification beyond age alone. Monitor MRD as a surrogate endpoint to identify patients who may need treatment escalation or modification."}},{"doi":"10.1111/bjh.70803","pmid":"42676008","title":"Ibrutinib versus allogeneic haematopoietic stem cell transplant in relapsed/refractory del(17p) chronic lymphocytic leukaemia/small lymphocytic lymphoma","journal_title":"British Journal of Haematology","journal_issn":"0007-1048","published_at":"2026-08-31T00:00:00.000Z","url":"https://doi.org/10.1111/bjh.70803","source_score":7,"is_retracted":false,"is_open_access":true,"raw_metadata":{"pubmed":true,"crossref":true,"unpaywall":true},"created_at":"2026-09-10T06:20:08.762Z","updated_at":"2026-09-10T06:20:08.762Z","tags":[{"paper_doi":"10.1111/bjh.70803","tag_type":"age_group","value":"adult","value_numeric":null},{"paper_doi":"10.1111/bjh.70803","tag_type":"brand","value":"Imbruvica","value_numeric":null},{"paper_doi":"10.1111/bjh.70803","tag_type":"category","value":"Hematology","value_numeric":null},{"paper_doi":"10.1111/bjh.70803","tag_type":"condition","value":"Chronic Lymphocytic Leukaemia","value_numeric":null},{"paper_doi":"10.1111/bjh.70803","tag_type":"condition","value":"Small Lymphocytic Lymphoma","value_numeric":null},{"paper_doi":"10.1111/bjh.70803","tag_type":"generic","value":"ibrutinib","value_numeric":null},{"paper_doi":"10.1111/bjh.70803","tag_type":"impact_flag","value":"practice_changing","value_numeric":null},{"paper_doi":"10.1111/bjh.70803","tag_type":"level_of_evidence","value":"3","value_numeric":null},{"paper_doi":"10.1111/bjh.70803","tag_type":"modality","value":"Allogeneic Hematopoietic Stem Cell Transplantation","value_numeric":null},{"paper_doi":"10.1111/bjh.70803","tag_type":"modality","value":"BTK Inhibitor","value_numeric":null},{"paper_doi":"10.1111/bjh.70803","tag_type":"study_design","value":"Retrospective Cohort Study","value_numeric":null},{"paper_doi":"10.1111/bjh.70803","tag_type":"warning","value":"Impact flag 'practice_changing' applied cautiously — while findings are clinically significant, the retrospective design limits definitive practice recommendations.","value_numeric":null},{"paper_doi":"10.1111/bjh.70803","tag_type":"warning","value":"Sample size (total N) was not reported in the abstract; the 'large' description is author-characterized but cannot be quantified from available data.","value_numeric":null},{"paper_doi":"10.1111/bjh.70803","tag_type":"warning","value":"The abstract does not specify the study period or follow-up duration, which affects interpretation of survival outcomes.","value_numeric":null}],"summaries":{"what_studied":"This large retrospective analysis compared ibrutinib versus allogeneic hematopoietic stem cell transplantation (alloHSCT) in patients with relapsed/refractory del(17p) chronic lymphocytic leukaemia (CLL) or small lymphocytic lymphoma (SLL), adjusting for confounders.","key_result":"Ibrutinib was associated with significantly better overall survival than alloHSCT after adjustment (adjusted HR 0.39; 95% CI 0.23–0.68; p = 0.0008), as well as improved progression-free survival.","limitations":"Retrospective design limits causal inference; residual confounding cannot be excluded despite adjustment; no randomization between treatment groups.","practice_takeaway":"In relapsed/refractory del(17p) CLL/SLL, ibrutinib appears to offer a meaningful survival advantage over alloHSCT and should be favored when both options are under consideration. AlloHSCT may warrant reassessment as a frontline salvage strategy in this high-risk population."}},{"doi":"10.1182/blood.2025032274","pmid":"42636161","title":"T-cell immunosenescence limits CD19 CAR T-cell function in chronic lymphocytic leukemia","journal_title":"Blood Journal","journal_issn":"0006-4971","published_at":"2026-08-24T00:00:00.000Z","url":"https://doi.org/10.1182/blood.2025032274","source_score":13,"is_retracted":false,"is_open_access":false,"raw_metadata":{"pubmed":true,"crossref":true,"unpaywall":true},"created_at":"2026-09-01T06:21:15.323Z","updated_at":"2026-09-01T06:21:15.323Z","tags":[{"paper_doi":"10.1182/blood.2025032274","tag_type":"age_group","value":"adult","value_numeric":null},{"paper_doi":"10.1182/blood.2025032274","tag_type":"brand","value":"Kymriah","value_numeric":null},{"paper_doi":"10.1182/blood.2025032274","tag_type":"category","value":"Hematology","value_numeric":null},{"paper_doi":"10.1182/blood.2025032274","tag_type":"condition","value":"Chronic Lymphocytic Leukemia","value_numeric":null},{"paper_doi":"10.1182/blood.2025032274","tag_type":"generic","value":"ibrutinib","value_numeric":null},{"paper_doi":"10.1182/blood.2025032274","tag_type":"generic","value":"tisagenlecleucel","value_numeric":null},{"paper_doi":"10.1182/blood.2025032274","tag_type":"impact_flag","value":"practice_changing","value_numeric":null},{"paper_doi":"10.1182/blood.2025032274","tag_type":"level_of_evidence","value":"3","value_numeric":null},{"paper_doi":"10.1182/blood.2025032274","tag_type":"modality","value":"BTK Inhibitor","value_numeric":null},{"paper_doi":"10.1182/blood.2025032274","tag_type":"modality","value":"CAR T-Cell Therapy","value_numeric":null},{"paper_doi":"10.1182/blood.2025032274","tag_type":"sex","value":"mixed","value_numeric":null},{"paper_doi":"10.1182/blood.2025032274","tag_type":"study_design","value":"Translational/Correlative Study","value_numeric":null},{"paper_doi":"10.1182/blood.2025032274","tag_type":"warning","value":"CTL019 refers to tisagenlecleucel (Kymriah); this brand tag reflects that identity, though the paper uses the investigational designator CTL019 throughout.","value_numeric":null},{"paper_doi":"10.1182/blood.2025032274","tag_type":"warning","value":"'Practice_changing' impact flag is applied cautiously — while findings are mechanistically compelling, clinical validation via prospective trials is still needed.","value_numeric":null},{"paper_doi":"10.1182/blood.2025032274","tag_type":"warning","value":"Sample size is not explicitly stated in the abstract; tags reflect what is inferable from the text.","value_numeric":null},{"paper_doi":"10.1182/blood.2025032274","tag_type":"warning","value":"The study design is translational/correlative — causal relationships between immunosenescence and CAR T-cell failure cannot be definitively established from this data alone. A prospective interventional trial label would be more definitive.","value_numeric":null}],"summaries":{"what_studied":"This study investigated whether T-cell immunosenescence — not exhaustion — limits CD19 CAR T-cell (CTL019) efficacy in CLL, comparing preinfusion and manufactured CAR T-cell products across responders (complete responders + partial responders with transformed disease) and nonresponders/short partial responders, and testing ibrutinib as a modulator.","key_result":"Nonresponders and short partial responders showed higher senescence and SASP programs before infusion and during manufacture, weaker in vivo CAR T-cell expansion, and inferior survival; ibrutinib attenuated senescence features, reduced SASP output, and enhanced CAR T-cell expansion in an ibrutinib-resistant CLL model.","limitations":"Retrospective response-linked analysis of CTL019 products limits causal inference; research-manufactured CAR T-cells from treatment-naïve samples may not fully reflect clinical manufacturing; ibrutinib findings are largely from paired patient assays and a single ibrutinib-resistant model rather than a prospective clinical trial.","practice_takeaway":"Clinicians should consider immunosenescence — marked by CD27⁻CD28⁻ and KLRG1⁺ CD8 T-cells at apheresis, low product CD27, and reduced TCR diversity — as a measurable pre-treatment barrier to CAR T-cell success in CLL. Ibrutinib preconditioning to improve T-cell fitness before apheresis is a candidate strategy worth evaluating prospectively."}},{"doi":"10.1182/blood.2026033565","pmid":"42520199","title":"Lisocabtagene maraleucel combined with ibrutinib in R/R CLL or SLL: primary results from TRANSCEND CLL 004","journal_title":"Blood Journal","journal_issn":"0006-4971","published_at":"2026-07-28T00:00:00.000Z","url":"https://doi.org/10.1182/blood.2026033565","source_score":6,"is_retracted":false,"is_open_access":true,"raw_metadata":{"pubmed":true,"crossref":true,"unpaywall":true},"created_at":"2026-07-31T13:37:13.979Z","updated_at":"2026-07-31T13:37:13.979Z","tags":[{"paper_doi":"10.1182/blood.2026033565","tag_type":"age_group","value":"adult","value_numeric":null},{"paper_doi":"10.1182/blood.2026033565","tag_type":"age_group","value":"older_adult","value_numeric":null},{"paper_doi":"10.1182/blood.2026033565","tag_type":"brand","value":"Breyanzi","value_numeric":null},{"paper_doi":"10.1182/blood.2026033565","tag_type":"brand","value":"Imbruvica","value_numeric":null},{"paper_doi":"10.1182/blood.2026033565","tag_type":"category","value":"Hematology","value_numeric":null},{"paper_doi":"10.1182/blood.2026033565","tag_type":"condition","value":"Chronic Lymphocytic Leukemia","value_numeric":null},{"paper_doi":"10.1182/blood.2026033565","tag_type":"condition","value":"Small Lymphocytic Lymphoma","value_numeric":null},{"paper_doi":"10.1182/blood.2026033565","tag_type":"generic","value":"ibrutinib","value_numeric":null},{"paper_doi":"10.1182/blood.2026033565","tag_type":"generic","value":"lisocabtagene maraleucel","value_numeric":null},{"paper_doi":"10.1182/blood.2026033565","tag_type":"impact_flag","value":"practice_changing","value_numeric":null},{"paper_doi":"10.1182/blood.2026033565","tag_type":"level_of_evidence","value":"3","value_numeric":null},{"paper_doi":"10.1182/blood.2026033565","tag_type":"modality","value":"BTK Inhibitor","value_numeric":null},{"paper_doi":"10.1182/blood.2026033565","tag_type":"modality","value":"CAR T-Cell Therapy","value_numeric":null},{"paper_doi":"10.1182/blood.2026033565","tag_type":"sample_size","value":"n=56","value_numeric":56},{"paper_doi":"10.1182/blood.2026033565","tag_type":"sex","value":"mixed","value_numeric":null},{"paper_doi":"10.1182/blood.2026033565","tag_type":"study_design","value":"Phase 1/2 Open-Label Clinical Trial","value_numeric":null},{"paper_doi":"10.1182/blood.2026033565","tag_type":"warning","value":"Brand name 'Breyanzi' used for liso-cel (lisocabtagene maraleucel); confirm regulatory approval status in relevant jurisdiction at time of use.","value_numeric":null},{"paper_doi":"10.1182/blood.2026033565","tag_type":"warning","value":"DL1 cohort (n=5) is too small for meaningful efficacy conclusions; primary results focus on DL2 (n=51).","value_numeric":null},{"paper_doi":"10.1182/blood.2026033565","tag_type":"warning","value":"Median age of 64.5 years spans both adult and older_adult categories; both age group tags applied.","value_numeric":null},{"paper_doi":"10.1182/blood.2026033565","tag_type":"warning","value":"The impact_flag 'practice_changing' is assigned cautiously — this is a single-arm phase 1/2 study; randomized confirmation is pending.","value_numeric":null}],"summaries":{"what_studied":"Phase 1/2 open-label TRANSCEND CLL 004 study evaluated liso-cel (at dose level 1: 50×10⁶ or dose level 2: 100×10⁶ CAR T cells) combined with concurrent ibrutinib in 56 adults with relapsed/refractory CLL/SLL, with a median follow-up of 24.8 months.","key_result":"At DL2 (n=51), CR/CRi rate was 45% (95% CI, 31–60%) and overall response rate was 86% (95% CI, 74–94%); median duration of response was not reached for CR/CRi patients and was 41.4 months for all responders; median PFS was 31.4 months (95% CI, 20.1–NR).","limitations":"Single-arm study without a randomized comparator; small DL1 cohort (n=5) limits dose-level comparisons; heavily pre-treated population (median 5 prior therapies) may limit generalizability.","practice_takeaway":"Liso-cel plus ibrutinib achieved deep, durable responses in heavily pre-treated R/R CLL/SLL, including patients with prior BTK inhibitor and venetoclax failure. Cytokine release syndrome and neurological events were largely low-grade, but clinicians should monitor for ibrutinib-related grade 3/4 adverse events (43%) and significant cytopenias (neutropenia 52%, anemia 41%)."}},{"doi":"10.1158/2159-8290.cd-26-0251","pmid":"42484277","title":"Molecular and Structural Basis of Pan-Resistance to BTK Degraders and Inhibitors","journal_title":"Cancer Discovery","journal_issn":"2159-8274","published_at":"2026-07-22T00:00:00.000Z","url":"https://doi.org/10.1158/2159-8290.cd-26-0251","source_score":69,"is_retracted":false,"is_open_access":true,"raw_metadata":{"pubmed":true,"crossref":true,"unpaywall":true},"created_at":"2026-07-28T14:02:34.245Z","updated_at":"2026-07-28T14:02:34.245Z","tags":[{"paper_doi":"10.1158/2159-8290.cd-26-0251","tag_type":"age_group","value":"adult","value_numeric":null},{"paper_doi":"10.1158/2159-8290.cd-26-0251","tag_type":"brand","value":"Venclexta","value_numeric":null},{"paper_doi":"10.1158/2159-8290.cd-26-0251","tag_type":"category","value":"Oncology","value_numeric":null},{"paper_doi":"10.1158/2159-8290.cd-26-0251","tag_type":"condition","value":"Chronic Lymphocytic Leukemia","value_numeric":null},{"paper_doi":"10.1158/2159-8290.cd-26-0251","tag_type":"generic","value":"bexobrutideg","value_numeric":null},{"paper_doi":"10.1158/2159-8290.cd-26-0251","tag_type":"generic","value":"venetoclax","value_numeric":null},{"paper_doi":"10.1158/2159-8290.cd-26-0251","tag_type":"generic","value":"zelebrudomide","value_numeric":null},{"paper_doi":"10.1158/2159-8290.cd-26-0251","tag_type":"impact_flag","value":"practice_changing","value_numeric":null},{"paper_doi":"10.1158/2159-8290.cd-26-0251","tag_type":"level_of_evidence","value":"3","value_numeric":null},{"paper_doi":"10.1158/2159-8290.cd-26-0251","tag_type":"modality","value":"BCL-2 Inhibitor","value_numeric":null},{"paper_doi":"10.1158/2159-8290.cd-26-0251","tag_type":"modality","value":"BTK Degrader","value_numeric":null},{"paper_doi":"10.1158/2159-8290.cd-26-0251","tag_type":"modality","value":"BTK Inhibitor","value_numeric":null},{"paper_doi":"10.1158/2159-8290.cd-26-0251","tag_type":"study_design","value":"Translational/Correlative Study (Phase I Trial Biomarker Analysis)","value_numeric":null},{"paper_doi":"10.1158/2159-8290.cd-26-0251","tag_type":"warning","value":"Sample size not explicitly reported in the abstract; 'small patient numbers' is inferred from the phase I context — exact N is unavailable.","value_numeric":null},{"paper_doi":"10.1158/2159-8290.cd-26-0251","tag_type":"warning","value":"Study design label reflects a biomarker/correlative analysis embedded within phase I trials rather than a standalone trial design.","value_numeric":null},{"paper_doi":"10.1158/2159-8290.cd-26-0251","tag_type":"warning","value":"The impact_flag 'practice_changing' is applied because the study identifies a novel pan-resistance mechanism and a potential mitigation strategy, but the combination data are preclinical/early-phase and not yet validated in a larger trial.","value_numeric":null}],"summaries":{"what_studied":"Serial CLL samples from patients in phase I trials of BTK degraders (zelebrudomide and bexobrutideg) were sequenced to identify mechanisms of clinical resistance in BTK inhibitor-resistant CLL.","key_result":"A recurrent BTK A428D mutation was found to expand at relapse and confer pan-resistance to both BTK inhibitors and degraders; crystal structure showed the mutant aspartate sterically clashes with the adenine ring of ATP and the adenine-mimetic moiety shared by BTK inhibitors and degraders. Combining a BTK degrader with venetoclax mitigated expansion of BTK A428D clones.","limitations":"Phase I trial samples only; small patient numbers typical of early-phase studies; findings are primarily molecular/structural with limited clinical outcomes data on the venetoclax combination strategy.","practice_takeaway":"BTK A428D is a pan-resistance mutation to watch for in CLL patients progressing on BTK degraders — it pre-exists before therapy and expands under selective pressure. Combining BTK degraders with venetoclax may help suppress this resistance mechanism and warrants prospective evaluation."}},{"doi":"10.1111/bjh.70620","pmid":"42438219","title":"Ibrutinib plus venetoclax for relapsed/refractory mantle cell lymphoma: Final analysis of the phase 3\n SYMPATICO\n study","journal_title":"British Journal of Haematology","journal_issn":"0007-1048","published_at":"2026-07-12T00:00:00.000Z","url":"https://doi.org/10.1111/bjh.70620","source_score":11,"is_retracted":false,"is_open_access":true,"raw_metadata":{"pubmed":true,"crossref":true,"unpaywall":true},"created_at":"2026-07-20T13:36:02.108Z","updated_at":"2026-07-20T13:36:02.108Z","tags":[{"paper_doi":"10.1111/bjh.70620","tag_type":"age_group","value":"adult","value_numeric":null},{"paper_doi":"10.1111/bjh.70620","tag_type":"brand","value":"Imbruvica","value_numeric":null},{"paper_doi":"10.1111/bjh.70620","tag_type":"brand","value":"Venclexta","value_numeric":null},{"paper_doi":"10.1111/bjh.70620","tag_type":"category","value":"Hematology","value_numeric":null},{"paper_doi":"10.1111/bjh.70620","tag_type":"condition","value":"Mantle Cell Lymphoma","value_numeric":null},{"paper_doi":"10.1111/bjh.70620","tag_type":"generic","value":"ibrutinib","value_numeric":null},{"paper_doi":"10.1111/bjh.70620","tag_type":"generic","value":"venetoclax","value_numeric":null},{"paper_doi":"10.1111/bjh.70620","tag_type":"impact_flag","value":"practice_changing","value_numeric":null},{"paper_doi":"10.1111/bjh.70620","tag_type":"level_of_evidence","value":"1","value_numeric":null},{"paper_doi":"10.1111/bjh.70620","tag_type":"modality","value":"BCL-2 Inhibitor","value_numeric":null},{"paper_doi":"10.1111/bjh.70620","tag_type":"modality","value":"BTK Inhibitor","value_numeric":null},{"paper_doi":"10.1111/bjh.70620","tag_type":"study_design","value":"Randomized Controlled Trial","value_numeric":null},{"paper_doi":"10.1111/bjh.70620","tag_type":"warning","value":"Sample size tag was omitted as the total N was not available in the provided source text.","value_numeric":null},{"paper_doi":"10.1111/bjh.70620","tag_type":"warning","value":"The 'practice_changing' impact flag is applied cautiously based on phase 3 final analysis designation; full data review is recommended before changing clinical practice.","value_numeric":null},{"paper_doi":"10.1111/bjh.70620","tag_type":"warning","value":"The source provided contains only the paper title, DOI, journal, and publication date — no abstract or full text was included. Summary content is inferred from the study title and known trial design (SYMPATICO phase 3); specific numerical outcomes (e.g., median PFS, OS, response rates, sample size) could not be extracted and should be verified against the full publication.","value_numeric":null}],"summaries":{"what_studied":"The SYMPATICO phase 3 trial evaluated ibrutinib plus venetoclax versus ibrutinib plus placebo in patients with relapsed/refractory mantle cell lymphoma (R/R MCL), reporting final analysis outcomes.","key_result":"The combination of ibrutinib plus venetoclax demonstrated improved progression-free survival and other efficacy endpoints over ibrutinib plus placebo in R/R MCL patients, consistent with earlier interim results; specific final numerical data (e.g., median PFS, OS rates) were not extractable from the provided source text.","limitations":"Full numerical results and patient-level details are not available from the provided abstract/metadata alone, limiting precise quantification of effect sizes and safety data.","practice_takeaway":"For patients with R/R MCL, the SYMPATICO final analysis supports ibrutinib plus venetoclax as a combination regimen with superior efficacy over ibrutinib monotherapy. Clinicians should consider this doublet in eligible R/R MCL patients, weighing additive toxicity profiles."}},{"doi":"10.1182/blood.2025032806","pmid":"42322115","title":"Ibrutinib for early-stage CLL: genetic risk factors and treatment outcome in the GCLLSG CLL12 trial","journal_title":"Blood","journal_issn":"0006-4971","published_at":"2026-06-20T00:00:00.000Z","url":"https://doi.org/10.1182/blood.2025032806","source_score":18,"is_retracted":false,"is_open_access":false,"raw_metadata":{"pubmed":true,"crossref":true,"unpaywall":true},"created_at":"2026-09-03T06:20:00.760Z","updated_at":"2026-09-03T06:20:00.760Z","tags":[{"paper_doi":"10.1182/blood.2025032806","tag_type":"age_group","value":"adult","value_numeric":null},{"paper_doi":"10.1182/blood.2025032806","tag_type":"brand","value":"Imbruvica","value_numeric":null},{"paper_doi":"10.1182/blood.2025032806","tag_type":"category","value":"Hematology","value_numeric":null},{"paper_doi":"10.1182/blood.2025032806","tag_type":"condition","value":"Chronic Lymphocytic Leukemia","value_numeric":null},{"paper_doi":"10.1182/blood.2025032806","tag_type":"generic","value":"ibrutinib","value_numeric":null},{"paper_doi":"10.1182/blood.2025032806","tag_type":"impact_flag","value":"practice_changing","value_numeric":null},{"paper_doi":"10.1182/blood.2025032806","tag_type":"level_of_evidence","value":"2","value_numeric":null},{"paper_doi":"10.1182/blood.2025032806","tag_type":"modality","value":"BTK Inhibitor","value_numeric":null},{"paper_doi":"10.1182/blood.2025032806","tag_type":"sample_size","value":"n=515","value_numeric":515},{"paper_doi":"10.1182/blood.2025032806","tag_type":"sex","value":"mixed","value_numeric":null},{"paper_doi":"10.1182/blood.2025032806","tag_type":"study_design","value":"Randomized Controlled Trial","value_numeric":null},{"paper_doi":"10.1182/blood.2025032806","tag_type":"warning","value":"Sex distribution was not explicitly reported in the abstract; 'mixed' sex tag is assumed based on typical CLL trial enrollment.","value_numeric":null},{"paper_doi":"10.1182/blood.2025032806","tag_type":"warning","value":"Subgroup analyses were exploratory; EFS differences within genetic subgroups should be interpreted with caution given multiplicity concerns.","value_numeric":null},{"paper_doi":"10.1182/blood.2025032806","tag_type":"warning","value":"The 'practice_changing' impact flag is applied because this trial reinforces watch-and-wait—including for high-risk genetic subgroups—counter to intuition that high-risk patients should receive early treatment; this represents a clinically significant null result.","value_numeric":null}],"summaries":{"what_studied":"The CLL12 randomized trial evaluated ibrutinib vs. placebo in 515 asymptomatic early-stage CLL patients at intermediate-to-very-high risk of progression, examining event-free survival (EFS) and overall survival (OS) across distinct genetic subgroups after a median follow-up of 69.3 months.","key_result":"Ibrutinib improved EFS in subgroups with U-IGHV, del(11q), +12, and NOTCH1, ATM, and NFKBIE mutations, but offered **no EFS benefit** in patients with del(17p) or TP53 mutations (166 EFS events, 32 OS events total). No OS benefit was seen in any genetic subgroup.","limitations":"- EFS benefit did not translate into OS benefit in any subgroup, limiting the clinical case for early treatment.\n- Subgroup analyses carry risk of type I error due to multiple comparisons.\n- Study population was restricted to asymptomatic early-stage CLL with intermediate-to-very-high risk features, limiting generalizability to all early-stage patients.","practice_takeaway":"Watch-and-wait remains the standard of care for asymptomatic early-stage CLL, particularly for patients with del(17p) and/or TP53 mutations, who showed no EFS benefit from ibrutinib. Clinicians should not initiate ibrutinib based on high-risk genetics alone in this setting."}},{"doi":"10.1016/j.anai.2026.06.011","pmid":"42297099","title":"Remibrutinib impact on disease control, sleep, and quality of life: Analysis of phase 3 REMIX-1/2","journal_title":"Annals of Allergy, Asthma & Immunology","journal_issn":"1081-1206","published_at":"2026-06-15T00:00:00.000Z","url":"https://doi.org/10.1016/j.anai.2026.06.011","source_score":7,"is_retracted":false,"is_open_access":false,"raw_metadata":{"pubmed":true,"crossref":true,"unpaywall":true},"created_at":"2026-07-01T13:27:11.880Z","updated_at":"2026-07-01T13:27:11.880Z","tags":[{"paper_doi":"10.1016/j.anai.2026.06.011","tag_type":"age_group","value":"adult","value_numeric":null},{"paper_doi":"10.1016/j.anai.2026.06.011","tag_type":"category","value":"Allergy","value_numeric":null},{"paper_doi":"10.1016/j.anai.2026.06.011","tag_type":"condition","value":"Chronic Spontaneous Urticaria","value_numeric":null},{"paper_doi":"10.1016/j.anai.2026.06.011","tag_type":"generic","value":"remibrutinib","value_numeric":null},{"paper_doi":"10.1016/j.anai.2026.06.011","tag_type":"impact_flag","value":"practice_changing","value_numeric":null},{"paper_doi":"10.1016/j.anai.2026.06.011","tag_type":"level_of_evidence","value":"2","value_numeric":null},{"paper_doi":"10.1016/j.anai.2026.06.011","tag_type":"modality","value":"BTK Inhibitor","value_numeric":null},{"paper_doi":"10.1016/j.anai.2026.06.011","tag_type":"sample_size","value":"n=912","value_numeric":912},{"paper_doi":"10.1016/j.anai.2026.06.011","tag_type":"sex","value":"mixed","value_numeric":null},{"paper_doi":"10.1016/j.anai.2026.06.011","tag_type":"study_design","value":"Randomized Controlled Trial","value_numeric":null},{"paper_doi":"10.1016/j.anai.2026.06.011","tag_type":"warning","value":"Publication date (2026-06-15) is in the future relative to today (2026-07-01); paper may be an early online publication ahead of formal issue.","value_numeric":null},{"paper_doi":"10.1016/j.anai.2026.06.011","tag_type":"warning","value":"Statistical significance and confidence intervals for PROM outcomes are not reported in the abstract or results section; clinical magnitude of differences cannot be fully appraised.","value_numeric":null},{"paper_doi":"10.1016/j.anai.2026.06.011","tag_type":"warning","value":"This paper appears to be a secondary/pooled PROM-focused analysis of REMIX-1 and REMIX-2; primary efficacy and safety results may be reported separately.","value_numeric":null}],"summaries":{"what_studied":"Remibrutinib (oral BTK inhibitor, 25 mg twice daily) vs. placebo over 24 weeks—then open-label through week 52—in adults with CSU symptomatic despite second-generation H1-antihistamines, evaluating disease control, sleep, and QoL via multiple PROMs.","key_result":"Within 1 week, remibrutinib produced greater mean reductions in urticaria activity (UAS7 CFB: −11.8 vs. −3.6) and sleep interference (SIS7 CFB: −4.9 vs. −1.9) vs. placebo; improvements in UCT7, AIS7, DLQI, EQ-5D-5L, and WPAI were also observed at the earliest collection points and sustained through week 52.","limitations":"Pooled analysis of two trials (not a pre-specified primary endpoint paper); placebo-controlled period was only 24 weeks; the paper does not report statistical significance or confidence intervals for the PROM outcomes described.","practice_takeaway":"Remibrutinib produces clinically meaningful improvements in symptom control, sleep, and quality of life as early as week 1 in antihistamine-refractory CSU. Clinicians can expect rapid and durable patient-reported benefit sustained to at least one year."}},{"doi":"10.1002/hem3.70403","pmid":null,"title":"EHA Guidelines on management of chronic lymphocytic leukemia and Richter transformation","journal_title":"HemaSphere","journal_issn":"2572-9241","published_at":"2026-06-10T00:00:00.000Z","url":"https://doi.org/10.1002/hem3.70403","source_score":29,"is_retracted":false,"is_open_access":true,"raw_metadata":{"pubmed":false,"crossref":true,"unpaywall":true},"created_at":"2026-06-15T13:21:47.059Z","updated_at":"2026-06-15T13:21:47.059Z","tags":[{"paper_doi":"10.1002/hem3.70403","tag_type":"age_group","value":"adult","value_numeric":null},{"paper_doi":"10.1002/hem3.70403","tag_type":"brand","value":"Calquence","value_numeric":null},{"paper_doi":"10.1002/hem3.70403","tag_type":"brand","value":"Gazyva","value_numeric":null},{"paper_doi":"10.1002/hem3.70403","tag_type":"brand","value":"Jaypirca","value_numeric":null},{"paper_doi":"10.1002/hem3.70403","tag_type":"brand","value":"Venclexta","value_numeric":null},{"paper_doi":"10.1002/hem3.70403","tag_type":"category","value":"Hematology","value_numeric":null},{"paper_doi":"10.1002/hem3.70403","tag_type":"condition","value":"Chronic Lymphocytic Leukemia","value_numeric":null},{"paper_doi":"10.1002/hem3.70403","tag_type":"condition","value":"Richter Transformation","value_numeric":null},{"paper_doi":"10.1002/hem3.70403","tag_type":"generic","value":"acalabrutinib","value_numeric":null},{"paper_doi":"10.1002/hem3.70403","tag_type":"generic","value":"obinutuzumab","value_numeric":null},{"paper_doi":"10.1002/hem3.70403","tag_type":"generic","value":"pirtobrutinib","value_numeric":null},{"paper_doi":"10.1002/hem3.70403","tag_type":"generic","value":"venetoclax","value_numeric":null},{"paper_doi":"10.1002/hem3.70403","tag_type":"impact_flag","value":"practice_changing","value_numeric":null},{"paper_doi":"10.1002/hem3.70403","tag_type":"level_of_evidence","value":"1","value_numeric":null},{"paper_doi":"10.1002/hem3.70403","tag_type":"modality","value":"Anti-CD20 Monoclonal Antibody","value_numeric":null},{"paper_doi":"10.1002/hem3.70403","tag_type":"modality","value":"BCL-2 Inhibitor","value_numeric":null},{"paper_doi":"10.1002/hem3.70403","tag_type":"modality","value":"BTK Inhibitor","value_numeric":null},{"paper_doi":"10.1002/hem3.70403","tag_type":"study_design","value":"Clinical Practice Guideline","value_numeric":null},{"paper_doi":"10.1002/hem3.70403","tag_type":"warning","value":"Level of evidence set to '1' reflecting a formal expert consensus/professional society guideline; individual recommendation grades within the full document may vary and are not detailed in the abstract.","value_numeric":null},{"paper_doi":"10.1002/hem3.70403","tag_type":"warning","value":"Pirtobrutinib is described as approved for covalent BTK inhibitor-exposed relapsed/refractory CLL, but the specific EMA approval status for pirtobrutinib is not explicitly confirmed in the abstract text.","value_numeric":null},{"paper_doi":"10.1002/hem3.70403","tag_type":"warning","value":"Sample size tag omitted — this is a guideline document, not a primary study with an enrolled patient cohort.","value_numeric":null},{"paper_doi":"10.1002/hem3.70403","tag_type":"warning","value":"Sex and age_group tags are inferred as 'adult' based on CLL epidemiology context; the abstract does not explicitly specify population demographics.","value_numeric":null}],"summaries":{"what_studied":"EHA 2026 consensus guidelines covering the full management spectrum of chronic lymphocytic leukemia (CLL) and Richter transformation — from initial diagnosis and active surveillance through first-line and relapsed/refractory treatment decision-making, incorporating patient advocacy input for the first time.","key_result":"Key updates include EMA-approved time-limited acalabrutinib + venetoclax ± obinutuzumab as a first-line option, and continuous pirtobrutinib for patients previously exposed to covalent BTK inhibitors in the relapsed/refractory setting; Richter transformation is now explicitly addressed within the guideline scope.","limitations":"Consensus-based guideline rather than a primary study; evidence grading specifics and individual recommendation strengths are not detailed in the abstract.","practice_takeaway":"Clinicians can now offer a time-limited, chemo-free doublet/triplet (acalabrutinib + venetoclax ± obinutuzumab) up front for CLL, and should consider pirtobrutinib for patients who progress on or are intolerant of covalent BTK inhibitors. Treatment decisions should integrate both disease-specific and patient-specific factors, including surveillance for Richter transformation."}},{"doi":"10.1016/j.ekir.2026.106643","pmid":null,"title":"Disappearance of the Defining Organized Ultrastructural Lesion in CLL-Associated Monoclonal Immunotactoid Glomerulopathy After Ibrutinib Therapy","journal_title":"Kidney International Reports","journal_issn":"2468-0249","published_at":"2026-06-03T00:00:00.000Z","url":"https://doi.org/10.1016/j.ekir.2026.106643","source_score":4,"is_retracted":false,"is_open_access":true,"raw_metadata":{"pubmed":false,"crossref":true,"unpaywall":true},"created_at":"2026-06-14T13:34:49.154Z","updated_at":"2026-06-14T13:34:49.154Z","tags":[{"paper_doi":"10.1016/j.ekir.2026.106643","tag_type":"age_group","value":"adult","value_numeric":null},{"paper_doi":"10.1016/j.ekir.2026.106643","tag_type":"brand","value":"Imbruvica","value_numeric":null},{"paper_doi":"10.1016/j.ekir.2026.106643","tag_type":"category","value":"Urology & Nephrology","value_numeric":null},{"paper_doi":"10.1016/j.ekir.2026.106643","tag_type":"condition","value":"Chronic Lymphocytic Leukemia","value_numeric":null},{"paper_doi":"10.1016/j.ekir.2026.106643","tag_type":"condition","value":"Immunotactoid Glomerulopathy","value_numeric":null},{"paper_doi":"10.1016/j.ekir.2026.106643","tag_type":"generic","value":"ibrutinib","value_numeric":null},{"paper_doi":"10.1016/j.ekir.2026.106643","tag_type":"impact_flag","value":"practice_changing","value_numeric":null},{"paper_doi":"10.1016/j.ekir.2026.106643","tag_type":"level_of_evidence","value":"5","value_numeric":null},{"paper_doi":"10.1016/j.ekir.2026.106643","tag_type":"modality","value":"BTK Inhibitor","value_numeric":null},{"paper_doi":"10.1016/j.ekir.2026.106643","tag_type":"study_design","value":"Case Report","value_numeric":null},{"paper_doi":"10.1016/j.ekir.2026.106643","tag_type":"warning","value":"Full text was not available — summary is based on title and journal metadata only; specific patient numbers, biopsy timing, and clinical outcomes could not be verified.","value_numeric":null},{"paper_doi":"10.1016/j.ekir.2026.106643","tag_type":"warning","value":"Impact flag 'practice_changing' is applied cautiously given the case-level evidence, but the ultrastructural resolution finding is clinically novel.","value_numeric":null},{"paper_doi":"10.1016/j.ekir.2026.106643","tag_type":"warning","value":"The paper appears to be a case report or very small series; sample size was not explicitly stated in the provided metadata, so sample_size tag was omitted.","value_numeric":null}],"summaries":{"limitations":"Case report or small series limits generalizability; causal inference between ibrutinib and ultrastructural resolution cannot be fully established without a control group.","what_studied":"This report evaluated whether ibrutinib therapy could resolve the defining organized ultrastructural deposits of immunotactoid glomerulopathy (ITG) associated with chronic lymphocytic leukemia (CLL), assessed by repeat kidney biopsy.","key_result":"Following ibrutinib treatment for CLL, the characteristic organized microtubular deposits of ITG disappeared on follow-up electron microscopy, suggesting disease remission at the ultrastructural level.","practice_takeaway":"In patients with CLL-associated immunotactoid glomerulopathy, treating the underlying CLL with ibrutinib may lead to resolution of the defining renal ultrastructural lesion — consider repeat biopsy to confirm response."}},{"doi":"10.1016/s2352-3026(26)00037-2","pmid":"42069409","title":"Safety and activity of pirtobrutinib in patients with relapsed or refractory Waldenström macroglobulinaemia: 5-year follow-up of the open-label, multicentre, phase 1/2 BRUIN trial","journal_title":"The Lancet Haematology","journal_issn":"2352-3026","published_at":"2026-05-01T00:00:00.000Z","url":"https://doi.org/10.1016/s2352-3026(26)00037-2","source_score":14,"is_retracted":false,"is_open_access":false,"raw_metadata":{"pubmed":true,"crossref":true,"unpaywall":true},"created_at":"2026-05-07T22:50:10.506Z","updated_at":"2026-05-07T22:50:10.506Z","tags":[{"paper_doi":"10.1016/s2352-3026(26)00037-2","tag_type":"age_group","value":"adult","value_numeric":null},{"paper_doi":"10.1016/s2352-3026(26)00037-2","tag_type":"age_group","value":"older_adult","value_numeric":null},{"paper_doi":"10.1016/s2352-3026(26)00037-2","tag_type":"category","value":"Hematology","value_numeric":null},{"paper_doi":"10.1016/s2352-3026(26)00037-2","tag_type":"condition","value":"Waldenström Macroglobulinaemia","value_numeric":null},{"paper_doi":"10.1016/s2352-3026(26)00037-2","tag_type":"generic","value":"pirtobrutinib","value_numeric":null},{"paper_doi":"10.1016/s2352-3026(26)00037-2","tag_type":"impact_flag","value":"practice_changing","value_numeric":null},{"paper_doi":"10.1016/s2352-3026(26)00037-2","tag_type":"level_of_evidence","value":"3","value_numeric":null},{"paper_doi":"10.1016/s2352-3026(26)00037-2","tag_type":"modality","value":"BTK Inhibitor","value_numeric":null},{"paper_doi":"10.1016/s2352-3026(26)00037-2","tag_type":"sample_size","value":"n=80","value_numeric":80},{"paper_doi":"10.1016/s2352-3026(26)00037-2","tag_type":"sex","value":"mixed","value_numeric":null},{"paper_doi":"10.1016/s2352-3026(26)00037-2","tag_type":"study_design","value":"Phase 1/2 Open-Label Single-Arm Trial","value_numeric":null},{"paper_doi":"10.1016/s2352-3026(26)00037-2","tag_type":"warning","value":"Median follow-up of 35 months is notable but long-term durability (e.g., median PFS/OS) is not fully reported in the abstract; progression-free survival data should be sought in the full paper.","value_numeric":null},{"paper_doi":"10.1016/s2352-3026(26)00037-2","tag_type":"warning","value":"The 'practice_changing' impact flag reflects a strong ORR in a setting with limited options post-covalent BTK inhibitor, but is based on a single-arm trial without a randomised comparator.","value_numeric":null},{"paper_doi":"10.1016/s2352-3026(26)00037-2","tag_type":"warning","value":"The primary phase 2 endpoint of BRUIN was ORR in CLL/SLL/MCL — the WM cohort is a secondary analysis, so formal hypothesis testing was not powered for this subgroup.","value_numeric":null}],"summaries":{"what_studied":"Pirtobrutinib (200 mg orally once daily), a non-covalent BTK inhibitor, was evaluated in 80 patients with relapsed/refractory Waldenström macroglobulinaemia (79% previously treated with covalent BTK inhibitors) in the open-label, multicentre, phase 1/2 BRUIN trial, with a median follow-up of 35 months.","key_result":"Overall objective response rate was 82.5% (95% CI 72.4–90.1); ORR was 81.0% in prior covalent BTK inhibitor-exposed patients and 88.2% in BTK inhibitor-naive patients. Grade ≥3 treatment-emergent adverse events occurred in 71% of patients; only 5% needed dose reductions and 15% discontinued due to adverse events.","limitations":"- Waldenström macroglobulinaemia was a secondary cohort; the phase 2 primary endpoint was in CLL/SLL/MCL, not WM.\n- Small sample size (n=80) limits precision of subgroup estimates.\n- Open-label, single-arm design with no comparator arm.","practice_takeaway":"For patients with relapsed/refractory Waldenström macroglobulinaemia who have failed or are intolerant to covalent BTK inhibitors, pirtobrutinib offers an ORR above 80% with a manageable safety profile and low discontinuation rate. Consider it as a next-line option after covalent BTK inhibitor exposure."}},{"doi":"10.1200/jco-25-01928","pmid":"42054619","title":"Integrative Molecular Analysis Reveals Determinants of Clinical Outcomes in\n TP53\n -Mutated Diffuse Large B-Cell Lymphoma","journal_title":"Journal of Clinical Oncology","journal_issn":"0732-183X","published_at":"2026-04-29T00:00:00.000Z","url":"https://doi.org/10.1200/jco-25-01928","source_score":22,"is_retracted":false,"is_open_access":false,"raw_metadata":{"ooir":{"day":"2026-05-08","doi":"10.1200/jco-25-01928","days":"7","issn":"0732-183X","rank":"9","field":"Clinical Medicine","score":"22","category":"Oncology","categories":["Oncology"],"_categories":["Oncology"]},"pubmed":{"doi":"10.1200/JCO-25-01928","title":"Integrative Molecular Analysis Reveals Determinants of Clinical Outcomes in ","journal":"Journal of clinical oncology : official journal of the American Society of Clinical Oncology","methods":"","results":"","abstract":"Mutations in \nClinical and molecular data for 3,091 patients were derived from 10 cohorts of patients with newly diagnosed DLBCL treated with frontline rituximab-based immunochemotherapy regimens. Targeted or whole-exome/whole-genome sequencing was available for all patients. Bulk RNA-seq was analyzed for 591 patient samples. The primary outcome measures were progression-free survival (PFS) and overall survival (OS).\nThe poor prognosis of ","keywords":[],"pubmed_id":"42054619","conclusions":"The poor prognosis of ","publication_date":"2026-04-29T00:00:00"},"crossref":{"DOI":"10.1200/jco-25-01928","URL":"https://doi.org/10.1200/jco-25-01928","ISSN":["0732-183X","1527-7755"],"link":[{"URL":"https://ascopubs.org/doi/pdfdirect/10.1200/JCO-25-01928","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"page":null,"type":"journal-article","issue":null,"score":1,"title":["Integrative Molecular Analysis Reveals Determinants of Clinical Outcomes in\n TP53\n -Mutated Diffuse Large B-Cell Lymphoma"],"author":[{"given":"Manik","family":"Uppal","sequence":"first","affiliation":[{"name":"Division of Hematology/Oncology, Icahn School of Medicine at Mount Sinai, New York, NY"},{"name":"Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY"}]},{"given":"Bhavneet","family":"Bhinder","sequence":"additional","affiliation":[{"name":"Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY"}]},{"given":"Andrew R.","family":"Marderstein","sequence":"additional","affiliation":[{"name":"Clinical Genetics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY"}]},{"given":"Connie","family":"Lee Batlevi","sequence":"additional","affiliation":[{"name":"Lymphoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY"},{"name":"Genentech, Inc, South San Francisco, CA"}]},{"given":"Lorenzo","family":"Falchi","sequence":"additional","affiliation":[{"name":"Lymphoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY"},{"name":"Department of Medicine, Weill Cornell Medical College, Cornell University, New York, NY"}]},{"given":"Paul","family":"Hamlin","sequence":"additional","affiliation":[{"name":"Lymphoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY"},{"name":"Department of Medicine, Weill Cornell Medical College, Cornell University, New York, NY"}]},{"given":"Steven","family":"Horwitz","sequence":"additional","affiliation":[{"name":"Lymphoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY"},{"name":"Department of Medicine, Weill Cornell Medical College, Cornell University, New York, NY"}]},{"given":"Anita","family":"Kumar","sequence":"additional","affiliation":[{"name":"Lymphoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY"},{"name":"Department of Medicine, Weill Cornell Medical College, Cornell University, New York, NY"}]},{"given":"Ariela","family":"Noy","sequence":"additional","affiliation":[{"name":"Lymphoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY"},{"name":"Department of Medicine, Weill Cornell Medical College, Cornell University, New York, NY"}]},{"given":"Andrew D.","family":"Zelenetz","sequence":"additional","affiliation":[{"name":"Lymphoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY"},{"name":"Department of Medicine, Weill Cornell Medical College, Cornell University, New York, NY"}]},{"given":"Jennifer K.","family":"Lue","sequence":"additional","affiliation":[{"name":"Lymphoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY"},{"name":"Department of Medicine, Weill Cornell Medical College, Cornell University, New York, NY"}]},{"given":"Pallawi","family":"Torka","sequence":"additional","affiliation":[{"name":"Lymphoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY"},{"name":"Department of Medicine, Weill Cornell Medical College, Cornell University, New York, NY"}]},{"given":"Zachary D.","family":"Epstein-Peterson","sequence":"additional","affiliation":[{"name":"Lymphoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY"},{"name":"Department of Medicine, Weill Cornell Medical College, Cornell University, New York, NY"}]},{"given":"Maria","family":"Arcila","sequence":"additional","affiliation":[{"name":"Hematopathology Service, Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY"}]},{"given":"Ahmet","family":"Dogan","sequence":"additional","affiliation":[{"name":"Hematopathology Service, Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY"}]},{"given":"Brandon","family":"Imber","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY"}]},{"given":"Joachim","family":"Yahalom","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY"}]},{"given":"Santosha A.","family":"Vardhana","sequence":"additional","affiliation":[{"name":"Lymphoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY"},{"name":"Department of Medicine, Weill Cornell Medical College, Cornell University, New York, NY"},{"name":"Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY"}]},{"given":"Andrew","family":"Intlekofer","sequence":"additional","affiliation":[{"name":"Lymphoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY"},{"name":"Department of Medicine, Weill Cornell Medical College, Cornell University, New York, NY"},{"name":"Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY"}]},{"given":"Sandeep","family":"Raj","sequence":"additional","affiliation":[{"name":"Department of Medicine, Weill Cornell Medical College, Cornell University, New York, NY"},{"name":"Cellular Therapy Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY"},{"name":"Adult Bone Marrow Transplant Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY"}]},{"given":"Roni","family":"Shouval","sequence":"additional","affiliation":[{"name":"Department of Medicine, Weill Cornell Medical College, Cornell University, New York, NY"},{"name":"Cellular Therapy Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY"},{"name":"Adult Bone Marrow Transplant Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY"}]},{"given":"Brendan","family":"Hodkinson","sequence":"additional","affiliation":[{"name":"Oncology Translational Research, Janssen Research and Development, Spring House, PA"}]},{"given":"Matthew E.","family":"Stokes","sequence":"additional","affiliation":[{"name":"Informatics and Predictive Sciences, Bristol Myers Squibb, Summit, NJ"}]},{"given":"Adam S.","family":"Kittai","sequence":"additional","affiliation":[{"name":"Division of Hematology/Oncology, Icahn School of Medicine at Mount Sinai, New York, NY"}]},{"given":"Joshua D.","family":"Brody","sequence":"additional","affiliation":[{"name":"Division of Hematology/Oncology, Icahn School of Medicine at Mount Sinai, New York, NY"}]},{"given":"Olivier","family":"Elemento","sequence":"additional","affiliation":[{"name":"Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY"}]},{"given":"Gilles","family":"Salles","sequence":"additional","affiliation":[{"name":"Lymphoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY"},{"name":"Department of Medicine, Weill Cornell Medical College, Cornell University, New York, NY"}]},{"given":"Erel","family":"Joffe","sequence":"additional","affiliation":[{"name":"Lymphoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New 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no outcomes or effect sizes are reported.","value_numeric":null},{"paper_doi":"10.1200/jco-25-01928","tag_type":"warning","value":"Design classification inferred as a cohort analysis; prospective vs retrospective methods and pooling approach are not specified.","value_numeric":null},{"paper_doi":"10.1200/jco-25-01928","tag_type":"warning","value":"Only a subset (591/3,091) had bulk RNA-seq; how this subset was used is unclear from the excerpt.","value_numeric":null},{"paper_doi":"10.1200/jco-25-01928","tag_type":"warning","value":"RNA-seq microenvironment data were available for only 591 of 3,091 patients, limiting generalizability of tumor microenvironment findings.","value_numeric":null},{"paper_doi":"10.1200/jco-25-01928","tag_type":"warning","value":"The impact_flag 'practice_changing' reflects the VAF-stratification and ibrutinib findings, but both require prospective validation; clinicians should interpret cautiously.","value_numeric":null},{"paper_doi":"10.1200/jco-25-01928","tag_type":"warning","value":"The Phoenix trial re-analysis is exploratory and retrospective; ibrutinib is not currently standard of care for DLBCL—prospective confirmation is needed before clinical adoption.","value_numeric":null}],"summaries":{"key_result":"TP53 mutations were 6× more prevalent than MYC/BCL2/BCL6 double-/triple-hit status but carried similar adverse prognostic risk. VAF ≥ 75% (loss of heterozygosity) conferred significantly worse PFS/OS, with downregulated interferon signaling and lower macrophage content. Re-analysis of the Phoenix trial showed ibrutinib added to R-CHOP improved PFS in TP53-mutant DLBCL and eliminated the high-VAF disadvantage, regardless of age.","limitations":"Retrospective, multi-cohort design with heterogeneous sequencing platforms and treatment regimens. RNA-seq data available only in a subset (591/3,091 patients). Phoenix trial re-examination is exploratory and not a pre-specified analysis.","practice_takeaway":"In TP53-mutant DLBCL, assess VAF at diagnosis—VAF ≥ 75% flags a markedly higher-risk subgroup. Phoenix trial data suggest ibrutinib augmentation of R-CHOP may offset this risk, warranting prospective validation.","what_studied":"Pooled clinical and molecular data from 3,091 patients with newly diagnosed diffuse large B‑cell lymphoma treated with frontline rituximab‑based immunochemotherapy across 10 cohorts, focusing on TP53‑mutated disease. Sequencing (targeted, WES, or WGS) was available for all patients; bulk RNA‑seq for 591, with progression‑free and overall survival as primary outcomes."}},{"doi":"10.1182/bloodadvances.2025018536","pmid":"41587482","title":"An indirect comparison of zanubrutinib vs acalabrutinib plus venetoclax in patients with treatment-naive CLL","journal_title":"Blood Advances","journal_issn":"2473-9529","published_at":"2026-04-15T00:00:00.000Z","url":"https://doi.org/10.1182/bloodadvances.2025018536","source_score":35,"is_retracted":false,"is_open_access":true,"raw_metadata":{"pubmed":true,"crossref":true,"unpaywall":true},"created_at":"2026-05-07T22:51:15.129Z","updated_at":"2026-05-07T22:51:15.129Z","tags":[{"paper_doi":"10.1182/bloodadvances.2025018536","tag_type":"age_group","value":"adult","value_numeric":null},{"paper_doi":"10.1182/bloodadvances.2025018536","tag_type":"age_group","value":"older_adult","value_numeric":null},{"paper_doi":"10.1182/bloodadvances.2025018536","tag_type":"brand","value":"Brukinsa","value_numeric":null},{"paper_doi":"10.1182/bloodadvances.2025018536","tag_type":"brand","value":"Calquence","value_numeric":null},{"paper_doi":"10.1182/bloodadvances.2025018536","tag_type":"brand","value":"Venclexta","value_numeric":null},{"paper_doi":"10.1182/bloodadvances.2025018536","tag_type":"category","value":"Hematology","value_numeric":null},{"paper_doi":"10.1182/bloodadvances.2025018536","tag_type":"condition","value":"Chronic Lymphocytic Leukemia","value_numeric":null},{"paper_doi":"10.1182/bloodadvances.2025018536","tag_type":"condition","value":"Small Lymphocytic Lymphoma","value_numeric":null},{"paper_doi":"10.1182/bloodadvances.2025018536","tag_type":"generic","value":"acalabrutinib","value_numeric":null},{"paper_doi":"10.1182/bloodadvances.2025018536","tag_type":"generic","value":"venetoclax","value_numeric":null},{"paper_doi":"10.1182/bloodadvances.2025018536","tag_type":"generic","value":"zanubrutinib","value_numeric":null},{"paper_doi":"10.1182/bloodadvances.2025018536","tag_type":"impact_flag","value":"confirms_prior","value_numeric":null},{"paper_doi":"10.1182/bloodadvances.2025018536","tag_type":"level_of_evidence","value":"3","value_numeric":null},{"paper_doi":"10.1182/bloodadvances.2025018536","tag_type":"modality","value":"BCL2 Inhibitor","value_numeric":null},{"paper_doi":"10.1182/bloodadvances.2025018536","tag_type":"modality","value":"BTK Inhibitor","value_numeric":null},{"paper_doi":"10.1182/bloodadvances.2025018536","tag_type":"sample_size","value":"n=872","value_numeric":872},{"paper_doi":"10.1182/bloodadvances.2025018536","tag_type":"sex","value":"mixed","value_numeric":null},{"paper_doi":"10.1182/bloodadvances.2025018536","tag_type":"study_design","value":"Post Hoc Indirect Comparison / Matching-Adjusted Indirect Comparison (MAIC)","value_numeric":null},{"paper_doi":"10.1182/bloodadvances.2025018536","tag_type":"warning","value":"Safety comparisons between zanubrutinib (SEQUOIA) and acalabrutinib-venetoclax (AMPLIFY) used the overall ITT population, not the fit subgroup, limiting direct applicability.","value_numeric":null},{"paper_doi":"10.1182/bloodadvances.2025018536","tag_type":"warning","value":"SEQUOIA enrolled older, less fit patients (median age 71 years) compared to AMPLIFY (median age 61 years); despite matching, residual confounding by fitness and age is likely.","value_numeric":null},{"paper_doi":"10.1182/bloodadvances.2025018536","tag_type":"warning","value":"Study design is ambiguous: this is a post hoc, cross-trial indirect comparison (MAIC), not a traditional RCT or observational cohort; level of evidence assigned as 3 reflects this limitation.","value_numeric":null},{"paper_doi":"10.1182/bloodadvances.2025018536","tag_type":"warning","value":"The study was funded by BeOne Medicines (manufacturer of zanubrutinib), and several authors are employees or receive compensation from BeOne Medicines; potential for industry bias should be considered.","value_numeric":null},{"paper_doi":"10.1182/bloodadvances.2025018536","tag_type":"warning","value":"The total sample size of n=872 combines fit-subgroup patients from SEQUOIA (zanubrutinib n=123, BR n=129) and AMPLIFY patients (acalabrutinib-venetoclax n=291, FCR/BR n=290); the MAIC effective sample size was 206 for zanubrutinib after reweighting.","value_numeric":null}],"summaries":{"what_studied":"This post hoc analysis used an unadjusted indirect comparison and anchored matching-adjusted indirect comparison (MAIC) to compare PFS outcomes of continuous zanubrutinib monotherapy (SEQUOIA trial, n=123 fit patients) vs fixed-duration acalabrutinib-venetoclax (AMPLIFY trial, n=291) in treatment-naive, fit CLL patients without del(17p) or TP53 mutations, over ~40 months of median follow-up.","key_result":"3-year investigator-assessed PFS was 89.2% with zanubrutinib vs 78.9% with acalabrutinib-venetoclax in the unadjusted fit-population analysis. Anchored MAIC showed significantly longer PFS with zanubrutinib (HR 0.45; 95% CI 0.23–0.88; P=.0197); age-adjusted analysis yielded HR 0.26 (95% CI 0.13–0.54; P<.0003).","limitations":"- Post hoc analysis, not powered to detect differences between zanubrutinib and acalabrutinib-venetoclax; cross-trial comparison introduces potential confounding.\n- SEQUOIA enrolled an older, less fit population (median age 71 vs 61 years in AMPLIFY), limiting direct comparability despite matching adjustments.\n- Comparison of continuous vs fixed-duration regimens does not capture PFS2 or retreatment outcomes, and longer follow-up is needed.","practice_takeaway":"In fit, treatment-naive CLL patients without del(17p)/TP53 mutations, continuous zanubrutinib monotherapy showed numerically better 3-year PFS than fixed-duration acalabrutinib-venetoclax across multiple indirect comparison methods. Until head-to-head data (e.g., CELESTIAL-TNCLL) are available, clinicians can use these results to inform discussions about continuous BTK inhibitor monotherapy as an alternative to combination fixed-duration regimens."}},{"doi":"10.1016/j.clml.2026.01.010","pmid":"41720666","title":"Pseudo-Richter Transformation Following BTKi Interruption in CLL: A Systematic Review of Clinical, Biological, and Pathologic Features","journal_title":"Clinical Lymphoma Myeloma and Leukemia","journal_issn":"2152-2650","published_at":"2026-01-29T00:00:00.000Z","url":"https://doi.org/10.1016/j.clml.2026.01.010","source_score":10,"is_retracted":false,"is_open_access":true,"raw_metadata":{"pubmed":true,"crossref":true,"unpaywall":true},"created_at":"2026-05-16T13:22:27.448Z","updated_at":"2026-05-16T13:22:27.448Z","tags":[{"paper_doi":"10.1016/j.clml.2026.01.010","tag_type":"age_group","value":"older_adult","value_numeric":null},{"paper_doi":"10.1016/j.clml.2026.01.010","tag_type":"category","value":"Hematology","value_numeric":null},{"paper_doi":"10.1016/j.clml.2026.01.010","tag_type":"condition","value":"Chronic Lymphocytic Leukemia","value_numeric":null},{"paper_doi":"10.1016/j.clml.2026.01.010","tag_type":"condition","value":"Pseudo-Richter Transformation","value_numeric":null},{"paper_doi":"10.1016/j.clml.2026.01.010","tag_type":"condition","value":"Richter Transformation","value_numeric":null},{"paper_doi":"10.1016/j.clml.2026.01.010","tag_type":"generic","value":"acalabrutinib","value_numeric":null},{"paper_doi":"10.1016/j.clml.2026.01.010","tag_type":"generic","value":"ibrutinib","value_numeric":null},{"paper_doi":"10.1016/j.clml.2026.01.010","tag_type":"generic","value":"zanubrutinib","value_numeric":null},{"paper_doi":"10.1016/j.clml.2026.01.010","tag_type":"impact_flag","value":"practice_changing","value_numeric":null},{"paper_doi":"10.1016/j.clml.2026.01.010","tag_type":"level_of_evidence","value":"4","value_numeric":null},{"paper_doi":"10.1016/j.clml.2026.01.010","tag_type":"modality","value":"BTK Inhibitor","value_numeric":null},{"paper_doi":"10.1016/j.clml.2026.01.010","tag_type":"sample_size","value":"n=15","value_numeric":15},{"paper_doi":"10.1016/j.clml.2026.01.010","tag_type":"sex","value":"mixed","value_numeric":null},{"paper_doi":"10.1016/j.clml.2026.01.010","tag_type":"study_design","value":"Systematic Review","value_numeric":null},{"paper_doi":"10.1016/j.clml.2026.01.010","tag_type":"warning","value":"Level of evidence rated 4 (case series/systematic review of cases) given the small n and retrospective nature; no control group.","value_numeric":null},{"paper_doi":"10.1016/j.clml.2026.01.010","tag_type":"warning","value":"Specific BTKi agents involved in the 15 cases are not enumerated in the abstract; ibrutinib, acalabrutinib, and zanubrutinib were tagged based on their common use in CLL but individual case-level drug data is not confirmed from the abstract text.","value_numeric":null},{"paper_doi":"10.1016/j.clml.2026.01.010","tag_type":"warning","value":"The 'practice_changing' impact flag is applied cautiously — while the finding is highly clinically relevant, the evidence base is limited to 15 cases.","value_numeric":null}],"summaries":{"what_studied":"A systematic review of pseudo-Richter transformation (pseudo-RT) — a transient large B-cell proliferation occurring after BTK inhibitor (BTKi) interruption in CLL patients — including a new index case, examining clinical, biological, and pathologic features across 15 identified cases.","key_result":"All 15 patients had complete clinical, laboratory, and radiologic resolution after BTKi reintroduction; pseudo-RT developed 3–13 days post-interruption, was associated with trisomy 12 (78%), unmutated IGHV (5/5), and TP53 disruption (6/15); no subsequent true Richter transformation occurred over 3–36 months of follow-up.","limitations":"Very small case series (n=15) with inherent publication bias toward identified/recognized cases; only 5/15 had IGHV testing and 9/15 cytogenetic data, limiting generalizability; retrospective design with variable follow-up (3–36 months).","practice_takeaway":"When a CLL patient on BTKi develops rapid lymphadenopathy, B symptoms, or lymphocytosis within 2 weeks of BTKi interruption, consider pseudo-RT before proceeding to aggressive treatment — restarting the BTKi leads to full resolution. Key histologic clues include CD5/CD23 retention and non-GCB phenotype on biopsy."}},{"doi":"10.1001/jamadermatol.2025.4892","pmid":"41499136","title":"Zanubrutinib for Immunoglobulin A Vasculitis With Monoclonal Gammopathy","journal_title":"JAMA Dermatology","journal_issn":"2168-6068","published_at":"2026-01-07T00:00:00.000Z","url":"https://doi.org/10.1001/jamadermatol.2025.4892","source_score":5,"is_retracted":false,"is_open_access":false,"raw_metadata":{"ooir":{"day":"2026-01-10","doi":"10.1001/jamadermatol.2025.4892","days":"7","issn":"2168-6068","rank":"10","field":"Clinical Medicine","score":"5","category":"Dermatology","categories":["Dermatology"],"_categories":["Dermatology"]},"pubmed":{"doi":"10.1001/jamadermatol.2025.4892","title":"Zanubrutinib for Immunoglobulin A Vasculitis With Monoclonal Gammopathy.","journal":"JAMA dermatology","methods":"","results":"","abstract":"This case report describes a patient in his 50s with immunoglobulin A vasculitis with monoclonal B-cell lymphocytosis who was successfully treated with zanubrutinib after failure of multiple treatments.","keywords":[],"pubmed_id":"41499136","conclusions":"","publication_date":"2026-01-07T00:00:00"},"crossref":{"DOI":"10.1001/jamadermatol.2025.4892","URL":"https://doi.org/10.1001/jamadermatol.2025.4892","ISSN":["2168-6068"],"link":[{"URL":"https://jamanetwork.com/journals/jamadermatology/articlepdf/2843486/jamadermatology_warp_2026_lo_250018_1766518252.04968.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"page":null,"type":"journal-article","issue":null,"score":1,"title":["Zanubrutinib for Immunoglobulin A Vasculitis With Monoclonal Gammopathy"],"author":[{"given":"Peyton V.","family":"Warp","sequence":"first","affiliation":[{"name":"Dr Phillip Frost Department of Dermatology and Cutaneous Surgery, University of Miami, Miami, Florida"}]},{"given":"Karishma R.","family":"Desai","sequence":"additional","affiliation":[{"name":"Dr Phillip Frost Department of Dermatology and Cutaneous Surgery, University of Miami, Miami, Florida"}]},{"given":"Alvaro J.","family":"Alencar","sequence":"additional","affiliation":[{"name":"Division of Hematology, Department of Medicine, Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida"}]},{"given":"Jonathan J.","family":"Cohen","sequence":"additional","affiliation":[{"name":"Division of Hematology, Department of Medicine, Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida"}]},{"given":"Andrea D.","family":"Maderal","sequence":"additional","affiliation":[{"name":"Dr Phillip Frost Department of Dermatology and Cutaneous Surgery, University of Miami, Miami, Florida"},{"name":"Associate Editor, JAMA 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open-label extension may introduce bias for longer-term outcomes.","value_numeric":null},{"paper_doi":"10.1001/jamadermatol.2025.0733","tag_type":"warning","value":"Only the 1200 mg/d dose showed significant benefit vs placebo in the data provided; results for lower doses were not detailed.","value_numeric":null},{"paper_doi":"10.1001/jamadermatol.2025.0733","tag_type":"warning","value":"Primary analysis was limited to omalizumab-naive patients (n=143), not all randomized participants.","value_numeric":null}],"summaries":{"what_studied":"A 52-week phase 2 randomized, double-blind, placebo-controlled, dose-ranging trial tested oral rilzabrutinib (400 mg qPM, 800 mg/d, or 1200 mg/d) vs placebo for 12 weeks in adults (18-80 years) with moderate to severe antihistamine-refractory chronic spontaneous urticaria across 12 countries; the primary analysis used omalizumab-naive patients (n=143). 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