Hematological Oncology最新文献

{"title":"A GLOBAL PHASE 1B STUDY OF JNJ-90014496, A CD19/CD20 BI-SPECIFIC CHIMERIC ANTIGEN RECEPTOR (CAR) T-CELL THERAPY, IN RELAPSED/REFRACTORY (R/R) LARGE B-CELL LYMPHOMA (LBCL)","authors":"K. Patel, J. M. Rhodes, L. Mountjoy, J. H. Christensen, M. Hutchings, P. Shaughnessy, N. Farhadfar, C. Tam, J. H. Baird, A. Ramakrishnan, M. Jak, K. Dorritie, A. Barraclough, D. Morillo, Y. Serroukh, M. Schwede, A. Abdulgawad, L. Magnano, M. O'Reilly, J. Kuruvilla, Y. Koh, U. Farooq, W. S. Kim, J. Bussolari, M. Beelen, J. S. Larsen, M. Suraneni, J. Wu, L. Slaets, A. Perales-Puchalt, A. Banerjee, M. Ku","doi":"10.1002/hon.70093_104","DOIUrl":"https://doi.org/10.1002/hon.70093_104","url":null,"abstract":"<p><b>Introduction</b>: CD19 CAR T-cell therapies have transformed the treatment (tx) of R/R LBCL, with complete response rates (CRR) of up to 58% in 3L or greater setting. However, most patients (pts) relapse, in part due to antigen escape. Dual targeting of 2 validated antigens may overcome drug resistance. In a first-in-human study in China, C-CAR039, an autologous anti-CD19/CD20 bispecific CAR T-cell therapy, showed a CRR of 86% in pts with R/R LBCL and PFS and OS were not reached at 30mo median follow up (FU). We report results from the first global phase 1b study of JNJ-90014496 (formerly C-CAR039) in adult pts with R/R LBCL (NCT05421663).</p><p><b>Methods</b>: Dose levels: 2.0 million (M) CAR+ T-cell/kg (weight-based); 150M and 75M CAR+ T-cells (fixed). Primary endpoints: safety and RP2D. Secondary endpoints: objective response rate (ORR), CRR, time to first response, pharmacokinetics (PK).</p><p><b>Results</b>: As of February 2025, 48 pts with CAR T-naive, heavily pretreated R/R LBCL were infused: 2.0M CAR+ T-cells/ kg, <i>n</i> = 18; 150M, <i>n</i> = 8; 75M, <i>n</i> = 22. 46% had ≥ 2 prior lines of therapy; 65% had bridging therapy. Median FU was 6mo.</p><p>Across all doses, 38 (79%) pts had CRS (grade [G]1, 52%; G2, 23%; G3, 4%): median time to onset and median duration of 3d (range, 1–6) and 5d (range, 1–42), respectively. 7 (15%) pts had ICANS (G1, 8%; G3, 6%): median onset and median duration of 3d (range, 3–12) and 8d (range 1–89), respectively. G3/4 and serious tx-emergent adverse events (TEAEs) were reported in 40 (83%) and 12 (25%) pts, respectively. No tx-related deaths occurred. G3/4 TEAEs ≥ 15% frequency were neutropenia (77%), leukopenia (21%), anemia (19%), and thrombocytopenia (17%); 6% of pts had G3 infections.</p><p>In 42 evaluable pts, investigator-assessed ORR and CRR by Lugano criteria were 90.5% (95% CI: 77.4–97.3) and 76.2% (95% CI: 60.5–87.9; Figure), respectively. Median time to response was 1.0mo (range, 0.8–1.9).</p><p>At RP2D of 75M CAR+ T-cells (<i>n</i> = 22), 19 (86%) pts had CRS (G1, 68%; G2, 18%; no G3/4). 1 (5%) pt had G1 ICANS (no G3/4 ICANS). At RP2D, 17 (77%) pts had G3/4 TEAEs and 5 (23%) pts had serious TEAEs. G3/4 TEAEs ≥ 15% frequency at RP2D were neutropenia (68%) and lymphopenia (18%); 1 pt had G3 infection.</p><p>At RP2D in 20 evaluable pts with 3-mo median FU, ORR was 95.0% (95% CI: 75.1–99.9) and CRR was 80.0% (95% CI: 56.3–94.3; Figure).</p><p>JNJ-90014496 C<sub>max</sub> and AUC<sub>0-29d</sub> at 75M CAR+ T-cells were comparable to 2.0M CAR+ T-cells/kg and 150M CAR+ T-cells. Median t<sub>max</sub> was seen on Day15 at 75M CAR+ T-cells versus on Day13 at other doses. High inter-pt variability was seen at each dose.</p><p><b>Conclusions:</b> The safety, efficacy, and PK profile support selection of 75M CAR+ T-cells as the RP2D of JNJ-90014496 in R/R LBCL. CRR of 80% and no G3/4 ICANS/CRS from this first global study are promising, confirm previous findings in Chinese pts, and compare favorabl","PeriodicalId":12882,"journal":{"name":"Hematological Oncology","volume":"43 S3","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hon.70093_104","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144299624","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"BENDAMUSTINE SUPERCHARGE PLUS BRENTUXIMAB VEDOTIN AS EARLY SALVAGE FOLLOWING FAILURE OF 2 ABVD CYCLES IN HL: LONG-TERM RESULTS OF A RETROSPECTIVE MULTICENTER STUDY","authors":"C. Giordano, M. Picardi, N. Pugliese, A. Vincenzi, S. Avilia, L. De Fazio, M. Lamagna, R. Reina, A. Scarpa, A. Lombardi, E. Vigliar, G. Troncone, M. Mascolo, C. Mainolfi, R. Fonti, S. Del Vecchio, V. Damiano, R. Bianco, F. Trastulli, M. Annunziata, A. Salemme, M. Carchia, F. Pane","doi":"10.1002/hon.70094_360","DOIUrl":"https://doi.org/10.1002/hon.70094_360","url":null,"abstract":"<p>Treatment intensification with salvage therapy, and high-dose chemotherapy (HDT) and autologous stem cell transplantation (ASCT) is the best course of action for patients aged ≤ 60 years with classic Hodgkin lymphoma (c-HL) who fail to obtain complete metabolic remission (CMR) to first-line therapy. However, the clinical impact of early treatment intensification in patients showing positron emission tomography (PET)-positive evaluation after two cycles of ABVD remains to be confirmed. Theoretically, sequential brentuximab vedotin and bendamustine supercharge, that is, Bv+Bs<sub>21</sub>, as 3-day outpatient i.v. infusions of 1.8 mg/kg Bv on day 1 and Bs on days 2 and 3 at a fixed dose of 120 mg/m<sup>2</sup>/day, is a promising salvage regimen in this setting. We carried out a multicenter retrospective study (NCT06295211) including 50 adult patients with c-HL who had PET-positive (Deauville scale score ≥ 4) scans after two cycles of ABVD from 1 September 2013 to 1 September 2023. In all, 46 of the 50 collected patients were enrolled (median age, 37 years; range, 19–60). In fact, 42 cases received the four 3-week courses of Bv+Bs<sub>21</sub> followed by ASCT, four cases received the scheduled Bv+Bs<sub>21</sub> regimen without ASCT (patient’s decision), and four patients were excluded for alternative salvage regimens (<i>n</i> = 3) and insufficient information (<i>n</i> = 1). The primary endpoint was 5-year progression-free survival (PFS) calculated for patients receiving four courses of Bv+Bs<sub>21</sub> plus HDT and ASCT, and for those who received only four courses of Bv+Bs<sub>21</sub>. Secondary endpoints were the overall response rate, overall survival (OS), toxicity, peripheral blood stem cell (PBSC) collection and bridge to transplant, and feasibility of Bv+Bs21 regimen. With a median follow-up of 60 months (range, 7–132 months), the overall enrolled population PFS rate was 82% (86% for patients undergoing ASCT and 50% for those not receiving ASCT). The PFS stratified according to the pre-salvage treatment FDG-PET was 100% for DS score of 4 (<i>n</i> = 12) and 78% for DS score 5 (<i>n</i> = 34). With a median follow-up of 60 months, the 5-year OS rate of the entire analyzed population was 90%. After Bv+Bs<sub>21</sub> regimen, 42 patients obtained CMR and four partial metabolic remissions, with a rate of overall response of 100%. PBSC mobilization and harvest were successful in all cases, with a median CD34+ cells/kg yield of 4.1 × 10<sup>6</sup> (range, 1.9–5.1 × 10<sup>6</sup>). Overall, the most common adverse events were hematological of any grade, while, due to the specific premedication against acute toxicity during the i.v. administration of Bv+Bs<sub>21</sub>, serious infusion related reactions occurred only in three patients. All patients were efficacy-evaluable patients having completed four courses of Bv+Bs<sub>21</sub>: ≤ 10% of patients received < 85% of the planned treatment. In our study, early treatment intensificat","PeriodicalId":12882,"journal":{"name":"Hematological Oncology","volume":"43 S3","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hon.70094_360","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144299644","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MATCH-ADJUSTED COMPARISON OF EPCORITAMAB VERSUS NON-ANTHRACYCLINE CHEMOIMMUNOTHERAPY IN NEWLY DIAGNOSED DIFFUSE LARGE B-CELL LYMPHOMA PATIENTS WITH HIGH CARDIOVASCULAR RISK","authors":"P. C. Johnson, E. Guo, G. Zhang, T. Wang, V. Patel, A. Mutebi, M. Atiya, J. Ukropec, A. Wang, S. Diness Vindeløv, J. Darrah","doi":"10.1002/hon.70094_291","DOIUrl":"https://doi.org/10.1002/hon.70094_291","url":null,"abstract":"<p><b>Introduction:</b> Anthracycline-containing (AC) chemoimmunotherapy (CIT) regimens may be unsuitable for patients (pts) with newly diagnosed diffuse large B-cell lymphoma (DLBCL) who are older and/or have specific comorbidities, due to elevated risk of cardiovascular toxicities. Consequently, pts with high-risk cardiovascular (HRCV) status are often treated with non-AC CIT. In the EPCORE DLBCL-3 (NCT05660967) trial, epcoritamab (epcor) monotherapy (mono) showed promising efficacy and manageable safety in pts with newly diagnosed DLBCL and HRCV status (Morschhauser F et al. <i>Blood.</i> 2024;144:867). This analysis compares the efficacy of epcor mono versus non-AC CIT in pts with newly diagnosed DLBCL and HRCV status.</p><p><b>Methods:</b> Individual pt data for first-line (1L) epcor from the EPCORE DLBCL-3 trial were compared with pts treated with 1L non-AC CIT in the real-world setting. Pts diagnosed with DLBCL from 2007–2017 were identified from the US National Cancer Institute Surveillance, Epidemiology, and End Results database for initial diagnosis records and linked to the US Medicare database for treatment details using diagnosis codes (ICD-O-3: 9680/9688). Non-AC CITs included R-CVP (rituximab, cyclophosphamide, vincristine sulfate, and prednisone) or R-CEOP (rituximab, cyclophosphamide, etoposide, vincristine, and oral prednisolone) and BR (bendamustine and rituximab). HRCV status was defined using the Cardio-Oncology Study Group of the Heart Failure Association of the European Society of Cardiology criteria (Lyon AR et al. <i>Eur J Heart Fail</i> 2020;22:1945) and based on age and/or presence of comorbidities, including heart failure, valvular disease, myocardial infarction, coronary revascularization, hypertension, diabetes, or kidney disease. Inverse probability of treatment weighting was used to balance treatment cohorts on key available variables: age, gender, Ann Arbor stage, HRCV score, and postdiagnosis time-to-treatment. The primary endpoint was overall survival (OS). Hazard ratios (HRs) were estimated by weighted Cox regression models; time-to-event Kaplan-Meier curves were compared using log-rank tests.</p><p><b>Results:</b> Eighty-one pts receiving non-AC CIT and 45 receiving epcor were included. Before adjustment, the epcor cohort had fewer females (60.0% vs. 70.4%), fewer pts aged ≥ 80 years (82.2% vs. 95.1%), fewer pts with Ann Arbor stage III/IV (66.7% vs. 72.8%), and lower mean HRCV score (7.0 vs. 8.4). Adjusted OS was significantly improved in epcor (median OS not evaluable) versus non-AC CIT cohorts (median OS 10.2; HR 0.30 [95% CI: 0.14–0.66; <i>p</i> = 0.0027]). Subgroup analyses were consistent for non-AC CIT regimens: epcor versus R-CVP/R-CEOP (HR 0.34 [95% CI: 0.16–0.74]; <i>p</i> = 0.0067]) and epcor versus BR (HR 0.21 [95% CI: 0.08–0.56]; <i>p</i> = 0.0019) (Figures A–C).</p><p><b>Conclusions:</b> In the 1L treatment of DLBCL with HRCV status, epcor mono demonstrated significantly improved OS versus non-AC","PeriodicalId":12882,"journal":{"name":"Hematological Oncology","volume":"43 S3","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hon.70094_291","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144299583","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MULTI-OMICS DISSECTION OF EBV-DRIVEN HETEROGENEITY, METABOLIC REMODELING, AND TUMOR CELLULAR LANDSCAPE IN ENKTL PROGRESSION","authors":"J. Liang, K. Du, W. Xu","doi":"10.1002/hon.70094_195","DOIUrl":"https://doi.org/10.1002/hon.70094_195","url":null,"abstract":"<p><b>Introduction:</b> ENKTL is an aggressive lymphoma associated with EBV infection. While predominantly involving the upper aerodigestive tract (UAT) with better-prognosis early-stage disease (<b>Model-I</b>), advanced UAT-ENKTL (<b>Model-II)</b> and non-UAT (NUAT; <b>Model-III</b>) exhibit worse survival outcomes, validated in our 341-patient cohort. We utilized multi-omics approach integrating EBV virome analysis with <b>tumor microenvironment</b> and <b>metabolic reprogramming</b> to decipher the molecular drivers of clinical heterogeneity.</p><p><b>Methods:</b> The study enrolled 65 ENKTL patients (pts) from our center. We profiled using DNA-target gene sequencing (<i>N</i> = 42), RNAseq (<i>N</i> = 35), metabolomic assay (<i>N</i> = 42) and scRNAseq with EBV tag (<i>N</i> = 23) (Figure A).</p><p><b>Results:</b> We classified ENKTL into five groups: early-stage TN (<b>GroupA</b>), early-stage PD (<b>GroupB</b>), advanced UAT-ENKTL TN (<b>GroupC</b>), non-UAT TN (<b>GroupD</b>), and non-UAT PD (<b>GroupE</b>). Single-cell RNAseq (<i>n</i> = 280,939 cells) revealed T/NK cells, macrophages, and fibroblasts as predominant cell types (Figure B). By leveraging EBV tags at single-cell resolution, we characterized EBV infection patterns, showing predominant infection of NK cells (10%–67%, except NK_C13) and Teff cells (Figure C). Contrary to prior understanding, all EBV+ NK/T cells exhibited latency type I infection (Figure D). EBV+ NK cells were more prevalent in nasal versus non-nasal lesions and in PD versus TN lesions (GroupB > A, E > D). InferCNV analysis identified malignant NK cells, and they distributed in distinct groups with different functions (Figure E). Widely distributed NK_C1/C3 displayed functional trends aligned with the above. Bulk RNAseq validated the associations of NK_C4/C8 with advanced stages and poor prognosis by ssGSEA score (Figure F-G). EBV+ NK_C3/C8/C11/C12/C14 showed enhanced DNA modification and innate immunity, whereas EBV- NK cells mediated adaptive immunity, migration, and energy metabolism (Figure H). Gene module analysis uncovered two mutually exclusive modules: Module 4 featured immune activation (NK_C1/C2/C4), while Module 8 involved metabolic reprogramming (glycolysis/nucleotide metabolism) linked to poor prognosis (Figure I–L). Serum metabolomics revealed lipid metabolism enrichment in Model-III versus deficiency in Model-I. Monocle2 analysis demonstrated increasing blast NK cells during progression, with early-stage pts dominated by mature NK cells retaining cytotoxic functions (Figure M–O). CytoTRACE analysis confirmed higher stemness in EBV+ versus EBV- NK subpopulations, supporting EBV-driven proliferation (Figure P). Spatial heterogeneity was observed in fibroblasts: groupA/B/C contained Fibroblasts_MMP1 mediating ECM remodeling, while groupD/E featured Fibroblasts_ADH1B involved in antigen presentation and IFN signaling (Figure Q–S).</p><p><b>Conclusions:</b> In this largest multi-omics study focu","PeriodicalId":12882,"journal":{"name":"Hematological Oncology","volume":"43 S3","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hon.70094_195","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144299623","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"THE TOLL-LIKE RECEPTOR 7/8 PATHWAY HAS PROGNOSTIC SIGNIFICANCE AND IS A THERAPEUTIC TARGET IN CNS LYMPHOMAS","authors":"H. Geng, M. Randall, A. Ballapuram, L. Chen, C. Yung, M. Lu, C. Lowell, J. L. Rubenstein","doi":"10.1002/hon.70093_116","DOIUrl":"https://doi.org/10.1002/hon.70093_116","url":null,"abstract":"<p><b>Introduction:</b> The tumor microenvironment (TME) likely contributes to therapeutic resistance in CNS lymphomas (CNSL). Tumor-associated myeloid cells (TAMs), both macrophages and microglia, likely suppress the adaptive immune response and facilitate lymphoma progression via several mechanisms. Stimulation of TAMs via toll like receptors (TLRs) may potentiate an anti-tumor immune response.</p><p><b>Methods:</b> We evaluated the phenotypes and prognostic significance of TAMs in clinical investigations and preclinical models and are investigating the pharmcodynamic impact of systemic and intratumoral injection of a TLR 7/8 agonist in a syngeneic A20 model of CNSL.</p><p><b>Results:</b> Reductions in anti-tumor M1 TAMs in the TME, with transcriptional features of IFN-ϒ activation, are associated with tumor progression in patients with relapsed CNSL treated with rituximab, methotrexate and lenalidomide. IFN-ϒ knockout mice exhibit accelerated CNS lymphoma progression in tumor models and TAMs from IFN-ϒ wild-type mice exhibit a transcriptional phenotype consistent with TLR7/8 pathway activation. Higher TLR8 expression by TAMs correlated with longer PFS in a discovery set of PCNSL cases, and was associated with longer OS and high CD8 expression in a multicenter validation series. Expression of TLR8 by human macrophages, differentiated from PBMCs, is induced with IFN-ϒ, yielding M1 macrophages, but not by IL-4. These data demonstrate that TLR8 is a novel marker of M1 macrophages with prognostic significance, and suggest that pharmacologic agonists of the TLR7/8 pathway have potential to activate the anti-tumor potential of TAMs in CNS lymphomas. In collaboration with Gilead, we performed preclinical evaluations of a human TLR8 agonist, which activates mouse TLR7, via stereotactic injection of non-tumor bearing brains in BALB/c mice, demonstrating pharmacodynamic potency and safety. Intra-CNS injection of TLR7 agonist, but not vehicle, induced marked and diffuse perivascular accumulation of Iba1+ /iNOS+ M1 macrophages. We detected accumulation of CD8+ T cells adjacent to the injection site in brains exposed to the TLR7/8 agonist, but not vehicle. These results demonstrate that pharmacologic activation of the TLR7/8 pathway induces accumulation of Iba1+ M1 macrophages, and CD8+ T cells, and suggest that TLR7 activation promotes macrophage entry via the cerebral vasculature, without toxicity. In a syngeneic CNS lymphoma model, weekly systemic administration of TLR7 agonist delayed intracranial tumor progression. Targeted intra-CNS administrations of TLR7 agonist, without systemic administration, resulted in tumor regression and at least a trend toward longer OS.</p><p><b>Conclusions:</b> These data suggest that pharmacologic activation of the TLR7/8 pathway, via systemic and/or intra-CNS delivery, is feasible and programs the myeloid TME to an anti-tumor phenotype, with significant translational therapeutic potential in monotherapy and combinatorial","PeriodicalId":12882,"journal":{"name":"Hematological Oncology","volume":"43 S3","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hon.70093_116","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144299677","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CDK7 ENABLES THE FUNCTIONAL CROSSTALK BETWEEN LYMPHOMA AND MICROENVIRONMENT (TME) CELLS IN PERIPHERAL T-CELL LYMPHOMA (PTCL)","authors":"K. Kouidri, D. Fiore, M. V. Revuelta, N. Di Siervi, S. Joshi, C. Kayembe, G. Inghirami, L. Cerchietti, N. Zamponi","doi":"10.1002/hon.70093_118","DOIUrl":"https://doi.org/10.1002/hon.70093_118","url":null,"abstract":"<p><b>Introduction:</b> PTCL cell survival and proliferation depend on crosstalk with TME cells. The acquisition of pro-tumoral phenotypes in TME cells requires transcriptional changes, creating a therapeutic vulnerability. This is critical for improving treatment of PTCL-NOS lacking actionable alterations.</p><p><b>Methods:</b> RNA-seq and multiparametric imaging of PTCL patient samples. Drug screening in stromal-lymphoma cocultures. In vivo efficacy, RNA-seq and proteomics of PTCL-NOS PDX.</p><p><b>Results:</b> To identify pro-tumoral TME pathways, we analyzed the cellular constitution and activity of PTCL TME using functional signature deconvolution (<i>n</i> = 845). Among four biologically and clinically relevant TME categories, we identified one with high pro-tumoral-polarized macrophages and cancer-associated fibroblasts (CAF). We established a co-culture of PDX-derived PTCL-NOS lymphoma cells (PDX-IL2) with matched CAF (PDX-IL2-CAF). PDX-IL2-CAF improved PDX-IL2 cell survival specifically, while mismatched PDX-CAF from four other PTCL PDX did not. RNA-seq of matched PDX-IL2-CAF showed upregulation of \"transcription\", \"DNA replication\", \"RNA POL2” and the \"CDK7 complex\". This suggests that CDK7, by enabling transcription initiation, is required to maintain the educated phenotype. We showed that CDK7 inhibition decreases oncogene-induced transcription, causing cytotoxicity in PTCL cells. To determine if CDK7 is required for establishing cell state-induced transcription in CAF, enabling crosstalk with lymphoma cells (LyC), we administered low-dose (10 mg/kg per day) of the covalently selective CDK7 inhibitor YKL5124 to PDX-IL2 bearing mice and conducted RNA-seq and proteomics of isolated LyC and CAF at two time points. Ligand-receptor analysis identified CXCL12 in CAF and CXCR4 in LyC as the main CDK7-dependent crosstalk interaction. In CAF, the acquisition of \"cytokine signaling\" and \"immune cell modulation\" phenotypes was CDK7 dependent. Functional validation using cytokine profiling of YKL5124-treated PDX-IL2-CAF showed decreased secretion of pro-inflammatory cytokines IL6, CCL2, ICAM1, and CXCL1. Meanwhile, LyCs showed activation of pathways likely to compensate for decreased CDK7-dependent transcription including \"stress response,\" \"RNA processing\" and \"protein synthesis\" with upregulation of ALYREF and EIF4E, previously identified as XPO1 targets. Because this may represent new therapeutic vulnerabilities, we conducted a viability screening of PDX-IL2 CAF and LyC co-cultures with a library of 40 clinical-phase compounds targeting these compensatory mechanisms. Two drugs, targeting XPO1 (Selinexor) and translation (Omacetaxine), were the most potent combination with YKL5124. These are being tested in PTCL-NOS PDX mice.</p><p><b>Conclusion:</b> CDK7 activity in both lymphoma and CAF is required to establish functional pro-tumoral crosstalk that can be exploited therapeutically.</p><p><b>Research</b> <b>funding declaration:</b> Funding for","PeriodicalId":12882,"journal":{"name":"Hematological Oncology","volume":"43 S3","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hon.70093_118","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144299678","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TIRABRUTINIB FOR THE TREATMENT OF RELAPSED OR REFRACTORY PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA: EFFICACY AND SAFETY FROM THE PHASE II PROSPECT STUDY","authors":"L. Nayak, C. Grommes, A. Kallam, D. Peereboom, P. Ambady, J. Mendez, D. Aregawi, A. Sumrall, A. Omuro, F. Iwamoto, J. Dietrich, Y. Umemura, R. Munker, U. Chukwueke, L. Schaff, S. Prados, A. Takazawa, A. Aoi, T. Batchelor","doi":"10.1002/hon.70093_88","DOIUrl":"https://doi.org/10.1002/hon.70093_88","url":null,"abstract":"<p><b>Introduction</b>: Primary central nervous system lymphoma (PCNSL) is a rare, aggressive form of non-Hodgkin lymphoma localized to the brain, cerebrospinal fluid, or eyes. For patients with PCNSL, treatment options are limited, standard of care is not well established, and prognosis is poor, particularly in the relapsed or refractory (r/r) setting. Tirabrutinib, a highly potent selective second-generation Bruton’s tyrosine kinase inhibitor, is approved in Japan, Taiwan, and South Korea based on a phase I/II study that demonstrated clinical activity in Japanese patients with r/r PCNSL. There are no currently approved drug therapies for PCNSL in the US or Europe. Here we report results from the PROSPECT study (NCT04947319) conducted in the US.</p><p><b>Methods</b>: In this open-label phase II study, patients with r/r PCNSL received oral tirabrutinib 480 mg as monotherapy once daily until disease progression or unacceptable toxicity. The primary endpoint was overall response rate (ORR) assessed by Independent Review Committee. Secondary endpoints included duration of response (DOR), time to response (TTR), best overall response (BOR), and safety. Overall survival (OS) and progression-free survival (PFS) were exploratory endpoints.</p><p><b>Results</b>: Forty-eight patients were enrolled. Median age was 65.5 y (range, 34–87). With a median follow-up of 11.2 mo as of November 1, 2024 (data cut-off), ORR was 66.7% (<i>n</i> = 32), with a complete response rate (CRR), confirmed (CR) + unconfirmed (CRu), of 43.8% (<i>n</i> = 21) and a partial response rate of 22.9% (<i>n</i> = 11). Median DOR was 9.3 mo (range, 0.0–23.5), and median TTR was 0.95 mo (range, 0.9–3.7). Median OS was not reached (range, 1.0–33.0); median PFS was 6.0 mo (range, 0.0–26.0). Overall incidence of any-grade treatment-emergent adverse events (TEAEs) was 97.9% (<i>n</i> = 47) and grade ≥ 3 was 56.3% (<i>n</i> = 27). Any-grade treatment-related adverse events (TRAEs) were experienced by 75.0% (<i>n</i> = 36), most frequently anemia (18.8%), fatigue (14.6%), neutrophil count decreased (14.6%), pruritus (14.6%), rash (14.6%), and maculo-papular rash (14.6%). Grade ≥ 3 TRAEs were experienced by 27.1% (<i>n</i> = 13), most frequently neutrophil count decreased (8.3%) and rash maculo-papular (4.2%). Deaths related to TEAEs occurred in 2 (4.2%) patients: 1 patient died from seizure and pneumonia, and the other from a fall; these grade 5 TEAEs were considered unrelated to study treatment. At data cutoff, 27.1% (<i>n</i> = 13) of patients remain on tirabrutinib treatment. Main reasons for discontinuation were disease progression (54.2%, <i>n</i> = 26) and death (8.3%, <i>n</i> = 4), and 1 (2.1%) patient discontinued due to an AE; deaths included the 2 patients with grade 5 TEAEs.</p><p><b>Conclusions</b>: With an ORR of 66.7%, CR/CRu rate of 43.8%, median DOR of 9.3 mo, and a manageable safety profile, the PROSPECT trial supports tirabrutinib monotherapy as a potentially effective treat","PeriodicalId":12882,"journal":{"name":"Hematological Oncology","volume":"43 S3","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hon.70093_88","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144299699","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"WHOLE GENOME SEQUENCING OF SERIAL FL BIOPSIES FROM 96 PATIENTS WITH FOLLICULAR LYMPHOMA REVEAL TREATMENT-SPECIFIC PATTERNS OF TUMOUR EVOLUTION","authors":"L. K. Hilton, M. Fujisawa, E. Tse, C. Sarkozy, A. C. Lo, K. Dreval, B. Meissner, M. Boyle, J. W. Craig, G. W. Slack, P. Farinha, A. Lytle, C. L. Freeman, A. S. Gerrie, D. Villa, K. J. Savage, L. H. Sehn, A. Karsan, R. D. Morin, C. Steidl, D. W. Scott","doi":"10.1002/hon.70093_80","DOIUrl":"https://doi.org/10.1002/hon.70093_80","url":null,"abstract":"<p><b>Introduction:</b> Follicular lymphoma (FL) is a heterogeneous disease in terms of clinical course, treatment landscape, and molecular features. Patients presenting with limited stage disease may be treated with radiation therapy (RT), which is effectively curative in over 50% of patients, while those with disseminated disease may be observed or treated with a range of systemic therapies depending on symptoms and extent of disease. Sequencing of serial FL biopsies has demonstrated the existence of a population of cells ancestral to the diagnostic tumour and subsequent FL progression and transformation. We hypothesized that different presentations, and treatments thereof, would have distinct effects on the genomic evolution of FL.</p><p><b>Methods:</b> Paired biopsies and matched constitutional DNA from 96 FL patients who experienced either FL progression (pFL) or histological transformation (tFL) to aggressive lymphoma were profiled with whole genome sequencing (WGS). 21 patients with limited-stage disease received RT with curative intent, and all but 3 relapses occurred outside of the RT field. For the remaining patients with advanced stage, 39 were treated with (immuno)chemotherapy and 36 were observed as the management between biopsies. The median time between biopsies was 2.6 y and was not significantly different between treatment groups. Within the RT group, the second biopsy was tFL in 6 patients (29%), compared to 16 (41%) and 12 (30%) in the systemic therapy and observation cohorts, respectively. Somatic variants were identified with an ensemble variant calling approach.</p><p><b>Results:</b> There were no significant differences in mutation frequencies of any known FL genes when comparing diagnosis versus relapse, pFL versus tFL, or treatment. Mutations in <i>KMT2D</i> and the <i>CREBBP</i> lysine acetyltransferase (KAT) domain were significantly more likely to be ancestral (identical variants in both tumours), while mutations in <i>BCR</i> were more likely to be divergent (exclusive to one tumour; FDR < 0.1; Figure A). We quantified degree of divergence between tumours as the percentage of mutations exclusive to one time point. Both diagnostic and relapsed tumours were significantly more divergent in patients treated with RT, and there were no significant differences in divergence between patients who were observed versus received systemic therapy (<i>p</i> < 0.05; Figure B). Divergence correlated with time between biopsies only in patients treated with RT (R 0.4–0.5, <i>p</i> < 0.05).</p><p><b>Conclusions:</b> Leveraging data from patients who experience lymphoma after curative-intent RT, the inferred ancestral clone is sparser in terms of mutation burden compared to advanced stage patients. These data suggest that the ancestor of relapses in these patients is more likely to be a pre-malignant precursor cell, reflecting the effectiveness of RT in eradicating the fully-developed FL in limited-stage patients.</p><p><b>Resea","PeriodicalId":12882,"journal":{"name":"Hematological Oncology","volume":"43 S3","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hon.70093_80","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144299769","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MECHANISMS OF RESISTANCE TO SMALL MOLECULE INHIBITORS","authors":"J. F. Seymour","doi":"10.1002/hon.70093_67","DOIUrl":"https://doi.org/10.1002/hon.70093_67","url":null,"abstract":"<p>The development of targeted small molecule inhibitors of key tumorigenic and survival mechanisms, especially those involved in the B-cell receptor (Bruton Tyrosine Kinase (BTK) and PI3-kinase (PI3K)) and apoptosis (BCL2) pathways, have transformed the treatment landscape for many indolent lymphoproliferative disorders. The relevant approved agents are: Ibrutinib, acalbrutinib and Zanubrutinib as covalent inhibitors, and Pirtobrutinib as a non-covalent inhibitor of BTK, Idelalisib as a PI3K inhibitor and Venetoclax as a BCL2 inhibitor. These agents have had the greatest impact in chronic lymphocytic leukemia (CLL) but also significant utility in mantle-cell lymphoma (MCL), Waldenström macroglobulinemia (WM) and marginal zone lymphoma (MZL). Focusing on CLL as the exemplar disease context, true primary resistance is uncommon and often reveals the presence of a transformed clone (Richter transformation). Emergence of secondary resistance increases with the duration of drug exposure and commonly involves the emergence and ultimate outgrowth of clones with acquired mutations in either the target gene (<i>BTK</i> or <i>BCL2</i>) or alternative activating or bypassing mutations or dysregulation in other pathway member genes which functionally mitigate the inhibitory action of the drug; examples are <i>PLCɣ</i> mutations downstream of BTK, or BCL-Xl or MCL1 as alternative anti-apoptotic molecules overcoming BCL2 inhibition. It is now recognised that there are often multiple sub-clones with a range of these acquired changes present simultaneously in varying proportions. These tumour restricted genomic mechanisms of resistance are often also accompanied by additional cell intrinsic metabolic and proliferation-related changes as well as micro-environmental adaptions assisting tumor cell survival. Another layer of complexity is being revealed with our increasing understanding that within the covalent BTK inhibitor drug class, the spectrum of acquired mutations differs between agents and there is variable cross-resistance of these mutations with the non-covalent inhibitor Pirtobrutinib that may influence treatment sequencing decisions. Although these pathway specific resistance mechanisms do not predict for intrinsic resistance to the other drug class (BTK vs. BCL2 inhibitors), early single-cell data suggest that “double class” resistant disease can involve both compound mutant clones (harboring both BTK and BCL2) mutations, or heterogeneous multi-clonal mechanisms. The mechanisms of acquired resistance to currently approved agents have significant implications both for clinical management and treatment sequencing decisions and the potential utility of novel agents targeting these same pathways (such as BTK-degraders BGB-16673 and NX-5984 and the BCL2 inhibitor sonrotoclax).</p><p><b>Keywords:</b> chronic lymphocytic leukemia (CLL); indolent non-Hodgkin lymphoma</p><p><b>Potential sources of conflict of interest:</b></p><p><b>J. F. Seymour</b></p><p><b>Con","PeriodicalId":12882,"journal":{"name":"Hematological Oncology","volume":"43 S3","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hon.70093_67","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144299773","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HIGH EFFICACY OF BRIEF BRAF AND MEK COINHIBITION, ALONE AND COMBINED WITH ANTI-CD20 IMMUNOTHERAPY, IN RELAPSED/REFRACTORY HAIRY CELL LEUKEMIA: A PHASE-2 TRIAL","authors":"L. De Carolis, M. Capponi, F. Falcinelli, C. Stelitano, A. Pulsoni, E. Simonetti, A. Romano, A. Mancini, G. M. D'Elia, J. Olivieri, P. L. Zinzani, M. Varettoni, S. Ferrero, M. Pini, R. Foà, E. Lucchini, M. Frezzato, B. Falini, E. Tiacci","doi":"10.1002/hon.70094_220","DOIUrl":"https://doi.org/10.1002/hon.70094_220","url":null,"abstract":"<p><b>Introduction:</b> ∼50% of HCL patients (pts) relapse after purine analogs (PA) chemotherapy. Vemurafenib (VEM), an oral inhibitor of the BRAF-V600E kinase mutation (genetic cause of HCL; Tiacci et al. <i>NEJM</i>, 2011), proved active when given for a few months to R/R pts (∼35% complete remissions/CR—Tiacci, Park et al. <i>NEJM</i>, 2015). Still, minimal residual disease/MRD persisted in the bone marrow (BM) even in CR pts and the median progression-free survival (PFS) was ∼1 year. Moreover, BM HCL cells often showed ERK phosphorylation (pERK+) despite ongoing BRAF inhibition by VEM, suggesting bypass MEK/ERK reactivation downstream of BRAF as resistance mechanism. BRAF+MEK coinhibition with dabrafenib + trametinib, given to BRAF inhibitor-naïve pts for an indefinite duration (median ∼3 years), led to 66% CR but still rare MRD-negativity (16%; Kreitman et al. <i>Blood</i>, 2023); such a continuous therapy sustained a high PFS at 2 years (94%) but led to frequent serious toxicities (35% of pts). Adding rituximab/RTX (8 doses) to a short VEM course (8 weeks) yielded 87% CR, frequent MRD-negativity (60%), 78% PFS at ∼3 years of median follow-up, and few clinically relevant toxicities (3% of pts) (Tiacci et al. <i>NEJM</i>, 2021).</p><p>To improve these results, we tested in R/R HCL a brief BRAF+MEK coinhibition (with VEM + cobimetinib/COB) combined to obinutuzumab/OBI (potentially more active than RTX), after establishing the currently unknown efficacy and safety of VEM+COB in HCL.</p><p><b>Methods:</b> We enrolled 19 R/R pts (median age 58 years; median of 3 previous therapies, including BRAF inhibitor ± RTX in 4 pts [21%]) in a phase-2 multicenter trial testing VEM (960 mg bid) + COB (60 mg daily, 21 days on/7days off) for 2–3 cycles (28 days each), followed at disease progression (PD) by another brief course of VEM+COB combined to OBI (8 doses over 6 cycles, starting together with VEM+COB).</p><p><b>Results:</b> VEM+COB toxicity was as expected and manageable. Clinical events (i.e., not laboratory-only abnormalities) were mostly grade 1–2, consisting mainly in rash due to either drug; arthralgia and photosensitivity due to VEM; and diarrhoea, oral aphthosis and serous retinopathy due to COB.</p><p>17/19 pts responded (89%), and 13 of 18 evaluable pts had a CR (72%; 1/13 MRD-). BM pERK+ HCL cells were detected in only 1/9 (11%) evaluable pts. Median PFS was long, 42 months, and a sizable pts subset (4/19, 21%) is free from PD at > 5 years.</p><p>Of 12 pts with PD, 5 have not (or not yet) received VEM+COBI+OBI for various reasons, while 7 were treated with this short regimen 22–79 months after VEM+COB. All 7 pts (100%) obtained MRD- CR, and are free from cytopenia recurrence at 4–51 months (<i>n</i> = 6 pts) or had a cytopenia relapse at 44 months (<i>n</i> = 1 pt); only 2 clinically relevant toxicities were recorded.</p><p><b>Conclusions:</b> Brief BRAF+MEK coinhibition with VEM+COB, especially if boosted by anti-CD20 immunotherapy throu","PeriodicalId":12882,"journal":{"name":"Hematological Oncology","volume":"43 S3","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hon.70094_220","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144299914","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}