Hematological Oncology最新文献

{"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}

{"title":"ANALYSIS OF COVID-19 INFECTIONS WITH FIXED-DURATION ACALABRUTINIB-VENETOCLAX COMBINATIONS IN TREATMENT-NAIVE CHRONIC LYMPHOCYTIC LEUKEMIA IN THE PHASE 3 AMPLIFY TRIAL","authors":"J. R. Brown, A. P. Kater, W. Jurczak, P. Ghia, B. Eichhorst, A. C. Peters, M. A. Pavlovsky, M. Yağcı, D. Lysak, K. Miller, T. Fujimori, S. Rule, M. de Borja, J. F. Seymour","doi":"10.1002/hon.70094_218","DOIUrl":"https://doi.org/10.1002/hon.70094_218","url":null,"abstract":"<p><b>Introduction:</b> An interim analysis of the ongoing phase 3 AMPLIFY trial (NCT03836261) showed significant progression-free survival benefit with both fixed-duration acalabrutinib-venetoclax combinations (± obinutuzumab; AV and AVO) versus investigator’s choice of fludarabine-cyclophosphamide-rituximab (FCR) or bendamustine-rituximab (BR) in patients (pts) with treatment (tx)-naive (TN) chronic lymphocytic leukemia (CLL), with initial data on COVID-19 adverse events (AEs) reported (Brown JR, et al., <i>NEJM</i>. 2025). We sought to further characterize COVID-19 AEs in AMPLIFY.</p><p><b>Methods:</b> Pts with TN CLL aged ≥ 18 y with ECOG ≤ 2 and without del(17p) or <i>TP53</i> mutation were randomized 1:1:1 to receive AV (oral acalabrutinib 100 mg BID [cycles (C) 1–14]; oral venetoclax QD [C3–14 with 5-wk dose ramp-up]), AVO (AV dosing as above, + intravenous obinutuzumab 1000 mg C2 [days 1, 8, and 15] and 3−7 [day 1]), or investigator’s choice of FCR or BR (C1−6). We report incidences of COVID-19 infections and deaths (during the tx-emergent period [up to earliest of 30 d after last dose or start of subsequent therapy] and up to the time of interim analysis [30 Apr 2024]), COVID-19 vaccination status, and COVID-19 deaths by pandemic waves.</p><p><b>Results:</b> In total, 867 pts were randomized from 2019 to 2021, including 291, 286, and 290 in the AV, AVO, FCR/BR arms, respectively, among whom 53.3% (AV), 50.0% (AVO), and 38.6% (FCR/BR) had ≥ 1 COVID-19 vaccination, most commonly tozinameran (Pfizer) in 35.4%, 31.5%, and 23.4% of pts. Among the 867 randomized pts, 321 had ≥ 1 COVID-19 event anytime during the trial, including 109 (37.5%), 131 (45.8%), and 81 (27.9%) pts in the AV, AVO, and FCR/BR arms, respectively, of whom 58.7%, 52.7%, and 12.3% experienced ≥ 1 event during the tx-emergent period. Median age among pts with ≥ 1 COVID-19 event was 60 y (23.1% > 65 y) versus 61 y (26.8% > 65 y) in the overall study population. Among study-treated pts (≥ 1 dose received), COVID-19 AEs were grade ≥ 3 in 29/291 (10.0%), 65/284 (22.9%), and 38/259 (14.7%) pts in the AV, AVO, and FCR/BR arms, respectively. COVID-19 AEs led to permanent discontinuation of ≥ 1 study tx in the regimen in 2.4% (AV), 8.1% (AVO), and 1.2% (FCR/BR) of pts. Death due to COVID-19 any time during the trial occurred in 10 (3.4%), 25 (8.7%), and 21 (7.2%) pts in the AV, AVO, and FCR/BR arms, respectively (of which 80.0%, 60.0%, and 33.3%, respectively, occurred during the tx-emergent period). Vaccination rates among all pts who died from COVID-19 were 0% (AV), 24.0% (AVO), and 9.5% (FCR/BR). COVID-19 death rates were highest during the second pandemic wave, with the highest rates in the AVO and FCR/BR arms (Figure).</p><p><b>Conclusions:</b> In this post hoc analysis, COVID-19–associated deaths occurred most frequently in the AVO and FCR/BR arms, followed by the AV arm. Vaccination rates were lower among pts with COVID-19 death versus overall. COVID-19 deaths were most","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_218","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144299922","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":"PRELIMINARY RESULTS OF THE ONGOING MULTICENTER, PHASE 2 STUDY OF RETREATMENT WITH VENETOCLAX PLUS OBINUTUZUMAB (ReVenG) IN PATIENTS WITH RECURRENT CLL","authors":"M. S. Davids, S. Robrecht, E. Tausch, S. Stilgenbauer, M. Choi, A. Skarbnik, C. Chyn Chua, L. Sivcheva, K. Kreuzer, M. Ritgen, T. Gaska, D. Heintel, C. Arrais-Rodrigues, R. Santucci Alves Da Silva, T. Illmer, Z. Liu, B. Chyla, W. Sinai, M. V. Pai, M. Porro Lurà, M. Hallek, B. Eichhorst, O. Al-Sawaf, K. Fischer","doi":"10.1002/hon.70094_211","DOIUrl":"https://doi.org/10.1002/hon.70094_211","url":null,"abstract":"<p><b>Introduction:</b> Venetoclax (Ven)-based retreatment of patients (pts) with recurrent CLL after frontline Ven has not previously been studied prospectively. Here, we report an exploratory, interim analysis of the ongoing ReVenG trial, the first prospective study of Ven-Obinutuzumab (Obi) retreatment.</p><p><b>Methods:</b> CLL pts are eligible for this study (NCT04895436) if they received first-line (1L), time-limited Ven-based therapy, achieved response of ≥ 12 months (mo.) after completing therapy, then progressed and met iwCLL treatment criteria. Cohort-1 (Co-1, main cohort) includes pts with progressive (PD) > 2 years after completing 1L treatment (planned <i>N</i> = 60), and cohort-2 (Co-2, exploratory cohort) includes pts with PD 1 to 2 years post 1L therapy (planned <i>N</i> = 15). Both cohorts receive 6 cycles of Ven-Obi, with Co-1 receiving 12 total cycles of Ven, and Co-2 receiving at least 24 cycles of Ven. The primary endpoint is overall response rate (ORR) 3 mo. after the end of combination therapy (EOCT + 3 mo.) for Co-1. Key secondary endpoints include safety, additional response and MRD endpoints, and PFS.</p><p><b>Results:</b> At data cut-off of 18 October 2024, 25 of 75 pts (33%) were enrolled, 22 in Co-1 and 3 in Co-2. The median age was 67 years (range 41–84), with 76% Binet stage B or C. 32% had lymph nodes ≥ 5 cm at study entry. Median time to starting study treatment after last dose of 1L treatment was 53.3 mo. (range 19–90). 8/21 (38%) were either <i>TP53</i>mut and/or del(17p), and 18/21 (86%) tested were IGHV unmutated Of the 21 pts assessed at time of PD after FD treatment with Ven in 1L, none had acquired a mutation in <i>BCL-2</i>. With regard to efficacy in Co-1, all 15 pts who have reached EOCT + 3 mo. to date have achieved response, including 3 pts with CR/CRi, 2 pts in PR with radiographic CR awaiting marrow biopsy, and 10 pts with PR. At EOCT + 3 mo., 11 of 13 pts with samples available had undetectable MRD in the peripheral blood by NGS (<i>n</i> = 2 at 10<sup>−4</sup>, <i>n</i> = 3 at 10<sup>−5</sup>, <i>n</i> = 6 at 10<sup>−6</sup>). 7 pts have reached end of treatment + 3 mo., including 3 in CR and 4 in PR. With a median follow-up time on study of 10.3 mo., one pt has progressed, and all 25 pts are alive. In the safety analysis in all 25 pts, the most common AEs were neutropenia (44%, including 28% Gr 3/4), diarrhea (28%), nausea (24%) and infusion related reaction (24%). Serious AEs occurred in 32% of pts, including 1 pt each with sinusitis, pancytopenia, lower respiratory tract infection, COVID-19, and sepsis. There were no Gr 4 infections, fatal AEs, or tumor lysis syndrome (TLS). 3 pts (12%) had dose reduction of Ven due to AEs, including 1 each due to neutropenia, diarrhea, and nausea, and none discontinued Ven due to toxicity.</p><p><b>Conclusions:</b> In this interim analysis of the initial pts on ReVenG, efficacy was observed, and the safety of Ven-Obi in these relapsed pts was similar to prio","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_211","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144299960","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":"MONITORING CIRUCLATING TUMOR DNA IMPROVES EARLY RELAPSE DETECTION AFTER STANDARD OF CARE 2L+ AXI-CEL IN LBCL: A PROSPECTIVE STUDY","authors":"S. Ananth, J. Mallampet, B. Chang, N. Agarwal, K. Kong, B. Sahaf, C. Lohman, N. Hossain, J. C. Cancilla, A. Bukhari, E. Dean, J. Speigel, I. Kirsch, A. Jacob, H. Simmons, L. W. Lee, J. Bacigalupi, C. Mackall, A. Rapoport, M. D. Jain, S. Dahiya, F. L. Locke, D. Miklos, M. Frank","doi":"10.1002/hon.70094_427","DOIUrl":"https://doi.org/10.1002/hon.70094_427","url":null,"abstract":"<p><b>Introduction:</b> Large B-cell lymphoma (LBCL) circulating tumor DNA (ctDNA)-based measurable residual disease (MRD) assessment is a prognostic tool for outcomes following CD19-CAR T-cell therapy and frontline treatment. CtDNA can risk stratify and predict outcomes providing additive benefit to standard PET-CT assessments for 3L+ Axicabtagene Ciloleucel (axi-cel, Frank et al., <i>JCO</i> 2021). The role for ctDNA monitoring for 2L axi-cel is unknown. Here, we present a prospective ctDNA analysis of 2L+ axi-cel patients with 6+ months (mo) of follow-up and compare this analysis to prior 3L+ data.</p><p><b>Method:</b> Plasma was collected from patients with LBCL receiving standard-of-care axi-cel at pre-lymphodepletion (PLD), days 14, and 28, totaling 222 plasma samples. (VDJ) clonotype (Clono-Seq) was identified from archival paraffin-embedded tissue to track MRD. PET-CT scans were performed before and at 1, 3, 6, and 12 mo post axi-cel; responses assessed per Lugano criteria (Deauville 1–3 was considered PET-negative). Any detectable ctDNA was considered detectable MRD. Significance for PFS was determined by log-rank <i>p</i> values and prognostic value of ctDNA was evaluated by a Cox proportional hazards model.</p><p><b>Results:</b> Patients in 2L+ (<i>n</i> = 84 enrolled 2022–2024) versus 3L+ (<i>n</i> = 64, enrolled 2018–2019) were median age of 65 (23–83) versus 59 (19–76), 61% versus 56% male, 55% versus 60% had elevated LDH, 73% versus 72% Stage 3/4, median 1 (1–5) versus 3 (1–7) prior lines (60% vs. 3% only 1 prior line; 12 % vs. 58% for 3+ prior lines). 60% (<i>n</i> = 50) versus 55% (<i>n</i> = 35) of 2L+ versus 3L+ patients received bridging. Median follow-up for 2L+ versus 3L+ was 18 versus 11 mo. Polatuzumab-based bridging (48% vs. 0%) was more common in 2L+; similar rates received radiation (36% vs. 26%). 2L+ versus 3L+ showed lower median PLD ctDNA levels (1.606307 [0–35,248] versus 63 [0–17,903] LG/mL) and a higher proportion of patients with undetectable MRD (uMRD) (38% vs. 26%) (Panel A). Lower levels of ctDNA suggests improved disease control and more effective bridging therapy in the 2L+ era.</p><p>For 2L+, ctDNA levels were prognostic before and at all time points in the early post-CAR-T setting. UMRD was associated with improved outcomes at all timepoints, including PLD (<i>p</i> = 0.04, HR 2.866, 1.287–6.382), Day 14 (<i>p</i> < 0.0001, HR 5.302, 2.342–12.00) and Day 28 (<i>p</i> = 0.001, HR 5.778, 2.606–12.81) (Panel A). PLD MRD levels did not associate with CRS or ICANS grade (not shown). MRD status at Day 14 and 28 stratified patients after 2L+ axi-cel (Panel B-C); uMRD was significantly associated with improved PFS. Patients with Day 28 radiographic PR/SD with uMRD (<i>n</i> = 12) versus detectable MRD (dMRD, <i>n</i> = 10) had improved PFS; 92% versus 40% of uMRD versus dMRD patients had durable remissions (panel D).</p><p><b>Conclusion:</b> This prospective study shows ctDNA assessments can predict for progres","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_427","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144299984","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}